FINAL 

Report on Carcinogens 

Background Document for 

Lead and Lead Compounds 

May 8, 2003 

Prepared for the: 

U.S. Department of Health and Human Services 

Public Health Service 

National Toxicology Program 

Research Triangle Park, NC 27709 

Prepared by: 

Technology Planning and Management Corporation 

Canterbury Hall, Suite 310 

4815 Emperor Blvd 

Durham, NC 27703 

Contract Number N01-ES-85421 

05/08/03 RoC Background Document for Lead and Lead Compounds 

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FOREWORD 

The Report on Carcinogens (RoC) is prepared in response to Section 301 of the Public 

Health Service Act as amended. The RoC contains a list of all substances (i) that either 

are known to be human carcinogens or may reasonably be anticipated to be human 

carcinogens and (ii) to which a significant number of persons residing in the United 

States are exposed. The Secretary, Department of Health and Human Services, has 

delegated responsibility for preparation of the RoC to the National Toxicology Program, 

which prepares the Report with assistance from other Federal health and regulatory 

agencies and nongovernmental institutions. 

Nominations for listing in or delisting from the RoC are reviewed by a formal process 

that includes a multi-phased scientific peer review and several opportunities for public 

comment. The review groups evaluate each nomination according to specific RoC listing 

criteria. This Background Document was prepared to assist in the review of the 

nomination of lead and lead compounds. The scientific information in this document 

comes from publicly available peer-reviewed sources. Any interpretive conclusions, 

comments, or statistical calculations made by the authors of this document that are not 

contained in the original source are identified in brackets [ ]. If any members of the 

scientific peer review groups feel that this Background Document does not adequately 

capture and present the relevant information, they will be asked to write a commentary 

for this Background Document that will be included as an addendum to the document. In 

addition, a meeting summary that contains a brief discussion of each review group’s 

review and recommendation for the nomination will be added to the Background 

Document, also as an addendum. 

A detailed description of the RoC nomination review process and a list of all nominations 

under consideration for listing in or delisting from the RoC can be obtained by accessing 

the NTP Home Page at http://ntp-server.niehs.nih.gov. The most recent RoC, the Ninth 

Edition, was published in May 2000 and may be obtained by contacting the National 

Institute for Environmental Health Sciences Environmental Health Information Service at 

http://ehis.niehs.nih.gov (800-315-3010). 
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Executive Summary 

Introduction

Lead can be used in its pure form as a metal, alloyed with other metals, or used in 

chemical compounds. Inorganic lead compounds usually consist of lead in the divalent 

state. Organic lead compounds were used in automotive gasoline additives in the United 

States until 1996. Lead and lead compounds were nominated by the National Institute of 

Environmental Health Sciences based on the 1987 finding by the International Agency 

for Research on Cancer (IARC) of sufficient evidence of carcinogenicity in experimental 

animals to identify lead and inorganic lead compounds as possibly carcinogenic to 

humans (Group 2B) and the subsequent publication of additional human and animal 

studies of lead and lead compounds. 

Human Exposure 

Use. In worldwide metal use, lead ranks behind only iron, copper, aluminum, and zinc. 

Its greatest use is in lead-acid storage batteries found in motor vehicles and general 

industry. Other common uses of lead metal include ammunition, cable covering, piping, 

brass and bronze, bearing metals for machinery, and sheet lead. Lead oxides are found in 

paint, glass, and ceramics. Organic lead was used in motor vehicle fuels as an anti-knock 

additive in the United States until 1996, when it was banned by the U.S. Environmental 

Protection Agency, following a phase-out initiated in the 1970s. Organic lead still is 

permitted for use in gasoline for aircraft and in fuels for racing vehicles and for non-road 

vehicles such as farm machinery, marine vessels, construction equipment, and 

recreational vehicles. Despite reductions in some lead applications and the legislated end 

to use of lead as a gasoline additive, the overall consumption of lead is growing, mainly 

due to increased production of lead-acid batteries. 

Production. Lead is refined from mined ore. Lead ore occurs most frequently in the form 

of lead sulfide, also known as galena. As of 2000, 19 mines, employing approximately 

1,000 workers, produced the vast majority of lead in the United States. Mined lead ore 

first is crushed and ground; then the various minerals are separated, resulting in a lead 

concentrate, which is shipped to a primary smelter for refining. At a primary smelter, lead 

concentrates are sintered, then roasted and subjected to a series of refining steps, resulting 

in lead metal that is 99.99% pure. In 2001, two primary lead smelter-refineries were 

operating, employing a total of approximately 400 people. Secondary smelters (recycling 

smelters) use scrap lead, mainly from used lead-acid batteries, as their supply. As of 

2001, 26 secondary lead smelters were operating within the United States, employing 

approximately 1,600 workers. In 2001, the United States produced 1,375,000 tons of 

lead, used 1,687,000 tons of lead, and recycled 1,099,000 tons of lead. 

Environmental exposure. Environmental exposure to lead results in absorption of lead 

into the body via inhalation (approximately 30% to 50% absorbed into the bloodstream), 

via ingestion (approximately 8% to 15% absorbed into the bloodstream) and, to a limited 

extent, through the skin. Air lead concentrations may be > 10 μg/m3

 near industrial 

sources such as smelters. A 1991 survey of lead levels in U.S. urban air revealed a 

maximum quarterly mean concentration of approximately 0.08 μg/m3. Rural 
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concentrations typically are lower, bringing the estimated U.S. mean air lead 

concentration to 0.04 μg/m3 in 1995. The average intake of lead by inhalation is estimated 

at 2 μg/day for an adult living in a U.S. urban setting. Lead concentrations in U.S. 

drinking water generally are below 5 μg/L. Lead also is found in food, cigarette smoke, 

and alcoholic beverages. In 1990, the estimated daily intake of lead from consumption of 

food, water, and beverages was approximately 4 μg/day for children 2 years of age and 

younger, 6 to 9 μg/day for children aged 14 to 16, 6 to 9 μg/day for adults aged 25 to 30, 

and 2 to 8 μg/day for adults aged 60 to 65. The most common source of environmental 

lead exposure for young children is direct ingestion of paint chips and leaded dusts and 

soils released from aging painted surfaces, which can contribute an additional intake of 5 

μg/day for a toddler engaging in normal hand-to-mouth activity. 

Occupational exposure. The most common route of occupational exposure to lead is 

inhalation of lead fumes or leaded dusts in air and absorption of lead through the 

respiratory system. Lead also may be ingested and absorbed in the gastrointestinal tract. 

The National Institute for Occupational Safety and Health has estimated that more than 

three million Americans potentially are occupationally exposed to some form of lead. 

Many occupations have the potential for high exposure to lead. Occupations having 

frequent high exposure to lead include battery-production workers, battery-recycling 

workers, foundry workers, lead chemical workers, lead smelter and refinery workers, 

leaded-glass workers, pigment workers, and radiator-repair workers. Occupations with 

moderate frequency of high exposures include firing-range instructors, house renovators, 

lead miners, newspaper printers, plastics workers, rubber workers, and steel welders and 

cutters. Occupations with low frequency of high exposure include automobile-repair 

workers, cable-production workers, construction workers, demolition workers, firingrange participants, flame-solder workers, plumbers and pipe fitters, pottery-glaze 

producers, ship-repair workers, and stained-glass producers. Mean lead air concentrations 

in U.S. industries, as monitored by the Occupational Safety and Health Administration, 

ranged from 165 μg/m3

 (secondary smelters) to 200 μg/m3 (storage-battery plants and 

brass, bronze, and copper foundries). 

Human Cancer Studies

IARC reviewed lead and lead compounds in 1987 and concluded that the evidence 

available at that time, which was very limited, was inadequate to demonstrate human 

carcinogenicity. The number of epidemiologic studies on the potential role of lead 

exposure in cancer has expanded since the last IARC update; 17 case-control and 17 

cohort studies have been published, as well as updates on previously studied populations 

and meta-analyses. Steenland and Boffetta (2000) calculated a fixed-effects rate ratio of 

1.04 (95% confidence interval [CI] = 1.00 to 1.09) for all cancers combined (N = 1,911) 

based on eight cohort studies of highly exposed workers. 

Lung cancer. Meta-analyses performed since the IARC review have reported 

significantly elevated relative risks (RRs) for lung cancer and lead exposure. Fu and 

Boffetta calculated RRs of 1.24 (95% CI = 1.16 to 1.33) based on 15 studies and 1.42 

(95% CI = 1.05 to 1.92) based only on studies of battery and smelter workers, who were 
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considered to have the highest exposure. Steenland and Boffetta (2000) calculated an RR 

of 1.30 (95% CI = 1.15 to 1.46; 675 lung-cancer deaths) based on eight cohort studies in 

which lead was the predominant exposure. In Section 3.3.1 of this background document, 

21 lead-exposed populations are evaluated; 15 of the 18 populations included in at least 

one cohort study had elevated risks of lung cancer, eight of which were statistically 

significant. Two of the three case-control studies of populations not included in cohort 

studies also reported weak associations between lead expsoure and lung cancer. 

Population-based cohort studies of environmental exposure to lead also have reported 

positive associations between lung cancer and blood lead levels. The addition of one 

environmental cohort study to the Steenland and Boffetta (2000) meta-analysis yielded an 

RR of 1.32 (95% CI = 1.16 to 1.50). Confounding by smoking or other occupational 

exposures, particularly to arsenic, may be partially responsible for the elevated risks seen 

in these studies. However, elevated risks also were observed in population studies that 

adjusted for cigarette smoking. 

Stomach and general digestive cancer. Meta-analyses conducted since the 1987 IARC 

review have reported elevated risks for stomach cancer with lead exposure; Fu and 

Boffetta (1995) reported an RR of 1.33 (95% CI = 1.18 to 1.49) for lead exposure based 

on ten studies and an RR of 1.50 (95% CI = 1.23 to 1.83) for battery or smelter workers 

only, and Steenland and Boffetta (2000) reported an RR of 1.34 (95% CI = 1.14 to 1.57). 

In Section 3.2, 21 studies are evaluated, approximately half of which reported a positive 

association between lead exposure and stomach cancer. 

Kidney cancer. Meta-analyses for kidney cancer were based on fewer studies and fewer 

cases or deaths among exposed individuals. Fu and Boffetta (1995) calculated an RR of 

1.19 (95% CI = 0.96 to 1.48) based on five studies, and Steenland and Boffetta (2002) 

calculated an RR of 1.01 (95% CI = 0.72 to 1.42) based on seven studies. For the review 

in Section 3.3.3 of this document, Steenland and Simonsen calculated an RR of 1.22 

(95% CI = 0.93 to 1.59) based on the same seven studies plus a recently published casecontrol study; because the recent study was large, it had a substantial effect on the RR. 

The low incidence of kidney cancer, resulting in a small number of cases, limits the 

evaluation of carcinogenicity. Of the four studies reviewed in Section 3.3.3 that had more 

than five cases in lead-exposed subjects, three reported a positive association between 

lead exposure and kidney cancer. 

Bladder cancer. Fu and Boffetta (1995) reported an RR of bladder cancer from lead 

exposure of 1.41 (95% CI = 1.16 to 1.71) based on five studies. Of seven studies 

reviewed in Section 3.3.4, six reported a positive association between lead exposure and 

bladder cancer. 

Other cancers. Other cancers with evidence linking them to lead exposure include 

cancers of the brain and central nervous system, liver, colon, and rectum, among which 

the evidence is strongest for brain and central nervous system cancers. The results of 

studies on paternal lead exposure and childhood cancer are conflicting and difficult to 

evaluate because of the limited number of studies and small sample sizes. 
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Summary. Overall, the evidence is consistent with the hypothesis that lead is carcinogenic 

to humans. This evidence is strongest for lung cancer, for which a largely consistent 

association has been demonstrated with occupations and industries entailing lead 

exposure, as well as with indices of individual lead exposure, including job history and 

biological monitoring of occupationally exposed and general populations. Evidence also 

suggests an association between lead and stomach cancer. 

Where exposure-response assessment was attempted, the strongest association with lung 

cancer usually was seen in the highest exposure group, but a monotonic increase with 

duration, intensity, or overall amount of exposure was not always observed. Here, 

interpretation again is complicated by the general lack of adequate statistical power to 

evaluate multiple exposure levels while controlling for smoking, age, gender, and other 

potential confounders or effect modifiers. Also, workers who experience acute lead 

toxicity tend to drop out of the exposed worker population, which could lead to 

underestimation of the association between lead and cancer. 

The observed associations, while consistent, generally are weak. The crude exposure 

measures used by most studies, such as treating whole plants or jobs as uniformly 

exposed, may have contributed to the modest size of most risk estimates. Confounding by 

lifestyle exposures, such as smoking for lung cancer or diet for stomach cancer, or by 

concomitant occupational exposures, such as arsenic, may partially explain these small 

associations. However, associations were also observed in studies that adjusted for 

potential lifestyle confounders or that were conducted in populations without systematic 

occupational exposures other than lead. Thus, confounding may not entirely account for 

the increase in cancer risk associated with lead exposure. 

Studies in Experimental Animals

Lead acetate (soluble), lead subacetate (soluble), and lead phosphate (insoluble) were 

found to be carcinogenic in rats and/or mice, inducing tumors of the kidney (adenoma 

and adenocarcinoma) and, in some studies, increased incidences of cerebral glioma and 

lung adenoma. Renal tumors were observed in male and female rats and mice and were 

not always accompanied by chronic lead-induced nephropathy. The studies used a variety 

of exposure routes, including oral, subcutaneous, intramuscular, transdermal, 

transplacental, and translactational; however, no inhalation studies were reported. Many 

of the studies focused on kidney toxicity and carcinogenicity, and thus did not include 

complete histopathological exams. However, the few studies that did examine other 

tissues found little evidence that lead induced tumors. Lead subacetate co-administered 

with 2-acetylaminofluorene was reported to enhance liver and kidney tumorigenicity in 

one study but not in two others and was shown to promote renal tumors in Wistar rats 

administered N-ethyl-N-hydroxyethylnitrosamine. In other studies, lead acetate increased 

the incidence of viral-induced lymphocytic leukemia in mice and was co-carcinogenic 

when administered with N-(4'-fluoro-4-biphenyl)acetamide to F344 rats, but lead acetate 

did not increase tumor incidences in Sprague-Dawley rats when co-administered with 

ethyl urea and sodium nitrite. 
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Genotoxicity 

Lead induced chromosomal aberrations in most studies in plants and in mammals (in 

vitro and in vivo) and DNA damage and fragmentation in mammals (in vivo; conflicting 

results were observed in in vitro studies) and cell-free systems (in the presence of 

hydrogen peroxide) and inhibited DNA and RNA polymerase in cell-free systems and 

mammalian cells (in vitro). Conflicting results were observed for sister chromatid 

exchange and micronucleus induction in mammalian studies (in vitro and in vivo). Lead 

was not mutagenic in bacteria, and conflicting results were observed in mammalian in 

vitro systems. Conflicting results may reflect differences in the model systems employed, 

the end points used to determine genotoxicity, and the lead compounds employed. In 

studies of humans occupationally exposed to lead, there is evidence to suggest that lead 

damages chromosomes or DNA; most studies were positive for induction of micronuclei, 

chromosomal aberrations, and DNA damage. Studies on sister chromatid exchange and 

studies in humans exposed environmentally to lead gave conflicting results. Studies in 

humans are sometimes difficult to evaluate, because little information is given on how the 

populations were selected for study and because of potential exposure to compounds 

from occupational or environmental sources that may act in conjunction with lead to 

increase its genotoxic potential. Likewise, personal habits such as smoking and alcohol 

consumption affect the genotoxic properties of various compounds, including lead. 

However, many of the more recent studies either controlled for smoking or reported an 

exposure-response relationship, suggesting that the genotoxic effects were due to lead 

exposure. Although lead(II) forms stable complexes with the nitrogenous bases and 

phosphate groups of purified DNA, it is unlikely that lead compounds are directly 

genotoxic. However, several mechanisms exist by which lead compounds could 

indirectly alter DNA replication, fidelity, and repair, resulting in genotoxicity. 

Other Relevant Data

Absorption, distribution, and excretion. Lead absorption in humans and laboratory 

animals is affected by age, the chemical form of lead, and minerals in the diet (e.g., iron, 

calcium, and zinc). Gastrointestinal absorption declines with age, with children absorbing 

lead to a greater extent than adults. Dietary deficiencies in iron, calcium, and zinc 

increase lead absorption and retention, whereas a high-protein diet appears to reduce 

absorption. After absorption, lead is distributed to blood plasma, nervous system, and soft 

tissues. It subsequently is redistributed and accumulates in bone; approximately 75% to 

90% of the lead body burden is found in bones and teeth. 

Toxicity. The toxic effects of lead include neurotoxicity and developmental, reproductive, 

and cardiovascular effects. Lead is a potent neurotoxin affecting the central nervous 

system (CNS) and the peripheral nervous system (PNS), and high levels of exposure 

result in profound cognitive impairments. Exposure of children to lower levels of lead has 

been associated with impairment of neurocognitive and behavioral development, 

including impairment of attention and hearing. 

Potential mechanisms of carcinogenicity. The mechanisms leading to the carcinogenic 

effects of lead are not understood. Lead compounds do not appear to be directly 

genotoxic but may cause genetic damage through several indirect mechanisms. These 

include inhibition of DNA synthesis and repair, oxidative damage, and interaction with 
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DNA-binding proteins and tumor-suppressor proteins. Interference with DNA synthesis 

and repair has been suggested as one possible explanation for the genotoxic and comutagenic properties of lead. It has been suggested that increased cell proliferation may 

play a role in lead’s induction of renal cancer in rodents; however, the mechanisms have 

not been established. Although exposure to lead also induces cell proliferation in the 

liver, the data suggest that the liver is not as susceptible as the kidneys to the 

carcinogenicity of this effect. No studies have associated liver tumors with lead exposure, 

and several studies have shown that lead-induced proliferative mitogenesis does not 

promote the formation of liver foci or nodules from initiated hepatocytes, as observed 

during regenerative mitogenesis. An association of renal adenocarcinoma with cystic 

nephropathy has been suggested but is uncertain.
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CONTRIBUTORS 

NIEHS/NTP Staff 

C. W. Jameson, Ph.D. Head, Report on Carcinogens, 

Environmental Toxicology Program, NIEHS 

Ruth M. Lunn, Dr. P.H. Report on Carcinogens Group, 

Environmental Toxicology Program, NIEHS 

Shawn Jeter, B.S. Report on Carcinogens Group, 

Environmental Toxicology Program, NIEHS 

AnnaLee Sabella Report on Carcinogens Group, 

Environmental Toxicology Program, NIEHS 

Support to the National Toxicology Program for the preparation of this background 

document was provided by Technology Planning and Management Corporation 

through NIEHS Contract Number NO1-ES-85421 

Ronald Thomas, Ph.D., Principal Investigator 

Sanford Garner, Ph.D., Co-Principal Investigator 

Stanley Atwood, M.S. 

Ashlee Duncan, M.S. 

Susan Goldhaber, M.S. 

Ibrahim Raphiou, Ph.D. 

Support staff 

Angie Fralick, B.S. 

Tracy Saunders, B.S. 

Consultants 

Susan Dakin, Ph.D., Independent Consultant, Durham, NC 

David Fleming, Ph.D., Department of Physics, Mount Allison University, New 

Brunswick, Canada 
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Brian Gulson, Ph.D., Graduate School of the Environment, Macquarie University, 

Sydney, Australia 

Ellen Silbergeld, Ph.D., Division of Environmental Health Engineering, Department of 

Environmental Health Sciences, Johns Hopkins University, Baltimore, MD 

Neal Simonsen, Ph.D., Department of Public Health and Preventive Medicine, Louisiana 

State University Health Sciences Center, New Orleans, LA 

Kyle Steenland, Ph.D., National Institute for Occupational Safety and Health, Cincinnati, 

OH 

Marshall Williams, Ph.D., Department of Molecular Virology, Immunology and Medical 

Genetics, Ohio State University, Columbus, OH 
05/08/03 RoC Background Document for Lead and Lead Compounds 

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Criteria for Listing Agents, Substances or Mixtures in the Report on Carcinogens 

U.S. Department of Health and Human Services 

National Toxicology Program 

Known to be Human Carcinogens: 

There is sufficient evidence of carcinogenicity from studies in humans, which 

indicates a causal relationship between exposure to the agent, substance or 

mixture and human cancer. 

Reasonably Anticipated to be Human Carcinogens: 

There is limited evidence of carcinogenicity from studies in humans, which 

indicates that causal interpretation is credible but that alternative explanations 

such as chance, bias or confounding factors could not adequately be excluded; or

There is sufficient evidence of carcinogenicity from studies in experimental 

animals which indicates there is an increased incidence of malignant and/or a 

combination of malignant and benign tumors: (1) in multiple species, or at 

multiple tissue sites, or (2) by multiple routes of exposure, or (3) to an unusual 

degree with regard to incidence, site or type of tumor or age at onset; or

There is less than sufficient evidence of carcinogenicity in humans or laboratory 

animals, however; the agent, substance or mixture belongs to a well defined, 

structurally-related class of substances whose members are listed in a previous 

Report on Carcinogens as either a known to be human carcinogen, or reasonably 

anticipated to be human carcinogen or there is convincing relevant information 

that the agent acts through mechanisms indicating it would likely cause cancer in 

humans. 

Conclusions regarding carcinogenicity in humans or experimental animals are based on 

scientific judgment, with consideration given to all relevant information. Relevant 

information includes, but is not limited to dose response, route of exposure, chemical 

structure, metabolism, pharmacokinetics, sensitive sub populations, genetic effects, or 

other data relating to mechanism of action or factors that may be unique to a given 

substance. For example, there may be substances for which there is evidence of 

carcinogenicity in laboratory animals but there are compelling data indicating that the 

agent acts through mechanisms which do not operate in humans and would therefore not 

reasonably be anticipated to cause cancer in humans. 
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Table of Contents 

Executive Summary.......................................................................................................................iii 

1 Introduction............................................................................................................................... 1 

1.1 Chemical identification of lead.................................................................................. 1 

1.2 Physical-chemical properties of lead ......................................................................... 1 

1.3 Chemical forms of lead.............................................................................................. 2 

1.3.1 Inorganic lead compounds.......................................................................... 3 

1.3.2 Organic lead compounds ............................................................................ 3 

1.4 Physical-chemical properties of lead compounds...................................................... 4 

1.5 Lead ionization and bioavailabilty............................................................................. 4 

1.6 Identification of metabolites ...................................................................................... 5 

2 Human Exposure..................................................................................................................... 17 

2.1 Use ........................................................................................................................... 17 

2.2 Production................................................................................................................ 18 

2.3 Analysis.................................................................................................................... 22 

2.3.1 Air............................................................................................................. 22 

2.3.2 Water......................................................................................................... 24 

2.3.3 Soil............................................................................................................ 24 

2.3.4 Food .......................................................................................................... 24 

2.3.5 Blood ........................................................................................................ 24 

2.3.6 Serum or plasma ....................................................................................... 24 

2.3.7 Urine ......................................................................................................... 25 

2.3.8 Biomarkers................................................................................................ 26 

2.3.9 Soft tissue ................................................................................................. 27 

2.3.10 Bone and teeth .......................................................................................... 27 

2.4 Environmental occurrence ....................................................................................... 28 

2.4.1 Air............................................................................................................. 28 

2.4.2 Water......................................................................................................... 29 

2.4.3 Soil............................................................................................................ 29 

2.4.4 Paint .......................................................................................................... 30 

2.5 Environmental fate................................................................................................... 30 

2.6 Environmental exposure .......................................................................................... 31 

2.7 Occupational exposure............................................................................................. 33 

2.8 Biological indices of exposure................................................................................. 38 

2.9 Regulations .............................................................................................................. 40

2.10 Guidance .................................................................................................................. 40 

3 Human Cancer Studies............................................................................................................ 41 

3.1 IARC assessments.................................................................................................... 41 

3.2 Studies published since 1987 or not included in the IARC update.......................... 43 
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3.2.1 Studies of adult cancer focused on specific occupational groups............. 44 

3.2.2 Studies of mixed occupational groups...................................................... 54 

3.2.3 Studies of occupations exposed to organic lead: case-control study 

of TEL workers......................................................................................... 58 

3.2.4 Cohort studies based on general population (environmental) 

exposures .................................................................................................. 59 

3.2.5 Case-control studies based on general population (environmental) 

exposures .................................................................................................. 60 

3.2.6 Studies of paternal lead exposure and childhood cancer.......................... 61 

3.3 Summary.................................................................................................................. 62

3.3.1 Lung and other respiratory cancers and occupational lead exposure ....... 64 

3.3.2 Stomach and general digestive cancer...................................................... 69 

3.3.3 Kidney cancer ........................................................................................... 71 

3.3.4 Bladder cancer .......................................................................................... 72 

3.3.5 Childhood cancers .................................................................................... 73 

3.3.6 Other adult cancers ................................................................................... 73 

3.3.7 General population exposures and cancer ................................................ 74 

3.4 Conclusion ............................................................................................................... 75

4 Studies of Cancer in Experimental Animals......................................................................... 103 

4.1 Mice ....................................................................................................................... 103 

4.1.1 Lead acetate or subacetate ...................................................................... 103 

4.1.2 Lead naphthenate.................................................................................... 108 

4.1.3 Lead chromate ........................................................................................ 108 

4.1.4 Tetraethyl lead ........................................................................................ 109 

4.2 Rats ........................................................................................................................ 109 

4.2.1 Lead acetate and lead subacetate ............................................................ 109 

4.2.2 Lead phosphate ....................................................................................... 113 

4.2.3 Lead chromate ........................................................................................ 113 

4.2.4 Other inorganic lead compounds............................................................ 113 

4.2.5 Co-administration with other compounds .............................................. 114 

4.3 Hamsters ................................................................................................................ 119

4.4 Monkeys................................................................................................................. 120

4.5 Summary................................................................................................................ 120 

5 Genotoxicity.......................................................................................................................... 123 

5.1 Prokaryotic systems: Induction of mutations in Salmonella typhimurium, 

Escherichia coli, and Serratia marcescens............................................................ 124 

5.2 Plants: in vivo assays.............................................................................................. 124 

5.3 In vitro studies using cell-free systems.................................................................. 128 

5.4 Mammalian systems............................................................................................... 129 

5.4.1 In vitro assays ......................................................................................... 129 

5.4.2 In vivo assays.......................................................................................... 138 
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5.5 Summary................................................................................................................ 151 

6 Other Relevant Data.............................................................................................................. 153 

6.1 Absorption, distribution, and excretion of lead in humans.................................... 153 

6.1.1 Inorganic lead ......................................................................................... 153 

6.1.2 Organic lead compounds ........................................................................ 157 

6.2 Other toxic effects of lead compounds .................................................................. 158 

6.2.1 Neurotoxicity .......................................................................................... 159 

6.2.2 Nephrotoxicity ........................................................................................ 159 

6.2.3 Hematoxicity and anemia ....................................................................... 159 

6.2.4 Reproductive toxicity ............................................................................. 160 

6.2.5 Developmental toxicity........................................................................... 160 

6.2.6 Cardiovascular toxicity........................................................................... 160 

6.2.7 Other effects in rodents........................................................................... 160 

6.3 Mechanisms of lead carcinogenesis....................................................................... 160 

6.3.1 Possible mechanisms of genotoxicity and carcinogenicity .................... 161 

6.3.2 Indirect mechanisms ............................................................................... 165 

6.4 Summary................................................................................................................ 166 

7 References............................................................................................................................. 169 

Appendix A: Lead Regulations................................................................................................... 199 

List of Tables 

Table 1-1. Physical and chemical properties of lead ...................................................................... 2 

Table 1-2. Uses and structures of insoluble lead compounds......................................................... 6 

Table 1-3. Uses and structures of soluble lead compounds.......................................................... 12 

Table 1-4. Physical-chemical properties of insoluble lead compoundsa ...................................... 14 

Table 1-5. Physical-chemical properties of soluble lead compoundsa.......................................... 16 

Table 2-1. Mine and smelter production of lead in the United States from 1990 to 1996 

(thousands of metric tons).......................................................................................................... 19 

Table 2-2. Number of U.S. suppliers of lead compounds............................................................. 20 

Table 2-3. Key world lead production and consumption statisticsa

.............................................. 21 

Table 2-4. Common methods for the analysis of lead in environmental samples ........................ 23 

Table 2-5. Common methods for the analysis of lead in biological samples ............................... 25 

Table 2-6. Biomarkers for lead exposure...................................................................................... 27

Table 2-7. Air lead concentrations in occupational settings, based on OSHA inspection 

data (1979–1985) ....................................................................................................................... 37 

Table 2-8. Air lead concentrations from NIOSH Health Hazard Evaluation and Technical 

Assistance Program (1994–1999).............................................................................................. 37 
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Table 2-9. Blood lead concentrations from various occupations and the general 

population .................................................................................................................................. 38 

Table 2-10. Bone lead concentrations from various occupations and referent populations ......... 39 

Table 2-11. Key regulations on lead and lead compounds in the United States........................... 40 

Table 3-1. Human epidemiologic studies of lead exposure and cancer: published studies 

on specific populations, by study design ................................................................................... 45 

Table 3-2. Studies of lead exposure and cancer: cohort ............................................................... 76 

Table 3-3. Studies of lead exposure and cancer: case-control...................................................... 91 

Table 3-4. Lead exposure and childhood cancer ........................................................................ 100 

Table 4-1. Summary of carcinogenicity studies of lead subacetate in mice............................... 105 

Table 4-2. Effects of lead acetate on body-weight gain and urethan-induced lung 

adenoma in female Swiss mice................................................................................................ 107

Table 4-3. Effects of lead acetate on mortality and spontaneous lymphocytic leukemia in 

female Swiss mice.................................................................................................................... 107 

Table 4-4. Renal tubular cell proliferative lesions in B6C3F1 mice following gestational 

and lactational exposure to lead acetate................................................................................... 108 

Table 4-5. Summary of carcinogenicity studies of lead subacetate and lead acetate in rats 

conducted before 1980............................................................................................................. 110 

Table 4-6. Tumor incidence in male Sprague-Dawley rats fed lead subacetate (PbSA) and 

calcium acetate (CA)................................................................................................................ 112 

Table 4-7. Summary of carcinogenicity studies of lead phosphate in ratsa................................ 115 

Table 4-8. Summary of carcinogenicity studies of lead subacetate co-administered with 2-

AAF in ratsa ................................................................................................................................ 116 

Table 4-9. The promoting or co-carcinogenic effects of lead acetate or lead subacetate in 

rats............................................................................................................................................ 117 

Table 4-10. Co-carcinogenic effects of lead acetate administered with FBPA to male 

Fisher-344 rats ......................................................................................................................... 119 

Table 5-1. Genotoxicity of lead compounds in prokaryotic systems.......................................... 125 

Table 5-2. Genotoxicity of lead compounds in plants in vivo .................................................... 127 

Table 5-3. Genotoxicity of lead compounds in vitro in cell-free systems (without 

metabolic activation)................................................................................................................ 130 

Table 5-4. Genotoxicity of lead compounds in mammalian systems in vitro ............................ 135 

Table 5-5. Genotoxicity of lead compounds to mammals in vivo .............................................. 141 

Table 5-6. Genotoxicity of lead compounds in vivo in humans ................................................. 149 

Table 6-1. Effects of nutritional elements on gastrointestinal lead absorption in animals......... 154 

Table 6-2. Mobilization of lead during gestation in Sprague-Dawley rats................................. 157 

Table A-1. CPSC regulations...................................................................................................... A-1 

Table A-2. EPA regulations........................................................................................................ A-1 

Table A-3. FDA regulations ....................................................................................................... A-6 
05/08/03 RoC Background Document for Lead and Lead Compounds 

xvii

Table A-4. OSHA regulations..................................................................................................... A-7 

List of Figures

Figure 1-1. Physical structure of lead ............................................................................................. 2 

Figure 2-1. Worldwide lead use by end consumption (2000)....................................................... 18 

Figure 2-2. Global lead mine production and consumption (1964–2001).................................... 22 

Figure 2-3. Lead used in gasoline and average blood lead levels measured in NHANES II ....... 32 

Figure 6-1. Curvilinear relationship of human serum lead to blood lead ................................... 155 
05/08/03 RoC Background Document for Lead and Lead Compounds 

xviii
05/08/03 RoC Background Document for Lead and Lead Compounds 

1

1 Introduction 

Two lead compounds, lead acetate and lead phosphate, have been listed in the Report on 

Carcinogens (RoC) since 1981 as reasonably anticipated to be human carcinogens (NTP 

2000). Lead and lead compounds were nominated by the National Institute of 

Environmental Health Sciences for possible listing in the RoC, based on the 1987 listing 

by the International Agency for Research on Cancer (IARC) of lead and inorganic lead 

compounds as possibly carcinogenic to humans (Group 2B) and the subsequent 

publication of additional human and animal studies of lead and lead compounds. 

1.1 Chemical identification of lead 

Elemental lead (Pb, atomic wt 207.2, CASRN 7439-92-1) is an odorless silver-bluish 

white soft metal that is insoluble in water. It also is known as C.I. 77575, C.I. pigment 

metal 4, KS-4, and lead (inorganic). Its melting point is 327.43°C, its boiling point is 

1,740°C, and its appearance varies depending on the physical structure of the specific 

compound. Lead exists in the valence states of +2 and +4 and has four naturally 

occurring isotopes: 204, 206, 207, and 208. Inorganic lead compounds usually consist of 

lead in the divalent state (+2). The chemistry of divalent lead is similar to that of other 

Group 2 metals, which include beryllium, magnesium, calcium, strontium, and barium. 

The major chemical forms of lead found in the environment, as well as in occupational 

exposures, are reviewed in this report. The U.S. Environmental Protection Agency (EPA) 

codes for lead and lead compounds are K005, K006, K007, K046, K061, K062, K069, 

U144, U145, U146, P110, and D008. The RTECS number for lead is OF7525000, and 

the shipping code is NA 1794 ORM-C. 

1.2 Physical-chemical properties of lead 

The physical structure of crystalline lead is cubic and close-packed, as illustrated in 

Figure 1-1. Lead is very soft, highly malleable, ductile, and a relatively poor conductor of 

electricity. It is very resistant to corrosion but tarnishes upon exposure to air. Lead alloys 

include pewter and solder. The physical and chemical properties of lead are listed in 

Table 1-1. 
05/08/03 RoC Background Document for Lead and Lead Compounds 

2

Source: WebElements 2000. 

Figure 1-1. Physical structure of lead 

Table 1-1. Physical and chemical properties of lead 

Property Information Reference 

Atomic weight 207.2 Budavari et al. 1996, ChemFinder 2000 

Color silver-bluish white Budavari et al. 1996, CRC 1998, 

ChemFinder 2000 

Odor odorless CRC 1998, HSDB 2002 

Physical state soft metal Budavari et al. 1996, CRC 1998, 

ChemFinder 2000 

Melting point (°C) 327.43 Budavari et al. 1996, CRC 1998, HSDB 

2002 

Boiling point (°C) 1,740 Budavari et al. 1996, CRC 1998, HSDB 

2002 

Density (g/cc at 20°C) 11.4 HSDB 2002 

Vapor pressure 

(mm Hg at 1,000°C) 1.77 HSDB 2002 

Crystal system cubic close-packed WebElements 2000 

Young’s modulus (GPa) 16 WebElements 2000 

Solubility: 

water at 20°C 

nitric acid 

hydrochloric acid 

insoluble 

insoluble as lead nitrate 

soluble as lead chloride 

Budavari et al. 1996, CRC 1998, HSDB 

2002, ChemFinder 2000 

1.3 Chemical forms of lead 

Lead is released into the environment in many different chemical forms. The chemical 

form of lead determines its water solubility, the types of chemical reactions that occur in 

the atmosphere, water, and soil, and the extent to which lead binds in soils (NSF 1977). 

The primary source of lead in the environment historically has been lead emissions from 

gasoline-containing lead additives. The use of leaded gasoline was banned in the United 

States after December 31, 1995, except for use in gasoline for aircraft and in fuels for 

racing vehicles and for non-road vehicles (ATSDR 1999) (see Section 2.1). Lead 

exposure from all chemical forms most commonly is measured in the body by 
05/08/03 RoC Background Document for Lead and Lead Compounds 

3

determining blood lead levels. The results are reported as micrograms of lead per deciliter 

of blood, and childhood blood lead levels of 10 μg/dL or higher are considered to present 

risks to children’s health (see Sections 2.6 and 2.10). Exposure to various chemical forms 

of lead also may be measured in urine, plasma, bones, teeth, and hair (see Sections 2.3.6 

to 2.3.10). 

1.3.1 Inorganic lead compounds 

Of the lead emitted from automobiles using leaded gasoline, 90% is in particulate form, 

and the remaining 10% exists as organic lead vapors (see Section 1.3.2). The particle size 

distribution varies with the engine operating conditions; however, generally, 20% to 30% 

of the lead particles are larger than 5 μm in diameter, 50% to 70% are in the 1- to 5-μm 

range, and 5% or fewer are smaller than 1 μm in diameter. Any particle less than 30 μm 

in diameter can be deposited in the nasopharyngeal region of the respiratory tract, and 

particles smaller than 5 μm can reach the bronchiolar region (Casarett et al. 1996). The 

majority of compounds detected consist of the lead halides: lead bromide (PbBr2), lead 

chloride (PbCl2), lead bromochloride (PbBrCl), and the alpha and beta forms of the 

double salt lead bromochloride ammonium chloride (2PbBrCl⋅NH4Cl) (NSF 1977).

Studies have shown that 95% of the particles emitted from secondary lead-smelting 

operations are less than 5 μm in diameter. The chemical forms most often detected are 

lead sulfide (PbS), lead sulfate (PbSO4), and elemental lead (NSF 1977). Another form 

emitted from mining operations and smelters is lead oxide⋅lead sulfate (PbO⋅PbSO4)

(ATSDR 1999). 

Once these lead compounds are present in the atmosphere, they are converted through 

chemical reactions into a large number of additional lead compounds. Some of the lead 

compounds identified in the atmosphere are 2PbBrCl⋅NH4Cl, PbSO4, lead carbonate 

(PbCO3), PbBr2, PbCl2, lead oxide (PbOx), lead hydroxychloride (Pb(OH)Cl), lead 

hydroxybromide (Pb(OH)Br), lead phosphate (Pb3(PO4)2), lead oxide⋅lead sulfate 

(3PbO⋅PbSO4), lead oxide⋅lead chloride (2PbO⋅PbCl2), and lead oxide⋅lead 

bromochloride (2PbO⋅PbBrCl) (NSF 1977). 

Inorganic lead compounds also are found in water and soil. The amount of lead in surface 

water depends on the pH and the dissolved salt content. In the environment, the divalent 

form (Pb2+) is the stable ionic form of lead. The forms of lead most often found in soil are 

PbSO4 and PbCO3, the same compounds identified as primary forms found in the 

atmosphere (NSF 1977). 

1.3.2 Organic lead compounds 

The tetraalkyl lead compounds, specifically tetraethyl lead (TEL) and tetramethyl lead 

(TML), are the primary organic lead compounds used as automotive gasoline additives in 

the United States until 1996 and still used today in racing-car and aviation gasoline. The 

phaseout of tetraethyl and tetramethyl lead from automotive gasoline was initiated in the 

1970s. These two compounds no longer are present in large amounts in the atmosphere; 

however, their degradation products still exist in the atmosphere. These compounds 
05/08/03 RoC Background Document for Lead and Lead Compounds 

4

decompose rapidly to trialkyl and dialkyl lead compounds when exposed to sunlight and 

eventually degrade to inorganic lead oxides (ATSDR 1999). 

In water, the tetraalkyl lead compounds are subject to photolysis and volatilization. The 

more volatile compounds are lost to the atmosphere by evaporation. As in air, the 

degradation process consists of trialkyl lead compounds degrading to dialkyl lead and 

finally to inorganic lead. Triethyl and trimethyl lead are more water soluble than are 

tetraethyl or tetramethyl lead and therefore are more often detected in aquatic 

environments (ATSDR 1999). 

Another source of organic lead in water is the conversion of inorganic lead to tetramethyl 

lead by microorganisms living in anaerobic lake sediments (Craig et al. 1980, ATSDR 

1999). However, if the water over the sediments is aerobic, the tetramethyl lead will be 

oxidized, resulting in release of lesser amounts of tetramethyl lead to the water (ATSDR 

1999). 

In soil, organic lead compounds such as tetramethyl and tetraethyl lead may be converted 

to highly water-soluble compounds, such as the trialkyl lead oxides. These compounds 

could be subject to leaching from the soil (ATSDR 1999). 

1.4 Physical-chemical properties of lead compounds 

Tables 1-2 and 1-3 present the chemical formulas, synonyms, uses, and structures of the 

major lead compounds, and Tables 1-4 and 1-5 present the physical-chemical properties 

of these same compounds. The tables are organized according to whether compounds are 

relatively insoluble in water (Tables 1-2 and 1-4) or relatively soluble in water (Tables 1-

3 and 1-5). Compounds are considered soluble or insoluble based on the following 

criteria: (1) If a solubility constant (Ksp) is available, a compound with a value greater 

than or equal to the Ksp for lead chloride (1 x 10-4) is considered soluble. (2) If a Ksp is 

not available, a compound is considered soluble if more than 2 g of the compound 

dissolves in 100 mL of water. (3) If no numeric solubility data are available, the 

compounds are considered soluble or insoluble based on a general rule of solubility of 

chemical species, as outlined in McQuarrie and Rock (1984). 

1.5 Lead ionization and bioavailabilty 

The physical-chemical properties of lead and lead compounds determine their availability 

to be absorbed into the body, as well as their other pharmacokinetic properties. Studies 

have shown that soluble lead compounds are more likely to be absorbed into the body 

than are insoluble compounds and that smaller inorganic lead particulates are absorbed to 

a greater degree than are larger particulates (Fleming 1998). The degree of absorption in 

the body also depends on the particular physical-chemical properties of the lead 

compound (see Section 6 for a discussion of the toxicokinetics of lead). In a study in 

which rats were fed lead in the diet, the percent absorption of metallic lead and several 

lead compounds was compared with that of lead acetate. The percent absorption was 

lowest for metallic lead (14%), followed by lead chromate (44%), lead naphthenate 

(64%), and basic lead carbonate (164%), for a 12-fold difference in absorption between 

metallic lead and basic lead carbonate (Barltrop 1975). In addition, studies of metals, 
05/08/03 RoC Background Document for Lead and Lead Compounds 

5

including lead, have emphasized the significance of chemical speciation, particularly 

ionization, in toxicity (Degawa et al. 1994, Ritchie et al. 2001). 

1.6 Identification of metabolites 

Metallic lead is not metabolized; however, metallic lead and lead compounds are 

transformed after entry into the body. These transformations are discussed in Section 6. 
05/08/03 RoC Background Document for Lead and Lead Compounds 

6

Table 1-2. Uses and structures of insoluble lead compounds 

Compound, formula, mol wt CASRN Synonyms Uses StructLead arsenate PbAsHO4

347.1271 

7784–40–9 acid lead orthoarsenate, acid lead 

arsenate, arsenic acid lead (2+) salt, arsinette 

formerly used as an insecticide and herbicide 

O

As

HO

O

Lead azide PbN6

291.2402 

13424–46–9 initiating explosive as an explosive 

N -

+

N -

N

P

Lead bromide PbBr2

367.008 

10031–22–8 lead(II) bromide (not available) 

Br Pb 

Lead carbonate PbCO3

267.2092 

598–63–0 carbonic acid, lead (2+) salt (1:1), 

lead(II) carbonate, and lead carbonate, 99.999% 

as a catalyst, in highpressure lubricating greases, and as a photoconductor for electrolithography, and in coatings for thermographic copying, formerly used in paint 

O

C

-O 

Pb
05/08/03 RoC Background Document for Lead and Lead Compounds 

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Compound, formula, mol wt CASRN Synonyms Uses StructLead chromate PbCrO4

323.1936 

7758–97–6 lead(II) chromate; lead(IV) 

chromate; chrome yellow; plumbous chromate; crocoite; lead chromate (VI); chromic acid, lead(2+) salt (1:1); canary chrome yellow 40-2250; chrome green uc61; chrome green uc74; chrome green uc76; chrome lemon; chrome yellow g; chrome yellow gf; chrome yellow lf; chrome yellow light 1066; chrome yellow light 1075; chrome yellow medium 1074; chrome yellow medium 1085; chrome yellow medium 1298; chrome yellow primrose 1010; chrome yellow primrose 1015; chrome yellow 5g; chromium yellow; CI 77600; C.I. pigment yellow 34; cologne yellow; C.P. chrome yellow light; C.P. chrome yellow medium; C.P. chrome yellow primrose; crociote; dianichi chrome yellow g; leipzig yellow; lemon yellow; paris yellow; pigment green 15; pure lemon chrome l3gs 

as a pigment in paints, rubber, and plastics 

O

Cr

O

OO

Lead fluoride PbF2

245.1969 

7783–46–2 lead difluoride, lead(2+) fluoride, 

and plumbous fluoride 

as a catalyst, in lowpower fuses, in lowmelting glasses, and in other electronic and optical applications 

Pb

F
05/08/03 RoC Background Document for Lead and Lead Compounds 

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Compound, formula, mol wt CASRN Synonyms Uses StructLead fluoroborate PbB2F8

380.8072 

13814–96–5 lead fluoborate, borate(1-), 

tetrafluoro-lead(2+), lead borofluoride, lead boron fluoride, and lead tetrafluoroborate 

in electroplating, as a curing agent for epoxy resins, and as a catalyst 

F

BF

F

F

Pb

Lead iodide PbI2

461.009 

10101–63–0 lead diiodide, lead(II) iodide, 

plumbous iodide 

in photographic emulsions, aerosols for cloud seeding, asbestos brake linings, and thermoelectric materials 

Pb

I 

Lead naphthenate Pb(C7H11

O2)2

461.5254 

50825–29–1 cyclohexanecarboxylic acid and 

lead salt 

as a varnish drier, catalyst, wood preservative, and insecticide 

Pb+2

C 

-

O

C

O

-

O
05/08/03 RoC Background Document for Lead and Lead Compounds 

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Compound, formula, mol wt CASRN Synonyms Uses StructLead oxide PbO 223.1994 

1317–36–8 lead(II) oxide, lead monoxide, 

lead oxide yellow, litharge, C.I. 77577, lead ocher, lead oxide(mono), lead protoxide, litharge yellow l-28, massicot, massicotite, pigment yellow 46, yellow lead ocher, plumbous oxide, lead(II) oxide yellow, and lead oxide, 99.99% 

in paint, glass, and ceramic products, as a vulcanizing agent in rubber and plastics, and as an intermediate in the manufacture of pigments 

Pb 

Lead phosphate Pb3O8P2

811.54272 

7446–27–7 lead orthophosphate, plumbous 

phosphate, trilead phosphate, perlex paste, trilead bis(orthophosphate), phosphoric acid lead(2+) salt (2:3), and lead(II) phosphate (3:2) 

as a stabilizer for styrene and casein plastics and in special glasses 

O

P

-

O

Pb+

O

P

-

O

Pb+2 

Lead stearate Pb(C18

H35

O2)2

774.1466 

1072–35–1 lead distearate, lead(II) 

noctadecanoate, and lead(II) 

stearate 

as a stabilizer for plastics and rubber processing 
05/08/03 RoC Background Document for Lead and Lead Compounds 

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Compound, formula, mol wt CASRN Synonyms Uses StructLead styphnatePbC6HO2(NO2)3

450.2000 

63918–97–8 initiating explosive lead 

styphnate, lead trinitroresorcinate, 

and styphnate of lead 

in munitions manufacture 

O

NO2

O2N

Lead sulfate PbSO4

303.2576 

7446–14–2 lead(II) sulfate, anglistlite, white 

lead, fast white, milk white, sulfuric acid lead (2+) salt (1:1), lead sulfate basic, lead sulfate 99.999%, and lead sulphate (lead(II) sulfate) 

in photography, in lithography, in earthfill dams, and roads, and with zinc in galvanic batteries 

O

O 

Pb

Lead sulfide PbS 239.26 

1314–87–0 galena, plumbous sulfide, lead(II) 

sulfide, lead monosulfide, lead sulfide 99.999%, and lead sulfide (1:1) 

in ceramics, as a semiconductor, as a catalyst, as a mirror coating, and as a humidity sensor in rockets 

Pb 

Lead tetraoxide Pb3O4

685.5976 

1314–41–6 mineral red, lead oxide, red lead 

oxide, orange lead, and lead(II,III) oxide 

in plasters, ointments, glazes, and varnishes, for coloring of rubber, in cement for glass, in storage batteries, and in paints 

Pb

O

Pb

OO

Lead thiocyanate Pb(SCN)2

323.3554 

592–87–0 isothiocyanic acid lead(2+) salt, 

lead dithiocyanate, lead(II) thiocyanate, lead isothiocyanate, and lead sulfocyanate 

in manufacture of safety matches and cartridges 

Pb

SN
05/08/03 RoC Background Document for Lead and Lead Compounds 

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Compound, formula, mol wt CASRN Synonyms Uses StructTetraethyl lead Pb(C2H5)4

323.446 

78–00–2 motor fuel anti-knock compound, 

lead tetraethyl, tetraethylplumbane, TEL, and tetraethyl lead (liquid) 

as an antiknock additive in gasoline, banned since 1996 in motor vehicles in the U.S. Pb

H2

C 

H3C 

H3C

H3C

Tetramethyl lead Pb(CH3) 4

267.3388 

75–74–1 lead tetramethyl, TLM, 

tetramethylplumbane, TML, and toluene blend no.2 

as an antiknock additive in gasoline, banned since 1996 in motor vehicles in the U.S. 

CH

Pb

H3C 

Sources: ChemFinder 2000, HSDB 2002. 
05/08/03 RoC Background Document for Lead and Lead Compounds 

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Table 1-3. Uses and structures of soluble lead compounds 

Compound, formula, mol wt CASRN Synonyms Uses StrucLead acetate PbC4H6O4 325.289 

301–04–2 acetic acid, lead(2+) salt, sugar of 

lead, lead diacetate, lead(II) salt acetic acid, normal lead acetate, neutral lead acetate, lead dibasic acetate, and dibasic lead acetate 

as a water repellant, for mildew prevention, as a coloring agent, and as a mordant in cotton dyes. 

P

O

C

H3C

O

Lead acetate trihydrate PbC4H12

O7

379.3346 

6080–56–4 salt of Saturn, lead acetate (II), 

trihydrate, acetic acid-lead(+2) salt trihydrate, bis(acetato)trihydroxy-trilead, lead diacetate trihydrate, and acetic acid-lead salt trihydrate 

in varnishes, chrome pigments, and antifouling paints, in historical paint manufacture, and as an analytical reagent 

OOH3C

C

H 

O

H

O

H 

P

Lead chloride PbCl2

278.106 

7758–95–4 lead(II) chloride and lead 

dichloride 

in manufacture of organolead compounds, in asbestos clutch or brake linings, as a catalyst, and as a flame retardant 

P

Cl 
05/08/03 RoC Background Document for Lead and Lead Compounds 

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Compound, formula, mol wt CASRN Synonyms Uses StrucLead nitrate PbN2O6331.2098 

10099–74–8 lead dinitrate, nitric acid-lead(2+) 

salt, lead(II) nitrate, and lead nitrate, 99.5% 

in manufacture of matches and explosives, as a heat stabilizer in nylon, and as a coating on paper for photothermography 

O

N+

-O 

P

O

N+

-O 

Lead subacetate Pb2C4H8O6

566.5036 

1335–32–6 bis(acetato-O)tetrahydroxytrilead, 

basic lead acetate, bis(acetato)tetrahydroxytrilead, bis(aceto)tetrahydroxytrilead, 

bis(aceto)dihydroxytrilead, BLA, monobasic lead acetate, and subacetate lead 

in sugar analysis and for clarifying solutions of organic substances 

H3C

C

O

OPb 

Sources: ChemFinder 2000, HSDB 2002. 
05/08/03 RoC Background Document for Lead and Lead Compounds 

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Table 1-4. Physical-chemical properties of insoluble lead compoundsa

Compound, formula 

Color and 

physical state 

Melting point 

(

oC) 

Boiling point 

(

oC) 

Density or 

specific gravity Solub

Lead arsenate PbAsHO4

white powder or crystals 280 NA 5.94 insoluble in 

acid and alk

Lead azide PbN6

white needles or powder NA explodes at 350 NA 230 mg/L at 

Lead bromide PbBr2

white crystalline powder 373 916 6.66 8,441 mg/L 

insoluble in 

Lead carbonate PbCO3

colorless rhombic crystals 315 NA 6.6 

Ksp = 1.1 x 1

ammonia, or and alkali 

Lead chromate PbCrO4

yellow or orange yellow powder 

844 decomposes NA 

Ksp = 1.7 x 1

< 0.1 g/100 

Lead fluoride PbF2

colorless to white crystals 824 1,293 8.44 (orthorhombic) 

7.75 (cubic) 

insoluble in ammonia; so

Lead fluoroborate PbB2F8

colorless crystalline powder 

NA NA 1.75 decomposes 

Lead iodide PbI2

bright yellow crystals or powder 

402 954 6.16 630 mg/L at 

alcohol 

Lead naphthenate Pb(C7H11

O2)2

yellow semi-transparent paste 

100 NA 1.15 insoluble in 

ethanol 

Lead oxide PbO 

yellow or reddish-yellow crystals 

888 1,470 9.53 insoluble in 

soluble in alacetic acid, a

Lead phosphate Pb3O8P2

white solid powder 1,014 NA 6.9 insoluble in 

soluble in al
05/08/03 RoC Background Document for Lead and Lead Compounds 

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Compound, formula 

Color and 

physical state 

Melting point 

(

oC) 

Boiling point 

(

oC) 

Density or 

specific gravity Solub

Lead stearate Pb(C18

H35

O2)2

white powder NA NA NA NA 

Lead styphnate PbC6HO2(NO2)3

orange-yellow crystals NA NA NA NA 

Lead sulfate PbSO4

white heavy crystal powder 

1,170 NA 6.2 

Ksp = 1.5 x 1

hydroxide; i

Lead sulfide PbS 

metallic black cubic crystals 

1,114 1,281 7.57–7.59 

Ksp = 1 x 10

acid; insolubhydroxide, o

Lead tetraoxide Pb3O4

bright-red heavy powder 500 NA 9.1 soluble in hy

acid; insoluboxidizing ma

Lead thiocyanate Pb(SCN)2

white crystals 190 NA 3.82 insoluble in 

hydroxide, thand lead sulf

Tetraethyl lead Pb(C2H5)4

colorless liquid or dyed red, orange, or blue, with a slight musty odor 

-136.8 200 1.659 

Ksp > 4 x 10

g/100 mL) in benzene, ethflash point is 

Tetramethyl lead Pb(CH3)4

colorless liquid or dyed red, orange, or blue, with a slight musty odor 

-27.5 110 1.995 insoluble in 

benzene, ethflash point is 

Sources: ChemFinder 2000, HSDB 2002. NA = not available. 
05/08/03 RoC Background Document for Lead and Lead Compounds 

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Table 1-5. Physical-chemical properties of soluble lead compoundsa

Compound, formula, mol wt 

Color and 

physical state 

Melting point 

(

oC) 

Boiling point 

(

oC) 

Density or 

specific gravity Solubilit

Lead acetate PbC4H6O4

colorless or white crystals, granules, or powder 

280 NA 3.25 at 20oC 

Ksp = 2 x 10-2; 1–5 g

slightly soluble (< 0ethanol; slightly soluDMSO; slightly soluin acetone; soluble i

Lead acetate trihydrate PbC4H12

O7 

white crystals 75 280 2.55 miscible in water; sl

ethanol and acetonesensitive to air; reagamino acids and hyd

Lead chloride PbCl2

white crystalline powder 

501 950 5.85 

Ksp = 1 x 10-4; solub

hydrochloric acid, anin ethanol 

Lead nitrate PbN2O6

colorless or white crystals 

470 NA 4.53 

Ksp = 2 x 10-2 ; solub

ethanol, alkali, and anitric acid oxidizing material 

Lead subacetate Pb2C4H8O6

white heavy powder 75 decomposes NA soluble in water and 

sensitive to air 

Sources: ChemFinder 2000, HSDB 2002. NA = not available. 
05/08/03 RoC Background Document for Lead and Lead Compounds 

17 

2 Human Exposure 

2.1 Use 

In worldwide metal use, lead ranks behind only iron, copper, aluminum, and zinc (Howe 

1981). Lead may be used in its pure form as a metal, alloyed with other metals, or used in 

chemical compounds. The utility of lead may be derived from its low melting point 

(327°C), high density (11.4 g/cm3), malleability, chemical stability, and resistance to acid 

corrosion (Howe 1981). The vast majority of lead used, both in the United States and 

internationally, is in lead-acid storage batteries found in motor vehicles and general 

industry. Other common uses of lead metal include ammunition, cable covering, piping, 

brass and bronze, bearing metals for machinery, and sheet lead (ATSDR 1999). In 

addition, lead-based metals are used in solders, shipping containers, radiation shielding, 

building construction, and metal cans. Lead oxides are found in paint, glass, and ceramics 

(Smith 2002a). However, in the United States, lead is no longer used as a solder in piping 

for drinking water, as a solder in food cans, or in house paints, because of environmental 

and health concerns (ATSDR 1999). 

In the early 1970s, the U.S. EPA began to regulate the lead content in gasoline. Before 

that, approximately 250,000 tons of organic lead (tetraethyl and tetramethyl lead) were 

added to gasoline annually in the United States as an anti-knock additive. By 1988, a lead 

phase-down program had reduced the total lead usage in gasoline to less than 1% of that 

in 1970. In 1996, lead was totally banned as an additive to fuel in motor vehicles in the 

United States (ATSDR 1999). However, organic lead still is permitted for use in gasoline 

for aircraft and in fuels for racing vehicles and for non-road vehicles, such as farm 

machinery, marine vessels, construction equipment, and recreational vehicles (Smith 

2000). 

Lead also is used in folk remedies and cosmetics, particularly in developing countries 

(UNEP-UNICEF 1997). There is evidence that traditional cosmetics containing lead, 

such as the eye cosmetic kohl, have been purchased and used in the United States (Parry 

and Eaton 1991). 

Despite reductions in some lead applications and the legislated end to use of lead as a 

gasoline additive, the overall consumption of lead is growing. From 1990 to 1996, the use 

of lead in the United States grew at an average annual rate of 3.3%. This trend was due 

primarily to increased production of lead-acid batteries. The proportion of lead used for 

this purpose increased from just below 80% to nearly 88% in this time span (ATSDR 

1999). The vast majority of lead-acid batteries find application as starting, lighting, and 

ignition batteries in motor vehicles. The remainder are designed for various industrial 

motive power and stationary power battery applications (Smith 2000). Figure 2-1 shows 

the end uses of lead worldwide in 2000 (neither the data nor the percentages of the uses 

are provided in the reference). 
05/08/03 RoC Background Document for Lead and Lead Compounds 

18 

Source: LDA 2002. 

Figure 2-1. Worldwide lead use by end consumption (2000) 

2.2 Production 

Lead is refined from mined ore. Lead ore occurs most frequently in the form of lead 

sulfide, also known as galena. Anglesite (PbSO4) and cerussite (PbCO3) are two other 

common ores (Howe 1981). In the United States, virtually all lead mines are 

underground, rather than open pits (ATSDR 1999). As of 2000, 19 mines produced the 

vast majority of lead in the United States (Smith 2000), employing approximately 1,000 

workers (Smith 2002b). Mines were located in Alaska, Idaho, Missouri, Montana, 

Nevada, New York, and Tennessee, with over 90% of the total mining occurring in 

Missouri and Alaska (Smith 2000). Mined lead ore first is crushed and ground. The 

various minerals are then separated by differential flotation, resulting in a lead 

concentrate which is shipped to a primary smelter for refining. In 2001, two primary lead 

smelter-refineries were operating in Missouri and one primary lead smelter was operating 

in Montana, employing a total of approximately 400 people (Smith 2002b). 

At a primary smelter, lead concentrates are sintered to remove sulfur dioxide and other 

volatile oxides, and the product is roasted with by-products and coke. Molten lead is 

formed in the blast furnace during the smelting process; impurities are collected in a slag. 

Drossing is performed to remove copper, lead oxide, and other compounds. Additional 

refining is performed to separate out minor quantities of silver, antimony, arsenic, copper, 

and bismuth. The resulting lead metal is 99.99% pure. 

Secondary smelters (recycling smelters) use scrap lead, mainly from used lead-acid 

batteries, as their supply. Used batteries are passed through a separation unit that removes 

leaded materials and processes the battery acid. The remaining leaded materials are 
05/08/03 RoC Background Document for Lead and Lead Compounds 

19 

passed through rotary, reverberatory, or blast furnaces, with an impure lead (or lead 

alloy) resulting (Howe 1981). The impure metal may then be refined, with its drosses 

submitted back for reprocessing. Lead recovery efficiencies of 98% may be achieved 

through secondary smelters. As of 2001, 26 secondary lead smelters were operating 

within the United States (Smith 2002b); approximately 98% of total lead recycling was 

carried out by seven companies operating a total of 15 plants in Alabama, California, 

Florida, Indiana, Louisiana, Minnesota, Missouri, New York, Pennsylvania, Tennessee, 

and Texas (Smith 2000). In total, secondary lead smelting employs approximately 1,600 

workers nationwide (Smith 2002a). From 1990 to 1996, the share of total lead metal 

production coming from secondary smelters rose from just under 70% to 77% (ATSDR 

1999). This trend toward secondary production is reflected in Table 2-1, which provides 

data on recent U.S. lead mining and smelting production (ATSDR 1999). 

Table 2-1. Mine and smelter production of lead in the United States from 1990 to 

1996 (thousands of metric tons) 

1990 1996 Percentage change 

Mining 484 436 -10 

Primary smelting 404 326 -19 

Secondary smelting 922 1,100 +19 

Source: ATSDR 1999. 

Statistical data are available on lead mining in the United States going back over 100 

years; in fact, there is information to indicate that lead was mined and smelted in North 

America as early as 1621. In the 1830s, annual U.S. production was reported at 2.7 

million kg. In 1976, U.S. production of lead was reported at 550 million kg, with imports 

at 208 million kg in 1976 and 318 million kg in 1978. Exports were reported at 5.3 

million kg in 1976, 9.0 million kg in 1977, and 8.0 million kg in 1978. 

Lead acetate was first produced in the United States in 1944, with imports in 1978 

reported at 112.7 kg (IARC 1980). U.S. production of lead acetate was approximately 

300,000 kg in 1977 and 200,000 kg in 1980, with imports reported at approximately 

52,000 kg in 1984 and 50,000 kg in 1985 (NTP 2000). Lead carbonate has been produced 

commercially in the United States since the 1600s; in 1976, U.S. production was 

1.48 million kg, with imports in 1978 of 178,000 kg (IARC 1980). Commercial 

production of lead naphthenate in the United States was first reported in 1944. In 1969, 

production of lead naphthenate was 8.2 million kg, with production dropping to 

2.2 million kg in 1977 (IARC 1980). Lead nitrate was first commercially produced in the 

United States in 1943, and imports of 480,000 kg were reported in 1978 (IARC 1980). 

U.S. production of lead oxide in 1976 was 120 million kg, with imports at 20 million kg 

(IARC 1980). Commercial production of lead subacetate was first reported in the United 

States in 1947 (IARC 1980); no production data are available. U.S. production of lead 

tetraoxide in 1976 was reported at 18 million kg, with imports at 800,000 kg in 1976 and 

1 million kg in 1979. In 1977, approximately 1 to 15 million kg were exported (IARC 

1980). 
05/08/03 RoC Background Document for Lead and Lead Compounds 

20 

Tetraethyl lead was first produced commercially in the United States in 1923, with 

266 million kg produced in 1964; production dropped in 1977 to 148 million kg. Imports 

of tetraethyl lead in 1978 were 17,000 kg (IARC 1980). Commercial production of 

tetramethyl lead in the United States began in 1960, with 54 million kg produced in 1977 

and 13,800 kg imported in 1974 (IARC 1980). 

Table 2-2 shows the number of U.S. suppliers of the lead compounds listed in Tables 2-2 

and 2-3. 

Table 2-2. Number of U.S. suppliers of lead compounds 

Lead compound Number of U.S. suppliers 

Lead acetate 26 

Lead acetate trihydrate 19 

Lead arsenate 3 

Lead azide (not reported) 

Lead bromide 13 

Lead carbonate 20 

Lead chloride 16 

Lead chromate 13 

Lead fluoride 17 

Lead fluoroborate 15 

Lead iodide 21 

Lead naphthenate (not reported) 

Lead nitrate 44 

Lead oxide 30 

Lead phosphate 4 

Lead stearate 10 

Lead styphnate (not reported) 

Lead subacetate 15 

Lead sulfate 8 

Lead sulfide 17 

Lead tetraoxide 9 

Lead thiocyanate 10 

Tetraethyl lead 3 

Tetramethyl lead 2 

Source: Chem Sources 2002. 

Worldwide production data from 2001 show that the United States is the major producer, 

user, and recycler of lead, and that Australia mines more lead than any other country (see 

Table 2-3). Global statistics show that lead production and consumption increased fairly 
05/08/03 RoC Background Document for Lead and Lead Compounds 

21 

steadily from 1964 to 2000, while worldwide mine production decreased slowly, 

remaining steady over the last few years (see Figure 2-2) [It is not stated in the reference 

whether these statistics are for metallic lead or lead compounds.]. 

Table 2-3. Key world lead production and consumption statisticsa

Lead (tons) 

Top mining countries 

Australia 714,000 

China 599,000 

United States 459,000 

Peru 289,000 

Canada 154,000 

Largest lead producers 

United States 1,375,000 

China 1,172,000 

United Kingdom 382,000 

Germany 375,000 

Japan 302,000 

Major users of lead 

United States 1,687,000 

China 650,000 

Germany 403,000 

United Kingdom 323,000 

South Korea 314,000 

Main recyclers of lead 

United States 1,099,000 

Germany 218,000 

United Kingdom 183,000 

Japan 175,000 

Italy 164,000 

Source: LDA 2002. 

*The statistics in this table do not include the amount of lead imported and exported; therefore the amount of 

lead produced is not equal to the amount of lead used by the countries cited in this table. 
05/08/03 RoC Background Document for Lead and Lead Compounds 

22 

Source: LDA 2002. 

Figure 2-2. Global lead mine production and consumption (1964–2001) 

2.3 Analysis 

The most common techniques for the analysis of lead in environmental or biological 

samples include atomic absorption spectrometry (AAS), graphite furnace atomic 

absorption spectrometry (GFAAS), particle-induced X-ray emission (PIXE), inductively 

coupled plasma mass spectrometry (ICP-MS), inductively coupled plasma atomic 

emission spectrometry (ICP-AES), and anode-stripping voltametry (ASV). Isotopedilution mass spectrometry (IDMS) is the best technique for applications involving very 

low lead concentrations (NRC 1993) but is not commonly used because of its equipment 

requirements and reliance on technical expertise (ATSDR 1999). A brief overview of the 

methods for lead analysis in various media is presented below, along with summary 

tables for the methods most commonly used for environmental lead analysis (Table 2-4) 

and biological lead analysis (Table 2-5). 

2.3.1 Air 

Lead in air may be given as a concentration of lead in particulate or gaseous form, 

usually expressed as micrograms of lead per cubic meter. The most common methods for 

the analysis of particulate lead in air are AAS, GFAAS, PIXE, and ICP-AES. A filtering 

approach is used to isolate particulate lead. GFAAS has a lower limit of detection than 

AAS (approximately 0.25 ng/m3

 and 100 ng/m3, respectively) but is more sensitive to 

spectral interference arising from the matrix (NRC 1993). Lead in gaseous form is 

organic lead and often is detected by GFAAS. Gas chromatography with AAS (GCAAS), with a detection limit of approximately 0.2 ng/m3

, also may be used to distinguish 

among species of organic lead (De Jonghe et al. 1981). 
05/08/03 RoC Background Document for Lead and Lead Compounds 

23 

Table 2-4. Common methods for the analysis of lead in environmental samples 

Matrix Preparation Procedure 

Detection 

limit Reference 

Air Collect particulates onto membrane filter, 

digest with nitric acid and hydrogen 

peroxide, heat, dilute with distilled water. 

GFAAS 2 μg/m3

(particulate) 

ATSDR 1999 

Collect particulates onto stretched-Teflon 

filter, mount into 3- mm slide frame. 

PIXE 0.6 ng/m3

(particulate) 

Eldred and Cahill 

1994 

Collect particulates onto cellulose nitrate 

filter, add 206Pb spike to filter, dissolve in 

sodium hydroxide, acidify with nitric 

acid, separate lead by electrodeposition. 

IDMS 0.008 ng/m3

(particulate) 

Völkening et al.

1988 

Filter gas, pass through iodine 

monochloride bubbler, convert lead 

compounds, extract with carbon 

tetrachloride solution, follow with acid 

extraction. 

GFAAS 0.25 ng/m3

(gaseous) 

Birch et al. 1980 

 Filter gas, trap gas cryogenically. GC/GFAAS 0.2 ng/m3

(gaseous) 

De Jonghe et al.

1981 

Water Filter water through membrane filter, 

dissolve particulates by wet ashing. 

AAS 100 μg/L 

(particulate) 

ATSDR 1999 

Filter water through membrane filter, 

dissolve particulates by wet ashing. 

ICP-AES 42 μg/L 

(particulate) 

ATSDR 1999 

Filter water through membrane filter, 

dissolve particulates by wet ashing. 

GFAAS 1 μg/L 

(particulate) 

ATSDR 1999 

Filter water, complex with sodium 

diethyldithiocarbamate, extract with 

pentane, run off water, butylate, extract 

sample with nonane. 

GC/AAS 2.5 ng/L 

(dissolved) 

Chakraborti et al.

1984 

Soil Dry ash, digest with hydrochloric and 

nitric acids (3:1), dilute with water. 

AAS 2 μg/g Beyer and 

Cromartie 1987 

Dry sample and sieve, digest with nitric 

acid, agitate, centrifuge. 

ICP-AES 0.09 μg/g Schmitt et al.

1988 

Food Digest with sulfuric acid and dry ash, 

dissolve in hydrochloric acid, dilute with 

water. 

GFAAS 5 ng/g 

(bread) 

Ellen and Van 

Loon 1990 

Dry ash sample; dissolve with nitric acid 

and water. 

ASV 1 ng/g 

(evaporated 

milk) 

Capar and Rigsby 

1989 

Dry ash sample with sulfuric acid; dilute 

with nitric acid and water. 

DPASV 0.4 ng/g 

(crops) 

Satzger et al. 1982 

Source: ATSDR 1999 (with additional references). 
05/08/03 RoC Background Document for Lead and Lead Compounds 

24 

2.3.2 Water 

Lead in water may be analyzed for concentration in particulate form or dissolved form, 

usually expressed as micrograms per liter or parts per billion. Techniques frequently used 

in the analysis of lead in water include AAS, GFAAS, and ICP-AES. ICP-MS is a more 

sensitive method, with a detection limit of about 1/1,000th that of ICP-AES (which is 

approximately 42 μg/L). For this reason, use of ICP-MS is becoming more widespread, 

not only for water lead analysis, but also for measurement of lead in other environmental 

and biological media. For dissolved lead analyses, GC-AAS can be used to separate 

organic lead into its various species (Chakraborti et al. 1984). 

2.3.3 Soil 

AAS, GFAAS, or ICP-AES may be used to determine lead concentrations in soil. Total 

lead or organic lead may be assessed. ICP-AES is the most sensitive technique in 

common application, with a detection limit of approximately 0.09 μg/g. As in analysis of 

other environmental media, GC-AAS may be used to distinguish among organic species 

of lead (Chau et al. 1979). 

2.3.4 Food 

Analyses of lead concentrations in food generally are similar to analyses of lead in soil. 

AAS, GFAAS, and ICP-AES are most common, although ASV and differential pulse 

anode-stripping voltametry (DPASV) have been introduced with good results (Satzger et 

al. 1982, Capar and Rigsby 1989). GFAAS has a detection limit of approximately 5 ng/g 

for measurement of lead in bread (Ellen and Van Loon 1990), and ASV has a detection 

limit of approximately 1 ng/g for measurement of lead in evaporated milk (Capar and 

Rigsby 1989). 

2.3.5 Blood 

Measurement of lead in whole blood is the most common biological means of monitoring 

exposure and is a routine occupational health procedure for many lead-exposed workers. 

Measurements of blood lead reflect exposure to all lead compounds (inorganic and 

organic) and all routes of exposure (inhalation, oral, and dermal). Blood lead gives 

information only about fairly recent absorption, since the half-life of lead in blood has 

been measured at 36 days (Rabinowitz et al. 1976) and 28 days (Griffin et al. 1975, as 

cited in ATSDR 1999). The most common approaches are AAS, ASV, GFAAS, and ICPMS. The sensitivities of these methods, whose detection limits range from approximately 

4 to 10 μg/L, are generally sufficient for either occupational or environmental lead 

exposure assessment. 

2.3.6 Serum or plasma 

Although lead more frequently is assessed in whole blood, it also is technically possible 

to analyze its concentration in serum or plasma, but with severe difficulties owing to the 

low lead concentrations. This analysis is desirable, since it is believed that the quantity of 

lead in blood plasma governs the amount available for distribution to tissue (Leggett 

1993, O'Flaherty 1993). Analysis of lead in plasma or serum is becoming more common 

with improved techniques, primarily involving ICP-MS. Recent studies have shown that 
05/08/03 RoC Background Document for Lead and Lead Compounds 

25 

lead in serum is 0.08% to 0.29% of that in whole blood, as measured by ICP-MS 

(Manton et al. 2001, Cake et al. 1996, Smith et al. 2002). As noted above for blood, lead 

concentrations in serum or plasma will reflect all routes of exposure to all lead 

compounds. 

Table 2-5. Common methods for the analysis of lead in biological samples 

Matrix Preparation Procedure 

Detection 

limit Reference 

Blood Digest with nitric, perchloric, and sulfuric 

acids (3:1:1), heat. 

ICP-AES 10 μg/L ATSDR 1999 

 Wet ash, combine with dithizone, extract. AAS 10 μg/L Gerhardsson et al.

1995a 

 Wet ash. GFAAS 4 μg/L Zhang et al. 1997 

Dilute with Triton X-100, nitric acid, and 

thallium internal standard; agitate. 

ICP-MS 0.06 μg/L Roberts et al.

2000 

Concentrate on mercury thin-film electrode, 

strip from electrode. 

ASV 1 pg NRC 1993 

Serum 

or 

plasma 

Dilute, add bismuth nitrate as internal 

standard. 

ICP-MS 0.015 μg/L Schütz et al. 1996 

Spike with lead isotope, heat in distilled 

nitric acid . 

ICP-MS 0.015 μg/L Manton et al.

2001 

Urine Wet ash with acid mixture and dissolve in 

perchloric acid. 

ASV 4 μg/L NIOSH 1977 

Extract with polydithiocarbamate resin and 

sodium hydroxide, agitate, filter, neutralize 

with sodium hydroxide, ash, heat, dilute 

with water. 

ICP-AES 0.5 μg/L ATSDR 1999 

Soft 

tissues 

Digest with sulfuric acid and dry ash, 

dissolve in hydrochloric acid, dilute with 

water. 

GFAAS 5 ng/g 

(bovine) 

Ellen and Van 

Loon 1990 

 Ash, add nitric acid, stir solution. GFAAS 2 ng/g 

(human) 

Gerhardsson et al.

1995b 

Bone Excitation of lead with partially planepolarized X-rays, characteristic lead L-shell 

X-rays detected. 

LXRF 5 μg/g 

(in vivo) 

Markowitz and 

Shen 2001 

Excitation of lead with 109Cd γ-ray source, 

characteristic lead K-shell X-rays detected. 

KXRF 6 μg/g 

(in vivo) 

Todd et al. 2000, 

Hu et al. 1995 

Source: ATSDR 1999 (with additional references). 

2.3.7 Urine 

Lead concentration in urine may be measured with good sensitivity by methods such as 

AAS, ASV, or ICP-AES. Detection limits for these methods range from approximately 

0.5 to 4 μg/L. Usually, measurement of blood lead concentration is considered a more 
05/08/03 RoC Background Document for Lead and Lead Compounds 

26 

direct biological approach to assessing current exposure. However, given the sampling 

limitations and the analytical difficulties of measuring lead in plasma, some researchers 

have used lead in urine as a proxy for lead in plasma that will provide an estimate of lead 

exposure from all routes and to all lead compounds (Tsaih et al. 1999, Gulson et al.

2000). Exposure to lead has on occasion been assessed by administration of a chelating 

agent, such as edetate calcium disodium (calcium disodium ethylenediaminetetraacetate 

dihydrate), followed by measurement of lead excreted in the urine. 

2.3.8 Biomarkers 

Biomarkers used to identify exposure to lead usually measure the level of total lead in 

tissues and fluids. Total lead measurements in the body reflect exposure to all lead 

compounds (inorganic and organic) from all sources of exposure (inhalation, oral, and 

dermal). Tetraalkyl lead compounds are the only lead compounds that may be measured 

in the breath, in addition to being measured in body tissues and fluids (ATSDR 1999). 

A variety of biomarkers are available for monitoring lead exposure, effects, and 

susceptibility (NRC 1993). Some of the most commonly used biomarkers are those based 

on disturbance of heme synthesis by lead (see Table 2-6). One of these assays measures 

erythrocyte protoporphyrin (EP) or zinc protoporphyrin (ZPP) concentration in blood, 

and another measures the activity of δ-aminolevulinate dehydratase (ALAD; also known 

as porphobilinogen synthetase). EP and ZPP increase following lead exposure, while 

ALAD activity decreases (NRC 1993). However, EP measurements many not accurately 

reflect lead levels in populations that may be iron deficient, such as low-income children, 

because iron influences EP levels (Mahaffey and Annest 1986). EP has a sensitivity of 

0.351 at blood lead levels of 15 μg/dL or higher, with sensitivity defined as the ability to 

detect a condition when it is present. This means that on average, the EP test will identify 

about 35% of children with blood lead levels of 15 μg/dL or higher and will fail to detect 

about 65% of these children. As the blood lead concentration increases, the EP test 

becomes more sensitive. For example, at blood lead concentrations of 30 μg/dL or 

higher, the sensitivity is approximately 0.87 (NRC 1993). Other biomarkers based on 

disturbance of heme synthesis are measurement of increased urinary δ-aminolevulinic 

acid (ALA) and the accumulation of coproporphyrin in urine. 

In addition, a number of biomarkers of lead exposure are not based on heme-synthesis 

effects (see Table 2-6). One biomarker measures lead’s inhibition of the enzyme 

pyrimidine-5'-nucleotidase (Py-5'-N), another measures decreased plasma concentrations 

of the hormonal metabolite 1,25-dihydroxyvitamin D, and a third measures inhibition of 

erythrocyte membrane Na+

,K+-ATPase (NRC 1993). 

Other biomarkers include measurement of lead in bones, teeth, and hair (see Section 

2.3.10 for a discussion of lead in bone and teeth). Hair has been used in the past and is 

currently being used as a biomarker of lead exposure. However, use of hair analysis in a 

clinical setting poses many problems, including inaccuracy of measurements due to 

exogenous contaminants (such as sweat, dust, and beauty treatments), variable analytic 

procedures, and low interlaboratory reliability (Frisch and Schwartz 2002). 
05/08/03 RoC Background Document for Lead and Lead Compounds 

27 

2.3.9 Soft tissue 

The analysis of lead in soft tissue normally is limited to autopsy studies (Barry 1975, 

Gerhardsson et al. 1995b) and has included measurements in kidney, liver, brain, lung, 

testis, and spleen. Analysis methods include AAS, GFAAS, ASV, and ICP-AES, with 

detection limits of 2 to 5 ng/g (ATSDR 1999). 

2.3.10 Bone and teeth 

Because the half-life of lead in bone is on the order of years to decades (Gerhardsson et 

al. 1993), analysis of bone lead is more reflective of long-term than short-term exposure. 

The two main approaches to in vivo bone lead measurement are L-shell X-ray 

fluorescence (LXRF) and K-shell XRF (KXRF). The lower energies involved in the 

LXRF technique mean that this measurement samples a more superficial component of 

bone than does the KXRF approach (Todd and Chettle 1994). Common bone sites for 

measurements include the tibia, calcaneus, and patella. Lead content in teeth also may be 

assessed, either in vivo by XRF methods or, more commonly, by techniques such as 

IDMS (Gulson 1996) or ASV (Kim et al. 1996) with shed deciduous teeth. 

Table 2-6. Biomarkers for lead exposure 

Lead effect Result 

Marker threshold, 

lead concentration 

(μg/dL) Comments 

Heme synthesis disturbances biomarkers 

Inhibition of ALAD 

activity 

accumulation of ALA in 

tissues and urine 

5 sensitive for current 

population blood lead 

concentrations; 

problematic relation to 

tissue effects 

Feedback stimulation of 

ALA synthetase activity 

minor contribution to 

total ALA in urine 

40 not a feasible marker 

Accumulation of urinary 

ALA 

-- 20–40 useful for population 

screening; limited in 

individual predictability; 

not useful for childhood 

screening 

Inhibition of heme 

formation from 

protoporphyrin IX 

accumulation of 

erythrocyte 

protoporphyrin in blood 

15–20 (children) 

25–30 (adults) 

most common screening 

marker for children and 

workers 

Impaired use of 

coproporphyrin 

accumulation of 

coproporphyrin in urine 

40 supplanted in popularity 

by EP measurement 

Non-heme synthesis biomarkers 

Inhibition of Py-5'-N 

activity in erythrocytes 

accumulation of 

ribosomal fragments in 

reticulocytes 

5–10 quite sensitive 
05/08/03 RoC Background Document for Lead and Lead Compounds 

28 

Lead effect Result 

Marker threshold, 

lead concentration 

(μg/dL) Comments 

Inbition of Na+, K+-

ATPase in erythrocyte 

membrane 

potassium loss and net 

sodium gain in cells; 

altered cell survival 

not established studies in lead workers; 

direct measure of lead’s 

presence; subject to 

contamination 

Inhibited hydroxylation 

of 25-OH-vitamin D 

reduction in hormonal 

metabolite 1,25-(OH)2-

vitamin D 

10–15 important health effect, 

not appropriate for use 

as biomarker 

Source: NRC 1993. 

2.4 Environmental occurrence 

Lead is a naturally occurring element found in the earth’s crust in trace quantities of 

approximately 8 to 13 ppm (Rudnick and Fountain 1995, Taylor and McLennan 1995). 

Lead exists in the crust in a number of ores, predominantly as lead sulfide (galena). In the 

absence of human activity, small amounts of lead would reach the surface environment 

by natural weathering processes to create a baseline exposure, which in localized areas 

such as mineral provinces can be very high. The abundant and widespread presence of 

lead in our current environment is largely a result of anthropogenic activity. In this 

respect, lead has a long history; evidence exists that lead has been used for approximately 

6,000 years (Hunter 1978). The ubiquity of lead in the environment has resulted in 

modern body burdens that are, by one estimate, 300 times those found in pre-industrial 

humans (Patterson et al. 1991). 

2.4.1 Air 

Lead is released to air by natural processes such as volcanic activity, forest fires, crustal 

weathering, and radioactive decay from radon. These natural contributions are of 

relatively minor consequence. The vast majority of lead in the atmosphere results from 

human activity. A major change in lead emission patterns in the United States resulted 

from the phasing out of tetraethyl lead as an anti-knock fuel additive. The overall 

emissions of lead to air dropped significantly beginning in the 1970s and continuing until 

a complete ban on lead in fuel went into effect in 1996. Nonetheless, as recently as the 

late 1980s, motor vehicle exhaust was the single largest source of lead emissions in the 

United States, resulting in the release of inorganic particulates (approximately 90% by 

mass) such as lead bromochloride and organic lead fumes (< 10% by mass) (ATSDR 

1999). 

Although numeric values are not available, it appears that the percentage of total lead in 

the atmosphere contributed by organic lead has dropped significantly as a result of the 

phase-out and the eventual ban of lead in fuel in 1996. When organic lead compounds are 

exposed to sunlight, they decompose rapidly to trialkyl and dialkyl lead compounds. 

These compounds eventually decompose to inorganic lead oxides, through a combination 

of photolysis and reactions with hydroxyl radicals and ozone. The half-lives of tetraethyl 

and tetramethyl lead in the summer are 2 and 9 hours, respectively, while in the winter, 

both compounds have half-lives up to several days (ATSDR 1999). 
05/08/03 RoC Background Document for Lead and Lead Compounds 

29 

Investigators have measured long-range transport of lead from motor vehicle exhausts in 

populated regions to pristine areas by comparing ratios of stable lead isotopes in remote 

areas with the isotope ratios characteristic of lead from industrial sources in various 

regions. Rosman et al. (1994a) measured lead isotopes in preserved layers of snow 

deposited in Greenland between 1960 and 1988 and found ratios of 206Pb/207Pb of 1.16 in 

the early 1960s, 1.18 in 1976, and 1.16 in the mid 1980s. They concluded that the 

elevated ratio of 206Pb to 207Pb indicated transport of lead from U.S. sources, particularly 

lead in gasoline, and they speculated that the decrease in the 1980s was due to the switch 

to unleaded gasoline for motor vehicles. In another study, the ratios of lead isotopes in 

samples from Antarctica in the 1980s indicated that the lead probably was from South 

America (Rosman et al. 1994b). 

Releases of airborne lead also occur during smelting, the manufacture of goods, and the 

incineration of municipal and medical wastes (ATSDR 1999). The largest of these 

sources is waste incineration; however, the contribution from this source is significantly 

less than the environmental release of lead to landfill (see Section 2.4.3). This is because 

the amount of lead in incinerated waste is less than that released to landfills and because 

not all of the lead in incinerated waste is released to air. 

EPA’s Toxics Release Inventory (TRI) estimated a release of 354,065 lb of lead from 832 

facilities and 1,224,315 lb of lead compounds from 1,045 facilities to air in 1999 in the 

United States (TRI99 2001). However, the TRI data are not exhaustive and should be 

used with caution, as only certain types of facilities are required to report releases. The 

June 2000 edition of EPA’s National Toxics Inventory (NTI) estimated that 5,253,736 lb 

of lead compounds were released into air in 1996 (EPA 2000). The NTI draws on data 

from the TRI, state and local agencies, and EPA databases. 

2.4.2 Water 

Lead enters groundwater from natural weathering of rocks and soil, indirectly from 

atmospheric fallout, and directly from industrial sources. In water, organic lead 

compounds undergo photolysis and volatilization. Degradation processes convert trialkyl 

lead to dialkyl lead and then to inorganic lead compounds (ATSDR 1999). EPA’s TRI 

estimated that in 1999, 8,368 lb of lead from 832 facilities and 65,600 lb of lead 

compounds from 1,045 facilities were released to surface water in the United States 

(TRI99 2001). The TRI data should be used with caution, since only certain types of 

facilities are required to report releases. An additional and distinct hazard to the water 

supply is lead piping or lead solder in older plumbing systems. Areas with a supply of 

soft (acidic) water are more susceptible to release of lead from plumbing, which can 

result in levels of lead in drinking water high enough to have significant effects on human 

health (Lee et al. 1989). 

2.4.3 Soil 

The largest amount of lead released into the environment is released to land, 

predominantly to landfill sites. Lead-containing wastes result from ore production, 

household renovation and remediation of lead paint, use of lead in ammunition, solder, 

weights, and bearing metals, and production of iron and steel. Although lead is now 
05/08/03 RoC Background Document for Lead and Lead Compounds 

30 

banned in motor fuels in the United States and several other countries, organic lead 

compounds continue to be present or actively deposited in the soil. Data suggest that 

tetraethyl and tetramethyl lead are converted to water-soluble lead compounds in soil 

(ATSDR 1999). EPA’s TRI estimated a direct release of 10,411,207 lb of lead from 832 

facilities and 311,467,762 lb of lead compounds from 1,045 facilities to land in 1999 in 

the United States. An additional 13,250 lb of lead and 8,142,009 lb of lead compounds 

were released in 1999 by underground injection (TRI99 2001). The TRI data should be 

used with caution, as not all types of facilities are required to report releases. 

2.4.4 Paint 

The release of lead from paint to the local environment deserves mention as an important 

source of environmental exposure. Leaded paints were most commonly used in the 

United States from approximately 1870 to 1940, although they persisted as recently as the 

late 1970s. Lead carbonate was the most frequently used lead pigment, and lead oxide 

and lead chromate also were common. Flaking or peeling of aging paint can be a major 

point source of environmental lead exposure, as well as sanding of painted surfaces 

during home renovation. By these processes, lead can become mobilized in dust to the air 

and soil. In a pooled analysis of 12 epidemiological studies, Lanphear et al. (1998) 

confirmed that lead-contaminated house dust was the major source of lead exposure in 

children. Additionally, young children may directly ingest chips of paint containing lead 

(ATSDR 1999). 

2.5 Environmental fate 

As an element, lead is not destroyed in the environment. When emitted into the 

atmosphere, tetraethyl and tetramethyl lead decompose via photolysis into trialkyl and 

dialkyl lead compounds and then to inorganic lead oxides and carbonates (ATSDR 1999). 

With restrictions on the use of lead in gasoline, industrial sources now produce the 

majority of lead emissions in the United States, and lead in the atmosphere is primarily in 

the form of lead sulfate and lead carbonate. Particulate lead is removed from the 

atmosphere by wet or dry deposition, resulting in its uptake by soil and water. Particle 

size is a determinant of atmospheric transport, with particles of diameter greater than 

2 μm remaining close to the point of emission and smaller particles demonstrating greater 

mobility (ATSDR 1999). 

The proportion of lead remaining in solution in surface water and groundwater generally 

is small, because of formation of the low-solubility compounds lead sulfate, lead 

carbonate, lead phosphate, and lead hydroxide. Lead is held strongly in soil and does not 

readily transport into groundwater, except in highly acid soil. Lead is bound within soil 

by ion exchange and specific adsorption (ATSDR 1999). However, in one study, metallic 

lead in soil from shotgun pellets deposited in a lime-deficient, acidic, sandy soil was 

detected 20 years later in small mammals. This study showed that metallic lead in the 

environment could be transformed to a biologically available form and transferred up the 

food chain (Ma 1989). 
05/08/03 RoC Background Document for Lead and Lead Compounds 

31 

2.6 Environmental exposure 

Environmental exposure to lead results in absorption of lead into the body via inhalation, 

via ingestion, and, to a limited extent, through the skin. The most efficient exposure route 

generally is inhalation; the proportion of inhaled lead absorbed into the bloodstream is 

believed to range from 30% to 50%, whereas approximately 8% to 15% of ingested lead 

is absorbed (O'Flaherty 1993, Staudinger and Roth 1998). Conditions favoring high 

solubility result in the absorption of greater proportions of inhaled or ingested lead into 

the bloodstream. Among the factors affecting the solubility of inhaled or ingested lead are 

the type of lead compound involved, particle size, site of contact within the body, acidity 

of the body fluid contacted, and physiologic status of the individual (Spear et al. 1998). 

Compared with typical pre-industrial populations, the contemporary U.S. population is 

exposed to high levels of lead (Patterson et al. 1991), but the levels are substantially 

lower now than they were 30 years ago. 

The most common way to measure environmental lead in the body is by measuring blood 

lead levels. Venous blood is usually analyzed by AAS or ASV (see Section 2.3.5), and 

the results commonly are reported as micrograms per deciliter (NRC 1993). The 

relationship between environmental lead exposure, lead uptake, and blood lead levels is 

complex. Several models have been used to predict blood lead concentrations in 

individuals exposed to lead in the environment. One of these models, EPA’s Integrated 

Exposure Uptake Biokinetic Model for Lead in Children (IEUBK), allows the user to 

input relevant absorption parameters, such as the fraction of lead absorbed from water, as 

well as intake from exposure to soil, dust, water, and air, and exposure rates. The IEUBK 

model calculates a complex set of equations to estimate the potential concentration of 

lead in the blood for a hypothetical child or population of children aged 6 months to 7 

years. Because the Centers for Disease Control and Prevention (CDC) has determined 

that childhood blood lead levels at or above 10 μg/dL present risks to children’s health 

(see Section 2.3.10), the IEUBK model calculates the probability that children’s blood 

lead concentrations will exceed 10 μg/dL (EPA 2002). Figure 2-3 shows the decrease in 

lead used in gasoline and the substantial reduction in blood lead levels from 1976 to 1980 

in the U.S. population, as measured in the Second National Health and Nutrition 

Examination Survey (NHANES II) (NRC 1993). 
05/08/03 RoC Background Document for Lead and Lead Compounds 

32 

Figure 2-3. Lead used in gasoline and average blood lead levels measured in 

NHANES II 

Source: NRC 1993. 

Air lead concentrations may be high (> 10 μg/m3) near industrial sources such as smelters 

(ATSDR 1999). A 1991 survey of lead levels in U.S. urban air revealed a maximum 

quarterly mean concentration of approximately 0.08 μg/m3 (EPA 1996). Rural 

concentrations typically are lower, bringing the estimated U.S. mean air lead 

concentration to 0.04 μg/m3 in 1995 (EPA 1996). Remote sites report air lead 

concentrations as low as 0.001 μg/m3

 (Eldred and Cahill 1994). 

Lead concentrations in U.S. drinking water generally are below 5 μg/L (ATSDR 1999). 

Lead pipes or soldering in the presence of corrosive water can result in water lead 

concentrations above 500 μg/L under extreme circumstances (EPA 1989). For example, 

in a town in Scotland, drinking water samples showed lead levels greater than 1,000 μg/L 

due to leaching of lead from the plumbing system by acidified drinking water (Nordberg 

et al. 1985). The concentration of lead in foods can range from 0.002 to 0.6 μg/g 

(ATSDR 1999). The phaseout of lead-soldered cans (from 1979 to 1991) has virtually 

eliminated a previously significant source of dietary lead. 
05/08/03 RoC Background Document for Lead and Lead Compounds 

33 

Cigarette tobacco contains lead at the level of 2 to 12 μg per cigarette, up to 6% of which 

may be inhaled (WHO 1977). Smoking a pack of cigarettes (20) per day, with 12 μg of 

lead per cigarette, and inhaling 6% of the smoke would result in daily exposure to 14 μg 

of lead. Relatively less common but potentially serious exposures are from alcoholic 

beverages held or served in leaded crystal, “moonshine” whiskey from leaded stills, food 

served or cooked in lead-glazed containers, and lead-containing folk medicine remedies 

and cosmetics. 

The average intake of lead by inhalation is estimated at 2 μg/day for an adult living in a 

U.S. urban setting (ATSDR 1999). A smoker has an additional intake of approximately 

6 μg/day, based on an estimated exposure of 14 μg/day and absorption of 30% to 50% of 

the inhaled lead into the bloodstream (O’Flaherty 1993). In 1990, the estimated daily 

intake of lead from consumption of food, water, and beverages was approximately 

4 μg/day for children 2 years of age and younger, 6 to 9 μg/day for children aged 14 to 

16, 6 to 9 μg/day for adults aged 25 to 30, and 2 to 8 μg/day for adults aged 60 to 65 

(ATSDR 1999). The most common source of environmental lead exposure for young 

children is direct ingestion of paint chips and leaded dusts and soils released from aging 

painted surfaces (CDC 1997, Lanphear et al. 1998). This source can contribute an 

additional intake of 5 μg/day for a toddler engaging in normal hand-to-mouth activity, 

and significantly more for a child demonstrating pica behavior (ATSDR 1999). 

2.7 Occupational exposure 

The most common route of occupational exposure to lead is inhalation of lead fumes or 

leaded dusts in air and absorption of lead through the respiratory system. Lead also may 

be ingested and absorbed in the gastrointestinal tract. Absorption through the skin occurs 

with organic lead (Bress and Bidanset 1991) and possibly also with the more soluble 

species of inorganic lead (Stauber et al. 1994). The National Institute for Occupational 

Safety and Health (NIOSH) has estimated that more than 3 million Americans potentially 

are occupationally exposed to some form of lead (Staudinger and Roth 1998). The 

National Occupational Exposure Survey, conducted by NIOSH between 1980 and 1983, 

indicated that approximately 25,000 workers were exposed to tetraethyl lead, 57,000 to 

lead oxides, 4,000 to lead chloride, and 577,000 to other species of lead (ATSDR 1999). 

Many occupations and job activities have the potential for relatively high exposures to 

lead (Fu and Boffetta 1995, ATSDR 1999). These occupations have been broadly divided 

into three lead exposure categories: (1) those having ongoing high exposure, (2) those 

having high exposure with moderate frequency or ongoing intermediate exposure, and 

(3) those having high exposure with low frequency or ongoing moderate exposure. 

Within these three categories, listed below, occupations are listed alphabetically, and 

asterisks indicate those that have been included in at least one epidemiologic study of 

lead exposure and cancer, as summarized in Section 3 of this document. The various 

occupations and job activities are described briefly below. 
05/08/03 RoC Background Document for Lead and Lead Compounds 

34 

Occupational exposure to lead may occur during the production of lead-acid batteries, in 

which grids are formed either by melting lead blocks and pouring molten lead into molds 

or by feeding rolled sheets of lead through punch presses. A lead oxide paste also is 

applied into grid spaces. Battery-recycling workers in secondary smelters are exposed as 

they convert used batteries and other leaded materials to lead of varying purity. Foundry 

workers may be exposed to lead through heating and casting operations or through the 

grinding and machining of components. This type of exposure may result from work with 

brass and bronze alloys, which contain some lead, mostly for ease of machining. Lead 

chemical production involves a wide range of end products, including the lead oxide used 

by the lead-acid battery industry. Production of tetraethyl and tetramethyl lead previously 

resulted in major occupational exposure, but tetraethyl lead has not been made in the 

United States since 1991 (ATSDR 1999). Lead smelter and refinery workers participate 

in operations such as sintering, roasting, smelting, and drossing, resulting in exposure to 

lead sulfide, sulfates, and oxides. 

Leaded glassware is made by combining lead oxide compounds with molten quartz. This 

process results in lead fumes and dusts, and glassblowing is an additional avenue for 

potential contact with lead. Production of pigments can involve lead oxide, lead 

carbonate, and lead chloride. Chromate workers are also exposed to lead chromate, 

acetate, and nitrate, and lead acetate and naphthenate may be involved in leaded paint 

 Category 1: High ongoing exposure 

Battery-production workers* Battery-recycling workers* 

Foundry workers Lead chemical workers* 

Lead smelter and refinery workers* Leaded-glass workers* 

Pigment workers* Radiator-repair workers 

 Category 2: High exposure, moderate frequency 

Firing-range instructors House renovators 

Lead miners* Newspaper printers* 

Plastics workers* Rubber workers 

Steel welders and cutters 

 Category 3: High exposure, low frequency 

Automobile-repair workers Cable-production workers 

Construction workers Demolition workers 

Firing-range participants Flame-solder workers 

Plumbers and pipefitters Pottery-glaze producers 

Ship-repair workers Stained-glass producers 
05/08/03 RoC Background Document for Lead and Lead Compounds 

35 

production. Although the use of lead pigments has been reduced in recent years, workers 

continue to be involved in their production for specialty applications. Radiator repair 

workers are exposed to leaded dusts during radiator cleaning and to lead fumes during 

flame soldering. Exhaust ventilation control systems have been introduced into such 

repair operations with successful results (Tharr and Ed 1993). 

Firing-range instructors, particularly in indoor ranges, are exposed to high levels of lead 

from both the lead projectile and lead styphnate used in the primer. Exposure is higher 

with non-jacketed pure lead bullets than with jacketed copper-coated bullets (Tripathi et 

al. 1990). The presence of leaded paints in homes built before 1978 continues to present a 

hazard to home renovators. Scraping, abrasive blasting, and heat-gun removal of paint in 

older homes can create leaded dusts. Lead miners and mine workers are involved in the 

extraction, crushing, grinding, and concentration of lead. The most commonly mined lead 

ore is galena (87% lead by weight), followed by anglesite (68%) and cerussite (78%). 

Miners of copper and zinc also are exposed to lead. In the past, newspaper printing has 

been associated with lead exposure, and this exposure is reflected in the epidemiologic 

studies summarized in Section 3. However, with the emergence of computerized printing 

techniques, lead exposure is no longer a significant concern in this profession. Workers in 

the plastics and vinyl industries may be exposed to lead when it is used as a stabilizing or 

coloring agent. Powdered pigments, such as lead chromate, are blended with plastic 

pellets and heated to form some plastic products. Similarly, lead has frequently been used 

in compounding rubber. Greater health awareness has led to reduction in applications of 

lead in plastics and rubber manufacture. Welders may be exposed to lead fumes resulting 

from gas-metal arc welding of structural steel (ATSDR 1999). Similar exposures occur 

for steel cutters. 

Automobile-repair workers may be exposed to lead through work around batteries and 

other parts, engine reconditioning, solder, and, until recently in the United States and 

several other countries, leaded gasoline. Lead continues to find application in the 

production of cable sheathing because of its workability, durability, and resistance to 

corrosion. Construction and demolition workers are exposed to some lead through their 

interactions with pipes and traps, sheet lead, solder, and (in older buildings) paint. Firingrange participants are exposed to lead in the air, although generally in smaller quantities 

than firing-range instructors. Typical solders contain 60% lead, and the high temperatures 

involved in flame solder work volatilize some of this lead. Plumbers and pipefitters work 

with older lead pipes and copper pipes soldered with lead. Lead oxide and other lead 

compounds have been used in the making of pottery glaze, and lead chromate may be 

used in decorative coatings. Ship-repair workers involved with cutting and welding steel 

carry a risk of lead exposure. Additionally, leaded coatings and paints have been applied 

to ships to prevent corrosion and inhibit the growth of marine life. Stained-glass 

producers use lead strips (no longer pure lead, but alloys) to form joints, and soldering is 

a common procedure. 

Air lead concentration may be monitored as a means of measuring occupational exposure 

in work areas. However, occupational exposure more frequently is inferred from 

measurement of blood lead concentration in individual workers. Less common methods 

include analysis of urinary lead concentration, ALA level, or coproporphyrin level. Other 
05/08/03 RoC Background Document for Lead and Lead Compounds 

36 

biological indices that will likely become more prevalent in the future are measurement 

of serum or plasma lead concentration and in vivo bone lead concentration. 

Various chemical forms of lead, or lead species, are present in occupational settings. In 

addition to the sheer quantity of exposure, the species of lead involved and the particle 

sizes encountered will influence how much lead ultimately is absorbed. In a primary 

smelter, for example, lead sulfide generally is dominant, with increasing quantities of 

lead sulfates and oxides near furnace areas (Spear et al. 1998). Lead sulfates and lead 

oxides are more soluble than lead sulfide and therefore more likely to be absorbed in the 

body. Likewise, smaller particles of leaded compounds in airborne dusts are absorbed 

more efficiently than larger particles. Particles less than 3 μm in diameter have a higher 

probability of reaching the deep lung (alveoli) and being absorbed into the bloodstream 

(Spear et al. 1998). Because speciation and particle size distribution usually are not 

available from conventional analyses of environmental media, these factors should be 

kept in mind when workplace lead exposure data are considered (Fleming 1998). 

Table 2-7 summarizes levels of occupational lead exposure from a variety of industries, 

expressed as air lead concentrations, as determined from monitoring by the Occupational 

Safety and Health Administration (OSHA) (Froines et al. 1990). In a study of airborne 

lead exposures among janitorial and custodial workers, 23 (44%) of 52 personal air 

samples collected had no detectable lead. The highest exposures were during power 

sanding of a wooden door (36 μg/m3

), melting of lead in an open ladle for plumbing 

repairs (26 μg/m3

), removal of lead and oakum (a type of caulk) from a plumbing joint 

(13 μg/m3), and removal and folding of the plastic sheeting used to contain dust during 

carpentry work (8 μg/m3) (NIOSH 1997). More extreme examples reported in the 

literature include mean occupational air lead concentrations as high as 1,200 μg/m3

 for 

structural steel welding (Fu and Boffetta 1995), 4,470 μg/m3 for smelting (Fu and 

Boffetta 1995), and 5,400 μg/m3

 within a storage battery plant (WHO 1977). Table 2-7 

shows representative U.S. lead industry exposure conditions in recent years. Based on the 

mean air lead levels presented in Table 2-7 and assuming a human occupational default 

minute volume of 10 m3

/8 h (EPA 1994), estimated lead exposure levels ranged from 

1,650 to 2,000 μg/day. These values are approximately 1,000 times greater than the 

average environmental lead exposure levels reported for adults living in U.S. urban 

settings (2 μg/day) (ATSDR 1999). 
05/08/03 RoC Background Document for Lead and Lead Compounds 

37 

Table 2-7. Air lead concentrations in occupational settings, based on OSHA 

inspection data (1979–1985) 

Industry 

Inspections 

(samples) 

% of Inspections w/ 

median air lead conc. 

> 50 (μg/m3) 

Mean 

conc. 

(μg/m3) 

Median 

conc. 

(μg/m3) 

Maximum 

conc. 

(μg/m3) 

Storage battery 

plants 

87 (969) 57 200 120 35,000 

Brass, bronze, 

and copper 

foundries 

118 (822) 42 200 65 54,500 

Primary lead 

smelters 

5 (72) 40 195 80 5,650 

Inorganic 

pigment plants 

25 (143) 52 175 100 4,800 

Secondary 

smelters 

86 (718) 43 165 140 5,200 

Source: Froines et al. 1990. 

NIOSH (2001) summarized the results of its Health Hazard Evaluation and Technical 

Assistance program for occupational exposure to lead for the period 1994 to 1999. In this 

program, requests are received from employers, employees, or others, and site visits are 

conducted to determine whether a health hazard exists from exposure to a chemical or 

biological agent. Table 2-8 summarizes the lead concentrations measured in the personal 

breathing zone or in the general work area of workers evaluated in a number of 

industries. 

Table 2-8. Air lead concentrations from NIOSH Health Hazard Evaluation and 

Technical Assistance Program (1994–1999) 

Industry Airborne lead concentration (μg/m3)

a

Law enforcement ND to 5,910 

Manufacturing and repairing ND to 495 

Lead abatement and lead-based paint ND to 27,000 

Abrasive blasting ND to 1,800 

Electric services ND to 2,300 

Other 7.4 to 280 

Source: NIOSH (2001). 

a

ND = not detected. 
05/08/03 RoC Background Document for Lead and Lead Compounds 

38 

2.8 Biological indices of exposure 

Lead exposure may be assessed from a number of biological indices (see Sections 2.3.5 

to 2.3.10). As discussed above (see Section 2.6), the most common means of monitoring 

recent exposure to lead is measurement of blood lead levels. The OSHA standard requires 

medical surveillance if a worker is exposed to lead in air at concentrations above the 

action level of 30 μg/m3

 for more than 30 days a year. Medical surveillance consists of 

testing of blood lead levels at least every six months after the initial blood lead test. If a 

worker’s blood lead concentration exceeds 40 μg/dL, the monitoring frequency must be 

increased to at least every two months and may not be reduced until two consecutive tests 

indicate a blood lead level below 40 μg/dL. If a worker’s blood lead level exceeds 60 

μg/dL, the worker must be removed from the work environment until the blood lead level 

falls to 40 μg/dL (OSHA 2002). Table 2-9 shows blood lead concentrations measured 

during the 1990s in occupations with the potential for lead exposure (both high and low 

to moderate), as well as the average for the U.S. population, as estimated from NHANES 

III. If sufficient data are available for a given individual, cumulative exposure to lead 

may be estimated by integrating blood lead readings over time (Fleming et al. 1997). 

Table 2-9. Blood lead concentrations from various occupations and the general 

population 

Population N 

Average blood lead 

concentration (μg/dL) 

Range 

(μg/dL)a Reference 

General lead industry 

workers, Korea (1997–

1999) 

798 32 (mean) 4–86 Schwartz et al. 2000 

Primary smelter workers, 

Sweden 

100 32 (median) 5.0–47.4 Gerhardsson et al.

1993 

Battery factory workers, 

Finland 

91 30 (mean) NR Erkkila et al. 1992 

Radiator-repair workers, 

Colorado (1992) 

63 29 (median) 6.6–94 Dalton et al. 1997 

Primary smelter workers, 

Canada (1994) 

381 23 (mean) NR Fleming et al. 1998 

Carpenters, New Jersey 

(1991) 

122 8.0 (mean) NR Smith 1995 

Laborers, Iowa and 

Illinois (1994–1996) 

80 7.6 (mean) 1.2–50 Reynolds et al. 1999 

Painters, Iowa and 

Illinois (1994–1996) 

83 5.9 (mean) 1.5–26.3 Reynolds et al. 1999 

General population, U.S. 

(1991–1994) 

13,642 2.3 (mean, ages 1 to ≥ 70) 

2.1 (mean, ages 20 to 49) 

3.1 (mean, ages 50 to 69) 

NR CDC 1997 

a

NR = not reported. 
05/08/03 RoC Background Document for Lead and Lead Compounds 

39 

Since 1987, CDC has sponsored the Adult Blood Lead Epidemiology and Surveillance 

program, which tracks cases of elevated blood lead levels in the U.S. population. Based 

on data from 25 states reporting during 1998 to 2001, the overall annual mean state 

prevalence rate for adults with blood lead levels of 25 μg/dL or higher was 13.4 per 

100,000 employed adults. In comparison, the overall rate for 1994 to 1997 was 15.2 per 

100,000. Yearly rates were 13.8, 12.9, 14.3, and 12.5 for 1998, 1999, 2000, and 2001, 

respectively. For adults with blood lead levels of 40 μg/dL or higher, the overall 

prevalence rate for 1998 to 2001 was 2.9 per 100,000 adults, compared with 3.9 for 1994 

to 1997. Yearly rates were 3.3, 2.5, 2.9, and 2.8, for 1998, 1999, 2000, and 2001, 

respectively (CDC 2002). 

Bone lead concentration is another biological index of exposure, one that directly reflects 

long-term accumulation of absorbed lead. Upwards of 90% of an individual’s lead body 

burden is contained in bone (Barry 1975). Noninvasive measurement of bone lead in 

occupationally exposed populations has some appeal, particularly where blood lead levels 

historically have not been well documented. Table 2-10 summarizes recent bone lead 

levels in various lead-industry and referent non-occupationally exposed populations, 

measured by Kα-XRF. 

Table 2-10. Bone lead concentrations from various occupations and referent 

populations 

Population Bone site N 

Average bone lead 

conc. (μg/g) Reference 

Primary smelter workers, Canada, 

early hires (1994) 

tibia 222 58 (mean) Fleming et al. 1998 

General lead industry workers, 

Korea (1997–1999) 

tibia 798 37 (mean) Schwartz et al. 2000 

Battery factory workers, Finland tibia 91 21 (mean) Erkkila et al. 1992 

Primary smelter workers, Canada, 

recent hires (1994) 

tibia 159 19 (mean) Fleming et al. 1998 

Primary smelter workers, Sweden tibia 100 13 (median) Gerhardsson et al. 1993 

Carpenters, New Jersey (1991) tibia 122 9.4 (mean) Smith 1995 

Referents, Korea (1997–1999) tibia 135 5.8 (mean) Schwartz et al. 2000 

Referents, Finland tibia 26 3.5 (mean) Erkkila et al. 1992 

Referents, Sweden tibia 41 3.4 (median) Gerhardsson et al. 1993 

Primary smelter workers, Canada, 

early hires (1994) 

calcaneus 222 103 (mean) Fleming et al. 1998 

Primary smelter workers, Sweden calcaneus 100 49 (median) Gerhardsson et al. 1993 

Primary smelter workers, Canada, 

recent hires (1994) 

calcaneus 159 28 (mean) Fleming et al. 1998 

Referents, Sweden calcaneus 41 12 (median) Gerhardsson et al. 1993 

Carpenters, New Jersey (1991) patella 22 14 (mean) Smith 1995 
05/08/03 RoC Background Document for Lead and Lead Compounds 

40 

2.9 Regulations 

A few of the key regulations on lead set by U.S. government agencies are summarized in 

Table 2-11, and a complete listing of lead regulations is provided in Appendix A. 

Table 2-11. Key regulations on lead and lead compounds in the United States 

Regulatory agency Lead compound Limit 

OSHA inorganic lead compounds 50 μg/m3

 in air, action level of 30 μg/m3

in air 

Health protection goals: 40 μg/dL blood, 

30 μg/dL blood (if intend to have 

children) 

Consumer Product Safety 

Commission 

all lead compounds 0.06% by weight in paints 

Food and Drug 

Administration 

all lead compounds none used in can solders 

 all lead compounds 0.5–3 μg/mL (leaching standard for 

ceramicware), 0.5–7 μg/mL (leaching 

standard for silver-plated hollowware) 

EPA tetraethyl lead none added to gasoline (motor vehicles) 

 inorganic lead compounds none used in plumbing 

 all lead compounds 1.5 μg/L in drinking water (action level) 

2.10 Guidance 

In 1991, CDC issued new guidelines for childhood blood lead levels associated with 

toxicity. They lowered the action level from 25 to 10 μg/dL and implemented a multitiered, graded response that depends on measured lead concentrations. Responses range 

from community-level actions to reduce lead exposure to emergency medical responses 

(NRC 1993). 

The American Conference of Governmental Industrial Hygienists recommends threshold 

limit values for worker exposure to lead of 0.05 mg/m3

 for inorganic lead compounds and 

0.15 mg/m3 for lead arsenate, averaged over an 8-hour day and 40-hour workweek 

(ACGIH 1999). NIOSH has set a recommended exposure limit of 0.05 mg/m3 for 

inorganic lead compounds and an immediately dangerous to life and health (IDLH) level 

of 100 mg/m3

 (NIOSH 1977). 
05/08/03 RoC Background Document for Lead and Lead Compounds 

41 

3 Human Cancer Studies 

Lead and lead compounds, in the form of inorganic lead, were classified as carcinogenic 

to animals by IARC (1987), but the evidence at that time was deemed inadequate to 

demonstrate human carcinogenicity. The epidemiologic literature on lead and cancer 

available to IARC was limited, but this literature has burgeoned in the interim. A metaanalysis of the literature was conducted in 1995 (Fu and Boffetta 1995), an overview of 

the evidence accompanied two new studies in 1997 (Vainio 1997), and a further metaanalytic review was conducted in 2000 (Steenland and Boffetta 2000). Continuing themes 

include accuracy of classification of lead exposure, simultaneous exposure to other 

substances that also may be carcinogens, and control for personal factors such as 

smoking. The cohort studies on workers provide a great deal of useful information; 

however, the ability to draw conclusions from these studies is limited by the fact that 

these workers almost always are exposed to multiple chemicals in the workplace. This 

section summarizes the findings and conclusions of the successive IARC Working Group 

evaluations of lead, reviews the wide body of relevant epidemiologic studies that have 

appeared since the 1987 IARC review, and summarizes their implications for the 

potential relationship between lead and human cancer. 

3.1 IARC assessments 

IARC has evaluated the evidence that lead exposure may cause cancer in a series of 

monographs published in 1972, 1973, 1976, 1980, and 1987. 

Epidemiologic evidence on lead salts was scarce at the time of the first monograph 

(IARC 1972). One cohort and one case-control study were available for review. 

Dingwall-Fordyce and Lane (1963) compared the causes of death occurring among 425 

male pensioners and employees from U.K. battery plants with cause-specific rates 

expected for the general population. Cancer deaths showed a nonsignificant elevation 

overall. When urinary lead measurements were used to divide the men into three 

exposure categories, however, no excess of deaths was observed in the highest exposure 

group (27 observed vs. 31 expected). Cerebrovascular events were more common among 

these workers, indicating that the absence of an association was probably not linked to a 

healthy worker effect. Jecklin (1956) found no significant differences in lead 

concentrations of postmortem lung tissue between five lung cancer patients and five 

control subjects dying of other causes. 

Tetraethyl and tetramethyl lead were considered in a separate monograph (IARC 1973), 

but no epidemiologic evidence was cited. Similarly, no epidemiologic studies were 

reviewed in the monograph on lead carbamate (IARC 1976). 

By the time of the 1980 IARC monograph, three additional studies of cancer in 

industrially exposed adults and three studies of childhood cancer in offspring of 

industrially exposed workers were available. 

Cooper and Gaffey (1975) studied battery and lead production workers in the United 

States. The mortality of a group of 7,032 lead production facility and battery plant 
05/08/03 RoC Background Document for Lead and Lead Compounds 

42 

workmen who had been employed for one or more years between 1946 and 1970, was 

followed through 1970. Although the lead absorption in many of these men greatly 

exceeded the accepted standards (as based on urinary and blood lead concentrations), 

their observed mortality by cause was comparable to that of the general population of 

United States males. Updated results for the same study population were summarized in a 

later IARC publication (Cooper et al. 1985), which is summarized in Section 3.2.1.1. 

Robinson (1976) followed up 153 tetraethyl lead workers matched by age and years of 

employment to 139 workers with no known occupational lead exposure. The only cancers 

occurring in the study population were skin cancers. Seven cases of cancer occurred in 

the lead-exposed group, compared with four cases in the nonexposed group. The small 

number of cases among exposed workers, combined with the fact that workers who had 

terminated employment for any reason (potentially including development of cancer) 

were not included in the cohort, makes the results of limited utility. 

Rencher et al. (1977) compared copper mine, smelter, and concentrator workers with the 

general population of the state of Utah or with workers in other operations. Workers in 

lead-exposed operations had triple the lung cancer risk of other workers; among workers 

in lead-exposed operations, those who developed lung cancer had higher estimated lead 

exposure than those who did not. Because workers with lung cancer had significantly 

higher estimated exposure to arsenic and sulfur dioxide, as well as lead, the observed 

lung cancer excess could not be directly attributed to lead. 

The other three studies addressed paternal occupations and childhood cancer. Fabia and 

Thuy (1974) compared the occupational categories of parents of children dying of cancer 

with those of children dying of other causes. Hydrocarbon-related occupations, such as 

motor-vehicle mechanic, machinist, miner, and painter, and potential exposure to lead in 

the course of tetraethyl lead production were significantly associated with cancer in the 

workers’ children.. A similar study by Hakulinen et al. (1976) found no association 

between hydrocarbon-related occupations and childhood cancer. Neither study measured 

lead exposure specifically and, thus, are not included in the summary table. Kantor et al. 

(1979) compared 149 Wilms’ tumor cases with age, gender, and race-matched controls. 

More fathers of Wilms’ tumor patients than of control subjects had lead-related 

occupations (22 vs. 6) or hydrocarbon-related occupations (22 vs. 10). Exposure 

assessment was derived from death certificate occupation listings; the IARC review 

concluded that the criteria used to identify lead-related jobs were questionable, 

potentially compromising the validity of all three studies. 

IARC’s 1987 update included a follow-up of one previous study and four new cohort 

studies of smelter, battery, or tetraethyl lead workers. Cooper et al. (1985) followed up 

6,819 U.S. battery and lead production workers from 1947 to 1980, updating the earlier 

Cooper and Gaffey (1975) study. Compared with national rates, standardized mortality 

ratios (SMRs) were significantly elevated for all cancers (SMR = 1.13, 95% confidence 

interval [CI] = 1.02 to 1.26) and all respiratory cancers (SMR = 1.24, 95% CI = 1.03 to 

1.49) in battery production workers. Among more site-specific cancers, significant 

excesses were found of stomach cancer (SMR = 1.68, 95% CI = 1.16 to 2.35) and lung, 

tracheal, or broncheal cancer (SMR = 1.24, 95% CI = 1.02 to 1.50). Nonsignificant 
05/08/03 RoC Background Document for Lead and Lead Compounds 

43 

excesses of liver and laryngeal cancers were observed, whereas the SMR for kidney 

cancer was nonsignificantly depressed. Nephritis and “ill-defined conditions” also 

showed significant excesses. Among lead production workers, nonsignificant excesses 

occurred for digestive and respiratory cancer, and no excesses were noted for kidney, 

brain, or lymphopoeitic system cancer. Cancer mortality did not increase with duration of 

employment. Lack of detailed exposure information precluded quantitative evaluation 

except by years of exposure. Concomitant exposures to other compounds could not be 

controlled for, and these exposures are likely to be most intense among lead production 

workers. As lead production workers showed lower SMRs than battery workers, any bias 

resulting from lack of control for other exposures probably made it more difficult to 

observe an effect. No data on smoking, diet, or other potential non-occupational risk 

factors were available. Nevertheless, the large sample size made this study one of the 

most important studies of lead-exposed workers to date. 

Malcolm and Barnett (1982) studied a cohort of 1,898 United Kingdom lead-acid battery 

workers. A non-significant excess of mortality from all cancers was mainly restricted to 

the most highly lead-exposed workers. The only significant excess in cancer at a specific 

site was for digestive cancers (21 observed, 13 expected) in non-exposed workers. The 

authors noted that blood lead monitoring indicated that by the end of follow-up, most of 

the difference between the moderate- and high-exposure groups had disappeared. 

However, the most critical exposure period would have been earlier in the period from 

1925 to 1976, so the decline in exposure among the high-exposure group probably did 

not have much effect on the results. Sweeney et al. (1986) compared TEL-exposed 

workers at a U.S. chemical plant with the national population, observing an excess of 

respiratory cancer (15 observed vs. 11 expected) and brain cancer (3 observed vs. 1.6 

expected) for white males. No excesses were observed for other cancers. The study was 

limited by its small size and the possiblity of a healthy-worker bias (total mortality = 131, 

vs. 167 expected). 

Smelter workers were studied by Selevan et al. (1985) in the United States and 

Gerhardsson et al. (1986) in Sweden. As both studies have been updated in the interim, 

their results are addressed below. 

Summarizing the evidence through its 1987 update, IARC cited the small excesses of 

respiratory cancer and potential confounding by smoking or exposure to other substances, 

such as arsenic, and again concluded that the epidemiologic evidence for carcinogenicity 

in humans was inadequate. 

3.2 Studies published since 1987 or not included in the IARC update 

Since the IARC update, an additional 17 case-control and 17 cohort studies of lead 

exposure and cancer have been identified (including analyses on new populations as well 

as extensions of follow-up or case-control investigations on previously studied 

populations), in addition to several subanalyses based on elements of these new studies. 

Seven new studies of parental lead exposure and childhood cancer also have been 

published. These additional works are discussed below, organized by study design and 

type of population investigated. 
05/08/03 RoC Background Document for Lead and Lead Compounds 

44 

Most studies focus on exposure through occupational sources, where the most intense 

exposure to lead can be expected. This exposure predominantly involves inorganic lead 

species. Studies focused on occupations with the greatest potential for inorganic lead 

exposure are considered first. Among these are smelter and battery-plant workers, along 

with leaded-pigment workers. Glass workers also may experience considerable exposure 

in production of leaded glass or, to a lesser degree, in the manufacture of stained glass 

with leaded joints or lead-containing coatings. Lead miners have the potential for 

substantial lead exposure, but generally to a lesser degree than smelter, battery, pigment, 

or leaded-glass workers. Newsprint workers, particularly compositors and typesetters, 

have had substantial exposure potential in the past, although current printing technologies 

have largely eliminated lead exposure in these occupations. Many other occupations have 

not been the object of a specific study, despite the fact that they may entail some degree 

of inorganic lead exposure; foremost among these occupations are radiator-repair 

workers, followed by steel welders and cutters. Examples of other potentially exposed 

occupations include some plastic and rubber industry workers, firing-range instructors, 

and building renovation and construction workers. Finally, in contrast to most job-related 

exposures, the manufacture of tetraethyl lead provides a potentially major source of 

exposure to organic lead. Detailed information regarding sources and magnitudes of 

occupational lead exposure can be found in Sections 2.7 and 2.8. 

Many occupations with potential for exposure to lead involve exposure to lead oxides but 

also are likely to involve exposure to multiple lead species (see Sections 1, 2, and 3.2). 

For the most part, good data on the relative contributions of different species or different 

particle sizes are not available for occupationally exposed individuals, and even when job 

exposure histories are available, classification into a few ordinal categories of exposure 

often is not entirely reliable. This limitation precludes assignment of risk estimates to 

specific inorganic lead species in the current review. Section 3.2.1 discusses studies not 

yet reviewed by IARC; these studies address cancers in adults in specific occupational 

groups exposed to inorganic lead. Groups are discussed in approximately descending 

order of potential exposure. Within these groups, cohort studies are described first, 

followed by case-control studies. 

Section 3.2.2 discusses studies of mixed occupational groups, again progressing from 

cohort to case-control designs. Section 3.2.3 discusses studies of TEL workers. Section 

3.2.4 discusses studies based on the general population, rather than on occupationally 

exposed persons. Finally, Section 3.2.5 discusses studies of childhood cancer in relation 

to parental lead exposure. 

3.2.1 Studies of adult cancer focused on specific occupational groups 

Although the ensuing discussion addresses studies not already reviewed by IARC, a 

comprehensive listing of studies addressing the association between lead and cancer is 

presented in Table 3-1 to provide an overview of the currently available literature. 

Studies are organized according to the occupational group of focus (e.g., smelter 

workers) in approximately descending order of exposure. For each grouping, all available 

studies conducted on a specific population are listed, subdivided by study design. Many 

populations have been the subject of more than one study. Thus, for example, workers at 

the same British battery factory have been the focus of two cohort studies (Dingwall-
05/08/03 RoC Background Document for Lead and Lead Compounds 

45 

Fordyce and Lane 1963, Malcolm and Barnett 1982) and one case-control study (Fanning 

1988). Summaries of each of the studies identified in Table 3-1 are presented in three 

additional tables. Cohort studies addressing the association between lead and cancer are 

summarized in Table 3-4, case-control studies in Table 3-5, and studies of parental lead 

exposure and childhood cancer in Table 3-6. 

Table 3-1. Human epidemiologic studies of lead exposure and cancer: published 

studies on specific populations, by study design 

Study design 

Study population Cohort 

Nested casecontrol Case-control 

Battery factory and/or smelter workers 

Lead-acid battery workers 

(U.K.) 

Dingwall-Fordyce and 

Lane 1963, Malcolm and 

Barnett 1982 

 Fanning 1988 

Battery and lead production 

workers (U.S.) 

Cooper and Gaffey 1975, 

Cooper et al. 1985, 

Wong and Harris 2000 

Cooper et al. 1989, 

Wong and Harris 2000 

(same publication as 

cohort study) 

Copper workers (Utah, U.S.) Rencher et al. 1977 

Zinc, cadmium, and lead 

smelter workers (U.K.) 

Ades and Kazantzis 

1988 

Ades and Kazantzis 

1988 (same 

publication as cohort 

study) 

Lead smelter workers (Idaho, 

U.S.) 

Selevan et al. 1985, 

Steenland et al. 1992 

 

Copper and lead smelter 

workers (Sweden) 

Gerhardsson et al. 1995a 

Copper and lead smelter 

workers (Sweden) 

(Lundström: full cohort; 

Englyst: sub-cohort) 

Gerhardsson et al. 1986, 

Lundström et al. 1997, 

Englyst et al. 2001 

 

Lead and zinc smelter workers 

(Sardinia) 

Cocco et al. 1996 

Lead and zinc smelter workers 

(Sardinia, but different from 

Cocco et al. 1996) 

Cocco et al. 1997 

Pigment-plant workers 

Lead and zinc pigment plant 

workers (U.S.) 

Sheffet et al. 1982 

Chromate (including leadchromate) workers (U.K.) 

Davies 1984a, 1984b 

Glass workers 

Glass workers (Italy) Cordioli et al. 1987 

Glass workers (Finland) Sankila et al. 1990 
05/08/03 RoC Background Document for Lead and Lead Compounds 

46 

Study design 

Study population Cohort 

Nested casecontrol Case-control 

Glass workers (Sweden) Wingren and Englander 

1990 

Wingren and Axelson 

1985, 1987, 1993 

Miscellaneous workers potentially exposed to inorganic lead 

Lead and zinc miners: females 

only (Sardinia) 

Cocco et al. 1994b 

Lead and zinc miners: male 

only (Sardinia) 

Cocco et al. 1994a, Carta

et al. 1994 

 

Newspaper plant workers 

(Italy) 

Bertazzi and Zocchetti 

1980 

 

Tetraethyl lead (TEL) workers 

TEL workers (U.S.) Robinson 1976 

TEL workers (U.S.) Fayerweather et al.

1997 

TEL workers (U.S.) Sweeney et al. 1986 

Mixed worker populations

Finnish workers via Cancer 

Registry 

Anttila et al. 1995 Anttila et al. 1996 

Sample of deaths due to cancer 

vs. noncancer deaths (Illinois, 

U.S.) 

 Mallin et al. 1989 

Population-based cases 

(Canada) 

 Risch et al. 1988 

Specific cancers vs. all cancers 

(Canada) 

 Siemiatycki et al.

1991 

Registry-derived liver cancer 

cases vs. stomach cancer or 

myocardial infarctions 

(Finland) 

 Kauppinen et al. 1992 

Brain cancer (U.S.) Cocco et al. 1998a 

Central nervous system cancer 

(U.S.) 

 Cocco et al. 1998b 

Stomach cancer (U.S.) Cocco et al. 1999 

Gliomas vs. noncancer patients 

(China) 

 Hu et al. 1998 

Meningiomas vs. noncancer 

patients (China) 

 Hu et al. 1999 

Renal-cell cancer vs. 

population controls (Germany) 

 Pesch et al. 2000 

NHANES II cohort mortality 

follow-up, general U.S. 

population 

Jemal et al. 2002, 

Lustberg and Silbergeld 

2002 

 

 
05/08/03 RoC Background Document for Lead and Lead Compounds 

47 

Study design 

Study population Cohort 

Nested casecontrol Case-control 

Laryngeal cancer among 

persons with no history of lead 

exposure (Greece) 

 Kandiloris et al.

1997 

Gall bladder cancer vs. 

gallstone patients (India) 

 Shukla et al. 1998 

Parental exposure and childhood cancer 

Childhood acute 

nonlymphoblastic leukemia 

cases vs. population controls 

(U.S. and Canada) 

 Buckley et al. 1989 

Wilms’ tumor cases vs. 

population controls (U.S.) 

 Kantor et al. 1979, 

Wilkins and Sinks 

1984a, 1984b, 

Olshan et al. 1990 

Children of union printers 

(Norway) 

Kristensen and Andersen 

1992 

 

3.2.1.1 Smelter and battery workers 

Smelter workers have a high potential for exposure to lead, much of it in the form of 

sulfides, in addition to highly absorbable sulfates and oxides. These workers also are 

typically exposed to other chemical species, such as arsenic and nickel, with wellestablished carcinogenic potential. Further, quantitative data adequate to differentiate 

between the magnitude of exposure to lead and these other potential carcinogens usually 

are not available. Battery plant workers share a high potential for lead exposure, and 

these plants often include smelter components. 

Smelter workers: cohort studies 

Ades and Kazantzis (1988) conducted a cohort study of lung cancer mortality among 

4,393 U.K. zinc, lead, and cadmium smelter workers. The SMR for the smelter workers, 

compared with national rates, was 1.25 (95% CI = 1.07 to 1.44), based on 182 lung 

cancer deaths. Most of the study, however, was devoted to a nested case-control analysis 

in which workers who died of lung cancer were matched to worker controls by birth date, 

employment start date, and death date. Cadmium exposure levels were quantified based 

on job history to determine whether cadmium accounted for the increased mortality; 

significant exposure to lead and several other compounds also was identified from job 

histories. Cadmium exposure showed little association with lung cancer. Significant lead 

and arsenic exposures were associated with lung cancer mortality, whereas associations 

with zinc or other substances were much weaker. Potential effects of lead could not be 

separated from those of arsenic, nor could other exposures be simultaneously adjusted 

for, because of inadequate numbers. The results are thus consistent with lead and/or 

arsenic potentially contributing more than cadmium or other compounds to the elevated 

lung cancer mortality associated with lead smelting; however, the excess mortality could 

be due to exposure to lead only, arsenic only, or the combination of the two. 
05/08/03 RoC Background Document for Lead and Lead Compounds 

48 

Steenland et al. (1992) monitored mortality among 1,990 U.S. male lead smelter workers 

employed from 1940 to 1965, with follow-up through 1988. A high-lead-exposure 

subgroup of 1,436 workers was identified based on air-monitoring records. The total 

cohort showed nonsignificantly elevated standardized mortality ratios (SMRs) for kidney, 

bladder, stomach, and lung cancer mortality. The excess for kidney cancer became 

statistically significant when the analysis was limited to the most highly exposed 

members of the cohort (SMR = 2.39, 95% CI = 1.03 to 4.71), but estimates for other 

cancers remained similar or fell (SMR = 1.33, 95% CI = 0.48 to 2.90 for bladder cancer; 

SMR = 1.28, 95% CI = 0.61 to 2.34 for stomach cancer; and SMR = 1.11, 95% CI = 0.82 

to 1.47 for lung cancer). Although the excess mortality from kidney cancer was greater 

among workers with the highest intensity of exposure, it did not increase with duration of 

exposure. Where elevated risks were observed in the general cohort, they did not 

consistently increase among those most exposed. Neither smoking nor coexposure to 

cadmium or arsenic could be controlled for, but monitoring data from a 1975 NIOSH 

survey indicated that average exposures to these metals in air were much less intense than 

exposure to lead, which averaged 3.1 mg/m3

, compared with the current OSHA standard 

of 0.05 mg/m3. For arsenic specifically, which has been linked to lung cancer in other 

studies, the cohort’s average exposure was estimated at 14 μg/m3

 in 1975, compared with 

the current OSHA standard of 10 μg/m3. A 1996 review of studies on arsenic-exposed 

worker cohorts concluded that no excess of lung cancer was found for arsenic exposures 

around the OSHA standard, and that where lung cancer excesses were observed, they 

appeared to occur in cohorts with much higher exposures (e.g., in the hundreds of 

micrograms per cubic meter) (Steenland et al. 1996). 

Gerhardsson et al. (1995a) extended the follow-up of male Swedish lead smelter workers 

begun by Gerhardsson et al. (1986), tracing cancer morbidity among 664 lead-exposed 

workers from 1969 to 1989. Exposed workers were identified from records of routine 

blood lead monitoring, and cancer incidence was compared with that of the population of 

the surrounding county. The standardized incidence ratio (SIR) for all cancers was 1.27 

(95% CI = 0.91 to 1.74), based on 40 tumors. SIRs for cancers at all specific sites except 

the brain were elevated, notably those for the respiratory system (SIR = 1.32, 95% CI = 

0.49 to 2.88), stomach (SIR = 1.88, 95% CI = 0.39 to 5.50), and colon (SIR = 1.46, 95% 

CI = 0.30 to 4.28). Because of the small numbers of tumors (only 6, 3, and 3, 

respectively, even for the aforementioned sites), the reliability of estimates for most sites 

is limited. Workers in the highest quartile of lead exposure showed further elevation in 

SIR for total gastrointestinal cancer (SIR = 2.34, 95% CI = 1.07 to 4.45, 9 tumors), but 

not respiratory cancer. Availability of blood lead measurements to confirm exposure is a 

key advantage of this study, along with a worker population likely to have much more 

intense exposure to lead than to other metals. However, the cases were too few for 

detailed exposure-response analyses. Lack of data on smoking further restricts 

interpretation of the results. 

Cancer-specific SMRs were calculated for 1,388 production and maintenance workers 

from an Italian lead and zinc smelter followed from 1950 to 1992 by Cocco et al. (1997). 

Deaths from lung cancer (31), stomach cancer (14), and all cancers (132) during 1965-

1992 were not elevated over regional rates, but those from cancer of the kidney (4), 

bladder (12), and brain (4) were, yielding SMRs of 1.75 (95% CI = 0.48 to 4.49), 1.45 
05/08/03 RoC Background Document for Lead and Lead Compounds 

49 

(95% CI = 0.75 to 2.53), and 2.17 (95% CI = 0.57 to 5.57), respectively. Risk of kidney 

cancer increased with years of exposure, whereas the relationship of lung cancer with 

years of exposure was inconsistent. Age, duration, and latency of exposure were 

addressed. The numbers of deaths were small for most cancers other than respiratory 

(33), and there was no control for smoking status. Although cadmium exposure was 

present, the levels of exposure to this metal were low. Direct lead exposure 

measurements were lacking, and job classifications were imprecise, but risk of reported 

lead toxicity did increase consistently with duration of employment. Lack of a strong 

association of lead exposure with mortality from lung cancer, despite the strong 

association of lead smelter work with pneumoconiosis and other respiratory disease 

(SMR = 4.47, 95% CI = 3.37 to 5.80 for national mortality rates), may reflect certificatebased misclassification of lung cancer deaths or other problems, since the excess of 

pneumoconiosis presumably reflected an excess of silicosis, which is thought to 

predispose individuals to lung cancer. 

In a further analysis, Cocco et al. (1996) studied Italian lead and zinc smelter workers 

whose glucose-6-phosphate dehydrogenase (G6PD) phenotype had been measured. 

Among all the workers, lung-cancer mortality was lower than expected and stomachcancer mortality higher, but these differences were based on few deaths (e.g., 2 observed 

vs. 0.6 expected for stomach cancer). Despite the thought that G6PD-deficient workers 

might be more vulnerable to the depletion of red blood cell glutathione associated with 

lead toxicity, mortality from cancer and from all causes was slightly lower among G6PDdeficient workers than among G6PD-normal workers. 

Lundström et al. (1997) followed 3,979 Swedish smelter workers from 1928 to 1987. 

Workers were further subdivided into those with high cumulative blood lead scores 

(mean times years exposed > 10 μmol/L), and those exposed to “lead only” (excluding 

those from departments thought to have significant exposures to other potential 

carcinogens, such as arsenic, or little exposure to lead). The lung cancer SMR was 2.8 

(95% CI = 2.0 to 3.8) for the total cohort, 2.8 (95% CI = 1.8 to 4.5) for the high-exposure 

subgroup, and reportedly similar for the subgroup exposed to lead only. With adjustment 

for a 15-year latency period, lung cancer SIRs likewise differed little between the total 

cohort and high-exposure subgroup; however, among workers with exposure to lead only, 

the SIR rose from 3.1 (95% CI = 1.7 to 5.2, 14 cases) for all workers to 5.1 (95% CI = 2.0 

to 10.5, 7 cases) for those with the highest exposure. With a 15-year latency period, 

elevated SIRs also were observed for cancer of the brain and nervous system (SIR = 1.6, 

95% CI = 0.4 to 4.2) and renal pelvis, ureter, or bladder (SIR = 1.8, 95% CI = 0.8 to 3.4) 

among the high-exposure subgroup. Non-respiratory cancers were too infrequent (5 total) 

in the high-exposure lead-only subgroup for meaningful analysis. This study’s size, 

extensive follow-up, and ability to integrate blood-based and job-based exposure indices 

give it unusual power. The apparent increase in cancer risk with higher cumulative lead 

exposure that appeared when workers thought to be potentially exposed to other metals, 

such as arsenic and nickel, were excluded also appeared to strengthen the evidence for a 

specific link between lead and respiratory cancer. A subsequent study by Englyst et al. 

(2001), however, cast doubt on the efficacy of the “lead only” grouping. 
05/08/03 RoC Background Document for Lead and Lead Compounds 

50 

Englyst et al. (2001) conducted additional analyses on one element of the Lundström et 

al. (1997) cohort. A total of 1,093 workers from the smelter’s lead department was 

followed up through 1997. Significantly elevated lung cancer SIRs were observed in all 

subcohorts, including the subcohort who had never worked in arsenic-exposed areas 

(SIR = 3.6, 95% CI = 1.2 to 8.3, [5 cases]). This subcohort is the same as the “lead-only” 

subgroup evaluated by Lundström et al. A review of detailed job histories obtained for all 

workers with lung cancer, however, indicated that 13 of the 15 had “considerable” 

exposure to arsenic as well as lead, including all but 1 in the “lead only” subcohort. 

Combined smelter and battery workers: cohort study 

Wong and Harris (2000) presented a further update of the U.S. lead battery and smelter 

worker cohort last reported on by Cooper et al. (1985) and described in Section 3.1. 

[Lead production workers sometimes are referred to as smelter workers (Cooper et al. 

1985)]. The updated study extended follow-up for an additional 15 years, through 1995, 

although employment history was not updated. The SMR for cancer of the lung, trachea, 

or bronchus among battery workers fell from 1.24 in the earlier analysis to 1.14 (95% CI 

= 0.99 to 1.30) in the update, narrowly missing statistical significance; among smelter 

workers, this finding was paralleled by change from a nearly identical SMR of 1.25 in the 

earlier analysis to 1.22 (95% CI = 1.00 to 1.47) in the update. The stomach cancer SMR 

remained significantly elevated at 1.53 (95% CI = 1.12 to 2.05) among battery workers 

and less elevated (SMR = 1.33, 95% CI = 0.75 to 2.20) among smelter workers. The only 

other cancer with a significantly elevated SMR was that of the thyroid for battery and 

smelter workers combined (SMR of 3.08; 95% CI = 1.33 to 6.07). Cancer mortality did 

not increase with earlier year of hire for lung, stomach, or thyroid cancer. Lung and 

stomach cancer mortality peaked among workers with 10 to 19 years of factory 

employment and declined with longer employment duration. Thyroid cancer mortality 

occurred exclusively among workers with 20 or more years of exposure. As noted 

regarding the earlier study of this cohort, concomitant exposures to other compounds 

could not be controlled for, but as these were likely to be most intense among lead 

production workers, whose SMRs were similar to or lower than those for battery workers, 

any bias resulting from such exposure probably was toward the null. No data were 

available to assess the possible role of smoking, diet, or other potential non-occupational 

risk factors in the results. 

A nested case-control analysis of this cohort also was carried out for stomach cancer 

mortality at the largest battery plant (as discussed below). It found no evidence of 

increased lead exposure among workers who died of cancer and no consistent increase in 

ORs with increasing exposure. This finding argues against a truly causal role for lead in 

the SMR results, although the study did not adjust for potential confounders. Overall, the 

additional follow-up maintained evidence for a modest increase in lung cancer and 

stomach cancer risk among the lead workers, but found no association with duration of 

employment and, for stomach cancer, no indication that workers who died of cancer had 

higher estimated lead exposure than those who did not. 

To explore the relationship with stomach cancer in more detail, a small nested casecontrol analysis also was conducted within the Wong and Harris (2000) cohort. Among 

workers employed at a Philadelphia lead battery plant, 120 controls were age-matched to 
05/08/03 RoC Background Document for Lead and Lead Compounds 

51 

30 workers who died of stomach cancer. Job title histories were collected for each subject 

and used to estimate total duration of employment at the plant and cumulative exposure 

based on job-specific intensities of exposure. Neither duration of employment nor degree 

of estimated lead exposure was elevated among the workers who died of stomach cancer; 

in fact, these measures were higher among controls, although the differences did not 

approach statistical significance. No exposure-dependent associations were observed 

across quartiles of lead exposure, regardless of whether exposure was computed over a 

10- or 20-year period before death. Apparently, few data were available on potential 

confounders. Italian and Irish immigrants were more common among case than control 

subjects. The authors speculated that in view of higher stomach cancer mortality rates 

among native Italians and Irish than the general U.S. population, confounding by 

immigrant status may have been at least partly responsible for the elevated SMR 

observed in the lead smelter and battery worker cohort. However, the proportions of 

immigrants in the lead battery plant were not compared with those expected in the 

corresponding general population. (A previous nested analysis, apparently including 

many of the same cases, with similarly negative findings, was published by Cooper et al. 

[1989]). 

Battery and other workers: case-control study 

Fanning (1988) studied deaths due to specific cancer types among battery and other 

factory workers in the United Kingdom from 1926 to 1985. High to moderate lead 

exposure resulted in ORs for lung and digestive cancer of 0.93 and 1.13, respectively, 

with the latter elevation due mainly to stomach cancer (OR = 1.34). No ORs reached 

nominal statistical significance, and no associations were noted for other cancer types. 

The excess of digestive cancer deaths was restricted to the 1926 to 1965 period, during 

which lead exposures would have been most intense. ORs for other cancers did not vary 

by period. Because each cancer case group was compared with a control group consisting 

of subjects who died from all other causes, including other cancers, ORs would have been 

biased downward if some of these other deaths also were lead-related. However, most 

deaths were due to nonmalignant respiratory or circulatory diseases other than 

hypertension, which mitigated the potential impact of such a bias. 

3.2.1.2 Leaded pigment workers 

Leaded pigment manufacture also carries great potential for exposure to lead compounds, 

which may include carbonates, nitrates, and acetates, among others. The key cohorts 

studied were involved in the manufacture of lead chromate, and thus were potentially 

coexposed to chromate, an established carcinogen. 

Pigment workers: cohort studies 

Sheffet et al. (1982) computed age- and calendar-year-specific SMRs for 1,946 workers 

at a U.S. lead and zinc chromate pigment plant vs. the national population. Lung, 

stomach, and pancreatic cancer SMRs for chromate workers were significantly elevated 

when persons of unknown vital status were assumed to be alive at the end of follow-up. 

When persons of unknown vital status were excluded, only the elevation for lung cancer 

remained significant (SMR = 1.6 in both whites and blacks, P < 0.05 in whites only). 

Nonsignificant elevations were found for stomach, rectal, pancreatic, and prostate cancer 

and Hodgkin’s disease, and deficits in intestinal and laryngeal cancer were observed 
05/08/03 RoC Background Document for Lead and Lead Compounds 

52 

among whites. Similar results for stomach, laryngeal, and pancreatic cancer were found 

in nonwhites. All but one of the lung cancers among workers of known smoking status 

occurred among smokers, indicating that if exposure to lead affects lung cancer risk, it 

does not do so independently of cigarette smoking. The relative degrees of lead and zinc 

chromate exposure were not determined, nor could coexposure to nickel and other 

compounds be controlled for. On the other hand, the presence of multiple coexposures 

would tend to make a true association with lead chromate harder to detect. 

Davies (1984a) studied 1,152 U.K. chromate pigment factory workers. A significant 

excess of lung cancer deaths were observed among these workers, but only for the two 

factories with combined zinc and lead chromate exposure. Excess lung cancer deaths 

were noted among workers exposed to both lead and zinc chromate, but not among 

workers exposed to lead chromate only. In a follow-up of 57 pigment factory workers 

who had been diagnosed with non-fatal lead poisoning (Davies 1984b), a small excess of 

lung cancer deaths was found (RR 1.45), but the number of deaths (4) was too small for 

statistical significance. 

3.2.1.3 Glass workers 

Leaded-glass workers, particularly those involved in glassblowing, constitute another 

potentially heavily exposed group, with lead oxides and dust prominent among the 

species involved. As with smelter workers, however, arsenic is a common coexposure, 

and antimony, silica, or even asbestos exposure may occur as well. 

Glass workers: cohort studies 

Three European studies followed up cohorts of glass workers. Cordioli et al. (1987) 

studied 468 Italian glass workers. Workers producing low-quality glass containers were 

classified as being exposed to lead. A small elevation in mortality from all cancer 

(SMR = 1.3, 95% CI = 0.8 to 1.8) among glass workers was driven by significant 

excesses in lung cancer (SMR = 2.1, 95% CI = 1.1 to 3.6) and laryngeal cancer 

(SMR = 4.5, 95% CI = 1.2 to 11.4). The small number of deaths among exposed workers 

(28 total, 13 lung, and 4 laryngeal cancer) limited the study’s statistical power. Sankila et 

al. (1990) compared the incidence of cancer in 1,803 male and 1,946 female Finnish 

glass workers with that of the national population. Glassblowers were considered to be a 

lead-exposed subgroup. Modest elevations in lung cancer risk were observed among glass 

workers for both men (SIR = 1.3, 95% CI = 1.0 to 1.7) and women (SIR = 1.1, 95% CI = 

0.5 to 2.3); no increase was observed for other cancers, and the increased risk of lung 

cancer was not specific to glassblowers. In the final study, Wingren and Englander 

(1990) compared mortality in Swedish glass workers from work areas with airborne lead 

levels ranging from < 0.001 up to 0.110 mg of Pb/m3

, noting a significant elevation for 

pharyngeal cancer (SMR = 9.9, 95% CI = 1.2 to 36.1) and nonsignificant elevations for 

lung and colon cancer compared to national rates. 

Glassworkers: case-control studies 

Wingren and Axelson (1985, 1987, 1993) conducted a case-control analysis comparing 

stomach, colon, and lung cancer mortality among Swedish glass workers with that of the 

surrounding regional populations. A small early study of three parishes (Wingren and 

Axelson 1985) was expanded to include 11 parishes, thus encompassing most of the 
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53 

Swedish glass-work industry (Wingren and Axelson 1987). For the final analyses 

(Wingren and Axelson 1993), total lead exposure was estimated, based on work histories, 

and characterized as “none,” “low,” or “high.” Because of the complex pattern of 

exposure of glass workers to metals and other agents over time, data on the consumption 

of metals linked with any particular type of production were obtained by means of a 

questionnaire submitted to 13 glass works in operation at that time, 7 of which provided 

answers. These metals were antimony, arsenic, cadmium, chromium, copper, lead, 

manganese, nickel, selenium, and zinc. 

ORs for mortality from cancer of the lung (OR = 1.7, 90% CI = 1.1 to 2.5), stomach 

(OR = 1.5, 90% CI = 1.1 to 2.0), and colon (OR = 1.6, 90% CI = 1.0 to 2.5) all were 

elevated among glass workers as a whole (Wingren and Axelson 1987). Among specific 

classes of glass workers, glassblowers had the highest ORs (2.3, 2.6, and 3.1 for lung, 

stomach, and colon cancer, respectively). When the data were analyzed according to 

estimated level of metal exposure, no consistent dose-response trend was found for lung 

cancer, and the association with stomach cancer was weaker for lead than for arsenic, 

copper, and other metals. Increasing exposure to either lead or antimony was associated 

with increased risk of colon cancer mortality; however, exposure to the two elements was 

strongly correlated. Elevated cardiovascular disease mortality in the population indicated 

a generally poor health experience. For all three cancers, the highest ORs were seen for 

glassblowers, who had potentially much higher inhalation exposure to manganese, 

chromium, and nickel than to lead. In addition to the presence of multiple exposures (e.g., 

chromium, nickel, and arsenic), the study did not control for other factors such as 

smoking and diet. 

3.2.1.4 Miners: cohort studies 

Lead miners obviously are subject to lead exposure, but copper and zinc miners also may 

experience secondary exposure to lead. The probability of exposure to other dusts and to 

radon greatly complicates the evaluation of potential associations between lead exposure 

and lung or other cancers in miners. 

Three papers described studies on Sardinian lead-, zinc-, and silica-exposed miners. Carta 

et al. (1994) and Cocco et al. (1994a) followed 1,741 male workers from two mines. 

SMRs based on age- and calendar-year-specific regional rates were not increased for 

mortality from all cancers (SMR = 0.94, 95% CI = 0.83 to 1.05). A significant excess 

(SMR = 3.67, 95% CI = 1.35 to 7.98) was seen for cancer of peritoneal tissues, based on 

6 deaths. Mortality from prostate, bladder, kidney, and nervous-system cancer and nonHodgkin’s lymphoma showed small excesses. All workers were subject to zinc exposure 

and either high silica or high radon-daughter exposure, and smoking was not controlled 

for. Among 526 female workers from the same mines, Cocco et al. (1994b) found a 

significant increase in liver cancer mortality (SMR = 5.02, 95% CI = 1.62 to 11.70) and a 

nonsignificant increase in lung cancer mortality (SMR = 2.32, 95% CI = 0.85 to 5.05). 

SMRs for other cancers were below unity. The excess lung cancer mortality was not 

restricted to workers with high radon-daughter or silica exposure, but was based on small 

numbers. 
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54 

3.2.1.5 Newspaper plant workers: cohort study 

Bertazzi and Zoccheti (1980) studied Italian newspaper plant workers, singling out 

compositors and stereotypers as having lead-exposed jobs. Mortality among workers 

from 1956 to 1975 was compared with national rates. Newspaper workers as a whole had 

elevated risk estimates for all cancer (SMR = 1.23, 95% CI = 0.92 to 1.62), digestivesystem cancer (SMR = 1.20, 95% CI = 0.72 to 1.88), and respiratory-system cancer 

(SMR = 1.56, 95% CI = 0.91 to 2.50) and for lung cancer specifically (SMR = 1.48, 95% 

CI = 0.79 to 2.53). No elevated risks were observed for compositors and stereotypers, but 

these estimates were based on a total of only 4 deaths from cancer of any types.

3.2.2 Studies of mixed occupational groups 

Summaries of the cohort and case-control studies described below are provided in Tables 

3-4 and 3-5, respectively. 

3.2.2.1 Mixed workers: cohort and nested case-control studies 

Anttila et al. (1995) linked 20,700 Finnish workers whose blood lead was monitored 

during 1973 to 1983 by the Finnish Institute of Occupational Health to the Finnish 

Cancer Registry. Exposure was subdivided according to highest peak blood level 

measured: low (0 to 0.9 μmol/L [0 to 18.6 μg/dL]), moderate (1.0 to 1.9 μmol/L [20.7 to 

39.4 μg/dL]), and high (2.0 to 7.8 μmol/L [41.4 to 161.6 μg/dL]). The total cohort 

showed no elevation in total or site-specific cancer mortality, based on an SMR analysis. 

Among male workers with moderate exposure, incidence of total respiratory cancer and 

lung cancer both were elevated (SIR = 1.4, 95% CI = 1.0 to 1.9 for both). Risks of total 

digestive, stomach, bladder, and nervous-system cancer also were modestly elevated. 

However, risks did not increase in the high-exposure group. Risks of mortality for all 

cancer for both men and women (RR = 1.4, 95% CI = 1.1 to 1.8) and lung or tracheal 

cancer (RR = 2.0, 95% CI = 1.2 to 3.2) were even stronger when a person-year analysis 

was applied to compare workers with moderate lead exposure to those with low exposure. 

Again, risks did not increase in the highest exposure group. This exposure group was 

smaller than the others, however, which limited the power of analyses specific for high 

exposure workers. Thus, for example, the numbers of lung or tracheal cancer deaths 

among men in the low-, moderate-, and high-exposure groups were 25, 34, and 11, 

respectively, for the person-year-based analyses. 

It should be noted that for cancer, cumulative exposure, particularly during the earlier 

part of the follow-up period, might be more relevant than peak exposure, although the 

two were reportedly highly correlated (r = 0.8) in the Finnish workers (Anttila et al.

1995). Case-referent substudies of lung cancer used different exposure criteria (Anttila et 

al. 1995). ORs increased most consistently with increasing cumulative exposure to lead. 

Among histologic subtypes, significantly elevated risk for squamous-cell cancer of the 

lung (OR = 4.1, 95% CI = 1.1 to 15) for the highest blood lead group persisted after 

adjustment for smoking, although with additional adjustment for engine exhaust and 

solvent exposure, the risk declined (OR = 3.4, 95% CI = 0.9 to 13). Results for female 

workers are not considered, as too few cancers (3 total) occurred to permit meaningful 

conclusions. Although the follow-up period was relatively short, the lung cancer 

association was analyzed in much greater detail than in most studies, and smoking was 
05/08/03 RoC Background Document for Lead and Lead Compounds 

55 

adjusted for. Although the association between lead exposure and lung cancer weakened 

with control for engine exhaust and solvent exposure, the OR remained well above 1. The 

highest OR of all was observed for estimated risk of lung cancer among workers with 

peak blood lead levels of at least 0.8 μmol/L [≥ 16.6 μg/dL] who were exposed to engine 

exhaust (OR = 14.9, 95% CI = 1.3 to 178, 11 cases). If engine exhaust was acting as an 

effect modifier, directly controlling for it might not have been appropriate. The exhaust 

could have served as a source of organic lead, as well. 

Anttila et al. (1996) presented a nested case-control analysis of 26 Finnish male workers 

with central nervous system (CNS) cancer and 200 controls, using the same Finnish 

occupational cohort as in Anttila et al. (1995). Detailed occupational histories and data on 

other potential risk factors were obtained from cancer patients or next of kin. For CNS 

cancer incidence, ORs rose with increasing peak lifetime blood lead level; however, the 

trend was not statistically significant. An association with mortality was confined to 

glioma. ORs for glioma mortality rose consistently and significantly with increasing peak 

and mean blood lead level, as well as duration of and estimated cumulative lead exposure 

(e.g., for low, medium, and high cumulative lead exposure vs. no exposure, ORs = 2.0, 

6.2, and 12, respectively, with a trend significant at P = 0.02). Adjustment for exposure to 

gasoline, cadmium, and other potential risk factors did not alter the results. Strengths of 

this study are the availability of blood lead measurements and control for reported 

cadmium and gasoline exposure. Limitations include the small number of cases (10 

gliomas among workers with complete exposure information), short follow-up time 

(maximum of 15 years), potential selection bias due to low response rates (60% for cases, 

56% for controls), and possible coexposures such as solvents or other metals. 

3.2.2.2 Mixed workers: case-control studies 

Mallin et al. (1989) used death certificates for Illinois males to compare deaths from 

seven specific cancers with a control group of 3,198 randomly selected deaths from other 

causes. Based on occupations from death certificates, the OR for cancer of the brain (3.0, 

P < 0.05) was significantly elevated in white male glass workers (as well as physicians 

and communications workers). No significant association was observed for other cancer 

sites, including lung and stomach. This isolated association is not consistent with the 

results for Swedish glass workers summarized above. No specific information on lead 

exposure other than the decedent’s occupation was available, and the analyses were not 

controlled for other established or potential risk factors. 

Risch et al. (1988) compared 826 Canadian men with histologically confirmed bladder 

cancer with 792 Canadian population controls. Reported occupational exposure to lead 

yielded a significantly elevated smoking-adjusted OR (2.0, 95% CI = 1.2 to 3.5) and a 

significant trend with duration of exposure. Of 17 other exposures examined, only one 

(tar and asphalt) was significantly associated with bladder cancer. Although these 

analyses relied on self-reported exposure, with the potential for inaccurate recall, this 

study design would be more likely to bias results toward the null than toward a positive 

association. The ability to control for smoking, education, ethnicity, and other factors are 

strength of the study; however, although no multivariate analyses adjusting for other 

occupational exposures were conducted. 
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56 

Siemiatycki et al. (1991) conducted a case-control study in Canada using 3,730 cases of 

various histologically confirmed cancers. Occupational exposure to 293 substances, 

including lead, was estimated from interview data. Elevated ORs were noted for cancer 

of the lung (OR = 1.1, 90% CI = 0.9 to 1.4), stomach (OR = 1.2, 90% CI = 1.0 to 1.6), 

bladder (OR = 1.3, 90% CI = 1.0 to 1.6), and kidney (OR = 1.2, 90% CI = 1.0 to 1.6). 

Factors controlled for included age, smoking, income, ethnicity, and blue vs. white-collar 

occupation. No evidence for exposure-response relationships was presented. Significant 

strengths of this study are adjustment for smoking and other potential risk factors and 

reliance on interview-obtained exposure data, rather than estimation of exposure from 

death certificates. Limitations include potential confounding by the other 292 

occupational exposures and low quantitative detail regarding lead exposure. 

Kauppinen et al. (1992) conducted a nested case-control study in Finland, matching 344 

primary liver cancer deaths by age and gender to 476 stomach cancer deaths and 385 

myocardial infarct deaths. Exposures were assigned based on work histories. Workers 

estimated to have potential lead exposure showed no elevation in OR (0.91, 95% CI = 

0.65 to 1.29). Few workers (4 in all) were deemed to have probable high cumulative 

exposure, limiting the power of the study, particularly in view of the potential-for 

exposure to metals, solvents, and welding fumes among the worker population. Although 

confounding due to alcohol intake was addressed, use of a control group with stomach 

cancer, which some other studies have linked to lead exposure, may have biased results 

toward a negative association. 

The National Cancer Institute, NIOSH, and the National Center for Health Statistics have 

assembled a database that integrates industry, occupation, and cause of death information 

from death certificates in 24 states. This resource provides a very large sample size for 

case-control analyses of occupational exposures. Three studies using these data are 

summarized below. All analyses based on this database share the following primary 

limitations: (1) no information is available on occupations or industries other than the 

primary one listed on the death certificate; therefore, some truly exposed subjects will be 

classified as unexposed; (2) no information is available on the duration of employment in 

the listed occupation or industry; and (3) cause of death may be misclassified on the 

death certificate; in combination these limitations will hamper accurate quantification of 

exposure and linkage of that exposure to outcome status. The net effect of the exposure 

and outcome misclassifications arising from these limitations most likely would be 

underestimation of the strength of any true association. 

Cocco et al. (1998a) matched all 27,060 brain cancer deaths occurring among persons 

aged 35 or older during 1984 to 1992 with four gender-, race-, age-, and region-matched 

deaths from non-malignant causes. A job-exposure matrix was used to assign subjects to 

low, medium, or high probability and intensity of exposure. Subjects were subdivided 

into four groups based on gender and race (white or African-American). Risk of brain 

cancer mortality increased consistently with rising intensity of lead exposure among 

African-American men but not among the other three race-gender groups. When 

probability of exposure alone was examined, no consistent association was observed for 

any group. However, among subjects with a high probability of exposure, risk increased 

with increasing intensity of exposure for all groups except African-American women, 
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57 

who had only a single lung cancer death in the high exposure probability group. Analyses 

were adjusted for age, marital status, urban residence, and socioeconomic status. Work in 

industries associated with lead exposure, such as chemical manufacturing and metal 

fabrication, may involve exposure to many potential carcinogens in addition to lead, so 

confounding is a possibility. 

Broadening the study to CNS cancer deaths, the same research team computed ORs for 

specific industries and occupations rather than particular substances (Cocco et al. 1998b). 

Notable elevations of CNS mortality risk were seen for the newspaper printing and 

publishing industry (OR = 1.4, 95% CI = 1.1 to 1.8, for white males; OR = 3.1, 95% CI = 

0.9 to 10.9, for African-American males); for typesetting and compositing among white 

males (OR = 2.0, 95% CI = 1.1 to 3.8), white women (1.3, 0.4 to 3.8), and AfricanAmerican women (OR = 4.2, 95% CI = 0.6 to 30.7); and for white male plumbers and 

pipefitters (OR = 2.4, 95% CI = 1.1 to 5.4). Among whites of both genders, positive 

associations also were found between CNS cancer and the petroleum refining and 

petroleum products industries. Results for groups lacking at least one significantly 

elevated OR (P < 0.05) were not presented; these groups included smelter, battery and 

paint manufacturing, parking-garage, and service-station workers. 

In the third 24-state death-certificate study, 41,957 stomach cancer deaths were matched 

with 83,914 deaths due to non-malignant causes (Cocco et al. 1999). A job-exposure 

matrix was used to assign subjects to low, medium, or high probability and intensity of 

exposure to lead and 11 other chemicals. ORs were adjusted for age, ethnicity, marital 

status, urban residence, and socioeconomic status. Elevated ratios occurred among white 

women (OR = 1.53, 95% CI = 1.10 to 2.12), African-American men (OR = 1.15, 95% CI 

= 1.01 to 1.32), and African-American women (OR = 1.76, 95% CI = 0.74 to 4.16) with 

high probability of lead exposure. Risks in the moderate-probability group were elevated 

only for African-American women (OR = 1.37, 95% CI = 0.58 to 3.21), and risk was not 

elevated for any exposure group among white males. Risk showed no consistent increase 

with intensity of exposure in any group. The absence of any association with lead 

exposure among the largest race-gender group, white males, is notable, as is the general 

absence of association with intensity of exposure. More consistent elevations of ORs for 

stomach-cancer mortality were observed for inorganic dust and nitrosamines than for 

lead. 

In a Chinese hospital-based case-control study, Hu et al. (1998) compared 218 patients 

with histologically confirmed primary gliomas with 436 patients with non-neurological, 

nonmalignant disease, matched by age, gender, and residence. Patients were interviewed 

to elicit details on occupational and chemical exposures for factory and farm occupations. 

An OR could not be calculated for occupational exposure to lead because no glioma 

patients reported such exposure. 

In a parallel study, Hu et al. (1999) compared 183 patients with histologically confirmed 

primary meningiomas with patients with non-neurological, nonmalignant disease, 

matched by age, gender, and residence. Patients were interviewed to elicit details on 

occupational and chemical exposures for factory and farm occupations. Reported 

occupational exposure to lead was associated with risk of meningioma in both men 
05/08/03 RoC Background Document for Lead and Lead Compounds 

58 

(OR = 7.20, 95% CI = 1.00 to 51.72) and women (OR = 5.69, 95% CI = 1.39 to 23.39). 

Results were adjusted for income, education, and consumption of fruits and vegetables, 

indicating that the increased cancer risk was not a consequence of lifestyle, but no 

attempt was made to control for other occupational exposures. Some elevation of ORs 

occurred in most of the 14 occupational exposures examined, including exposure to 

cadmium. Exposure to two or more agents, regardless of type, was a stronger predictor 

than exposure to any specific agent, suggesting that lead exposure may have been simply 

a surrogate for occupational chemical exposure in general. 

Finally, Pesch et al. (2000) investigated occupational exposure to potential carcinogens 

among 935 Germans newly diagnosed with renal-cell cancer and 4,298 controls selected 

from regional population registries and matched by age, gender, and area of residence. 

Lifetime job histories and information on smoking habits and other potential risk factors 

were collected by interview. Cumulative exposure to lead, as well as cadmium, solder 

fumes, welding fumes, and metals in general, was estimated based on previously 

published job exposure matrices and grouped into four ascending categories; separate 

estimates of lead exposure were calculated based on British- and German-developed 

matrices. After adjustment for age and smoking, ORs for renal cancer were elevated in 

men (OR = 1.5, 95% CI = 1.0 to 2.3) and women (OR = 2.6, 95% CI = 1.2 to 5.5) with 

the highest lead exposure, compared with the low-exposure groups based on the British 

matrix. When exposure was based on the German matrix, the OR was less elevated 

among men (OR = 1.3, 95% CI = 0.9 to 2.0); no results for women were reported. 

Limited indications of increased risk with increasing exposure were reported for men but 

not for women. Strengths of the study are its size and population base. The primary 

limitation is uncertainty regarding the specificity of the results for lead. Significant 

associations also were noted for exposure to cadmium, solder fumes, and organic solvents 

among men, for example, but no analyses attempting to account for other exposures were 

reported. It is thus unclear how much of the observed risk associated with lead exposure 

may be secondary to exposure to cadmium or other agents (or, more generally, to what 

extent the true association may be obscured by confounding due to these exposures). 

3.2.3 Studies of occupations exposed to organic lead: case-control study of TEL 

workers 

Fayerweather et al. (1997) studied mortality in a U.S. TEL production plant. Cases 

included 735 cancer deaths during 1956 to 1987 among men identified by the company’s 

cancer and mortality registries, excluding cases of bladder cancer deemed likely to have 

been due to benzidine or beta-naphthalamine exposure. Controls were time-, age-, 

gender-, and payscale-matched plant workers who died of causes other than cancer. 

Cumulative exposure to TEL was derived by summing yearly exposure over time to yield 

ranks of none, low, medium, high, and very high TEL exposure. TEL exposure was 

associated with digestive cancers in general; most of the association was limited to very 

high cumulative TEL exposure (OR = 2.2, 90% CI = 1.2 to 4.0), with a weaker 

association for high exposure (1.3, 90% CI = 0.7 to 2.7) and no association with lower 

exposures. 

Among specific digestive cancers, rectal cancer showed a strong association with everexposure to TEL (3.7, 90% CI = 1.3 to 10.2). The risk of rectal cancer increased with 
05/08/03 RoC Background Document for Lead and Lead Compounds 

59 

cumulative exposure; compared with no exposure, the OR was 1.7 (90% CI = 0.4 to 8.3) 

for low or medium exposure and 5.1 (90% CI = 1.6 to 16.5) for high or very high 

exposure. The authors reported that control for smoking habits and addition of a 10-year 

lag increased the strength of the association between lead exposure and rectal-cancer 

mortality. Colon cancer also showed a mild association with ever-exposure to TEL 

(OR = 1.3, 90% CI = 0.7 to 2.5), apparently limited to high or very high cumulative TEL 

exposure (OR = 1.7, 90% CI = 0.8 to 4.0). Adjustment for smoking and exposure to 

nitriles did not affect the results, but restriction to cancer of the sigmoid colon reportedly 

produced an exposure-response gradient (OR = 3.6, 90% CI = 0.5 to 28.0 for high 

exposure; no OR reported for low-to-medium exposure). TEL exposure also was 

associated with mortality from Hodgkin’s disease (OR = 2.7, 90% CI = 0.6 to 12.0), 

although the small number of cases (8) precluded in-depth analysis. Results for other 

cancers were not presented, as they were judged to show no association with TEL 

exposure. Results were not sensitive to lag time and were unaffected by adjustment for 

smoking or exposure to aromatic amines, radioactive materials, or asbestos, eliminating 

confounding by these factors as a source of the observed association. Overall, the study 

found a significant relationship between TEL exposure and risk of digestive and 

particularly rectal cancer, not reported in previous studies of TEL-exposed workers, but 

did not find relationships with any of the cancers associated with TEL or lead exposure in 

previous studies. The absence of associations with other cancers could be a consequence 

of failure to include cancer deaths among pensioned workers or those who left 

employment early because of illness. 

3.2.4 Cohort studies based on general population (environmental) exposures 

Jemal et al. (2002) conducted the first biomarker-based general population cohort study 

of lead exposure and cancer. The study employed the subsample of 3,592 white U.S. 

participants in NHANES II (1976 to 1980) who had undergone blood lead level 

determinations at time of entry. Deaths among this population were enumerated through 

1992 by linkage to the National Death Index (NDI) and Social Security Administration 

Death Master File, as part of the NHANES II Mortality Study. 

Adjusted for age, smoking, drinking, region, year, and gender, risk of mortality from any 

cancer rose across quartiles of blood lead level, but this trend was not statistically 

significant. The trend across quartiles was not consistent in gender-specific analyses, 

although relative risks were elevated for the highest quartile of blood lead level in both 

men and women (RR = 2.0 for men and 1.6 for women). The RR for lung cancer based 

on comparison of subjects with blood lead levels above or below the median was 1.5 in 

the combined population, with higher risk observed among women (RR = 2.5, 95% CI = 

0.7 to 8.4) than men. The highest risks were observed for cancer of the esophagus (RR = 

3.7, 95% CI = 0.2 to 89), pancreas (RR = 3.6, 95% CI = 0.6 to 19.8), and stomach (RR = 

2.4, 95% CI = 0.3 to 19.1); no elevations were noted for cancers of other sites. 

The lack of statistically significant results reflects the small number of deaths during 

follow-up, which limited the study’s power; of the nine major sites examined, the number 

of deaths ranged between 5 and 16 for all sites except the lung. Detailed exposureresponse analyses were restricted to all cancers combined, although potential effects 

could have been strongly target-organ specific. In addition, the use of quartile cutpoints 
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60 

based on the distribution of lead concentrations estimated for the total U.S. population 

resulted in relatively small numbers in the referent group (lowest exposure quartile) for 

males and in the high-exposure quartile for females. Use of a biomarker provided an 

objective measure of lead exposure. Nevertheless, reliance on a single blood lead 

measurement produces less reliable estimates than would be obtained through multiple 

measurements and precludes addressing temporal changes in lead exposure over the 

follow-up period. Lack of control for exposure to occupational carcinogens other than 

lead and potential residual confounding by duration and intensity of tobacco smoking 

also could have biased the results, especially for men. 

Lustberg and Silbergeld (2002) carried out another biomarker-based general population 

study based on the same NHANES II mortality cohort used by Jemal et al. (2002). This 

study did not exclude non-whites, however (thus gaining 524 subjects) and employed 

more extensive adjustment for potential confounding factors than the Jemal et al. (2002) 

analyses (i.e., education, body mass index, and exercise were included in the regression 

models, although alcohol intake was not). In addition, persons with blood lead levels of 

30 μg/dL or higher were excluded in order to restrict comparisons to levels below the 

OSHA standard for lead exposure. Persons with levels below 10 μg/dL served as the 

referent group. Survival analyses adjusted for potential confounders found a relative risk 

for cancer mortality of 1.5 (95% CI = 0.9 to 2.5) for those with blood lead levels of 10 to 

19 μg/dL, compared with those with levels below 10 μg/dL, rising to 1.7 (1.0 to 2.8) for 

those with levels of 20 to 29 μg/dL. Separate analyses of lung-cancer and non-lungcancer deaths yielded estimates of increased risk for moderate- or high-exposure groups, 

compared with the referent population, both for lung cancer and non-lung cancer. 

However, none of the estimates reached the P < 0.05 level of statistical significance, and 

the results for non-lung cancers showed no evidence of an exposure-response 

relationship. 

As with Jemal et al. (2002), the use of a biomarker for exposure and the prospective 

design of the study are strengths. Its attempts to control for potential confounders were 

more extensive, and its choice of cutpoints for the referent category yielded more males 

in the referent group, although that group still included less than 20% of the study 

population. However, it is notable that blood lead levels rose significantly with smoking 

level. The models included terms for former smoking, current light smoking, and current 

heavy smoking (> 1 pack per day). Nevertheless, some degree of residual confounding 

due to smoking might have remained, which could have contributed to the estimated risk 

of lung cancer for the highest exposure category (RR = 2.2, 95% CI = 0.8 to 6.1). Such 

residual confounding would have had less effect on the results for non-lung cancer. As 

noted regarding the other NHANES-based study, however, mortality due to cancers of 

other sites was too uncommon to allow for reliable site-specific comparisons. 

3.2.5 Case-control studies based on general population (environmental) exposures 

Kandiloris et al. (1997) compared blood lead levels and aminolevulinic acid dehydratase 

activity in 26 laryngeal carcinoma patients with no history of lead exposure or toxicity 

and 53 patients with no history of cancer from the same hospital. Cases and controls 

reportedly had comparable demographic characteristics. Blood lead levels were similar, 
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61 

but ALAD activity was significantly lower in cancer patients. As an indicator of 

subclinical lead toxicity, the lower ALAD activity in laryngeal cancer patients supports 

the authors’ hypothesis that lead exposure at subclinical levels may contribute to 

laryngeal cancer risk. However, the small sample and the potential influence of the 

disease process on ALAD activity make this conclusion highly speculative. 

Shukla et al. (1998) examined heavy metal content in bile drawn from 38 patients with 

newly diagnosed, histologically confirmed gall bladder cancer and 58 patients with 

gallstones diagnosed at the same surgical unit, matched by geographic area within India. 

Bile lead concentrations were markedly higher in patients with cancer of the gall bladder 

(mean ± standard error [SE] = 58.38 ± 1.76 mg/L) than in those with gallstones (mean ± 

SE = 3.99 ± 0.43mg/L). Cadmium and chromium levels also were elevated in bile from 

cancer patients, but not as much as lead levels. Exposure to metals was assumed to occur 

through the heavily contaminated waters common to the area. No attempt was made to 

control for the higher cadmium and chromium levels that accompanied elevated lead 

level. However, the fact that lead levels differed more dramatically than levels of other 

metals argues against cancer-induced perturbation of bile concentrations as the source of 

these results. No data on personal risk factors or potential occupational exposures to other 

carcinogens were collected; therefore, the possible contribution of such factors relative to 

lead could not be established. 

3.2.6 Studies of paternal lead exposure and childhood cancer 

Buckley et al. (1989) compared 204 children with acute nonlymphoblastic leukemia 

(ANLL) with randomly selected age- and gender-matched local population controls in the 

United States and Canada. During telephone interviews with the parents, a questionnaire 

on occupational exposures, including lead, was completed. Duration of paternal exposure 

to lead was categorized as 0, 1 to 1,000, or > 1,000 days. Paternal lead exposure was rare, 

with 1 to 1,000 days’ exposure reported for 5 cases and 5 controls. However, all six 

paternal exposures of > 1,000 days occurred among cases. Also of interest is the strong 

association noted for paternal exposure to petroleum products (53 cases vs. 31 controls 

exposed > 1,000 days, OR = 2.4, 95% CI =1.3 to 4.1); however, TEL exposure was not 

directly assessed. The small number of paternal lead exposures limited the study’s 

statistical power. 

Olshan et al. (1990) matched 200 Wilms’ tumor cases in children across the U.S. with 

population controls of the same age and area. Detailed job history data were collected 

from the fathers of these children via a self-administered questionnaire. A NIOSH jobexposure matrix was used to estimate occupational lead exposure. The results showed 

little evidence for association of occupational lead exposure with Wilms’ tumor, although 

the OR for paternal lead exposure in the postnatal period was slightly elevated (OR = 1.3, 

95% CI = 0.6 to 2.8). These results contradict the significant association with lead 

exposure reported by Kantor et al. (1979). It should be noted that IARC (1990) 

questioned the exposure assessment methodology used in the Kantor study. 

Kristensen and Andersen (1992) traced the cancer incidence in 12,440 offspring of Oslo 

printers’ union members through linkage with the Norwegian Cancer Registry. No 

elevation in cancer incidence was observed for children of printers as a whole or for those 
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62 

with parental lead exposure. Because only 33 cancers of all types occurred, the analyses 

had little power and could not focus on specific rare cancers linked with lead exposure in 

some earlier studies, such as ANLL or Wilms’ tumor (see Table 3-6 for a summary of the 

studies on childhood cancer and parental lead exposure). 

3.3 Summary 

The evidence for carcinogenicity is summarized below by cancer type. Where successive 

studies have been conducted on the same basic population, all studies of a particular 

cancer in those populations are considered as a whole. This summary also discusses 

results of meta-analyses by Fu and Boffetta (1995) and Steenland and Boffetta (2000). 

The studies included in the meta-analyses of Fu and Boffetta (1995) and Steenland and 

Boffetta (2000) and the cancer sites examined are summarized in Tables 3-2 and 3-3, 

respectively. It should be noted that Steenland and Boffetta (2000) calculated a fixedeffects rate ratio of 1.04 (95% CI = 1.00 to 1.09) for all cancers combined (N = 1,911) 

based on eight cohort studies of highly exposed workers. Given the potential sitespecificity of lead, as well as other risk factors, however, this summary focuses on 

evaluating the evidence for the specific cancers that have been most strongly associated 

with lead exposure in published studies. Potential differences between the carcinogenic 

potentials of organic and inorganic lead are unclear, as is the possibility of different sitespecificity for organic lead compounds. Since it is reasonable to consider the 

carcinogenicity of exposure to both inorganic and organic lead, studies of TEL workers 

are considered in this summary. 

In addition to studies addressing the association between lead exposure and cancer 

directly, a number of investigators have assessed the relationship between occupational 

lead exposure and markers of genotoxicity. Sections 5.4 and 5.5 review the results of 

these studies in detail. About half of these studies found indications of increased 

chromosomal aberrations, sister chromatid exchanges, or other genotoxicity end points 

among lead-exposed workers. 
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63 

Table 3-2. Studies included in the meta-analysis of Fu and Boffetta (1995). 

Cancer site 

Study Study type Lung Stomach Kidney Bladder 

Ades and Kazantzis (1988) Case-control 4 

Bertazzi and Zocchetti (1980) Cohort 4 4 

Cooper (1989)a Case-control 4 

Cooper and Gaffey (1975)a Cohort 4 4 

Cooper et al. (1985)a Cohort 4 4 4

Cordioli et al. (1987) Cohort 4 

Davies (1984b) Cohort 4 

Fanning (1988) Case-control 4 4 

Gerhardsson et al. (1986) Cohort 4 4 

Goldstein et al. (1970) Cohort 4 

Michaels et al. (1991) Cohort 4 4 4

Risch et al. (1988) Case-control 4

Sankila et al. (1990) Cohort 4 4 4 4

Selevan et al. (1985)b Cohort 4 4 4 4

Sheffet et al. (1982) Cohort 4 4 

Siemiatycki (1991) Case-control 4 4 4 4

Steenland et al. (1992)b Cohort 4 4 4 4

Wingren and Axelson (1987)c Case-control 4 4 

Wingren and Axelson (1993)c Case-control 4 

Wingren and Englander (1990) Cohort 4 a

Three papers by Cooper and co-workers were based on the same study population. 

b

Papers by Selevan et al. and Steenland et al. were based on the same study population. c

Two papers by Wingren and Axelson were based on the same study population. 
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64 

Table 3-3. Studies included in the meta-analysis of Steenland and Boffetta (2000). 

Cancer site 

Study All cancers Lung Stomach Kidney 

Anttila et al. (1995) 4 4 4 4

Cocco et al. (1997) 4 4 4 4

Fanning (1988) 4 4 4

Gerhardsson et al. (1995a) 4 4 4 4

Lundström et al. (1997) 4 4 4 4

Steenland et al. (1992) 4 4 4 4

Wong and Harris (2000a) 4 4 4 4

Wong and Harris (2000b) 4 4 4 4 a

 Battery workers 

b

 Smelter workers 

3.3.1 Lung and other respiratory cancers and occupational lead exposure 

Lung cancer is both the most common type of cancer and the type that has been most 

studied with respect to lead exposure. Fu and Boffetta (1995) conducted a meta-analysis 

of 13 cohort and 4 case-control studies of lead exposure and lung cancer. For studies with 

compatible quantitative risk estimates, a weighted summary risk estimate across all 

studies was derived. Combining 15 studies (multiple papers based on the same study 

population were counted as one study), Fu and Boffetta derived a fixed-effects RR for 

lung cancer of 1.24 (95% CI = 1.16 to 1.33) for lead exposure. Fixed-effects models are 

based on the assumption of no significant heterogeneity of effect, however, and when this 

assumption is violated, they may produce invalid estimates of the statistical significance 

of a summary estimate of effect. To account for heterogeneity, random-effects models 

add an extra component of variance to the usual variance calculated for the summary 

relative risk in a fixed-effects analysis. Because of significant heterogeneity across 

studies of lung cancer, a random-effects RR also was calculated for the 12 studies with 

the requisite information for this approach, yielding a RR of 1.29 (95% CI = 1.10 to 

1.50). A statistically significant association between lung cancer and lead exposure thus 

appeared when results from the available literature were pooled, and it was similar in 

magnitude regardless of whether all 15 available studies were included using a fixed 

effects approach or only the subset of 12 studies meeting the requirements for the more 

robust summary estimate provided by a random effects approach were included. A 

separate random-effects estimate also was generated from studies of just the subset of 

battery and smelter workers, who were considered to have the highest exposure to lead. 

This analysis yielded a RR for lung cancer of 1.42 (95% CI = 1.05 to 1.92), consistent 

with the idea that risk should be greatest among the worker populations with the most 

exposure. 

A meta-analysis of eight occupational cohort studies on lung cancer was published in 

2000 by Steenland and Boffetta, who argued that the occupational cohort studies 
05/08/03 RoC Background Document for Lead and Lead Compounds 

65 

provided the clearest information, because high exposure generally was documented. 

Studies were limited to those in which lead was established as the predominant exposure, 

except for one smelter study (Lundström et al. 1997) in which arsenic exposure was 

appreciable and could have confounded the lead effect estimates (see the discussion of 

Englyst et al. 2001). The meta-analysis showed significant heterogeneity due to the 

relatively high risk estimate from Lundström et al. (RR = 2.9, compared with 1.14, 1.22, 

1.19, 0.93, 0.82, 1.8, and 1.32 in the other seven studies). Use of a random-effects model 

to account for this heterogeneity yielded a combined RR across the eight studies of 1.30 

(95% CI = 1.15 to 1.46, 675 lung-cancer deaths). Excluding Lundström et al. (1997) 

eliminated the heterogeneity while still yielding a significantly elevated combined RR of 

1.14 (95% CI = 1.04 to 1.25) based on a fixed effects model. This parallels the findings 

of the earlier meta-analysis by Fu and Boffetta (1995) insofar as both random and fixed 

effects approaches yielded a statistically significant association between lung cancer and 

lead exposure. It may be argued in this instance that the random effects estimate is more 

meaningful since it is based on one additional study (Lundström et al. 1997) that could 

not validly be included in deriving the fixed effects estimate. Also of note is that the 

random effects RR of 1.30 is very similar in magnitude to the RR of 1.29 obtained in the 

earlier random effects analysis by Fu and Boffetta (1995), which had included a larger 

number of studies since it did not bar case-control designs. As a counter argument to this, 

the RR of 2.9 observed in the Lundström et al. (1997) study could be viewed as an 

outlier, in which case the fixed effects estimate based on the subset of 7 studies might 

better reflect the actual relative risk for cohorts of lead-exposed workers as a whole. For 

the overview in this background document, Steenland and Simonsen re-examined the 

Steenland and Boffetta (2000) meta-analysis; however, no occupational studies on lead 

exposure and lung cancer had been published since that analysis. 

This review considers 36 publications of studies addressing occupational lead exposure 

and lung cancer risk in 21 different populations. Of the 18 populations included in at least 

one cohort study, elevated risk estimates for lead exposure were reported in 15, with the 

elevation reaching statistical significance in 8. Only one study reported a reduced risk 

(Cocco et al. 1997), which was not statistically significant. Of the three case-control 

studies of populations for which no cohort analysis was available, two (Fayerweather et 

al. 1997, Mallin et al. 1989) found no association between lead exposure and lung cancer, 

and one (Siemiatycki et al. 1991) found a weak association. The studies reviewed here 

include two based on TEL workers; one study found evidence of an association with 

respiratory cancer (Sweeney et al. 1986) and the other did not (Fayerweather et al. 1997); 

however, the findings did little to alter the basic thrust of the evidence. Overall, the 

picture is one of an association between lead exposure and lung cancer. 

Characterization of lead exposure for assessment of a potential link between occupational 

exposure and cancer should be based on the most accurate assessment possible of each 

individual’s exposure. The measures employed in one or more of these studies include 

biomarkers, ambient air measurements, job histories with or without the use of job 

exposure matrices, history of employment in a given factory, and simply last known or 

predominant occupation. In considering the relative strengths and weaknesses of these 

methods, their influence on the results of particular studies and whether the results vary 
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66 

systematically with the measure used, this discussion focuses on studies of inorganic lead 

exposure and on the most recent analysis of each population. 

Biomarkers such as blood and urinary lead levels reflect lead that has been absorbed and 

circulated to tissues, thus eliminating variability in the exposure received from a given 

ambient lead level due to the effects of individual physiology, protective gear, 

workstation ventilation, and other factors. However, although biomarkers offer the key 

advantage of demonstrating whether an individual has absorbed lead and to what degree, 

blood or urinary lead measurements may fluctuate over time even when actual lead 

absorption has not changed. Integration of multiple measurements over an individual’s 

employment history reduces this problem. 

Three occupational cohort studies (Gerhardsson et al. 1995a, Anttila et al. 1995, 

Lundström et al. 1997) used extensive blood lead concentration data. Geometric mean 

blood lead levels among the Swedish smelter workers in Gerhardsson et al. and 

Lundström et al. were roughly similar, declining from around 3.0 μmol/L (62.2 μg/dL) at 

the start to 1.6 μmol/L (33.2 μg/dL) at the end of both studies. Lead levels among the 

general Finnish worker population studied by Anttila et al. were lower, declining from 

1.7 (35.2 μg/dL) to 0.7 μmol/L (14.5 μg/dL) over the study period. All three studies 

noted positive associations with lung cancer; this association was statistically weakest in 

the Gerhardsson et al. study, whose smaller size precluded reliable risk estimates when 

exposure was categorized beyond whether or not lead ever was detected in a worker’s 

blood. 

Dingwall-Fordyce and Lane (1963) and Wong and Harris (2000) assessed urinary lead 

levels, although only the former based exposure classification on this measure. Nearly 

half of the U.K. battery workers in the former study had levels exceeding 100 μg/L, 

consistent with the means of 130 and 170 μg/L observed among U.S. battery and smelter 

workers, respectively, in the latter study. The SMR for all cancers showed no consistent 

increase across ascending exposure categories in the U.K. study, which, among the 

biomarker-based studies, included the smallest number of monitored workers. 

In the studies reviewed here, lead exposure most commonly was estimated from job 

histories. Detailed job histories allow estimation of exposure through application of a jobexposure matrix and/or rating of exposure probability by an industrial hygiene expert. In 

some studies, job histories were bolstered by ambient air monitoring data (Wingren and 

Englander 1990, Steenland et al. 1992). Other studies simply followed up workers 

employed in a factory or operation known to have high potential for lead exposure (e.g., 

the follow-up of lead and zinc pigment plant workers by Sheffet et al. [1982]). This 

approach was modified in one study that followed up pigment-factory workers diagnosed 

with lead poisoning (Davies 1984b). Use of only a general occupational history, without 

details regarding specific types of work performed, precludes categorization of workers 

by risk of exposure within a given occupation. Exposure estimates based on occupation 

as reported on death certificates can be expected to be the least reliable of the job-historybased methods, being subject to the use of nonstandardized classification criteria by the 

person entering the occupational data and to the potential for missing previous leadexposed occupations (Mallin et al. 1989; Cocco et al. 1998a, 1998b, 1999). Further, one 
05/08/03 RoC Background Document for Lead and Lead Compounds 

67 

of these studies (Mallin et al. 1989) computed estimates for each of 30 industry and 29 

occupation groupings that were not designed specifically to capture lead exposure, and 

presented no quantitative estimates of risk for groups that did not show a statistically 

significant association with lung cancer. 

The studies reviewed here generally found positive associations, of varying strengths, 

between lead exposure and risk of cancer; the exception was the one study based on 

occupation as reported on death certificates (Mallin et al. 1989). Studies using blood lead 

levels consistently observed positive associations between lead and lung cancer, with risk 

estimates ranging from 1.32 (Gerhardsson et al. 1995a) to 2.9 (Lundstrom et al. 1997). 

The study using urinary lead levels yielded no consistent dose-response pattern despite an 

overall cancer SMR of 1.2 for battery factory workers (Dingwall-Fordyce and Lane 

1963). Relative risk estimates from studies using job history in combination with ambient 

air or other monitoring ranged from 1.1 (Steenland et al. 1992) to 1.40 (Wingren and 

Englander 1990). Use of job histories alone yielded estimates of 0.82 (Cocco et al. 1997) 

to 2.32 (Cocco et al. 1994a) from studies that provided quantitative risk estimates. The 

study relying on death certificate-derived occupation reported no association with lung 

cancer for metal or glass workers, although no specific risk estimate was provided for 

those groups (Mallin et al. 1989). The most consistent evidence of association thus was 

seen in studies based on blood lead levels, the most objective measure of exposure, 

whereas no significant association was seen in the study based on the exposure 

assessment method with the greatest potential for misclassification, a death-certificatederived occupational characterization that was not specifically designed to separate lead 

workers from metal workers in general. 

Despite the relatively consistent direction of results across studies, a number of factors 

complicate drawing of potential causal inferences from the available epidemiologic 

literature. Foremost among these complications are potential confounding of lead 

exposure with smoking status, concomitant exposure to other carcinogens and other 

potential risk factors, and insufficient data for assessment of exposure-response 

relationships. 

The risk of lung cancer due to cigarette smoking dwarfs that which could be expected 

from lead exposure based on any available evidence. Most studies of lead exposure and 

lung cancer to date have lacked data on smoking status, and thus their results could be 

confounded by smoking if lead-exposed groups smoked more than unexposed groups. 

The potential effect of confounding by smoking depends upon the comparison being 

made. It has been estimated that the effect of confounding due to smoking in a 

comparison of lung cancer risk between occupational groups and the general population 

is likely to be on the order of a 20% increase, that is, enough to generate a relative risk of 

1.2 or less (Siemiatycki et al. 1988, Axelson and Steenland 1988). However, when the 

number of persons classified as lead-exposed is small, as in many studies of lead and 

cancer, most or all of the exposed group could be smokers, resulting in a much greater 

effect on the relative risk. On the other hand, in studies that controlled for cigarette 

smoking, the association between lead exposure and lung cancer remained, suggesting 

that the observed associations between lead exposure and lung cancer across the studies 

as a whole were not due to confounding by smoking. No other known non-occupational 
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68 

risk factors for lung cancer are potentially as important as smoking. In studies that have 

controlled for such factors, they have had little impact on observed association between 

lead exposure and cancer. 

Concomitant exposure to other potential carcinogens is ubiquitous in lead-exposed 

populations. Improved study designs with better monitoring (e.g., use of biomarker data 

or detailed personal job history data to facilitate estimation of arsenic exposure) can 

address this issue to some degree, but ruling out the potential roles of other metals 

nonetheless remains a difficult problem. This problem was illustrated when part of the 

Swedish smelter cohort studied by Lundström et al. (1997) was reexamined; detailed 

examination of the job histories of lung cancer patients in one department revealed that 

13 of 15 also had been significantly exposed to arsenic (Englyst et al. 2001). Estimation 

of the potential effect of confounding due to other occupational carcinogens thus presents 

a different situation than that for smoking. Although exposure to arsenic, for example, 

could not be expected to increase a worker’s risk to the degree that heavy smoking does, 

it is possible that a large proportion of the workers in lead-exposed operations also are 

significantly exposed to arsenic, whereas such exposure might be much less common in 

most other operations in the same plant and, unlike smoking, would be relatively rare in 

the general population of most regions. This could result in lead-exposed workers having 

an estimated lung cancer risk approaching that of arsenic-exposed workers simply 

because of confounding by arsenic exposure. In addition, joint confounding by arsenic 

and other exposures could produce additive or even synergistic effects; such synergy has 

been proposed, for example, with smoking (Hertz-Picciotto et al. 1992). 

In a review by Steenland et al. (1996), the relative risk of lung cancer was 3.7 for heavily 

arsenic-exposed workers from six cohorts compared with unexposed workers. Assuming 

that this risk reflects the effect of substantial exposure to arsenic in combination with 

smoking and possibly contributions by substances such as cadmium, it appears that 

confounding by arsenic and/or smoking could theoretically produce risk estimates of the 

magnitude commonly seen for occupational lead exposure. Countering this is the 

observation that lead exposure shows an association with lung cancer in many different 

exposure contexts, including ones with minimal potential for coexposure to arsenic, 

suggesting that the observed risk is to some degree due to lead exposure itself. A further 

consideration is the possibility that lead may act synergistically with other occupational 

carcinogens. Some evidence to support this hypothesis is available from animal studies 

(e.g., Shakerin et al. 1965, Tanner and Lipsky 1984, Hiasa et al. 1983; see Section 4.2.5 

for details) and in vitro experiments with direct-acting genotoxic agents such as radiation 

(see Section 6.1.3.4). If so, one might expect much or all of any cancer excess resulting 

from lead exposure to be concentrated among persons co-exposed to other carcinogens, 

much as Englyst et al. (2001) observed with arsenic exposure. 

Most studies of lead and cancer to date are limited by small sample size and the lack of 

good quantitative exposure data, which hinder assessment of exposure-response 

relationships and the ability to control for other exposures. Where exposure-response 

assessment was attempted, the strongest association with lung cancer usually was seen in 

the highest exposure group, but a monotonic increase with duration, intensity, or overall 

amount of exposure was not always observed. This could reflect the absence of a true 
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69 

monotonic response, the use of quantitative exposure measures that may not accurately 

reflect the individual’s true exposure, or inadequate adjustment for other risk factors. 

Here, interpretation again is complicated by the general lack of adequate statistical power 

to evaluate multiple exposure levels while controlling for smoking, age, gender, and other 

potential confounders or effect modifiers. Another factor potentially affecting exposureresponse analyses is the possibility that workers who experience acute lead toxicity tend 

to drop out of the exposed worker population. This factor could lead to underestimation 

of the association between lead and cancer if such an association actually exists but is 

most pronounced at lead exposures near or above those that cause acute toxic effects. A 

related concept is that subgroups of the population that are more susceptible to leadinduced carcinogenesis because of metabolic or other differences may likewise be more 

susceptible to acute toxicity; thus, the higher the exposure level they encounter, the more 

likely they are to leave employment before the induced cancer occurs. Such a 

progressively greater loss of the most highly susceptible subpopulations at increasing 

exposure levels could blunt or distort the exposure-response curve for occupational lead 

exposure and cancer. The study that followed up a group of workers diagnosed with lead 

poisoning found an RR of 1.45 for lung cancer among that group, compared with the 

general population (Davies et al. 1984b), which exceeds the summary RRs of 1.14 to 

1.30 obtained from meta-analyses of occupation cohorts (Steenland and Boffetta 2000). 

Nevertheless, the small numbers of lead-poisoned workers (57) and of lung cancers 

among those workers (4) prevent the difference between their estimated risk and that for 

exposed cohorts as a whole from approaching statistical significance. 

Evidence from the totality of epidemiologic studies is consistent with a mild elevation in 

risk of lung cancer with lead exposure. In meta-analyses, either broadly inclusive of casecontrol and cohort studies (Fu and Boffetta 1995) or narrowly focused on studies of 

populations with the strongest documentation of significant lead exposure (Steenland and 

Boffetta 2000), the estimated increase in lung-cancer risk associated with lead exposure 

has reached statistical significance. However, the average magnitude of the increased risk 

observed across studies is small enough that the hypothesis of no effect cannot be 

definitively eliminated. It can be argued that given the modest estimated increase in risk, 

residual confounding due to smoking, exposure to additional occupational carcinogens, or 

other factors cannot be conclusively ruled out as the source of the elevated risk estimate. 

However, in the absence of an effect threshold, even a small real elevation of risk due to 

lead exposure would have a significant impact at the population level, given the ubiquity 

of low-level lead exposure. 

3.3.2 Stomach and general digestive cancer 

In their meta-analysis, Fu and Boffetta (1995) combined 10 studies with a quantitative 

estimate of risk to derive a fixed-effects RR of 1.33 (95% CI = 1.18 to 1.49) for lead 

exposure and stomach cancer. Because no significant heterogeneity was apparent across 

studies of stomach cancer, no random-effects RR was calculated. For battery or smelter 

populations, which were presumed to have the heaviest occupational exposure to lead, an 

RR of 1.50 (95% CI = 1.23 to 1.83) was obtained. 

In their meta-analysis of eight cohort studies of highly exposed workers, Steenland and 

Boffetta (2000) found that a fixed-effects analysis was justified by the homogeneity of 
05/08/03 RoC Background Document for Lead and Lead Compounds 

70 

risk estimates for lead exposure and stomach cancer across the studies (1.13, 1.43, 1.53, 

1.33, 1.36, 0.97, 1.07, 1.88). They calculated a fixed-effects combined RR of 1.34 (95% 

CI = 1.14 to 1.57, N = 181). 

This overview considers 21 studies that examined the relationship between lead exposure 

and stomach cancer or digestive cancer in general. 

Seven case-control studies included stomach cancer. One large study focused entirely on 

stomach cancer (Cocco et al. 1999), using the U.S. 24-state death certificate registry and 

finding positive associations between lead-related occupations and stomach cancer for 

black men and women and white women, but not white men. A small case-control study 

of stomach cancer nested in a larger cohort found no association with exposure among 

battery production workers (Wong and Harris 2000). Five studies included stomach 

cancer as part of a series of case-control comparisons. Studies of U.K. battery workers 

(Fanning 1988) and Swedish glass workers (Wingren and Axelson 1993) and a large 

study of the Montreal population (Siemiatycki et al. 1991) found statistically significant 

elevations in stomach cancer with occupational lead exposure. Studies of Illinois males 

(Mallin et al. 1989) and U.S. TEL workers (Fayerweather et al. 1997) did not. 

Discounting two small studies of glass workers (Cordioli et al. 1987, Wingren and 

Englander 1990) for inadequate case numbers, twelve cohort studies involving ten 

distinct populations addressed stomach or digestive cancer and lead exposure. Of the 

studies of smelter workers, three found positive associations (Steenland et al. 1992, 

Cocco et al. 1996, Wong and Harris 2000) and two found negative associations (Cocco et 

al. 1997, Lundström et al. 1997). A positive association was noted for U.S. (Sheffet et al.

1982) but not for U.K. (Davies 1984a, 1984b) pigment workers. A significantly elevated 

risk also was observed for a cohort of U.S. battery plant workers, compared with the 

general U.S. population (Wong and Harris 2000), although the nested study including 

cases and controls from the largest plant (discussed above) found no evidence of 

association with lead exposure (Wong and Harris 2000). A nonsignificant increase in 

stomach cancer risk was observed among Finnish glassblowers (Sankila et al. 1990) and 

Finnish workers with elevated blood lead levels (Anttila et al. 1995). No association was 

noted in Sardinian lead and zinc miners (Cocco et al. 1994a, 1994b). Results for stomach 

cancer thus are not as consistent as those for lung cancer. Interpretation of these results is 

subject to the same caveats discussed above with respect to lung cancer, and the issue of 

inadequate statistical power is exacerbated by the relative rarity of stomach cancer. 

The strongest potential evidence for a link between lead and cancer would be provided by 

studies with clearly defined lead-specific exposures, relatively large sample sizes, and 

ability to evaluate exposure-response relationships. Cocco et al.’s (1999) case-control 

study is by far the largest available, with nearly 42,000 stomach cancer deaths and 84,000 

noncancer deaths. It also is one of the few studies to include differing levels of lead 

exposure (based on death-certificate-listed occupation). Further, it is one of the only 

studies to adjust for socioeconomic status, which is inversely associated with stomach 

cancer. Although risks appeared elevated with high exposure among most age-race 

groups in this study, no elevation was observed for the largest group, white males. Anttila 

et al. (1995) employed blood-based exposure indices, which were used to construct a 
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71 

large (20,700 worker) population-based cohort. In this study, lead exposure showed a 

positive, but not statistically significant, association with stomach cancer, with no 

consistent exposure-response pattern. 

Surveying the epidemiologic evidence overall, approximately half of the relevant studies 

of lead and stomach cancer note a positive association of modest size. The small number 

of stomach cancers and infrequency of high lead exposure in most studies limited their 

statistical power; the positive associations observed within particular studies thus usually 

were not statistically significant. When studies were combined through meta-analysis, 

however, a statistically significant estimate of increased risk across the pooled study 

populations was obtained (Fu and Boffetta 1995, Steenland and Boffetta 2000). Evidence 

of consistent exposure-response patterns is lacking, as most studies have been unable to 

address this issue because of insufficient numbers and/or lack of detailed exposure data. 

Most studies did not include the information needed to adjust for socioeconomic status 

and dietary factors such as nitrosamine exposure, which are potentially significant 

confounders (nitrosamine exposure, for example, may reflect greater consumption of 

cured meats by blue-collar workers, who more likely to be lead-exposed, than by whitecollar workers, who are less likely to be lead-exposed). Common to all studies of lead 

exposure is the problem of concomitant exposures to other potential carcinogens such as 

nickel and chromium, which few studies of stomach cancer have addressed and none has 

fully resolved. 

3.3.3 Kidney cancer 

In their meta-analysis of five studies of kidney cancer and lead exposure, Fu and Boffetta 

(1995) estimated a combined RR of 1.19 (95% CI = 0.96 to 1.48). The RR for heavy 

exposure rose only slightly, to 1.26 (95% CI = 0.70 to 2.26). They concluded that an 

effect of lead on kidney cancer risk could not be confirmed or ruled out based on the 

available evidence. 

A meta-analysis of seven occupational cohort studies of lead exposure and kidney cancer 

was published in 2000 by Steenland and Boffetta. The results of the seven studies were 

not heterogeneous, and a fixed-effects meta-analysis yielded an RR of 1.01 (95% CI = 

0.72 to 1.42) based on only 40 cancer deaths or cases. The RRs in the seven studies were 

0.52, 0.93, 1.93, 1.75, 0.90, 0.72, and 0.80. Steenland and Simonsen recomputed this 

meta-analysis with the addition of the population-based case-control study by Pesch et al. 

(2000). For consistency with the rest of the studies, only workers from the highest 

category of estimated lead exposure (“substantial exposure” estimated from job exposure 

matrices) were included. Addition of these workers did not result in sufficient 

heterogeneity across the eight studies to preclude a fixed-effects analysis. The fixedeffects RR with the addition of 40 kidney cancers from Pesch et al. was 1.22 (95% CI = 

0.93 to 1.59). It should be cautioned that the Pesch study, a large population-based casecontrol study, carried enormous weight in the meta-analysis, because it included as many 

highly exposed cases as the remaining seven studies, all occupational cohorts, combined. 

Despite the weight carried by this study, the confidence interval for the combined 

estimated RR again included 1.0. 
05/08/03 RoC Background Document for Lead and Lead Compounds 

72 

The incidence of kidney cancer was too low to provide sufficient numbers of cases in 

most studies of lead exposure. Eight studies reported results for renal cancer. Among 

three cohort studies of smelter workers, Steenland et al. (1992) found a significantly 

elevated risk based on 8 cancers among the subcohort most heavily exposed to lead. 

Cocco et al. (1997) reported a positive association, but Lundström et al. (1997) did not; 

however, both studies’ results were based on too few cases to be reliable. A mixed cohort 

of battery and smelter workers (Wong and Harris 2000) showed no increase in kidney 

cancer, but lead and zinc miners did (Cocco et al. 1994a), although lead exposure was not 

directly quantified in the latter group. Exposure to lead was associated with death due to 

kidney cancer in a case-control study based on the population of Montreal, Canada 

(Siemiatycki et al. 1991) and with incident kidney cancer in a German case-control study 

(Pesch et al. 2000); however, peak blood lead among a cohort of Finnish workers was not 

associated with increased risk of kidney cancer (Anttila et al. 1995). The Canadian results 

approached statistical significance (OR 1.2, 95% CI = 1.0 to 1.6), and the use of other 

cancer deaths as a control group may have biased this estimate downward. The German 

study was based on the highest number of cancers by far, 935, followed by 88 for the 

Canadian, 10 for the Finnish, and 8 for the lead-exposed smelter-worker study. Thus, of 

the four studies with more than 5 cases in the exposed group, three observed positive 

associations. Nevertheless, the German study also found elevated kidney-cancer risks for 

other exposures, including those to cadmium and solder fume, none of which were 

controlled for in the risk estimates for lead exposure. 

The small number of kidney cancers available in most studies precluded statistically 

definitive results, clear demonstration of exposure-response relationships, or adjustment 

for potentially covarying metal or other occupational exposures. 

3.3.4 Bladder cancer 

In their meta-analysis of five studies on bladder cancer and lead exposure, Fu and 

Boffetta (1995) estimated a combined RR of 1.41 (95% CI = 1.16 to 1.71). No relative 

risk for heavy exposure was calculated, because not enough battery or smelter studies 

included results for bladder cancer. They concluded that while the combined risk estimate 

for the studies was statistically significant, the small number of studies reporting findings 

for bladder cancer may have indicated that negative findings were not being published, 

thus biasing the results toward a positive association. 

Seven studies of bladder cancer are included in this overview. All three studies of U.S. 

smelter workers (Steenland et al. 1992), Sardinia (Cocco et al. 1997), and Sweden 

(Lundström et al. 1997) reported positive associations with lead exposure. Risk estimates 

ranged from 1.3 to 1.8, and deaths among the exposed from 6 to 12; no elevated risks 

were statistically significant, and no consistent exposure-response pattern was noted. 

Elevated risk of bladder cancer (SMR = 1.15) also was seen among lead and zinc miners 

(Cocco et al. 1994a). A borderline significant elevation (OR = 1.3, 95% CI = 1.0 to 1.6) 

was observed among French Canadians in a population-based Montreal case-control 

study, though the OR did not increase among those thought to have the most substantial 

exposure (Siemiatycki et al. 1991). A stronger association (OR = 2.0, 95% CI = 1.2 to 

3.5) was noted in a second Canadian case-control study (Risch et al. 1988), including a 

significant trend with duration of exposure, and this study was able to adjust for smoking, 
05/08/03 RoC Background Document for Lead and Lead Compounds 

73 

socieconomic status, and other personal risk factors. The lone exception to the pattern 

was provided by the lack of association of bladder cancer with peak blood lead 

measurements in a general cohort of Finnish workers (Anttila et al. 1995). 

A positive association of lead exposure with bladder cancer thus was very consistent in 

studies published to date. It persisted when smoking was controlled for, and limited direct 

evidence was found for an exposure-response relationship, as well as indirect evidence of 

consistently elevated risks among smelter workers, with their potential for intense lead 

exposure. On the other hand, as suggested by Fu and Boffetta (1995), publication bias 

cannot be eliminated as a contributor to the preponderance of positive results. Further 

limiting the conclusiveness of the evidence is the limited size and low statistical power of 

most studies. 

3.3.5 Childhood cancers 

Five studies have examined the relationship of paternal lead exposure to childhood 

cancer. Three case-control studies focused on Wilms’ tumor. The earliest of these studies 

(Kantor et al. 1979) reported a markedly elevated OR among children with fathers in 

lead-related industries. Two subsequent studies failed to replicate this finding (Wilkins 

and Sinks 1984a, 1984b, Olshan et al. 1990). IARC (1990) questioned the criteria used 

by Kantor et al. (1979) to assign lead exposure status to the paternal occupation listed on 

the childrens’ death certificates. Olshan et al. (1990) obtained detailed job histories via 

questionnaire and assigned lead exposure status from a standard exposure matrix. Faulty 

exposure classification or a chance finding stemming from examination of multiple 

exposures in a small study may account for the discrepancy. 

Buckley et al. (1989) linked fathers’ occupational lead exposure of long duration to 

childhood nonlymphoblastic leukemia in a study of 204 cases and matched population 

controls. The association was striking, with 6 leukemia patients and no control subjects 

having exposed fathers. However, the statistical strength of these results is limited by the 

small number of paternal exposures. 

A large cohort study of children of printers yielded an inconsistent association between 

estimated paternal lead exposure and development of cancer (Kristensen and Andersen 

1992). The study was limited by the small number of casees, which made it necessary to 

combine all types of cancer, and by the absence of control for other potential risk factors. 

Overall, the literature to date is characterized by a scarcity of studies and by small sample 

sizes, hampering the ability to draw firm conclusions from the available data (see Table 

3-6). 

3.3.6 Other adult cancers 

Other cancers with some evidence linking them to lead exposure in the reviewed 

literature include cancers of the brain and central nervous system, liver, colon, and 

rectum. 

Positive results were most common for brain and central nervous system cancers, with 

eight studies reporting evidence of an association with lead exposure. Based on seven 
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74 

cohort studies of highly exposed workers, Steenland and Boffetta (2000) calculated a 

fixed-effects combined RR of 1.06 (95% CI = 0.81 to 1.40) for brain cancer (N = 69). A 

fixed-effects analysis was justified by the relative homogeneity of risk estimates across 

the seven studies (0.75, 0.75, 2.17, 1.10, 0.72, 1.14, 1.48, 1.23), taking into account their 

small sample sizes and wide confidence intervals. No additional relevant studies have 

become available since that meta-analysis was conducted. The positive associations 

observed in most studies is suggestive, although it is notable that a meta-analysis 

restricted to the cohorts with the most definitive lead exposure produced a nonsignificant 

risk estimate barely above 1.0. The fundamental problem is that the rarity of these 

cancers generally limits the statistical power of studies. 

3.3.7 General population exposures and cancer 

The population-based cohort studies of Jemal et al. (2002) and Lustberg et al. (2002) are 

a unique resource. The first study’s findings are provocative in that they connect 

increased blood lead levels in the general U.S. population with mild elevations in risk of 

the same types of cancer, lung and stomach, most consistently associated with leadexposed occupations. As discussed in Section 3.3.1, Steenland and Simonsen concluded 

that no relevant occupational studies of lead and lung cancer had been published since the 

Steenland and Boffetta (2000) meta-analysis. The only subsequent study involving 

populations with clearly established lead exposure was Jemal et al. (2002). With that 

study added to the meta-analysis, the data no longer exhibited sufficient heterogeneity to 

preclude a fixed-effects analysis even with Lundström et al. (1997) included. The 

expanded meta-analysis yielded a fixed-effects RR for lung cancer of 1.32 (95% 

CI = 1.16 to 1.50) over the nine cohorts, very similar to the random-effects RR obtained 

without Jemal et al. (2002). Inclusion of Jemal et al. (2002) must be accompanied by the 

caveat that the magnitude of lead exposure in the population-based cohort (whose 

exposure was defined as blood lead levels above the median observed in the general 

population) was not truly comparable to that expected in workers with substantial lead 

exposure. This cohort was not added to the revised meta-analysis for kidney cancer 

described in Section 3.3.3 because of inadequate numbers (only 5 cases in males) and the 

low exposure cutoff. Interpretation of the results of Jemal et al. (2002) is limited 

primarily by low statistical power, particularly for sites other than the lung, lack of 

adjustment for other risk factors (such as smoking) in the site-specific analyses, and the 

absence of data on exposure to other occupational carcinogens. 

Lustberg et al. (2002) analyzed predominantly the same data as Jemal et al. (2002), using 

different techniques and analytical assumptions, yet reaching conclusions also linking 

cancer to lead exposure. Further, unlike Jemal et al., Lustberg et al. limited the cohort to 

persons with blood lead levels below the OSHA standard for lead exposure. However, 

exclusion of persons with blood lead levels in the range typical of workers considered to 

be lead-exposed precluded inclusion of this study in the revised meta-analysis by 

Steenland and Simonsen. In considering the evidence provided by Lustberg et al. that 

lead could exert effects even at levels commonly found in the general population, it must 

be kept in mind that this study shares the limitations cited above for Jemal et al. (2002). 

The case-control studies of Kandiloris et al. (1997) and Shukla et al. (1998) reported 

evidence mildly linking lead exposure with cancers of the larynx and gall bladder. These 
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75 

studies’ small sample sizes and lack of control for other potential risk factors limit the 

conclusions that can be drawn from them. 

3.4 Conclusion 

Many epidemiologic studies on the potential role of lead exposure in cancer have been 

published since the IARC (1987) update. The evidence is consistent with the hypothesis 

that lead is modestly carcinogenic to humans. This evidence is strongest for lung cancer, 

for which a largely consistent association has been demonstrated with occupations and 

industries entailing lead exposure, as well as with indices of individual lead exposure, 

including job history and biological monitoring. Evidence also suggests an association 

between lead and stomach cancer. However, the observed associations generally are 

sufficiently weak that they could be due at least partially to confounding by nonoccupational risk factors, such as smoking in the case of lung cancer, or to effects of 

other occupational exposures that accompany lead exposure, particularly arsenic 

exposure. Such exposures are ubiquitous in smelting operations, battery manufacture, and 

other intense sources of lead exposure. Most studies to date have done little to control for 

non-occupational risk factors and occupational co-exposures, but more studies are 

beginning to do so, in most cases without weakening the observed association between 

lead exposure and cancer. Further, the crude exposure measures used by most studies, 

such as considering whole plants or occupations to be uniformly exposed, may have 

resulted in underestimation of risk, because individuals who truly had high lead exposure 

may have been combined with those who did not. Evidence from studies of human 

populations thus are compatible with mild increases in risk for lung cancer and, to a 

lesser degree, stomach cancer, although this evidence must be weighed against the 

potential for confounding by co-exposures. 
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Table 3-4. Studies of lead exposure and cancer: cohort Reference Study population Exposure Effects Dingwall-Fordyce and Lane 1963 

425 male employees drawing pensions from U.K. battery plants 

Employees were compared with national population counterparts. Urinary lead excretion was also used to categorize workers by estimated exposure (none, light, or heavy): 80 lightly and 187 heavily (at least 100 μg/L) exposed. 

SMR (95% CI); no. observed deaths All cancer: 1.2 (0.8–1.7); 267 no consistent increase in SMRs across categories of increasing lead exposure 

Cooper and Gaffey 1975: see Cooper et

al. 1985 
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Reference Study population Exposure Effects Rencher et al. 1977 Utah copper workers (numbers not 

reported) employed in smelting, mining, or concentrator operations, followed from 1959–1969 Mortality was compared with the state population and with workers in other operations. Cause of death was identified from death certificate. 

Exposure to lead, arsenic, amd other substances was estimated by operation type. Within smelter workers, cumulative exposure to lead (units not specified) was calculated for deceased workers. 

Age-adjusted respiratory cancer rates (per 10,000): 

smelter workers 10.1 mine workers 2.1 state population 3.3 

Age-adjusted non-respiratory cancer rat(per 10,000): 

smelter workers 16.6 mine workers 10.0 

Percentage of deaths from lung cancer: 

smelter workers 7 mine workers 2.2 

Cumulative lead and arsenic exposure: 

17 smelter workers dying of respiratocancer 154.5 (Pb) 110 (As) smelter workers dying of other respircauses 78.6 (Pb) 38.5 (As) smelter workers dying of non-respiratcauses 93.4 (Pb) 47.0 (As) 
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Reference Study population Exposure Effects Bertazzi and Zocchetti 1980 

700 Italian newspaper plant workers employed for at least 5 years between 1940 and 1955 Mortality was compared with national rates. 

Compositors and stereotypers were considered to be exposed to lead. 

SMR (no. of deaths) Lead-exposed workers: 

all cancers 0.44 (4) digestive 0.59 (2) respiratory 0.42 (1) lymphatic 2.00 (1) no 

P-values < 0.05 

All newspaper workers: 

all cancers 1.23 (51) digestive 1.20 (19) respiratory 1.56 (17) lymphatic 1.17 (3) no 

P-values < 0.05 

Sheffet et al. 1982 1,946 U.S. lead and zinc chromate 

pigment plant workers employed at any time from 1940–1969 Mortality was compared with age and calendar-year-specific national rates. 

All workers were considered to be exposed to lead. 

Lung, stomach, and pancreatic cancer risignificantly elevated (persons of unknovital status assumed to be alive at end ofollow-up) Lung cancer SMR: 1.6 (whites, blacks; 

P < 0.05 in whites o

Whites: nonsignificantly elevated risks for stomrectal, pancreatic, and prostate cancer, Hodgkin’s disease; decreased risks of intestinal and laryngeal cancer Nonwhites: mildly elevated risks of stomach and pancreatic cancer; decreased risk of larycancer 
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Reference Study population Exposure Effects Malcolm and Barnett 1982 (follow-up of Dingwall-Fordyce and Lane 1963) 

1,898 U.K. lead-acid battery workers High, medium, and no 

lead exposure were based on job history. 

Proportionate mortality ratio (PMR) All cancers: 

1.15 (136 deaths), 

P > 0.05 

By exposure: 

no 1.02 medium 1.06 high 1.30 

no significant excesses for individual casites except for digestive cancer PMR oP < 0.01, among non-exposed workers 

Davies 1984a 1,152 U.K. chromate pigment factory 

workers employed for at least one year by 1975 Three factories: one lead chromate only, two lead and zinc chromate Mortality was compared with national rates. 

High to moderate exposure to chromate dust was based on job history. 

RR (no. of deaths) significant excess of lung cancer deaths chromate-exposed workers with mixed and lead chromate exposure: Factory A: 

entrants from 1932–1954 2.2 (21) no excess for entrants after 1955 

Factory B: 

entrants from 1948–1960 4.4 (11 ) 

no excess among workers exposed only chromate; no consistent increase with duof service 
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Reference Study population Exposure Effects Davies 1984b (follow-up of Davies 1984a) 

57 U.K. chromate pigment factory workers who had been diagnosed with lead poisoning between 1930 and 1945 Mortality was compared with national rates. 

Workers ever clinically diagnosed with lead poisoning were considered to be exposed to lead. 

RR (95% CI); no. of deaths Lung cancer: 

1.45 (0.39–2.71) (4) 

All other cancers combined: 

0.8 (3) 

Cooper et al. 1985 

(follow-up of Cooper and Gaffey 1975) (followed up by Wong and Harris 2000) (see also nested casecontrols by Cooper et al. 1989 and Wong and Harris 2000) 

U.S. battery (4,519) and lead production (2,300) workers employed for at least one year between 1946 and 1970 Mortality was compared with national age- and gender-specific rates (SMR) and age-, gender-, and race-specific rates (PMR) Cause of death was identified from death certificate. 

(1) battery plant workers (2) lead production workers Workers also were stratified by cumulative years of employment (1–9, 10–19, 20+) 

SMR (95% CI) Battery plant workers: 

all cancer 1.13 (1.02–1.26) all respiratory 1.24 (1.03–1.49) stomach 1.68 (1.16–2.35) lung, trachea, bronchus  1.24 (1.02–1.50) liver and laryngeal: nonsignificant exkidney: nonsignificant deficit 

Production workers: 

digestive and respiratory: nonsignificincrease kidney, brain, or lymphopoietic systeexcess 

PMR analyses controlled for race yieldesimilar results. 

Selevan et al. 1985: see Steenland et al. 

1992 
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Reference Study population Exposure Effects Gerhardsson et al.1986: see Gerhardsson et al. 1995 Sweeney et al. 1986 2,510 male east Texas chemical plant 

workers employed 1952–1959 Mortality compared with national rates. 

TEL was the major product from 1952–1959; thereafter, ethylene dibromide, inorganic lead, and vinyl chloride also were major products. 

RR (observed vs. expected) Respiratory: 

1.4 (15 vs. 11) 

Brain: 

1.8 (3 vs. 1.6) 

Mortality from all causes: 

0.8 

no excesses for other cancers 

Cordioli et al. 1987 468 Italian glass workers employed 

for at least one year between 1953 and 1967 

Workers producing lowquality glass containers were classified as leadexposed. 

SMR (95% CI); no. of deaths All cancer 1.3 (0.8–1.8); 28 Lung 2.1 (1.1–3.6); 13 Laryngeal 4.5 (1.2–11.4); 4 
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Reference Study population Exposure Effects Ades and Kazantzis 1988 

4,393 male U.K. zinc, lead, and cadmium smelter workers followed up for lung cancer mortality Mortality was compared with national rates. Nested case-control analysis also was conducted that quantitatively assessed cadmium and, secondarily, arsenic, lead, and other metal exposures among 174 cases. 

Job histories were used to quantify cadmium exposure and assign ordinal ranks for exposure to lead and other metals. 

SMR (95% CI); no. of deaths Cohort: 

Lung 1.25 (1.07–1.44) (174increased significantly with duration employment 

nested case-control analyses did not impany department or process, nor did cadmzinc, sulfur dioxide, or dust exposure acfor the observed increase cumulative exposure to lead and to arseboth showed positive associations with cancer, but the relative importance of thtwo exposures could not be determined 

Sankila et al. 1990 1,803 male and 1,946 female glass 

workers employed for at least 3 months at one of 2 Finnish glass factories in 1953–1971 or 1941–1977 Cancer incidence was compared with age-, gender-, and calendar-yearspecific national rates. 

Stomach, lung, and skin cancer rates also were compared separately for 201 male and 34 female glassblowers and nonglassblowers. 

SIR (95% CI); no. of cases Lung cancer, all glass workers: 

male 1.3 (1.0–1.7); 62 female 1.1 (0.5–2.3); 7 

lung cancer risk showed no specificity fglassblowers Skin cancer, M & F combined: 

all workers 1.5 (0.8–2.7); 11 little difference between genders glassblowers 6.2 (1.3–18.3); 3 

Stomach cancer, M & F combined: 

glassblowers 2.3 (0.9–5.0); 6 no increase in other glass workers 

no increase in cancers of other sites 
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Reference Study population Exposure Effects Wingren and Englander 1990 (same population as in case-control analyses of Wingren and Axelson 1985, 1987, 1993) 

625 Swedish glass workers employed for at least 1 month between 1964 and 1985 Mortality was compared with national rates. 

Workers from areas with airborne lead levels up to 0.110 mg Pb/m3 were 

classified as exposed. 

SMR (95% CI) Pharyngeal: 

9.9 (1.2–36.1) 

Lung: 

1.4 (0.5–3.1) 

Colon: nonsignificant 

Steenland et al. 1992 

(follow-up of Selevan et al. 1985) 

1,990 male workers employed for at least 1 year in a lead-exposed department at a U.S. lead smelter in Idaho during 1940–1965 

High-lead-exposure subgroup consisted of 1,436 workers from departments with an average of least 0.2 mg/m3 airborne lead or 

≥

50% of jobs showing 0.40 mg/m3 or greater in 

a 1975 survey. 

SMR (95% CI); no. of deaths Total cohort: nonsignificantly elevated RRs: kidney, bladder, stomach, and lung cancer High-lead-exposure subgroup: 

kidney 2.39 (1.03–4.71); 8 bladder 1.33 (0.48–2.90); 6 stomach 1.28 (0.61–2.34); 10 lung 1.11 (0.82–1.47); 49 

Cocco et al. 1994a (expansion of Carta et al. 1994) 

1,741 male Sardinian lead and zinc miners from two mines employed at least one year between 1931 and 1971 Mortality was compared with age- and calendar-year-specific regional rates 

All miners were considered to be exposed to lead. 

SMR (95% CI); no. of deaths 

all cancer 0.94 (0.83–1.05); 293 prostate 1.21; 16 bladder 1.15; 17 kidney 1.28; 7 nervous system 1.17; 8 oral 0.61; 8 lymphohemopoietic 0.91; 21 digestive 0.83; 86 peritoneum 3.67 (1.35–7.98); 

no other 

P-values < 0.05 
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Reference Study population Exposure Effects Cocco et al. 1994b 526 female Sardinian lead and zinc 

miners from the same mines as in Cocco et al. 1994a 

Mortality was compared with age- and calendar-year-specific regional rates 

All miners were considered to be exposed to lead. 

SMR (95% CI) liver 5.02 (1.62–11.70) lung 2.32 (0.85–5.05) other cancers showed nonsignificantly rrates 

Gerhardsson et al.1995a (follow-up of Gerhardsson et al. 1986) 

684 male Swedish lead smelter workers with lead exposure, followed from 1969–1989 Incidence was compared with county rates. 

Lead exposure was defined as a detectable blood lead level. 

SIR (95% CI); no. of cases All malignancies: 

1.27 (0.91–1.74); 40 

Respiratory: 

1.32 (0.49–2.88); 6 

All gastrointestinal: 

cohort 1.84 (0.92–3.29; highest quartile 2.34 (1.07–4.45); 

Stomach: 

1.88 (0.39–5.50); 3 

Colon: 

1.46 (0.30–4.28); 3 

SIRs for all other sites except brain wernonsignificantly elevated; too few cases 
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Reference Study population Exposure Effects Anttila et al. 1995 20,700 Finnish workers with at least 

one blood lead measurement between 1973 and 1983 by the Finnish Institute of Occupational Health, linked to the Finnish Cancer Registry through 1988. No loss to follow-up. Cause of death was identified from death certificate. Mortality and incidence compared with gender-, 5-year age, and 4-year calendar-year matched national rates. 

Exposure was categorized according to the highest peak blood level measured: low: 0–0.9 

μmol/L 

[0 to 18.6 

μg/dL] 

moderate: 1–1.9 

μmol/L 

[20.7 to 39.4 

μg/dL] 

high: 2–7.8 

μmol/L 

[41.4 to 161.6 

μg/dL] 

Total cohort: 

no elevation in total or site-specific cmortality 

Moderately exposed: 

total respiratory and lung cancer: SIR = 1.4 (95% CI = 1.0–1.9) for bottotal digestive, stomach, bladder, and nervous system: nonsignificant elevat

Highly exposed: 

no increase in risks 

All cancer: 

RR = 1.4 (95% CI = 1.1–1.8) 

Lung or tracheal: 

RR = 2.0 (95% CI = 1.2–3.2) no increase in high-exposure group 

no RRs reported for other cancers Case-referent substudies: 

lung cancer ORs increased with increcumulative exposure to lead highly exposed: squamous-cell lung cOR = 4.1 (95% CI = 1.1–15) after adjustment for smoking 
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Reference Study population Exposure Effects Cocco et al. 1996 1,222 male Sardinian lead and zinc 

smelter workers whose G6PD phenotypes had been determined, employed any time from 1973–1990 Mortality was compared with regional rates. 

Workers were subdivided into G6PD-normal and -deficient groups. 

SMR (no. of deaths) all cancer and lung cancer: lower than expected stomach cancer: higher (2 observed vs. expected) G6PD-normal 0.26 (10) G6PD-deficient 0.18 (2) G6PD deficiency had little apparent effemortality: cancer and all-cause mortality slightly lower among G6PD-deficient wthan among G6PD-normal workers 

Cocco et al. 1997 1,388 male production and 

maintainance workers employed for at least 1 year at a Sardinian lead and zinc smelter between June of 1932 and July of 1971. Mortality was compared with age- and calendar-year-specific regional rates. National rates could not be used for comparison, because the regional population showed large departures from them, limiting the analysis to the period from 1965–1992 for which regional rates were available, instead of the entire 1950–1992 follow-up period. 

All workers were considered to be exposed to lead. 

SMRs vs. regional rates (95% CI); no. odeaths lung 0.82 (95% CI 0.56–1.16stomach 0.97 (0.53–1.62); 14 all cancers 0.93 (0.78–1.10); 132 kidney 1.75 (0.48–4.49); 4 bladder 1.45 (0.75–2.53); 12 brain 2.17 (0.57–5.57); 4 kidney cancer showed a significant trentoward increasing risk with increasing dof exposure no significant trends were noted for lung other cancers brain cancer excess was limited to workemployed for 10 years or less 
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Reference Study population Exposure Effects Lundström et al. 1997 

(follow-up of Gerhardsson et al. 1986) (see also subcohort analyses of Englyst et al. 2001) 

3,979 Swedish copper and lead smelter workers, subdivided into 1,992 belonging to departments exposed to lead only and 1,026 with high cumulative exposure Mortality and incidence compared with age-, year-, gender-, and countyspecific rates 

The lead-only group consisted of workers in lead-only departments; the high cumulative exposure group consisted of workers with blood lead levels 

≥ 10 

μmol/L 

[≥ 207 

μg/dL], based on 

summing mean blood lead monitoring results for each year exposed. 

SMR (95% CI); no. of deaths Lung: 

total cohort 2.8 (2.0–3.8); 39 highly exposed 2.8 (1.8–4.5); 19 

SIR (95% CI); no. of cases Lung with 15-year lag: 

total cohort 2.9 (2.1–4.0); 42 highly exposed 3.4 (2.2.–5.2); 23 lead-only 3.1 (1.7–5.2); 14 lead-only highly exposed 5.1 (2.0–1

Other highly exposed (total cohort), with 15-year lag: 

brain 1.6 (0.4–4.2); 4 renal pelvis, ureter, bladder 1.8 (0.8–3kidney 0.9 (0.2–2.5); 3 all cancer 1.1 (0.9–1.4); 83 
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Reference Study population Exposure Effects Wong and Harris 2000 (follow-up of Cooper et al. 1985) 

U.S. lead battery plant (4,518) and smelter (2,300) workers followed from 1947 through 1995 follow-up of Cooper et al. 1985 with more detailed exposure data and nested case-control component for stomach cancer Mortality was compared with U.S. national age-, calendar-year-, and gender-specific rates. Cause of death was identified from death certificates (See entry under case-control studies for nested study of stomach cancer.) 

(1) battery plant workers (2) lead smelter workers Workers also were stratified by cumulative years of employment (1–9, 10–19, 20+), date of hire (pre-1946 vs. 1946 on), and lag between exposure and cancer (< 20, 20–34, > 34 years). 

SMR (95% CI) Battery plant workers: 

all cancer 1.05 (0.97–1.13) all respiratory 1.13 (0.98–1.29) stomach 1.53 (1.12–2.05), signlung, trachea, bronchus 1.14 ( 0.99–1.30) thyroid, Hodgkin’s: nonsignficant bladder 0.49 (0.23significant depression 

Smelter workers: 

digestive, respiratory, thyroid: nonsignificant lung 1.22 (1.00–1.47) 

Battery plant and smelter workers comb

all cancer 1.04 (0.97–1.11) all respiratory 1.15 (1.03–1.28) stomach 1.47 (1.13–1.90) lung, trachea, bronchus 1.16 ( 1.04–1.30) thyroid/endocrine 3.08 (1.33–6.07), 

lung and stomach risks lower for pre-19hires; higher for workers employed 10–years than < 10, but lower for > 19 yearSMRs peaked with 20- to 34-year latenclung, but < 20 years for stomach 
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Reference Study population Exposure Effects Englyst et al. 2001 (follow-up and subanalysis of Lundström et al. 1997) 

Limited to 1,093 workers in the smelter’s lead department, followed through 1997 Incidence was compared with county rates; age-specific SIRs with 15-year lag. 

Workers were divided into Subcohorts I and II for ever and never worked in areas generally associated with exposure to arsenic or other known carcinogens (701 and 383 workers, respectively). Detailed individual assessment of arsenic exposure was made for all lung-cancer cases. 

SIR (95% CI); no. of cases Subcohort I (co-exposed): 

lung 2.4 (1.2–4.5); 10 

Subcohort II (not co-exposed): 

lung 3.6 (1.2–8.3); 5 

subjects with lung cancer found to have history of “considerable” exposure to ar9/10 among Subcohort I, 4/5 among SubII 

Jemal et al. 2002 

(same cohort as in Lustberg and Silbergeld 2002 except for inclusion criteria) 

3,592 U.S. white participants from the 1976–1980 NHANES II health and nutrition survey who had blood lead measured at entry, followed through 1992 via NDI and SSADMF RRs were adjusted for age and smoking. 

Blood lead (

μg/dL) was 

measured by atomic absorption and used to classify subjects into exposure quartiles or groups above vs. below median exposure. 

RR (95% CI); no. of deaths Lung (above vs. below median): 

Total cohort 1.5 (0.7–2.9); 71 M 1.2 (0.6–2.5); 52 F 2.5 (0.7–8.4); 19 

Stomach (above vs. below median):

Total cohort 2.4 (0.3–19.1); 5 M 3.1 (0.3–37.4); 4 F no deaths in referent group 

All cancer: total cohort by quartile (ageadjusted) 1.0, 1.2, 1.3, 1.5 (

P for trend 0
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Reference Study population Exposure Effects Lustberg and Silbergeld 2002 (same cohort as Jemal et al. 2002 except for inclusion criteria) 

4,190 U.S. participants from the 1976–1980 NHANES II health and nutrition survey who had blood lead measured at entry and whose levels fell below 30 

μg/dL. Followed up 

through 1992 via NDI and SSADMF. Age- and multivariate-adjusted relative risk. 

Blood lead (

μg/dL) 

measured by atomic absorption and used to classify subjects into exposure groups: low: < 10 medium: 10-19 high: 20–19 

RR (95% CI) All cancer, vs. low exposure: 

medium 1.5 (0.9–2.5) high 1.7 (1.0–2.8) 

Lung, vs. low exposure: 

medium 1.7 (0.6–4.8) high 2.2 (0.8–6.1) 

Non-lung, vs. low exposure: 

medium 1.5 (0.8–2.8) high 1.5 (0.8–2.8) 
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Table 3-5. Studies of lead exposure and cancer: case-control Reference Study population Exposure Effects Robinson 1976 Cases: 139 U.S. TEL workers with 20 

or more years in exposed jobs Controls: 139 workers with no known occupational lead exposure, matched by age, gender, race, and years of employment 

Workers were classified as TEL-exposed if they worked in exposed jobs for at least 20 years. 

Skin cancer: 7 in lead-exposed, 4 in nonexposed grouno cancers of other sites in either group 

Fanning 1988 (Cases overlap those occurring in the Dingwall-Fordyce 1963 and Malcolm 1982 cohorts) 

Cases: 2,073 deceased males identified through pension records of battery and other factory workers in the U.K. Controls: workers dying from a specific cancer were compared with a control group consisting of workers dying from all other causes 

High or moderate lead exposure vs. little or no exposure was based on job titles. 

OR (95% CI) 76 lung cancer deaths 0.93 (0.8–1.31 stomach cancer deaths 1.34 (1.10–1no associations for other cancer types; elevations in stomach and total digestive cancers limited to the period before 196

Risch et al. 1988 Cases: 826 Canadian men with 

histologically confirmed bladder cancer during 1979–1982 Controls: 792 controls from Canadian population, matched on age, gender, and area 

Subjects were interviewed regarding length of occupational exposure to lead compounds, as well as 17 other substances. 

OR (95% CI) 61 men ever exposed to lead (smokingadjusted): 

2.0 (1.2–3.5) 

Trend per 10 years’ duration of exposur

1.45 (1.09–2.02) 

no other substances showed significant associations with bladder cancer adjustment for marital status, socioeconstatus, education, ethnicity, urban vs. ruorigin had no effect on results 
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Reference Study population Exposure Effects Cooper et al. 1989 

(based on cohort in Cooper et al. 1985) (succeeded by Wong and Harris 2000) 

Cases: 39 male gastric cancer deaths from a Scandanavian battery and lead production worker cohort Controls: 120 controls from the same cohort 

Exposure was categorized by duration of employment, in quartiles. 

OR Second quartile vs. first: 0.3 Third quartile vs. first: 1.7 Fourth quartile vs. first: 0.4 increasing lead exposure showed no association with gastric cancer 

Mallin et al. 1989 Cases: random sample of 10,013 

deaths from 7 specific cancers, identified from death certificates for Illinois males between 1979 and 1984 Controls: 3,198 randomly selected 

deaths from other causes 

Exposure was based on ccupations abstracted from death certificates. 

Brain cancer, white male glass workersOR = 3.0, P < 0.05 

no significant associations for other cansites 

Siemiatycki et al.

1991 

Cases: 3,730 various histologically confirmed cancers Controls: specific cancer types were compared with other cancers as a control group, excluding lung cancer Separate subgroup analysis was restricted to French Canadians 

Occupational exposure to 293 substances, including lead, was estimated from interviews. Exposure was classified as “any”; a subgroup with “substantial” exposure also was identified. 

OR (90% CI); no. of cases 

Any exposure to lead: 

lung 1.1 (0.9–1.4); 326 (French Canadians only) stomach 1.2 (1.0–1.6); 126 bladder 1.3 (1.0–1.6); 155 (French Canadians only) kidney 1.2 (1.0–1.6); 88 

ORs rose in the “substantial” exposure subgroup for stomach and lung, but not bladder or kidney cancer 

Kauppinen et al. 1992 Cases: 344 primary liver cancer 

deaths reported to the Finnish Cancer Registry in 1976–1978 or 1981 Controls: registry-reported stomach cancer (476) or myocardial infarction 

Questionnaires regarding job history and personal habits were sent to the closest available relative. U.K. based job-exposure 

OR (95% CI) 52 workers with potential lead exposure

0.91 (0.65–1.29) 

11 women with potential lead exposure: 
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Reference Study population Exposure Effects 

(385) deaths in the same hospitals, frequency matched by age and gender 

matrix was used to rate potential exposure to 50 substances, including lead compounds Industrial hygienists also inspected histories to identify those with highly probable exposure and rate it as high, low, or moderate (< 10 years high or 10+ years low exposure) 

1.84 (0.83–4.06) 

5 men with probable moderate exposure

2.28 (0.68–7.67) 

none had high exposure and only 1 had exposure, whereas 4 controls had high exposure female controls appeared to underreport job history 

Wingren and Axelson 1987, 1993 (update of Wingren and Axelson 1985, same basic cohort as in Wingren and Englander 1990) 

Source population: 5,498 men aged 45 or older in 11 Swedish parishes, including 887 glass workers Cancer-specific nested case-control analysis: Cases: deaths due to stomach, colon, and lung cancer from 1950–1982 Controls: deaths due to causes other than cancer or cardiovascular disease 

Glass workers were considered exposed. Occupations also were categorized as low, moderate, or high lead exposure based on job matrix. 

OR (90% CI); no. of deaths All glass workers: 

lung 1.7 (1.1–2.5); 86 stomach 1.5 (1.1–2.0); 206 colon 1.6 (1.0–2.5); 79 

Glassblowers: 

lung 2.3 stomach 2.6 colon 3.1 

ORs for high or moderate vs. low exposshowed no consistent increase for lung ostomach cancer, mild upward trend for ccancer 
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Reference Study population Exposure Effects Anttila et al. 1996 (See Anttila et al. 1995 for basic 

information on the source population.) Nested case-control analysis: Cases: 26 Finnish men with CNS cancer Controls: 200 Finnish men without CNS cancer 

Occupational history and other risk-factor data were obtained from patients or next of kin. Exposure based on peak blood lead levels was categorized as 0.1–0.7, 0.8–1.3, and 1.4–4.3 

μg/L. 

Cumulative lead exposure as the sum of mean annual blood lead level was categorized as 0, 1–6, 7–14, or 15–49 

μg/L. 

OR (no. of cases or deaths) CNS cancer incidence (26 cases): 

rose with increasing peak lifetime blolead measurements; not significant 

Glioma mortality (16 deaths): rose consistently and significantly with and mean blood lead level, duration of exposure, and cumulative exposure Mortality by cumulative exposure, contrfor cadmium, gasoline, and year monitobegan: 

low (13 subjects) 2.0 (2) medium (14 subjects) 6.2 (2) high (16 subjects) 12.0 (5) 

1 death among 26 subjects with no expotest for trend significant at 

P = 0.02 

Kandiloris et al. 1997 Cases: 26 patients with histologically 

confirmed laryngeal carcinoma and no history of lead exposure or toxicity Controls: 53 patients with similar demographic profiles and no history of cancer from the same hospital 

Blood lead levels and ALAD activity were measured. 

blood lead levels were similar, but ALAactivity was significantly lower in cases controls 
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Reference Study population Exposure Effects Fayerweather et al.

1997 

Cases: 735 cancer deaths during 1956–1987 among male workers at a U.S. TEL production plant, identified by the company’s cancer and mortality registries, excluding bladder 

cancers deemed likely due to benzidene or beta-napthalamine exposure Controls: time-, age-, gender-, and payscale-matched plant workers 

Exposure to lead was ranked as none, low, medium, high, and very high, with cumulative exposure derived by summing yearly exposure over time. 

OR (95% CI) Digestive in workers ever TEL-exposed 

very high 2.2 (1.2–4.0) high 1.3 (0.7–2.7) 

no association for lower exposures Rectal: 

ever 3.7 (1.3–10.2) low or medium 1.7 (0.4–8.3) high or very high 5.1 (1.6–16.5) 

Colon:

ever 1.3 (0.7–2.5) high or very high 1.7 (0.8–4.0) low or medium 0.8 (0.4–1.8) 

Hodgkin’s disease: 

ever 2.7 (0.6–12.0) 

other cancers showed no association witexposure 

Cocco et al. 1998a Cases: all 27,060 brain cancer deaths 

occurring among persons aged 35 or older during 1984–1992, from U.S. 24-state death certificate registry Controls: 4 gender-, race-, age-, and region-matched controls per case selected from deaths due to nonmalignant causes Subjects were subdivided into 4 groups by gender and race (white or African-American) for all analyses. 

A job-exposure matrix was applied to death certificate-listed occupations to categorize persons as having low, medium, or high probability and intensity of exposure. 

risk of brain cancer mortality increased consistently with intensity of exposure among African-American males, but noother race-gender groups probability of exposure alone was not consistently associated with risk in the high-probability group, risk increwith exposure intensity for all groups exAfrican-American women (only 1 death the high-probability group) 
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Reference Study population Exposure Effects Cocco et al. 1998b Cases: all 28,416 CNS cancer deaths 

occurring among persons aged 35 or older during 1984–1992, from U.S. 24-state death certificate registry Controls: 4 gender-, race-, age-, and region-matched controls per case selected from deaths due to nonmalignant causes Subjects were subdivided into 4 groups by gender and race (white or African-American) for all analyses. 

Industry and occupation were identified from death certificates. 

OR (95% CI) all occupations or industries with ORs a1.0 and 

P-value < 0.05 in at least one ra

gender group were reported Newspaper printing and publishing indu

white M 1.4 (1.1–1.8) black M 3.1 (0.9–10.9) 

Typesetting and compositing: 

white M 2.0 (1.1–3.8) white F 1.3 (0.4–3.8) black F 4.2 (0.6–30.7) 

no deaths among black males 
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Reference Study population Exposure Effects Cocco et al. 1999 Cases: all 41,957 stomach cancer 

deaths occurring among persons aged 35 or older during 1984–1996, from U.S. 24-state death certificate registry Controls: 2 gender-, race-, age-, and region-matched controls per case selected from deaths due to nonmalignant causes Subjects were subdivided into 4 groups by gender and race (white or African-American) for all analyses. 

A job-exposure matrix was applied to death certificate-listed occupations to categorize persons as having low, medium, or high probability and intensity of exposure. 

OR (95% CI) adjusted for age, ethnicity, marital statuurban residence, and socioeconomic staElevated ORs: 

white F, high prob. 1.53 (1.10–2.12black M, high prob. 1.15 (1.01–1.32black F, high prob. 1.76 (0.74–4.16

highly exposed group included 1,503 wand 453 black men and 65 white and 10 women; no pattern of increase across exposure levels intensity of exposure showed no associawith stomach cancer except for black women: 

low 1.82 (1.04–3.18) moderate 1.39 high 1.25 

Shukla et al. 1998 Cases: 38 patients with newly 

diagnosed, histologically confirmed gall bladder cancer cases assembled from an Indian surgical unit Controls: 58 patients with gall stones diagnosed at the same surgical unit, matched on by geographic area, served as controls 

Heavy metal content was measured in bile drawn from the gall bladder at time of surgery. 

Bile lead content: mean (SE) (mg/L): gall bladder cancer: 58.38 (1.76) gallstones: 3.99 (0.43) cadmium and chromium levels also werelevated in cancer patients, but less than 
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Reference Study population Exposure Effects Hu et al. 1998 Cases: 218 patients with 

histologically-confirmed primary gliomas occurring during 1989–1996 at 6 Chinese hospitals Controls: 436 patients with nonneurological, nonmalignant disease., matched by age, gender, and residence from the same hospitals except a cancer-only center 

Patients were interviewed, and those with factory or farm occupations were further interviewed to identify exposure to lead (or other potentially toxic substances). 

no occupational exposure to lead was reported for any glioma patients, but wareported for 4 controls 

Hu et al. 1999 Cases: all 383 patients with 

histologically confirmed primary meningiomas occurring during 1989–1996 at 6 Chinese hospitals Controls: 366 patients with nonneurological, nonmalignant disease matched bu age, gender, and residence from the same hospitals except a cancer-only center 

Patients were interviewed, and those with factory or farm occupations were further interviewed to identify exposure to lead (or other potentially toxic substances). 

OR (95% CI); no. of cases Occupational exposure to lead: M 7.20 (1.00–51.72); 6 F 5.69 (1.39–23.39); 10 ORs adjusted for income, education, and and vegetable intake, plus cigarette packyears for the women 

Wong and Harris 2000 

Case-control study nested in Wong and Harris 2000 cohort Cases: the 30 stomach cancer cases occurring in a Philadelphia lead battery plantControls: 120 age-matched cohort members 

Job titles were used to classify lead exposure as low, intermediate, or high; total months of any exposure, of intermediate or high exposure only, and of cumulative exposure, with months weighted by 1, 2, or 3 if spent in low-, intermediate-, or highexposure job. 

mean months of employment, of intermor high exposure, or of weighted exposulead were all nonsignificantly lower amcases OR for cumulative weighted exposure in 10 years prior to death: 

First quartile 1.00 Second quartile 0.62 Third quartile 0.82 Fourth quartile 0.61 

P for trend = 0.47; ORs showed no posiassociation with any index of exposure 
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Reference Study population Exposure Effects Pesch et al. 2000 Cases: 935 renal-cell cancer patients 

in five German areas Controls: 4,298 region, age, and gender-matched controls from the surrounding population ORs were adjusted for age, center, and smoking, 

Exposure to cadmium, lead, and other potential carcinogens was estimated from detailed job histories and rated as low vs. medium, high, or substantial. British and German job-exposure matrices were used. 

OR (95% CI); no. of cases Substantial lead exposure based on Britmatrix: 

M 1.5 (1.0–2.3); 29 F 2.6 (1.2–5.5; 11 

Substantial lead exposure based on Britmatrix:

M 1.3 (0.9–2.0); 30 F not reported 
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Table 3-6. Lead exposure and childhood cancer Reference Design Study population Exposure Effects Kantor et al.1979 

casecontrol Cases: 149 Connecticut childhood Wilms’ tumor cases 

from 1935–1973 Controls: 149 age-, gender-, and race-matched controls 

Paternal occupation was identified from birth certificate as lead-related or, lead/hydrocarbonrelated. 

Lead-related industry: OR = 5.0 Hydrocarbon- or lead-related industry: OR = 3.4 

Wilkins and Sinks 1984a, 1984b 

casecontrol Cases: 62 Ohio childhood Wilms’ tumor cases from 

1950–1981 Controls: 62 matched controls 

Paternal occupation was identified from birth certificate as lead-related or hydrocarbon-related. 

OR “not significant for lead or for hydrocarbon-related occupations” 

Buckley et al.

1989 

casecontrol Cases: 204 childhood ANLL cases from 1980–1984 

Controls: 204 age-, gender-, area-matched controls identified by random-digit dialing 

Cumulative paternal occupational exposure to lead was determined in telephone interviews with fathers and categorized as 0, 1–1,000, > 1,000 days. 

178 case-control pairs with occupational exposure data: 

1–1,000 days: OR = 1.0 (5 cases) > 1,000 days: not calculable; 6 cases, 0 controls exposed 

P for trend = 0.03 

Olshan et al.

1990 

casecontrol Cases: 200 histologically confirmed U.S. Wilms’ tumor 

cases (less-common sarcomatous subtype excluded) occuring from 1984–1986 Controls: 200 age- and areamatched population controls 

A self-administered questionnaire on job history was used to identify lead exposed jobs and the years worked. 

OR (95% CI); no. of cases Timing of paternal lead exposure: preconception 1.1 (0.6–2.0); 37 pregnancy 1.1 (0.6–2.4); 24 postnatal 1.3 (0.6–2.8); 21 
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Reference Design Study population Exposure Effects Kristensen and Andersen 1992 

cohort 12,440 offspring of Oslo 

printers’ union members, followed from 1965–1987 

Union employment records were used to identify lead-exposed occupations (compositors, monotype casters, stereotypers) and leadand solvent-exposed occupations. 

SIR (95% CI); no. of cases Cancer at age 0–14: 

lead 0.8 (0.2–2.3); 3 lead & solvent 0.3 (0.0–1.4); 1 

Cancer at age 14+: 

lead 1.4 (0.6–2.6); 9 lead & solvent 0.6 (0.2–1.4); 5 
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4 Studies of Cancer in Experimental Animals 

IARC reviewed the carcinogenic potential of lead and lead compounds administered to 

mice, rats, and hamsters and concluded that there was sufficient evidence that lead 

subacetate is carcinogenic to mice and rats and that lead acetate and lead phosphate are 

carcinogenic to rats (IARC 1980, 1987). Most of the available carcinogenicity studies of 

lead in experimental animals were published before 1980 and were included in the IARC 

review. A brief summary of the primary findings and data from these studies is presented 

below. Carcinogenicity studies that were not included in IARC’s review are discussed in 

more detail. 

Lead chromate compounds were not included in the IARC monographs for lead and lead 

compounds (IARC 1980, 1987) but were included in the monographs for chromium and 

chromium compounds (IARC 1973, 1990). Because the carcinogenic effects of lead 

chromates generally are associated with toxicity of chromium rather than lead, these 

compounds are not discussed in detail in the following sections. 

4.1 Mice 

Lead compounds have been administered to mice in the diet, by intraperitoneal (i.p.) 

injection, by subcutaneous (s.c.) injection, by skin application, and in drinking water. 

Most of these studies have investigated the carcinogenicity of lead administered to young 

adult mice; however, the two most recent studies investigated the effects of lead on 

chemical- and viral-induced tumors (Blakley 1987) or in prenatal and neonatal mice 

exposed during gestation and lactation (Waalkes et al. 1995). The compounds studied 

include lead subacetate, lead acetate, lead naphthenate, lead chromate, and tetraethyl lead. 

The results from these studies are presented below. 

4.1.1 Lead acetate or subacetate 

Van Esch and Kroes (1969) fed lead subacetate at 0.1% and 1.0% in the diet to groups of 

25 male and female Swiss mice for two years. The 1.0% level was decreased to 0.5% 

beginning in the fourth month because of excessive toxicity; however, the authors 

reported that most mice in the high-dose groups “died before tumors could be induced.” 

No renal tumors developed in the control group. Six male mice in the 0.1% group and 

one female mouse each in the 0.1% and 1.0% groups developed renal tumors (Table 4-1). 

Other tumors occurred but were not associated with lead exposure. 

Groups of 20 male and female strain A/Strong mice were given i.p. injections of lead 

subacetate dissolved in tricaprylin for 5 weeks (for total doses of 30, 75, and 150 mg/kg 

body weight [b.w.]) and observed for up to 30 weeks (Shimkin et al. 1977, Stoner et al.

1976). The incidence of pulmonary adenoma was significantly higher in the high-dose 

group than in vehicle controls or untreated controls (Table 4-1). 

Using strain A mice, Poirier et al. (1984) investigated the inhibition of lead subacetateinduced lung tumors by magnesium and calcium acetate. Lead subacetate dissolved in 

tricaprylin was injected i.p. at 10 mg/kg b.w. (0.04 mmol/kg) alone or in combination 

with calcium acetate or magnesium acetate. Calcium acetate and magnesium acetate were 
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administered at 1, 3, and 10 times the molar concentration of lead subacetate. Groups of 

30 mice received three injections per week, for a total of 9 (magnesium acetate studies) to 

20 (calcium acetate studies) injections. Lead subacetate induced a statistically significant 

increase in lung tumors in strain A mice; however, simultaneous treatment with either 

calcium acetate or magnesium acetate at all molar ratios significantly decreased this 

response (Table 4-1). 

Blakley (1987) investigated the effects of lead on chemical- and viral-induced tumors in 

female Swiss mice. In the first experiment, lead acetate was given in the drinking water at 

0, 50, 200, or 1,000 μg/mL for 15 weeks beginning at three weeks of age. At six weeks of 

age, mice in each group received i.p. injections of 1.5 mg/g urethan or saline. Incidences 

of lung adenoma were reported at the end of the exposure period. In the second 

experiment, 8-week-old mice, with the same genetic background as in the first study, 

were given lead acetate in drinking water at 0, 50, or 1,000 μg/mL for 40 weeks and 

examined for lymphocytic leukemia of thymic origin. These mice have a high incidence 

(approximately 50%) of spontaneous lymphocytic leukemia. No clinical manifestations 

of lead poisoning were observed in either experiment, and neither body-weight gain nor 

water consumption was affected. Lead exposure did not affect the number or size of 

pulmonary adenomas induced by urethan (Table 4-2). The spontaneous tumor incidence 

was less than 2 tumors per mouse in all treatment groups injected with saline. In the 

second experiment, lead exposure increased incidences of viral-induced lymphocytic 

leukemia and tumor-related deaths (Table 4-3). The authors concluded that the 

immunosuppressive effects of lead allowed for increased expression of the murine 

lymphocytic leukemia virus. 

A dose-related increase in renal proliferative lesions (including atypical hyperplasia, 

adenoma, and adenocarcinoma) was evident in B6C3F1 mice following gestational and 

lactational exposure to lead (Waalkes et al. 1995). Pregnant B6C3F1 mice were given 

lead (as lead acetate) in the drinking water ad libitum at 0, 500, 750 or 1,000 ppm from 

gestation day 12 to four weeks postpartum. These drinking-water levels of lead were 

estimated to provide doses of 0, 100, 150, or 200 mg/kg b.w. per day, respectively. After 

weaning, the offspring were grouped by sex (23 to 25 per group) and observed for up to 

112 weeks. Other groups of offspring received a tumor promoter (500 ppm sodium 

barbital) ad libitum in the drinking water for the balance of the study. Lead exposure did 

not affect litter size, growth of exposed offspring, or survival. A significant dose-related 

trend was noted in total renal proliferative lesions in male progeny mice exposed to lead 

alone (P < 0.001) or lead and sodium barbital (P = 0.022). In addition, male mice in the 

high-dose group showed a significantly increased incidence of renal tubular cell adenoma 

and renal tubular cell atypical hyperplasia (Table 4-4). Female progeny mice exposed to 

lead alone showed a significant dose-related trend (P = 0.017) in total renal proliferative 

lesions; however, lesion incidences were not significantly elevated at any dose level 

(Table 4-4). In the control groups, atypical tubular hyperplasia occurred in one male 

mouse, but no tumors were observed. Postnatal exposure of the mice to sodium barbital 

did not promote tumor development. The authors noted that the renal tumors observed in 

this study developed without evidence of concurrent lead-induced nephropathy (i.e., 

intranuclear inclusion bodies, interstitial fibrosis, or cystic hyperplasia).
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Table 4-1. Summary of carcinogenicity studies of lead subacetate in mice 

Tumor incidence (%)a 

Kidney Lung Strain 

and age 

Exposure route and 

duration 

Sex and 

no.b Exposure groupc Adenoma Carcinoma Adenoma Multiplicityd 

Swiss (5 wk) 

diet for 2 yr M (25)

M (25) M (25) F (25) F (25) F (25) 

0 0.1% 1.0% to 0.5%e

0 0.1% 1.0% to 0.5%e

0 (0) 

2 (NR) 

0 (0) 0 (0) 

1 (NR) 

0 (0) 

0 (0) 

4 (NR) 

0 (0) 0 (0) 0 (0) 

1 (NR) 

3 (NR) 1 (NR) 1 (NR) 3 (NR) 5 (NR) 1 (NR) 

NR NR NR NR NR NR 

van E1969 

Strain A (6–8 wk) 

15 i.p. doses (3/wk), examined at 30 wk 

M/F (19) M/F (18) M/F (17) M/F (12) M/F (15) 

untreated vehicle 30 mg/kg 75 mg/kg 150 mg/kg 

NR NR NR NR NR 

NR NR NR NR NR 

6 (31) 8 (44) 6 (35) 5 (42) 

11 (73) 

0.28 ± 0.07 

0.5 ± 0.12 

0.35 ± 0.09 

0.5 ± 0.14 

1.47 ± 0.38* 

Stone
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Tumor incidence (%)a 

Kidney Lung Strain 

and age 

Exposure route and 

duration 

Sex and 

no.b Exposure groupc Adenoma Carcinoma Adenoma Multiplicityd 

Strain A (6–8 wk) 

20 i.p. doses (3/wk), examined at 30 wk 9 i.p. doses (3/wk), examined at 30 wk 

M/F (26) M/F (26) M/F (20) M/F (23) M/F (18) M/F (16) M/F (21) M/F (29) M/F (20) M/F (1) M/F (13) M/F (18) 

vehicle vehicle + CA Pb (10 mg/kg) Pb + CA (1:1) Pb + CA (1:3) Pb + CA (1:10) vehicle vehicle + MA Pb (10 mg/kg) Pb + MA (1:1) Pb + MA (1:3) Pb + MA (1:10) 

NR NR NR NR NR NR NR NR NR NR NR NR 

NR NR NR NR NR NR NR NR NR NR NR NR 

NR NR NR NR NR NR NR NR NR NR NR NR 

0.35 ± 0.09 

0.62 ± 0.17 

0.86 ± 0.20*

0.21 ± 0.10†

0.22 ± 0.10†0.13 ± 0.09† 

0.29 ± 0.11 

0.45 ± 0.09 

1.65 ± 0.36*

NRf

0.08 ± 0.08†

0.28 ± 0.11†

Poirie

*P < 0.05 compared with vehicle controls. †Significantly less (

P < 0.05) than in the lead subacetate group. 

aNR = not reported. bThe number of surviving animals except for van Esch and Kroes (1969), which reported only the initial number of animals. 

M/F = male and female not given separately; total number of animals reported. 

cPb + CA = lead subacetate plus calcium acetate (molar ratio) ; Pb + MA = lead subacetate plus magnesium acetate (molar ratio) dThe average number of tumors per mouse 

± S.E. 

eDosage decreased because of high mortality. fOnly one of 30 animals survived. 
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Table 4-2. Effects of lead acetate on body-weight gain and urethan-induced lung adenoma in 

female Swiss mice 

Lead 

concentration 

(μg/mL) 

Weight gain 

mean ± SE 

(g/day) 

Tumors/mouse 

mean ± SE 

(No. of mice) 

Tumor size 

mean ± SE 

(mm) 

0 

50 

200 

1,000 

0.18 ± 0.006 

0.18 ± 0.004 

0.17 ± 0.006 

0.17 ± 0.005 

36.0 ± 5.8 (22) 

39.0 ± 6.0 (19) 

49.6 ± 12.8 (24)

34.0 ± 4.9 (24) 

0.71 ± 0.03 

0.67 ± 0.04 

0.70 ± 0.04 

0.68 ± 0.02 

Source: Blakley 1987. 

Table 4-3. Effects of lead acetate on mortality and spontaneous lymphocytic leukemia in 

female Swiss mice 

Lead 

conc. 

(μg/mL) 

Median 

survival 

time (days) 

Mice 

surviving to 

the end of 

studya

Leukemia 

deaths (%)a

Other neoplasiarelated deathsbSurvival 

probabilityc

0 

50 

1,000 

223.5 

170.6 

165.5 

20 

13 

10 

24 (48) 

34 (68) 

38 (76) 

2 

0 

1 

0.007 

0.0124d

0.0034d

Source: Blakley 1987. 

a

50 mice per group. One surviving animal in each group had evidence of leukemia at the end of the study. 

b

Mammary tumors (controls) and leukemia of non-thymic origin (high-dose group). 

c

Probability that the three treatment groups had the same survival distribution, based on the Lee-Desu statistic. 

d

Probabilities for lead-exposed groups are for pairwise comparison with the control group. 
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Table 4-4. Renal tubular cell proliferative lesions in B6C3F1 mice following gestational and 

lactational exposure to lead acetate 

Lesion incidence (%) Exposure 

groupa 

(ppm) 

No. of 

mice 

Atypical 

hyperplasia Adenoma Carcinoma Total 

Males 

0 

500 

750 

1,000 

SB 

500 + SB 

750 + SB 

1,000 + SB 

23 

25 

25 

25 

24 

25 

25 

25 

1 (4) 

3 (12) 

5 (20) 

7 (28)* 

2 (8) 

2 (8) 

5 (20) 

2 (8) 

0 (0) 

0 (0) 

0 (0) 

5 (20)* 

0 (0) 

1 (4.0) 

1 (4.0) 

5 (20.0)* 

0 (0) 

1 (4) 

1 (4) 

0 (0) 

0 (0) 

0 (0) 

1 (4) 

1 (4) 

1 (4) 

4 (16) 

6 (24) 

12 (48)* 

2 (8) 

3 (12) 

7 (28) 

8 (32)* 

Females 

0 

500 

750 

1,000 

SB 

500 + SB 

750 + SB 

1,000 + SB 

25 

24 

25 

25 

25 

25 

25 

25 

0 (0) 

0 (0) 

0 (0) 

4 (16) 

0 (0) 

0 (0) 

0 (0) 

1 (4) 

0 (0) 

0 (0) 

1 (4) 

0 (0) 

0 (0) 

0 (0) 

1 (4) 

0 (0) 

0 (0) 

0 (0) 

0 (0) 

0 (0) 

0 (0) 

0 (0) 

0 (0) 

1 (4) 

0 (0) 

0 (0) 

1 (4) 

4 (16) 

0 (0) 

0 (0) 

1 (4) 

2 (8) 

Source: Waalkes et al. 1995. 

*P < 0.05, compared with appropriate controls. 

a

Concentrations of lead in the drinking water given to the dams; SB = Sodium barbital at 500 ppm in drinking water. 

4.1.2 Lead naphthenate 

Baldwin et al. (1964) tested the carcinogenicity of several engine oil additives, including lead 

naphthenate, in male albino mice. A 20% (v/v) solution of lead naphthenate in benzene was 

applied to the shaved backs of mice once or twice per week. The study was terminated at 648 

days, for a total application of 6 mL. Lead naphthenate did not induce a significant carcinogenic 

response in mouse skin. Only 2 of 59 mice developed benign skin tumors. Marked kidney 

damage was reported; however, the nature and extent of damage was not specified. Four mice 

developed renal tubular adenoma, and one mouse developed a renal carcinoma. No controls were 

used. 

4.1.3 Lead chromate 

The IARC (1990) monograph included only one study of mice exposed to lead chromate. Two 

lymphomas and three lung adenocarcinomas were observed in 17 female NIH-Swiss weanling 

mice given intramuscular (i.m.) injections of 3 mg of lead chromate dissolved in trioctanoin 
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every 4 months for 24 months. Lymphomas occurred in 1 of 15 untreated controls and 2 of 22 

vehicle-injected controls, while lung adenocarcinomas occurred in 1 of 15 untreated controls and 

1 of 22 vehicle-injected controls. 

4.1.4 Tetraethyl lead 

Subcutaneous administration of tetraethyl lead to infant male and female Swiss mice resulted in 

significantly increased incidences of lymphoma in the females (Epstein and Mantel 1968). A 

single rangefinding dose of 2 mg on the first day of life was lethal to all 69 mice tested before 

weaning. Mice received four divided doses of tetraethyl lead dissolved in tricaprylin at a 

concentration of 1 mg/mL (109 mice, total dose of 0.6 mg) or 2 mg/mL (79 mice, total dose of 

1.2 mg) between birth and 21 days of age. Both dose levels were toxic, resulting in 20% and 

92% mortality in the low- and high-dose groups, respectively, before weaning. Malignant 

lymphomas were found between 36 and 51 weeks in 5 of 41 (12%) low-dose females, 1 of 26 

(4%) low-dose males, 1 of 39 (3%) control males, and none of the female controls. No renal 

tumors or nephropathy were observed in the lead-exposed mice. 

4.2 Rats 

Lead compounds were administered to rats in the diet, by gavage, in drinking water, by injection, 

or through lactation. The compounds studied include lead subacetate, lead acetate, lead 

phosphate, lead chromate, lead arsenate, and lead powder. Several studies also investigated the 

modifying effects of other compounds (e.g., dietary calcium, tumor promoters, and other 

carcinogens) on lead carcinogenicity. The results from these studies are presented below. 

4.2.1 Lead acetate and lead subacetate 

The carcinogenicity of lead acetate and lead subacetate in rats was reported in the 1960s and 

1970s (Boyland et al. 1962, van Esch et al. 1962, Shakerin and Paloucek 1965, Mao and Molnar 

1967, Zawirska and Medras 1968, 1972, Ito et al. 1971, Ito 1973). The results from these studies 

are summarized in Table 4-5. Other researchers investigated the carcinogenic effects of lead 

compounds when co-administered with other compounds (see Section 4.2.4). In general, these 

early studies investigated only carcinogenic effects in the kidney; however, a few studies 

examined other tissues. 
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Table 4-5. Summary of carcinogenicity studies of lead subacetate and lead acetate in rats conducted before 

Kidney tumor incidences (%)a Strain 

and initial age 

Compound, 

exposure 

route, and 

duration 

Sexb

and no. 

Exposure 

group Adenoma Carcinoma Total Comment

Wistar (10 wk) 

lead acetate or sedormid, diet, 1 yr 

M (20) M (20) 

0.5% sedormidc

1.0% leadc

0 (0) 1 (6.3) 

1 (5.9)d

14 (87.5) 

1 (5.9)d

15 (93.8) 

Percentages based on animaleast 320 days (17 in sedormlead group). No untreated co

Wistar (weanling) 

lead subacetate, diet, 24 to 29 mo 

M/F (55) M/F (32) M/F (24) 

0 0.1% 1% 

0 (0) 8 (25) 7 (29.2) 

0 (0) 3 (9.4) 6 (25) 

0 (0) 

11 (34.4) 13 (54.2) 

Study duration of 29 months and 24 months for 1% diet. approximately equally dividmales and females. 

Wistar (young) 

lead subacetate, diet, 92 wk 

NR (40) NR (40) 

0 0.5%–1.0% 

0 (0) 

NR 

0 (0) 

NR 

0 (0) 

NR 

Data reported in a meeting arats primarily developed adebeginning at six months incrnumber thereafter. A few adhypernephromas, or undiffercarcinomas were observed. 

Wistar (NR) 

lead subacetate, diet, up to 677 days 

M (20) M (40) 

0 1% 

0 (0) 

NR 

0 (0) 

NR 

1 (5) 

31 (77.5) 

The tumor in the control grocell sarcoma. Tumor incidencorrelated with exposure duranimals exposed to lead for developed tumors. 

Wistar (NR) 

lead acetate, diet, 18 mo 

M/F (32) M/F (126) 

0 3–4 mg/day 

0 (0) 

55 (43.7) 

0 (0) 

17 (13.5) 

0 (0) 

72 (57.1) 

Leydig-cell tumors of the tereported in 23/94 treated maincidence in controls was no

Wistar (6–8 wk) 

lead subacetate, diet, 48 wk 

M (10) 1.5% 6 (60) 4 (40) 10 (100) The carcinomas included on

carcinoma and three dark ce

Wistar (30 wk) 

lead acetate, diet, 60–504 days 

M/F (62) M/F (94) 

0 3 mg/day 

0 (0) 

12 (12.8) 

0 (0) 0 (0) 

0 (0) 

12 (12.8) 

Other tumors included 10 ceand 17 pituitary, 11 thyroid, 15 adrenal, 11 prostatic, and adenomas. 
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Kidney tumor incidences (%)a Strain 

and initial age 

Compound, 

exposure 

route, and 

duration 

Sexb

and no. 

Exposure 

group Adenoma Carcinoma Total Comment

Wistar (6–8 wk) 

lead subacetate, diet, 23–48.5 wk 

M (13) M (11) M (11) 

1.5% 1.5% + nephe

1.5% 

0 (0) 

NR NR 

0 (0) 

NR NR 

0 (0) 2 (18.2) 9 (81.8) 

First two groups were treateand the third group was treaweeks. Rats in the second grunilaterally nephrectomizedtumors, 7 were adenomas ancarcinomas. 

aNR = not reported. bM/F = male and female not given separately; total number of animals reported.cAfter one year, surviving animals were placed on the basal diet and were sacrificed when they became ill or had a palpable tumor. Sed

hypothesis that porphyrinuria may be responsible for lead-induced renal tumors. Both lead and sedormid caused chronic cystic nephriti

dEpidermoid carcinoma of the renal pelvis that was not likely related to treatment. eneph = nephrectomized. 
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Kasprzak et al. (1985) investigated the interaction of dietary calcium with lead carcinogenicity in 

4-week-old male Sprague-Dawley rats. Rats were divided into seven groups (30 per group) and 

fed diets containing 0 or 1% lead subacetate and 0, 0.3%, 1%, 3%, or 6% calcium acetate for 79 

weeks. Body weight gains were significantly depressed in lead-exposed animals, and the 

depressive effect was enhanced with increasing exposure to calcium acetate. Exposure to lead 

and calcium acetate also increased the organ/body weight ratios for the liver and kidneys. Kidney 

tumors were not observed in the control or calcium-acetate-only groups. Renal tumors occurred 

in approximately 45% of the lead-only group and in 62.1% to 78.6% of the lead and calcium 

acetate groups (Table 4-6). Bilateral tumors occurred in 48% of the tumor-bearing rats. Primary 

tumors in other organs were not observed in the lead-only group but occurred in a few animals in 

the lead- and calcium-exposed groups (Table 4-6). 

Table 4-6. Tumor incidence in male Sprague-Dawley rats fed lead subacetate (PbSA) and 

calcium acetate (CA) 

Kidney tumor incidence (%) 

Exposure group

(%) 

No. rats 

at riska Adenoma 

Adenocarcinoma Total Other tumors (no.)b

Control 

CA (3) 

PbSA (1) 

PbSA (1) + CA (0.3) 

PbSA (1) + CA (1) 

PbSA (1) + CA (3) 

PbSA (1) + CA (6) 

30 

29 

29 

30 

29 

30 

28 

0 (0) 

0 (0) 

11 (37.9) 

16 (53.3) 

11 (37.9) 

15 (50.0) 

15 (53.6) 

0 (0) 

0 (0) 

2 (6.9) 

5 (16.7) 

7 (24.1) 

7 (23.3) 

7 (25.0) 

0 (0) 

0 (0) 

13 (44.8) 

21 (70.0) 

18 (62.1) 

22 (73.3)* 

22 (78.6)* 

schwannomas (2) 

odontoma (1) 

none 

HCA (1), SCC (1), PAP (?) 

PC (1), PAP (?) 

osteoma (1) 

none 

Source: Kasprzak et al. 1985. 

*P < 0.05 (compared to lead only group) 

a

Rats surviving at least 58 weeks. 

b

HCA, hepatocellular adenoma; SCC, squamous-cell carcinoma; PAP, papilloma; PC, pituitary carcinoma; (?), a 

total of three papillomas reported in groups 4 and 5 combined. 

Bogden et al. (1991) also investigated the modifying effects of dietary calcium on lead tissue 

concentrations, blood pressure, and incidences of kidney tumors in rats. Forty-eight five-weekold male Wistar rats were randomly assigned to groups fed a low-calcium (0.2%) or highcalcium (4.0%) diet and given drinking water containing 0, 1.0, or 100 μg/mL lead for 31 

weeks. Lead acetate trihydrate was used in the treatment groups, and sodium acetate trihydrate 

was used in the control groups. The lead concentrations were expected to produce blood lead 

concentrations similar to those found in individuals in the U.S. population with low or moderate 

exposure to lead. Tissue lead concentrations were not lower in groups on the high-calcium diet. 

All rats exposed to high calcium and high lead concentrations developed hyperplasia or 

transitional cell carcinoma in the kidney. These lesions were not observed in the other groups. 

The authors concluded that the high-calcium diet enhanced lead-induced renal carcinogenesis. 
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4.2.2 Lead phosphate 

IARC (1980) reviewed three carcinogenicity studies of lead phosphate parenterally administered 

to rats (Zollinger 1953, Baló et al. 1965, Roe et al. 1965). No other studies with lead phosphate 

were identified. Renal tumors occurred in 36% to 66% of the albino rats given lead phosphate 

but were not observed in controls (Table 4-7). 

4.2.3 Lead chromate 

IARC (1990) reviewed several studies of lead chromates adminstered to rats by interbronchial 

implantation, intrapleural implantation, s.c. injection, or i.m. injection. Bronchial carcinomas 

were observed in a few rats (1% or less) administered various lead chromate compounds via 

interbronchial implantation, but the incidences were not statistically significant. Following 

intrapleural administration, implantation-site tumors (tumor type unspecified) occurred in 3 of 34 

rats after 27 months, compared with 0 of 34 in the control group. In contrast, injection-site 

sarcomas were frequent in rats given a single s.c. injection of lead chromate (26/40, 65%), basic 

lead chromate (27/40, 67.5%), or molybdenum orange (a mixture of lead chromate, sulfate, and 

molybdate) (36/40, 90%), but were not observed in 60 control animals. Results from i.m. 

injection studies were inconsistent. Injection-site tumors were observed in 1 of 33 (3%) rats in 

one study and 31 of 47 (66%) in another. No injection-site tumors occurred in controls. In 

addition, renal-cell carinomas occurred in 3 of 23 (13%) rats injected i.m. with 8 mg of lead 

chromate once per month for nine months. The IARC (1990) Working Group noted that the renal 

tumors may have been attributable to the lead content. 

4.2.4 Other inorganic lead compounds 

Although studies with lead acetate, lead subacetate, and lead phosphate show clear evidence of 

carcinogenicity in rats, other lead compounds have not been associated with carcinogenicity. 

IARC (1980) reviewed the carcinogenicity of lead arsenate and lead carbonate administered in 

the diet, lead nitrate administered in drinking water, and lead powder administered by gavage or 

i.m. injection. These studies are summarized briefly below. No additional studies of these or 

other lead compounds were identified. 

No tumors were found in 49 young male white rats fed 0.1% lead arsenate or in 55 rats fed 0.1% 

lead carbonate for two years. However, the authors reported kidney changes, including 

cytomegaly, vesiculation of nuclei, and accumulation of brown granules in the convoluted 

tubules (Fairhall and Miller 1941). 

A study of male and female Wistar rats fed lead arsenate in the diet at a concentration of 463 or 

1,850 ppm for two years did not provide clear evidence of carcinogenicity (Kroes et al. 1974). 

Eighty animals (40 of each sex) were included in the low-dose group and 48 (19 females and 29 

males) in the high-dose group. No differences were observed between groups in the numbers of 

malignant or benign tumors. The incidence of malignant tumors was 1 of 28 (3.6%) in the highdose group and 6 of 78 (7.7%) in the low-dose group, compared with 11 of 98 (11%) in controls. 

The authors suggested that the only tumors that may have been induced by lead arsenate were a 

renal cortical adenoma and a bile-duct carcinoma found only in the high-dose group. 

Male Long-Evans rats exposed to lead (as lead nitrate) in drinking water at 25 μg/L from 

weaning until death did not show increased mortality or tumor incidence (Schroeder et al. 1970). 
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114

Tumors, unspecified with respect to location or type, were observed in 7 of 43 (16%) exposed 

rats and 10 of 50 (20%) controls. 

Lead powder administered by i.m. injection or gavage did not increase tumor incidence in male 

or female F344 rats (Furst et al. 1976). Rats received nine monthly i.m. injections of 10 mg of 

lead powder, followed by three monthly injections of 5 mg. An injection-site sarcoma observed 

in one female rat was thought to be a random occurrence. The incidences of lymphoma or 

lymphocytic leukemia in exposed rats did not differ from those in controls. When lead powder 

was administered by gavage in corn oil (10 mg twice a month for 12 months), no tumors 

occurred in the gastrointestinal tract or kidneys. Lymphoma and leukemia occurred in both 

exposed and control animals; however, the incidences were not signficantly different. 

4.2.5 Co-administration with other compounds 

Three studies from the same laboratory (Shakerin et al. 1965, Hass et al. 1967, Oyasu et al.

1970) investigated the interaction of dietary lead subacetate with 2-acetylaminofluorene (2-

AAF). Kidney, liver, urinary bladder, brain, and other tumors were reported; however, most of 

these occurred in rats given both 2-AAF and lead. Shakerin et al. (1965) reported a higher 

incidence of hepatic and renal carcinomas with metastasis to the lungs in rats fed both lead 

subacetate and 2-AAF than in groups fed either compound alone. Hass et al. (1967) reported that 

the combination of 2-AAF, lead subacetate, and linseed oil increased the anaplastic character of 

hepatocellular carcinomas but did not significantly increase their incidence. No other significant 

interactions were reported. However, lead subacetate was associated with kidney and brain 

tumors (Table 4-8). 

Several studies published after the IARC (1980) review investigated the promoting or cocarcinogenic effects of lead administered to rats. Hiasa et al. (1983) investigated the promoting 

effects of lead subacetate in male Wistar rats treated with N-ethyl-N-hydroxyethylnitrosamine 

(EHEN). The animals were divided into six treatment groups that received diets containing: (1) 

no EHEN or lead subacetate (controls), (2) 500 ppm EHEN, (3) 1,000 ppm EHEN, (4) 1,000 

ppm lead subacetate, (5) 1,000 ppm EHEN followed by 1,000 ppm lead subacetate, and (6) 500 

ppm EHEN followed by 1,000 ppm lead subacetate. EHEN was given during the first two weeks 

of the study, lead acetate from week 3 to week 22, and the control diet from week 23 to week 32. 

Animals were sacrificed at 32 weeks and examined for kidney tumors. No tumors were observed 

in groups 1, 2, or 4. Exposure to lead subacetate significantly increased the incidence and size of 

renal-cell tumors induced by EHEN (Table 4-9). In addition, hepatocellular carcinomas were 

found in two rats in group 3 and one rat each in groups 5 and 6. 
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Table 4-7. Summary of carcinogenicity studies of lead phosphate in ratsa

Kidney tumor incidence (%)a

Strainb

Exposure route and 

duration 

Sex and 

no. 

Exposure 

group Adenoma Carcinoma Total Comments 

Albino s.c., up to 16 

mo. 

NR (40) NR (29) 

0 

20 mg/wk 

0 (0) 

NR 

0 (0) 

NR 

0 (0) 

19 (66) 

Total doses ranged from 40 to 76in the renal cortex occurred in ramore than 10 mo and receiving band 680 mg. Renal papilloma analso reported. 

Albino s.c., 18 mo. NR (20) 

NR (80) 

0 

20 mg/wk 

0 (0) 

29 (36) 

0 (0) 0 (0) 

0 (0) 

29 (36) 

The total dose was 1.3 g, and adeappeared after 354 days. 

Albino Chester Beatty 

s.c. and i.p., 34 wk 

M (24) M (23) M (23) M (3) 

0 

29 mgd

145 mge

450 mgf

0 (0) 0 (0) 

NR 

2 (67) 

0 (0) 0 (0) 6 (26) 0 (0) 

2 (8)g

0 (0) 

14 (61)h

2 (67) 

All groups began with 24 animalis based on animals surviving at Treatment groups received 4 s.c. followed by 21 to 25 i.p injectionvariable periods of no treatment study (see footnotes). Most of thcuboidal-cell, tubular, or papillaradenocarcinomas arising in the rSeveral non-renal tumors occurreassociated with lead. 

aNR = not reported. bAges not reported. cAs cited in IARC (1980). These papers were not published in English. dWeekly injections of 1 mg: 4 s.c. injections + 7 i.p. injections + no treatment for 3 wk + 4 i.p. injections + no treatment for 2 wk, + 14 i.p. injections. eSame as above except dose was 5 mg per injection. fFour s.c. injections (25 mg) + 7 i.p. injections (25 mg) + no treatment for 9 wk, + 14 i.p. injections (12.5 mg). gIncludes one undifferentiated malignant tumor and one transitional cell carcinoma arising in the renal pelvis. hIncludes one undifferentiated malignant tumor and 13 adenomas or adenocarcinomas. 
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Table 4-8. Summary of carcinogenicity studies of lead subacetate co-administered with 2-AAF in ratsa

Kidney tumor incidence (%)a

Strain and age 

Exposure route and 

duration 

Sexb and 

no. Exposure groupc Adenoma Carcinoma Total Comm

Wistar (NR) 

 (NR) 

(NR) 

M (40) 

2-AAF (0.06%) Pb (1%) Pb (1%)+ 2-AAF (0.06%) 

NR NR NR 

NR NR NR 

NR NR NR 

Reported incidencand renal tumors group either lead 2-AAF groups alo

SpragueDawley(6–8 wk) 

diet, 30–52 wk diet, 52–74 wk 

M (32) M (13) M (11) M (32) M (32) M (11) M (39) M (42) 

2-AAF + indole Pb + indole Pb + LO + indole Pb + LO + indole + 2-AAF 2-AAF + indole Pb + indole Pb + LO + indole Pb + LO + indole + 2-AAF 

0 (0) 8 (61.5) 0 (0) 

10 (31.3) 

0 (0) 

11 (100) 20 (51.3) 19 (45.2) 

0 (0) 3 (23.1) 1 (9.1) 

11 (34.4) 

0 (0) 8 (72.3) 

13 (44.8) 14 (33.3) 

0 (0) 

NR NR NR 

0 (0) 

11 (100) 

NR NR 

Lead acetate conc0.5% to 1% of the (1.6%) was added 2-AAF (0.06%) liBrain tumors (gliin 3, 2, 4, and 8 arespective treatme(including interim animals) but were spontaneous tumo

SpragueDawley (6 wk) 

 M/F (325) 

M (17) M (41) M (72) 

controls Pb (1%) Pb + indole (1.6%) Pb + indole + 2-AAF (0.06%) 

0 (0) 

NR NR NR 

0 (0) 

NR NR NR 

0 (0) 

13 (76.5) 25 (61.0) 36 (50.0) 

Gliomas were obscontrol animal (0of 130 (8.5%) rattreatment groups 

Gliomas occurred rats in the Pb onlyand Pb + indole + treatment groups, Combining lead anot increase tumo

aNR = not reported. bM/F = male and female not given separately; total number of animals reported.cLO = linseed oil containing a “lead drier” with 0.2% lead. 
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Table 4-9. The promoting or co-carcinogenic effects of lead acetate or lead subacetate in rats Strain and age 

Exposure route and 

duration 

Sex and 

no. Exposure group (ppm)a

Kidney tumors 

incidence (%) Comments 

Wistar (7 wk) 

diet, 22 wk M (24) 

M (24) M (18) M (24) M (17) M (22) 

Control EHEN (500) EHEN (1,000) PbSA (1,000) EHEN (1,000) + PbSA (1,000) EHEN (500) + PbSA (1,000) 

0 (0) 0 (0) 9 (50)*b

0 (0) 

17 (100)*c

10 (45)*d

Surviving animals were sacrificed weeks. Incidences of renal tumors diameter were 0%, 0%, 10%, and 7tumor-bearing animals treated with alone, lead subacetate alone, 500 pplus lead, and 1,000 ppm EHEN plrespectively. 

SpragueDawley (weanling) 

drinking water, 76 wk 

M (7) M (8) M (7) M (10) M (16) 

Control EU/NaNO2 

EU/NaNO2 + PbA (26) EU/NaNO2 + PbA (2,600) PbA (2,600) 

0 (0) 0 (0) 0 (0) 6 (60) 

13 (81) 

The first renal tumor was observed weeks. All animals in the groups trEU/NaNO2 developed one or more 

types (lymphosarcoma being the mcommon), but renal tubule carcinomthe only tumor observed in the leadgroup. 

*P < 0.05. aEHEN = 

N-ethylN-hydroxyethylnitrosamine; EU/NaNO2 = ethyl urea and sodium nitrite; PbSA = lead subacetate; PbA = lead acetate

bCompared with the control group (

χ2 test). cCompared with the EHEN 1,000-ppm group (

χ2 test). dCompared with the EHEN 500-ppm group (

χ2 test). 
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Koller et al. (1985) investigated the carcinogenic effects of lead acetate administered 

with sodium nitrite and ethyl urea to male Sprague-Dawley rats. The five treatment 

groups included the following: (1) untreated controls, (2) ethyl urea (EU) and sodium 

nitrite (NaNO2) (3) ethyl urea, sodium nitrite, and 26 ppm lead as lead acetate, (4) ethyl 

urea, sodium nitrite, and 2,600 ppm lead, and (5) 2,600 ppm lead. Groups 1 through 4 had 

10 animals and group 5 had 16 animals. Lead was administered in the drinking water for 

76 weeks. Ethyl urea (6.36 g/kg) and sodium nitrite (2 g/kg) (precursors of the 

carcinogenic agent ethylnitrosourea) were mixed in the diet and administered for 20 

weeks beginning 28 weeks after initiation of lead exposure. Early deaths from pneumonia 

reduced the effective group sizes to 7, 8, and 7 for groups 1, 2, and 3, respectively. At the 

end of the study, all rats fed ethyl urea and sodium nitrite (groups 2, 3, and 4) had tumors. 

Lymphosarcoma was the most prevalent, with an incidence of at least 50% in each of 

these groups. Only kidney tumors were observed in group 5 (lead only). No kidney 

tumors were detected among the controls, the EU+NaNO2 group (group 2), or the lowdose lead and EU+NaNO2 group (group 3). Renal tubular carcinomas were observed in 

both groups receiving lead at 2,600 ppm (Table 4-9). However, tumor incidences were 

not increased by co-administration of lead with urea and sodium nitrite. 

Tanner and Lipsky (1984) studied the effects of lead acetate on induction of renal 

carcinogenesis by N-(4'-fluoro-4-biphenyl)acetamide (FBPA) in male Fischer-344 rats. 

Four groups of 50 rats each were used; however, mortality from acute toxicity was high 

in the treatment groups. Five to 10 rats were sacrificed in each group after 16, 24, 36, and 

52 weeks of exposure and examined for kidney tumors. Group 1 (controls) was fed a 

semi-synthetic diet, group 2 was fed the control diet with 400 ppm lead as lead acetate, 

group 3 was fed the control diet with 10,000 ppm lead as lead acetate, and group 4 was 

fed the control diet with 400 ppm FBPA plus 10,000 ppm lead as lead acetate. No lesions 

were observed in the controls, but karyomegaly, hyperplasia, and microscopic nodules 

were seen in all lead-exposed groups. Renal adenocarcinoma occurred in groups 2, 3, and 

4 after 36, 52, and 24 weeks, respectively. Kidney tumor incidence was higher in group 4 

(lead acetate and FBPA) than in either the lead-only or FBPA-only group (Table 4-10). 

Exposure to lead acetate generally accelerated the onset and development of all renal 

lesions; however, karyocytomegaly was not correlated with the later appearance of 

hyperplasia, microscopic nodules, or adenocarcinomas. These researchers concluded that 

lead probably was acting synergistically with FBPA as a co-carcinogen by accelerating 

the neoplastic process in the proximal tubule epithelial cells. 
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Table 4-10. Co-carcinogenic effects of lead acetate administered with FBPA to male 

Fisher-344 rats 

Renal lesion incidence (%) 

Treatment group (ppm) 

No. of 

rats 

Treatment 

duration (wk) Hyperplasia

Microscopic 

adenoma 

Adenocarcinoma 

(1) Controla 5–10 

5–10 

5–10 

5–10 

16 

24 

36 

52 

0 

0 

0 

0 

0 

0 

0 

0 

0 

0 

0 

0 

(2) FBPA (400) 7 

7 

7 

5 

16 

24 

36 

52 

4 (57) 

7 (100) 

5 (71) 

3 (60) 

0 

2 (29) 

3 (43) 

3 (60) 

0 

0 

4 [57] 

4 (80) 

(3) PbA (10,000 as elemental Pb) 8 

8 

10 

5 

16 

24 

36 

52 

4 (50) 

4 (50) 

10 (100) 

3 (60) 

0 

0 

1 (10) 

1 (20) 

0 

0 

0 

1 (20) 

(4) FBPA (400) + PbA (10,000 as 

elemental Pb)

8 

9 

5 

5 

16 

24 

36 

52 

8 (100) 

9 (100) 

5 (100) 

5 (100) 

3 (38) 

6 (67) 

5 (100) 

4 (80) 

0 

1 (11) 

4 (80) 

5 (100) 

Source: Tanner and Lipsky 1984. 

a

The number of control rats sacrificed at each interval was not reported but was between 5 and 10. 

4.3 Hamsters 

In male and female golden hamsters (45 or 46 per group) fed control diet or lead 

subacetate at 0.1% and 0.5% in the diet for up to two years, lead exposure did not 

significantly increase the frequency of renal tumors, although pleomorphic cells and 

intranuclear inclusion bodies were found in the proximal renal tubules. The overall 

incidences of other tumors and hyperplasias in the low-dose, high-dose, and control 

groups were 25 of 46 (54%), 18 of 46 (39%), and 36 of 45 (80%), respectively (van Esch 

and Kroes 1969). 

Four groups of Syrian golden hamsters (15 per sex) were given 10 weekly intratracheal 

injections of lead oxide (1 mg), benzo[a]pyrene (1 mg), or a combination of lead oxide 

and benzo[a]pyrene (1 mg of each). Animals were sacrificed when moribund or 60 weeks 

after the first treatment. The hamsters did not develop any lung tumors when 

administered either lead oxide or benzo[a]pyrene alone; however, lead oxide induced 

hyperplastic and squamous metaplastic foci in the alveolar region. Atypical epithelial 

proliferations in the lungs (11 adenomas, 1 adenocarcinoma) were observed only in 

animals given the combination of lead oxide and benzo[a]pyrene. The investigators 
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120 

concluded that lead oxide exerted a co-carcinogenic effect with benzo[a]pyrene in the 

lungs (Kobayashi and Okamoto 1974). 

4.4 Monkeys 

Krugner-Higby et al. (2001) reported on a case of chronic myelocytic leukemia that may 

have been related to lead exposure in a juvenile female rhesus macaque. This monkey 

was part of a study that investigated the behavioral effects of subclinical neonatal 

exposure to lead. Lead acetate was administered in milk formula during the first six 

months postpartum (beginning on day 8). After weaning, lead acetate was given daily in a 

fruit-flavored vehicle for 1.5 years to achieve a blood lead level of 35 μg/dL. At 25 

months of age, an increased white blood cell count and immature white blood cells were 

detected during a routine complete blood count. The animal was monitored and received 

chemotherapy treatments but was euthanized four months later because of deteriorating 

clinical conditions. No evidence of past or present viral infection or other risk factors for 

leukemia was observed. The authors concluded that the possible role of lead exposure in 

chronic myelocytic leukemia should be investigated. 

4.5 Summary 

Both soluble (lead acetate and lead subacetate) and insoluble (lead phosphate) lead 

compounds were found to be carcinogenic in rats and/or mice by a variety of exposure 

routes, including oral, subcutaneous, intramuscular, transdermal, and transplacental, and 

translactational. Inhalation carcinogenicity studies of lead compounds have not been 

conducted in experimental animals. 

Other lead compounds found to be carcinogenic in experimental animals include lead 

chromates and tetraethyl lead. Exposure to lead chromates increased the incidence of 

injection-site sarcomas in rats, but these effects were likely due to chromate. However, 

renal-cell carcinomas were reported in one study of rats administered lead chromate by 

i.m. injection. Female infant Swiss mice administered tetraethyl lead by s.c. injection 

developed malignant lymphomas, but this effect was not observed in male Swiss mice. 

Most of the studies of inorganic lead compounds focused on kidney toxicity and 

carcinogenicity; therefore, complete histopathological examinations were not conducted. 

However, the few studies that examined tissues other than the kidney found little 

evidence that lead induced tumors. The available data indicate that the primary target site 

for lead-induced neoplasia in experimental animals is the kidney (adenoma and 

adenocarcinoma), but increased incidences of cerebral glioma and lung adenoma were 

reported in some studies. 

Lead subacetate was reported to enhance liver and kidney tumorigenicity of 2-AAF in 

one study but not in two others and was shown to promote renal tumors in Wistar rats 

administered EHEN. In other studies, lead acetate increased the incidence of viralinduced lymphocytic leukemia in mice and was co-carcinogenic when administered with 

FBPA to F344 rats. However, lead acetate did not increase tumor incidences in SpragueDawley rats when co-administered with ethyl urea and sodium nitrite. 
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Overall, renal tumors were observed in male and female rats and mice exposed to lead 

compounds, and were not always accompanied by chronic lead-induced nephropathy. 
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5 Genotoxicity 

Numerous studies have been conducted to determine whether lead compounds are 

genotoxic and, if so, by what mechanism(s). Most of these studies were performed before 

1990. A comprehensive review by the Agency for Toxic Substances and Disease Registry 

(ATSDR 1999) summarized their results, concluding that various inorganic lead 

compounds (lead acetate, chloride, and nitrate) were not genotoxic in microorganisms, 

with and without metabolic activation, based on various end points (mutations, DNA 

modification, and recombination). Conversely, in vitro assays using mammalian test 

systems (Syrian and Chinese hamster ovary cells) gave conflicting test results when cells 

were examined for chromosomal aberrations. In vivo studies using Drosophila 

melanogaster and various mammalian model systems also gave conflicting results 

concerning the genotoxic effects of lead acetate and lead nitrate. Evaluation of the 

genotoxicity of lead exposure in humans focused on in vitro and in vivo studies of 

chromosomal aberrations and sister chromatid exchange in lymphocytes from healthy 

individuals and from occupationally or environmentally exposed individuals. These 

studies also gave conflicting results. ATSDR concluded that the mechanism(s) of the 

genotoxicity of lead probably was indirect (see Section 6 for a discussion of lead’s 

mechanism of action). 

The literature through 1987 concerning the genotoxicity of lead compounds also was 

extensively reviewed by IARC (1972, 1973, 1976, 1980, 1987). The IARC reviews 

concluded that divalent lead compounds (lead acetate and lead chloride) reacted with 

purified DNA and decreased the fidelity of DNA replication in vitro, but were not 

mutagenic in bacterial test systems and did not enhance mitotic recombination in the 

Saccharomyces cerevisiae D3 assay. In plants, lead acetate (at concentrations of 20 to 

30 mM) induced chromosome aberrations in Allium cepa root tips, and lead chloride 

(0.1 mM) was weakly mutagenic in rice seeds. In vitro and in vivo studies using 

mammalian systems yielded conflicting results for the genotoxicity of lead compounds. 

Many factors contribute to the conflicting results concerning the genotoxic effects of 

lead. These factors include differences not only in model systems employed and end 

points used to determine genotoxicity, but also in the lead compounds used. As discussed 

in Section 1, lead is highly reactive and forms numerous compounds that have very 

different physical-chemical properties. One important property in biological systems is 

solubility. Lead compounds vary greatly in solubility: compounds such as lead acetate, 

lead chloride, and lead nitrate are extremely soluble in water, with solubility constants 

(Ksp) of 2 x 10-2, 1 x 10-4, and 2 x 10-2, respectively, whereas other lead compounds, such 

as lead chromate and lead sulfide, are virtually insoluble in water (Ksp of 1.7 x 10-14 and 

1 x 10-28, respectively). Solubility affects the bioavailability of these compounds. Humans 

are occupationally and environmentally exposed to numerous lead compounds over the 

course of a lifetime. Likewise, personal habits such as smoking, alcohol, and drug intake 

can influence genotoxicity data obtained in human subjects, and it is difficult to account 

for the effects that these cofactors might have on lead genotoxicity. This section reviews 

relevant genotoxicity data reported since 1989. 
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5.1 Prokaryotic systems: Induction of mutations in Salmonella typhimurium, 

Escherichia coli, and Serratia marcescens

Maslat and Haas (1989) determined the mutagenic effects of lead bromide, a combustion 

product of the gasoline additives TEL and 1,2-dibromoethane, in Serratia marcescens, 

Escherichia coli KMBL 1851, and the Salmonella typhimurium tester strains TA 1535 

(point mutations) and TA 1537 (frameshift mutations). S. marcescens mutants were 

scored on their inability to produce the pigment prodigiosin, E. coli mutants were scored 

for resistance to rifampicin, and S. typhimurium mutants were scored for histidine 

auxotrophy. Bacteria were exposed for various times (not reported) to concentrations of 

PbBr2 ranging from 1.91 to 4.63 mM for S. marcescens, 1.91 to 3.27 mM for E. coli, and 

0.5 to 68 μg/plate for S. typhimurium. The frequency of white colonies arising from S. 

marcescens exposed to PbBr2 ranged from 0.42 ± 0.01% to 2.0 ± 0.10 % for exposure at 

1.91 and 4.63 mM PbBr2, respectively. The mutation frequency for non-exposed controls 

was 0.05%. The frequency of rifampicin-resistant mutants arising following exposure of 

E. coli to 3.27 mM PbBr2 was 0.26% x 10-4 (non-exposed control = 0.0066% x 10-4). The 

number of S. typhimurium TA 1535 revertants ranged from 0 to 977 after plating on 

PbBr2 medium containing 0.5 and 34 μg of PbBr2, respectively. No significant increase in 

revertants was seen with S. typhimurium strain TA 1537 (see Table 5-1). 

5.2 Plants: in vivo assays 

Reddy and Vaidyanath (1978) investigated the mutagenic activity of metallic salts, 

including lead chloride, on chlorophyll mutations in rice. Rice seeds were exposed to a 

10-4 M aqueous solution of lead chloride for 24 hours. The pooled results of three 

replicates indicated mutant frequencies of 0.65% in the M1 and 0.04% in M2 generations. 

These values represent relatively weak mutagenic acticity compared with that reported 

for other metallic salts, including barium (6.36% in the M1 and 0.68% in the M2) and 

cadmium (5.23% in the M1 and 0.46% in the M2). 

Sandhu et al. (1989) evaluated the clastogenicity of lead tetraacetate in the Tradescantia 

micronucleus assay, using Tradescantia paludosa clone 4430, as described by Ma et al.

(1983). Plant cuttings were exposed for 30 hours by hypotonic uptake through stems, 

with no time for recovery. Results were expressed as micronuclei per 100 tetrads. Of the 

compounds tested (aldrin, arsenic trioxide, 1,2-benz[a,h]anthracene, dieldrin, heptachlor, 

lead tetraacetate, and tetrachloroethylene), lead tetraacetate was the most clastogenic, 

inducing 17.79 ± 8.56, 18.93 ± 2.90, and 13.07 ± 5.50 micronuclei/100 tetrads at 

concentrations of 0.44, 2.55, and 11.75 ppm, respectively. Micronucleus formation was 

significantly greater (P < 0.05) than in the solvent control (2.90 ± 2.0). 
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Table 5-1. Genotoxicity of lead compounds in prokaryotic systems 

Resultsa

Species (test system) End point 

With 

metabolic activation 

Without 

metabolic 

activation Compound Concentrationb 

lead acetate NA Bruce 

Dunke

lead nitrate 22–180 μM Kharab lead chromate 0.2 mg Nestm

S. typhimuriumE. coli Bacillus subtilis

mutation or DNA modification 

– – 

lead chloride and acetate 

25 mM Nishio

S. typhimurium (TA 1535) S. typhimurium (TA 1537)E. coli (KMBL 1851)S. marcescens 

mutation ND + 

– 

+ + 

lead bromide 0.5–68 μg/plate 

0.5–68 μg/plate 1.91–3.27 mM 1.91–4.63 mM 

Maslat 

lead chloride NA Fukunalead nitrate 22–180 μM Kharab lead chromate 25 mM Nestm

S. cerevisiae gene conversion 

or mitotic recombination 

– – 

lead acetate 5% (v/v) Simmo

Source: ATSDR 1999. aND = not determined.bNA = not available. cNot reviewed in the text; source: ATSDR 1999. 
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Ma et al. (1992) determined the synergistic effects of mixtures of lead tetraacetate, 

arsenic trioxide, dieldrin, and tetrachloroethylene on genotoxicity in the Tradescantia

micronucleus assay. Lead tetraacetate (0.44 ppm) alone increased the frequency of 

micronucleus formation in plants exposed for 30 hours over that in the solvent controls. 

Gill and Sandhu (1992) determined the genotoxic effects of arsenic trioxide, dieldrin, and 

lead tetraacetate alone and in combination in the Tradescantia micronucleus assay. The 

chemicals or their mixtures were either (1) mixed into soil, and exposure to the target 

cells was through the roots of intact plants grown in the soil, or (2) prepared as an 

aqueous solution, and exposure was by absorption through the stems of plant cuttings. 

Lead tetraacetate was tested at concentrations of 4 μg/mL in the aqueous test system and 

and 4 mg/kg in the soil test system. Soil-grown plants exposed to lead tetraacetate had 

significantly more (P < 0.05) micronuclei than did the controls (11.2 ± 2.3 vs. 5.1 ± 0.6 

micronuclei per 100 tetrads, respectively). No difference was observed between the leadexposed and control plants grown in aqueous media (2.9 ± 0.5 vs. 2.3 ± 0.1 micronuclei 

per 100 tetrads, respectively). The clastogenicity of lead tetraacetate was altered by the 

ratio of individual chemicals in the aqueous or soil media. 

Lerda (1992) determined the effect of lead nitrate (at concentrations of 0.1, 1.0, 10, 50, 

100, or 200 ppm) on root growth, cell proliferation, and chromosomal aberrations in 

Allium cepa. The effect of lead nitrate on root growth was determined by measuring the 

length of 10 to 20 roots per onion bulb at 24-hour intervals for 96 hours. Lead nitrate at a 

concentration of 100 or 200 ppm completely inhibited root growth. At lower 

concentrations, the rate of growth was reduced in a dose-dependent manner. Likewise, 

cell proliferation, which was determined at the root tip 12, 24, and 48 hours after 

exposure, was progressively reduced at high concentrations. However, this inhibition was 

transient; proliferation had recovered by 48 hours after exposure. No difference from 

controls was observed in cell proliferation at concentrations up to 10 ppm. At each 

exposure level, 5,000 cells were examined for chromosomal aberrations. The frequency 

of chromosomal aberrations in cells from onions exposed to lead nitrate at 0.1 or 1.0 ppm 

did not differ from that of the non-exposed controls. However, significantly (P < 0.05) 

more cells contained chromosomal aberrations in plants exposed at 10 ppm than in nonexposed controls (0.18 vs. 0 per 5,000 cells). The author stated that these results 

supported those of his previous studies demonstrating that lead compounds induced 

chromosomal aberrations in persons occupationally exposed to lead (Lerda 1992). 

Minissi et al. (1998) examined the genotoxicity of sediments from the Tiber River and its 

tributaries in the urban area of Rome, using a micronucleus assay in Vicia faba root tips. 

All samples were collected in July 1992. Sediments were assayed for content of the 13 

most important chemicals of the polycyclic aromatic hydrocarbon (PAH) group and for 

some heavy-metal ions (cadmium, chromium, copper, nickel, lead, and zinc). The lead 

concentration in the sediments ranged from 12.4 to 43.5 ppm. The frequency of 

micronuclei was significantly (P < 0.01) higher in plants exposed to sediment collected 

from 8 of the 10 sites than in the controls. These sites also contained significant amounts 

of PAHs and other metal ions (see Table 5-2).
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Table 5-2. Genotoxicity of lead compounds in plants in vivoSpecies End point Results Compound Concentration Reference Tradescantia clone 4430 

micronucleus formation 

+ lead tetraacetate 0.44 to 11.75 ppm in 

water; 4 μg/kg in soil 

Sandhu et al. 1989, Maet al. 1992, Gill and Sandhu 1992 

inhibition of root growth 

+ lead nitrate 0.1, 1, 10, 50, 100, 

200 ppm 

Lerda 1992 

cell proliferation + lead nitrate 0.1, 1, 10, 50, 100, 200 

ppm 

Lerda 1992 

Allium cepa 

chromosomal aberrations 

+ lead nitrate 0.1, 1, 10, 50, 100, 200 

ppm 

Lerda 1992 

Vicia faba micronucleus 

formation 

+ lead with other 

metals 

12.4 to 43.1 ppm Minissi et al. 1998 
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5.3 In vitro studies using cell-free systems 

Roy and Rossman (1992) reported that exposure of supercoiled plasmid DNA with lead 

acetate (1 mM) for 30 minutes at room temperature in a Tris-HCl buffer (pH 7.5) did not 

induce nicks or strand breaks in the DNA, as determined by agarose gel electrophoretic 

analysis. Addition of hydrogen peroxide (H2O2, 0.3 mM) to the reaction mixture induced 

the formation of nicks and double-stranded breaks in the DNA. The levels of DNA 

damage in the samples exposed simultaneously to H2O2 and lead acetate were greater 

than those observed in DNA exposed to either lead acetate or H2O2. The investigators 

suggested that lead(II) did not damage DNA directly, but caused damage indirectly by 

participating in a Fenton reaction to generate hydroxyl radicals in the presence of H2O2. 

Calsou et al. (1996) investigated the ability of several heavy metal ions, including 

lead(II), to inhibit nucleotide excision repair in vitro. These investigators determined the 

effect of these metal ions on lesion recognition and strand incision/displacement steps in 

a whole-cell extract from HeLa cells. The incision assay was performed with ultraviolet- 

(UV-) treated pBluescript phagemid vector DNA, as described by Calsou and Salles 

(1994). Lesion recognition (UV damage) was tested in a mobility-shift assay, in which 

the protein-DNA complex was detected via electrophoresis. Lead chloride (0.1, 0.3, and 

1.0 mM) inhibited incision repair activity in a dose-dependent manner, with 

approximately 50% of the activity inhibited at 1 mM. Likewise, lead chloride (1 mM) 

inhibited recognition of UV DNA damage by the cell extract. The investigators reported a 

good correlation between the inhibitory effects of several metal ions, including lead(II), 

on the excision activity of NER and a reduced protein-binding activity to damaged DNA. 

Yang et al. (1999) reported that treatment of supercoiled plasmid DNA with lead acetate 

(0.3 mM) in HEPES buffer (10 mM, pH 6.8) at 37o

C for 3 to 24 hours resulted in timedependent DNA strand breakage. In studies with a 24-hour incubation period, the DNA 

strand breaks also were dose-dependent (over lead acetate concentrations of 0.1 to 

0.3 mM), and DNA strand breakage also occurred in Tris-HCl buffer (1 to 10 mM, pH 

6.8). To determine whether H2O2 was involved in the reaction, DNA was treated with 

0.1 mM lead acetate for 1 hour at 37o

C in the presence and absence of H2O2 (1 or 5 mM). 

Under these conditions, neither lead acetate nor H2O2 induced nicks or strand breaks in 

the plasmid, but treatment with lead acetate and H2O2 in combination increased the 

incidence of DNA strand breaks. Although the investigators stated that the effect of H2O2 

was dose-dependent, no numerical data were reported to support this premise, and only 

two concentrations of H2O2 were employed. The singlet oxygen scavengers sodium azide 

and 2,2,6,6-tetramethyl-4-piperidone (TEMP) inhibited lead-induced DNA strand 

breakage more efficiently than did the hydroxyl radical scavengers, mannitol and 5,5-

dimethyl-1-pyrroline-1-oxide. Deuterium oxide, a singlet oxygen enhancer, increased 

lead-induced DNA strand breakage, while catalase and superoxide dismutase did not 

protect the DNA from lead-induced breaks. Enhancement of lead-induced breaks by 

H2O2 was inhibited by sodium azide, TEMP, edetate calcium disodium, catalase, and 

glutathione, and was potentiated by superoxide dismutase and mannitol. 

To further examine the potential role of reactive oxygen species-intermediates on leadinduced DNA damage, studies were performed to determine whether 8-

hydroxydeoxyguanosine (8-OHdG) was formed in calf thymus DNA following its 
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129 

exposure for 1 hour at 37°C to lead acetate (0.1, 0.5, and 1 mM) in the presence and 

absence of H2O2 (5 mM). Under these conditions, neither lead acetate nor H2O2 

significantly increased the amount of 8-OHdG in DNA over that in non-treated controls 

(average 6.6 ± 0.7 8-OHdG per 105

 deoxyguanosine residues). However, treatment of the 

DNA with lead acetate (1 mM) and H2O2 (5 mM) in combination resulted in a 14.4-fold 

increase in the amount of 8-OHdG (95.2 ± 10.8 8-OHdG per 105

 deoxyguanosine 

residues). The investigators interpreted the data to suggest that lead(II) induced DNA 

damage through a Fenton-like reaction and that a singlet oxygen was the principal 

oxygen species involved in inducing the damage (see Table 5-3). 

5.4 Mammalian systems 

5.4.1 In vitro assays 

5.4.1.1 Lead acetate, lead chloride, lead nitrate, and lead sulfide 

Frenkel and Middleton (1987) reported that lead acetate did not inhibit DNA and RNA 

synthesis in HeLa cells even after exposure to 0.5 mM of lead acetate for 18 hours. 

Conversely, DNA and RNA synthesis were inhibited in intact nuclei (50% inhibition 

concentration [IC50] = 150 and 80 μM, respectively). Likewise, HeLa DNA polymerase α

and RNA polymerase II activities were inhibited by lead acetate (IC50 = 150 and 20 μM, 

respectively). E. coli DNA polymerase I was more sensitive to inhibition by lead acetate 

(IC50 = 10 μM) than was HeLa DNA polymerase α, but the sensitivity of the E. coli RNA 

polymerase was the same as that of the HeLa enzyme. 

To investigate the genotoxicity of soluble and insoluble lead compounds, Zelikoff et al.

(1988) used Chinese hamster ovary (CHO) cells (V79) as a model system to determine 

the mutagenic potential and the ability of the compounds to induce sister chromatid 

exchange (SCE) and Syrian hamster embryo (SHE) cells to determine their cell 

transformation potential. For the mutagenicity assays, V79 cells were treated with lead 

sulfide (insoluble) for 1 day or lead nitrate (soluble) for 5 days, and their resistance to 6-

thioguanosine was determined. For the SCE assay, exponentially growing V79 cells were 

treated for 24 hours. Bromodeoxyuridine (5 μg/mL) was added for two cell cycles, 

followed by colcemid treatment. Two hours later, mitotic cells were collected by 

mechanical agitation, fixed, and stained using a modification of the technique described 

by Schneider et al. (1978). A minimum of 30 mitotic cells was counted, and the number 

of SCE per chromosome was determined. The cytotoxicity of lead acetate, lead nitrate, 

and lead sulfide to V79 cells was determined by clonogenic assay. The 50% lethal doses 

(LD50) were 0.58, 2.55, and 2.95 mM for lead sulfide, lead acetate, and lead nitrate, 

respectively. Treatment of V79 cells with lead nitrate or lead sulfide increased the 

frequency of mutation of the hprt gene compared to non-treated controls. The increased 

mutation frequency was 6.2-fold higher in cells treated with 0.5 mM lead nitrate for 5 

days. At higher concentrations, the mutation frequency decreased but remained 2-fold 

greater than background. Lead sulfide (376 μM, 24-hour treatment) induced a 5.5-fold 

increase in the mutation frequency. Neither lead nitrate nor lead sulfide induced a 

significant increase in the frequency of SCE, nor did they induce DNA single-strand 
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Table 5-3. Genotoxicity of lead compounds in vitro in cell-free systems (without metabolic activation) Species or test system End point Results Compound Concentration Reference 

lead chloride 0.05–2 mM Hoffman and Niyogi 

1977a

E. coli RNA polymerase and avian myeloblastosis DNA polymerase 

inhibition of RNA or DNA biosynthesis 

+ + lead chloride 4 mM Sirover and Loeb 1976a

DNA polymerase and RNA polymerase II in HeLa cell extracts 

DNA and RNA polymerase inhibition 

+ lead acetate 25–500 μM Frenkel and Middleton 

1987 

Whole-cell (HeLa) extract 

inhibition of DNA damage incision activity 

+ lead chloride 0.1–1 mM Calsou et al. 1996 

Supercoiled plasmid DNA 

DNA strand breaks 

with H2O2

without H2O2

+ 

– 

lead acetate 1 mM Roy and Rossman 1992 

Supercoiled plasmid DNA 

DNA strand breaks 

with H2O2

without H2O2 

without H2O2

+ 

– 

+ 

lead acetate 

0.1 mM (1 h) 0.1 mM (1 h) 0.3 mM (3–24 h) 

Yang et al. 1999 

aNot reviewed in the text; source: ATSDR 1999. 
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breaks, as measured by alkaline elution. For the cell transformation assay, SHE cells 

isolated from embryos 12 to 24 days after gestation were treated with lead acetate for 24 

hours, washed, and re-treated for an additional 24 hours. Fresh media was added, and 

plates were incubated for an additional 10 days or until colonies (> 50 cells) were 

observed. Lead acetate (10, 25, and 50 μM) induced cellular transformation of SHE cells 

in a dose-dependent manner. The investigators interpreted these results to mean that lead 

compounds were genotoxic by an indirect mechanism and to support the view that lead 

might be a carcinogen. 

To determine whether the genotoxic effects of lead(II) were due to indirect effects rather 

than to direct DNA damage, Hartwig et al. (1990) used CHO (V79) and HeLa cells to 

examine the effects of lead acetate on DNA repair processes as they relate to 

genotoxicity. Cytotoxicity was determined by clonogenic assay. Survival values 

following treatment of V79 cells withlead acetate for 24 hours were 92.0%, 53.1%, 

41.5%, 37.5%, and 32.1% at concentrations of 1, 3, 5, 10, and 25 μM, respectively. Lead 

acetate did not increase the frequency of hprt gene mutations in V79 cells, nor did 

exposure to lead(II) increase the frequency of SCE. Lead(II) also did not induce DNA 

strand breaks in HeLa cells, as determined by nucleoid sedimentation. However, for all 

the end points tested, lead ions interfered with the processing of UV-induced DNA 

damage. Mutation frequency in UV-irradiated CHO cells was increased by treatment with 

lead acetate (at 0.5, 1, 3, and 5 μM) for 20 hours prior to irradiation. Pretreatment of 

CHO cells with lead acetate (1, 5, and 10 μM) before UV irradiation also significantly 

increased (P < 0.1) the frequency of SCE. The investigators also concluded, based on 

nucleoid sedimentation assays with HeLa cells, that lead acetate inhibited repair of UVdamaged DNA. 

Hartwig (1994, 1995) published two reviews concerning the relationship between 

inhibition of DNA repair processes by metal ions and their genotoxicity. In these reviews, 

she summarized previous studies concerning the genotoxicity of a variety of metal ions, 

including lead(II). With respect to lead(II), she concluded, based on research primarily 

with CHO (V79) cells, that the direct genotoxicity of lead(II) was weak and restricted to 

toxic concentrations. Lead(II) induced DNA strand breaks only at toxic levels (Roy and 

Rossman 1992), but not at lower concentrations, and it did not induce DNA protein 

crosslinks as determined by alkaline elution (Zelikoff et al. 1988) or nucleoid 

sedimentation (Hartwig et al. 1990). Hartwig concluded that the mutagenic potential of 

soluble lead compounds was low (Roy and Rossman 1992) and that lead acetate and lead 

sulfide did not significantly increase the frequency of SCEs in exposed V79 cells 

(Zelikoff et al. 1988, Hartwig et al. 1990). Hartwig also summarized data that she 

believed demonstrated that lead compounds acted as co-mutagens (Hartwig et al. 1990, 

Roy and Rossman 1992), possibly by inhibiting nucleotide excision repair (Hartwig et al.

1990). However, as she pointed out, this explanation was controversial even at that time, 

because studies in HeLa cells demonstrated that while lead chloride (250 μM) inhibited 

the recovery of DNA synthesis after X irradiation, suggesting inhibition of DNA repair 

(Skreb and Habazin-Novak 1977), lead acetate had no effect on the resealing of X-rayinduced DNA strand breaks (Snyder et al. 1989). Hartwig suggested interference with 

DNA repair processes as a possible mechanism for the genotoxicity of metal ions, 
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132 

including lead(II), because these genotoxic effects were observed at low, nontoxic 

concentrations. 

Using a transgenic CHO cell line (G12) derived from V79 cells, Roy and Rossman 

(1992) reported that exposure to lead acetate (1.7 mM) for 5 days increased the frequency 

of gpt recorder gene mutations approximately fivefold. Mutation frequency was not 

increased at lower concentrations of lead acetate (0.5 and 1 mM), nor at any 

concentration of lead nitrate (0.5, 1, 1.7 mM). However, pre-exposure of G12 cells for 24 

hours to lead acetate at a nonmutagenic and slightly cytotoxic concentration (0.4 mM) 

increased the cytotoxicity and mutagenicity of N-methyl-N'-nitro-N-nitroguanidine and 

UVC light. The investigators concluded that lead(II) was weakly mutagenic and only at 

toxic doses (LD50 = 1.7 mM for lead acetate and 1.5 mM for lead nitrate), but that lead(II) 

might act as a co-mutagen at non-lethal concentrations. 

Lin et al. (1994) reported that lead nitrate (1, 5, 20, 30 μM) was not overtly cytotoxic to 

CHO cells (cell line not stated) (18.5% to 19.6% decrease in viability, based on trypan 

blue staining) following treatment for 16 hours. However, low concentrations of lead 

nitrate (1 and 3 μM) significantly increased the mitotic activity of exposed cells. Higher 

concentrations of lead nitrate (10 and 30 μM) did not significantly increase the mitotic 

index of exposed cells (number of cells in division/total number of cells x 100). 

Genotoxicity was assessed with assays for micronucleus formation, chromosomal 

aberrations, and SCE frequency. None of the concentrations of lead nitrate tested induced 

micronuclei or significantly increased chromosomal aberrations. However, lead nitrate (3, 

10, and 30 μM) did induce a significant increase (1.45- to 2.48-fold) in SCE. The 

investigators suggested that SCE may be the most sensitive end point for examining the 

genotoxicity of metal ions. 

Yang et al. (1996) reported that exposure of CHO cells (hprt+ cell line K1) to lead acetate 

(0.5 to 1.5 mM) for 24 hours increased the mutation frequency in a dose-dependent 

manner, ranging from a 3.36-fold increase at 0.5 mM to a 7.92-fold increase at 1.5 mM 

(the LD50). Reverse-transcriptase-polymerase chain reaction (PCR) and genomic-DNA 

PCR analyses of cDNA and genomic DNA from mutants from the various exposure 

groups suggested that G:C base pairs might be the primary target sites for lead 

mutagenesis. Furthermore, molecular analyses indicated that G:CÆC:G transversions 

predominated in low-mutation-frequency populations and G:CÆA:T transitions in highmutation-frequency populations. The authors suggested that lead might induce mutations 

by different mechanisms, possibly including interaction of the metal with DNA and 

subsequent reactive-oxygen-species- (ROS-) mediated damage and interference with 

DNA polymerase fidelity and DNA repair enzymes. 

Using the CHO cell line AA8, Cai and Arenaz (1998) reported that lead nitrate was 

cytotoxic in a concentration-dependent manner to cells exposed for 3 or 12 hours. Four 

concentrations of lead nitrate ( 0.5 to 1 μM) were tested, and cytotoxicity was determined 

with a clonogenic assay. Cells were exposed to lead nitrate (0.1, 0.5, 1 μM) for 24 or 36 

hours, and chromatids were differentially stained as described by Perry and Wolff (1974). 

A significant increase in SCE frequencies was observed at all lead nitrate concentrations 

tested, but there was no increase in the frequency of chromosomal aberrations. 
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133 

Hwua and Yang (1998) examined the effect of 3-aminotriazole, an inhibitor of catalase, 

peroxidase, and cytochrome P450 2E1, on anchorage independence and on the 

mutagenicity of cadmium acetate and lead acetate in primary diploid human fibroblasts. 

Exponentially growing cells were treated with 80 mM 3-aminotriazole 1 hour before 

exposure to cadmium acetate and lead acetate for 24 hours. The concentrations of lead 

acetate used in these studies were 0.5, 1.5, and 2 mM. After removal of the metal ions, 

the cells were maintained in exponential growth for 7 or 9 days before mutation and 

anchorage-independence assays, respectively, were performed. The cytotoxicity of lead 

acetate was determined by clonogenic assay. The concentration required to reduce the 

survival of treated cells to 37% was 0.8 mM. Lead acetate exposure significantly induced 

anchorage-independent growth in a dose-dependent manner. The numbers of anchorageindependent colonies induced per 106

 viable cells were 182.6 ± 16.9 at 1.5 mM and 

262.7 ± 37.8 at 2.0 mM. Exposure to lead acetate did not increase the frequency of hprt

gene mutations. Lead-induced anchorage independence and cytotoxicity were not 

affected by 3-aminotriazole cotreatment, but 3-aminotriazole did significantly increase 

lead uptake and accumulation in human fibroblasts. The investigators concluded that 

lead(II) might act as a tumor promoter, and that ROS were more important in cadmiumthan in lead-induced cytotoxicity and anchorage independence. 

In a series of studies using the transgenic CHO cell line AS52, Ariza and coworkers 

(Ariza and Williams 1996, 1999, Ariza et al. 1998) demonstrated that low, relatively 

nonlethal concentrations (0.1 to 1.0 μM) of lead chloride were mutagenic. At these 

concentrations, lead chloride was minimally cytotoxic to cells exposed for 1 hour (Ariza 

and Williams 1996). At the highest lead chloride concentration tested (1 μM), viability 

was reduced only by 28% in a clonogenic assay. Exposure of AS52 cells to lead chloride 

(at eight concentrations from 0.1 μM to 1 μM) for 1 hour resulted in a dose-dependent 

increase in the frequency of gpt transgene mutations. The increase in mutation frequency 

ranged from 2.5-fold at 0.1 μM to 6.2-fold at 1 μM. 

Multiplex PCR and Southern blot analyses were used to examine 138 lead-induced, 29 

ROS-induced, and 20 spontaneously arising mutants for point and deletion mutations in 

the gpt gene (Ariza and Williams 1999). Lead(II) induced significantly fewer point 

mutations (48%) than were observed in cells exposed to reactive oxygen intermediates 

(90%) or in spontaneous mutants (90%). Further examination of the data demonstrated 

that at lead chloride concentrations of 0.4 μM or lower, the majority of the mutations in 

the gpt gene were point mutations, while at higher concentrations, deletions (partial and 

complete) were predominant. These results are consistent with the hypothesis that soluble 

lead compounds induce mutations in eukaryotic cells by at least two distinct mechanisms 

(Yang et al. 1996, Ariza et al. 1998). 

5.4.1.2 Lead chromate 

Chromium metal salts, including lead chromate, have been classified as human 

carcinogens based on epidemiological and experimental data (IARC 1990). Several end 

points have been employed to assess the genotoxic potential of lead chromate, including 

enhancement of simian adenovirus transformation of SHE cells (Schechtman et al. 1986, 

Elias et al. 1989), morphological transformation of C3H/10T1/2 cells (Patierno et al.

1988, Patierno and Landolph 1989), morphological transformation of human 
05/08/03 RoC Background Document for Lead and Lead Compounds 

134 

osteosarcoma cells (Sidhu et al. 1991), induction of mutation in CHO cells (Patierno and 

Landolph 1989), induction of DNA strand breaks and DNA-protein crosslinks in CHO 

cells (Xu et al. 1992), and clastogenic effects in CHO and human fibroblasts (Wise et al.

1992, 1993, Blankenship et al. 1997). However, these studies did not separate the 

genotoxic effects of lead from those of chromium; therefore, they are not considered in 

this review. 

Wise et al. (1994), using CHO (AA8) cells, performed a series of studies designed to 

elucidate the relative roles of lead and chromium in the clastogenic activity of lead 

chromate. Cell-mediated extracellular dissolution of lead chromate resulted in 

intracellular accumulation of both lead and chromium. Accumulation of chromium was 

time- and concentration-dependent, and was maximal following a 24-hour exposure to 

lead chromate at 8 μg/cm2

. Accumulation of lead also was dose-dependent, but its timedependency was more variable. Under these conditions, the intracellular concentration of 

chromium was 2.75 ± 0.3 mM, and the concentration of lead was 97 ± 58 μM. In similar 

studies with lead glutamate (500 μM), the maximum intracellular lead ion concentration 

was 834 ± 63 μM. The clastogenic activity of lead chromate was 21% ± 7% at 0.8 μg/cm2

and 66% ± 17% at 8 μg/cm2. These percentages were significantly greater (P < 0.005) 

than in the vehicle control (3% ± 1%). Exposure of cells to sodium chromate (2 or 4 μM) 

resulted in a significant increase (P < 0.005) in chromosomal aberrations (12% ± 2% and 

23% ± 8%). Lead nitrate (0.5 to 1 mM) did not induce chromosomal aberrations. 

Although lead glutamate at a concentration of 1 mM significantly increased the frequency 

of chromosomal aberrations (11%), this effect was not observed at lower (0.5 mM) or 

higher (2 mM) concentrations. Pretreatment of cells with vitamin E reduced sodium 

chromate- and lead chromate-induced clastogenesis 54% to 93%, respectively, but the 

vitamin had no effect on lead glutamate-induced clastogenesis. The authors concluded 

that although lead ion was weakly clastogenic, chromate ion was the major clastogen in 

lead chromate (see Table 5-4).
05/08/03 RoC Background Document for Lead and Lead Compounds 

135 

Table 5-4. Genotoxicity of lead compounds in mammalian systems in vitro 

End point Test system Results Compound Concentration Reference 

Chromosomal aberrations 

CHO cells + lead acetate 0.001–10 mM Bauchinger and Schmid 1972a

Chromosomal aberrations 

CHO cells + lead acetate 0.05–1 mM Robison et al. 1984a

Chromosomal aberrations 

CHO cells + lead nitrate 0.1, 0.5, 1 

μM Cai and Arenaz 1998 

Chromosomal aberrations 

CHO cells + lead nitrate 0.5, 1, 2 mM Wise et al. 1994 

Chromosomal aberrations 

CHO cells – lead nitrate 3–30 

μM Lin et al. 1994 

SCE CHO cells – 

– 

lead nitrate lead sulfide 

500–3,000 

μM 

133–938 

μM 

Zelikoff et al. 1988 

SCE CHO cells – lead acetate 1–25 μM Hartwig et al. 1990 SCE CHO cells + lead nitrate 1–30 

μM Lin et al. 1994 

SCE CHO cells + lead nitrate 0.1–1 

μM Cai and Arenaz 1998 

Micronucleius formation 

CHO cells – lead nitrate 3–30 

μM Lin et al. 1994 

Micronucleus formation 

Sprague-Dawley rat kidney cells 

+ lead acetate 0.56–1.8 mM Robbiano et al. 1999 

Mitotic disturbance 

CHO cells + lead acetate 0.001–10 mM Bauchinger and Schmid 1972a

Mitotic disturbance 

CHO cells + lead sulfate 10, 20, 40 μM Costa et al. 1982a

Mitotic index CHO cells + lead nitrate 3–30 

μM Lin et al. 1994 
05/08/03 RoC Background Document for Lead and Lead Compounds 

136 

End point Test system Results Compound Concentration Reference 

Mutation in hprt gene 

CHO cells + lead nitrate 

lead sulfide 

50–2,000 

μM 

100–938 

μM 

Zelikoff et al. 1988 

Mutation in hprt gene 

CHO cells + lead acetate 0.5–2.0 mM Yang et al. 1996 

Mutation in hprt gene 

CHO cells – lead acetate 1 to 25 μM Hartwig et al. 1990 

Mutation in hprt

gene 

primary diploid human fibroblasts 

– lead acetate 0.5 to 2 mM Hwua and Yang 1998 

Mutation in gpt

gene 

transgenic CHO cells 

+ lead chloride 0.1–1 μM Ariza and Williams 1996, 1999, Ariz

al. 1998 

Mutation in gpt

gene 

transgenic CHO cells 

+ 

– 

lead acetate lead nitrate 

500–1,700 

μM 

500–1,700 

μM 

Roy and Rossman 1992 

Cell transformation 

SHE cells + lead acetate 10, 25, 50 μM Zelikoff et al. 1988 

DNA strand breaks 

CHO cells – 

– 

lead nitrate lead sulfide 

500–3,000 

μM 

133–938 

μM 

Zelikoff et al. 1988 

DNA strand breaks 

HeLa cells – lead acetate 100–2,000 μM Hartwig et al. 1990 

DNA repair CHO cells + lead acetate 0.05–1 mM Robison et al. 1984aDNA fragmentation 

Sprague-Dawley rat kidney cells 

+ lead acetate 0.56–1.8 mM Robbiano et al. 1999 

DNA damage transgenic CHO 

cells 

+ lead chloride 0.1–1 μM Ariza et al. 1998 

Inhibition of DNA and RNA synthesis 

HeLa cells – lead acetate 500 

μM Frenkel and Middleton 1987 
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137 

End point Test system Results Compound Concentration Reference 

Inhibition of DNA and RNA synthesis 

intact nuclei of HeLa cells 

+ lead acetate 80 

μM (RNA) and 

150 

μM (DNA) 

Frenkel and Middleton 1987 

Inhibition of DNA and RNA polymerase 

HeLa cells and E. coli

+ lead acetate 10–150 

μM Frenkel and Middleton 1987 

Studies of lead as a co-factor or co-mutagen 

Mutation in hprt gene, SCE, and nucleoid sedimentation 

CHO cells + 

increased 

genotoxicityb

UV irradiation pre-exposure to lead acetate 1–10 μM 

Hartwig et al. 1990 

Mutation in gpt

gene 

transgenic CHO cells 

+ 

increased 

mutagenicityc

N-methylN'-nitroNnitroguanidine 

or UVC pre-exposure to lead acetate 0.4 mM 

Robison et al. 1984 

aNot reviewed in text; source: ATSDR 1999. bThe authors proposed that the genotoxic effects of pretreatment with lead acetate resulted from inhibition of DNA repair. cThe authors proposed an increase in DNA nicks due to inhibition of DNA ligase as a possible mechanism for the effects of lead acetate 
05/08/03 RoC Background Document for Lead and Lead Compounds 

138 

5.4.2 In vivo assays 

5.4.2.1 Reproductive genotoxicity studies 

Nayak et al. (1989) determined the embryotoxicity and genotoxicity of lead nitrate using 

pregnant randomly bred ICR Swiss Webster mice (6 to 8 weeks old). Lead nitrate

dissolved in normal saline was given intravenously (i.v.) at doses of 100, 150, or 200 

mg/kg body weight on the ninth day of gestation. Fetuses were removed on the 18th day 

of gestation and used for cytogenetic and chemical studies. For cytogenetic studies, bone 

marrow cells were obtained from the femurs of three dams from each exposure group, 

and liver or lung tissues from three fetuses per dam. The cytogenetic studies included an 

analysis of numerical and gross cytogenetic changes in G-banded chromosomes, 

frequency of SCE, frequency of nucleolar organizing regions (NORs), and analysis of 

changes in G-banded karyotypes. The lead levels in maternal mice ranged from 0.04 ppm 

in non-exposed controls to 19.18 ppm in animals given 200 mg/kg of lead nitrate. The 

lead content in fetal tissue also increased (to a maximum 0.17 ppm in fetuses from dams 

given lead nitrate, compared with 0.07 ppm in fetuses from non-exposed controls). The 

percentage of resorptions was significantly higher (P < 0.05) in the lead-exposed animals 

than in non-exposed controls. The frequency of SCE also was significantly higher (P < 

0.05) in dams given lead nitrate at either 150 mg/kg (4.87 ± 0.16 SCEs/cell) or 200 

mg/kg (5.51 ± 0.17 SCEs/cell) than in the controls (3.40 ± 0.15 SCEs/cell). No 

significant difference was observed in the frequencies of SCE or NORs between fetuses 

from exposed animals and those from controls. The frequency of NORs per cell was 

significantly reduced (P < 0.05) at the two highest lead nitrate dose levels; the 

frequencies were 2.50 ± 0.39 at 150 mg/kg, 2.31 ± 0.23 at 200 mg/kg, and 4.1 ± 0.38 for 

controls. Aneuploidy was frequently associated with the lowest dose level of lead nitrate 

(100 mg/kg). Deletions also occurred frequently and involved several chromosomes. 

Kristensen et al. (1993) performed dominant-lethal studies of lead chloride and 

cyclophosphamide to quantify the genotoxic effects of lead chloride in late 

spermatogenesis. Male mice (Mus musculus strain NMRI) were randomly assigned to 

four treatment groups (6 per group), and two groups received drinking water containing 

1.33 g/L of lead chloride for six weeks. One week (seven days) before mating, one leadexposed group received an i.p. injection of cyclophosphamide (120 mg). Blood lead 

concentrations (μmol/L [μg/dL]) at time of mating were as follows: control group, 0.03 ± 

0.02 [0.6 ± 0.4]; lead group, 1.24 ± 0.24 [34.3 ± 5.0]; cyclophosphamide group, 0.01 ± 

0.02 [0.2 ± 0.4]; and lead plus cyclophosphamide group, 1.15 ± 0.14 [23.8 ± 2.9]. After 

mating, female mice were examined for the number of implants, number of live implants, 

number of resorptions, number of late implant losses, and mortality. Although the 

frequency of resorptions was lower in females mated with lead-treated males, the 

difference was not statistically significant. The data suggest that inorganic lead does not 

influence the mutagenicity of cyclophosphamide in the dominant-lethal assay. 

Foster et al. (1996) investigated the effect of chronic lead exposure on semen quality in 

healthy cynomolgus monkeys (Macaca fascicularis) aged 15 to 20 years with mean (± 

SD) blood lead levels of 10 ± 3 μg/dL (range = 6 to 20 μg/dL, N = 4) and 56 ± 49 μg/dL 

(range = 22 to 148 μg/dL, N = 7) compared with a reference group with blood lead levels 

< 1.0 μg/dL (N = 8). Monkeys had been exposed to lead acetate (50, 100, 500, or 2,000 
05/08/03 RoC Background Document for Lead and Lead Compounds 

139 

μg/kg body weight) since birth. Blood and semen samples were collected once from each 

monkey in five different months. Serum testosterone levels were determined by 

radioimmunoassay, and lead effects on chromatin structure were analyzed by flow 

cytometry. No effects of treatment were observed on circulating levels of testosterone or 

parameters of semen quality such as sperm count, viability, motility, or morphology. A 

single sperm sample from each monkey was analyzed for effects on chromatin structure 

(Evenson 1990). In the flow-cytometric-based assay, sperm with abnormal chromatin 

structure are defined as having an increased susceptibility to acid denaturation, resulting 

in a shift from green to red fluorescence, expressed as αt and determined by the ratio of 

red fluorescence to total fluorescence. Sperm from lead-exposed monkeys had 

significantly different (P < 0.03) αt values than that from the controls. Sperm quality also 

differed significantly (P < 0.05) among the lead-exposed groups. The authors concluded 

that chronic lead exposure altered sperm chromatin structure. 

5.4.2.2 Genotoxicity studies in mammals 

Dhir et al. (1993) determined the effects of Phyllanthus emblica fruit extract (PFE) and 

ascorbic acid on the ability of lead to induce SCE in the bone marrow of Swiss albino 

male mice (Mus musculus). The mice were 6 to 8 weeks old, weighed 25 to 30 g, and 

were divided into exposure groups of five animals each. Mice were treated with a single 

priming dose of PFE by oral gavage (685 mg/kg b.w.) or with ascorbate (16.6 mg/kg 

b.w.) for seven consecutive days before exposure to lead nitrate. Bromodeoxyuridine 

(BrdU) was implanted subcutaneously in the abdomen as described by Sharief et al.

(1986). Immediately after, mice were injected i.p. with lead nitrate in saline at 

concentrations of 10, 20, or 40 mg/kg b.w. Mice were injected i.p. with colchicine 22 

hours after BrdU implantation and sacrificed by cervical dislocation 2 hours later. Bone 

marrow cells were obtained from femurs, and differential staining was performed as 

described by Perry and Wolff (1974) and Giri et al. (1987). Sixty intact second-division 

metaphase cells per animal were scored for SCEs, for a total of 300 cells per exposure 

group. In vivo exposure to lead nitrate resulted in a significant (P < 0.001) dosedependent increase in SCE frequency over that in the control group. The increase was 

2.5-, 3.7-, and 4.2-fold for mice exposed to lead nitrate at 10, 20, and 40 mg/kg, 

respectively. No difference was noted in the proliferation index. Pretreatment with PFE 

or ascorbate significantly (P < 0.001) reduced the increase in SCE, compared with that 

observed in animals exposed to lead nitrate alone. 

To determine the clastogenic effect of lead nitrate, Jagetia and Aruna (1998) employed 

the micronucleus assay. Swiss albino mice (either sex) were injected i.p. with lead nitrate 

at 0, 0.625, 1.25, 2.5, 5, 10, 20, 40, or 80 mg/kg b.w., and animals were sacrificed at 12, 

24, or 36 hours post-treatment. Bone marrow cells from femurs were prepared as 

described by Jagetia and Jacob (1992). The frequencies of micronucleated polychromatic 

erythrocytes (MPCE) and micronucleated normochromatic erythrocytes (MNCE) at 12, 

24, and 36 hours after treatment were significantly higher in exposed mice than in 

controls. The increase in frequency of micronuclei was not dose-related and was greater 

in male than in female mice. Lead nitrate exposure also resulted in increased 

erythropoiesis, as the ratios of polychromatic to normochromatic erythrocytes (P/N ratio) 

were significantly higher in lead-exposed mice than in controls at 12, 24, and 36 hours 
05/08/03 RoC Background Document for Lead and Lead Compounds 

140 

post-exposure. The P/N ratio was significantly higher in females than in males at 12 and 

24 hours post-exposure. 

Robbiano et al. (1999) examined five chemicals, including lead acetate, that are known to 

induce tumors in rats; these chemicals induce DNA damage and micronuclei formation in 

primary cultures of rat and human kidney cells and in the kidneys of intact rats (SpragueDawley male albino rats). DNA damage was tested with the comet (single-cell gel 

electrophoresis) and micronucleus assays. Primary cells were exposed to lead acetate 

(0.56, 1, or 1.8 mM) for 20 hours and immediately used for the comet assay or were 

cultured for a total of 48 hours for the micronucleus assay. Cytotoxicity was determined 

following 20 hours of exposure to the compound, and relative survival was based on 

trypan blue exclusion. The relative survival of primary rat and human kidney cells ranged 

from 84% to 96%. Data from the comet assay, based on cells pooled from three different 

rats and cells from three different human donors, demonstrated that lead acetate induced a 

dose-dependent increase in both tail length and tail moment, indicating DNA 

fragmentation. DNA fragmentation was significantly (P < 0.05) greater than in vehicle 

controls. Similar results were obtained with the micronucleus assay. Lead acetate induced 

a 3.7- to 6.4-fold increase in micronucleated primary rat cells and a 3.6- to 7.1-fold 

increase in micronucleated primary human kidney cells; these increases were statistically 

significant (P < 0.05). Consistent with the results observed in vitro, statistically 

significant increases in the average frequency of both DNA breaks and micronucleated 

cells were detected in the kidneys of rats given a single dose of lead acetate (0.5 LD50) or 

three successive daily doses (0.33 LD50). DNA fragmentation, based on the Comet assay, 

increased 5.3-fold at a lead acetate concentration of 107 mg/kg (three successive daily 

doses). The frequency of micronucleated cells increased 3.2-fold in animals given a 

single dose of lead acetate (160 mg/kg b.w.) and 3.8-fold in animals given three 

successive daily doses of 107 mg/kg b.w. 

To determine whether lead enhanced the genotoxic effect of the pyrethroid cypermethrin 

[(RS)-α-cyano-3-phenoxybenzyl(1RS)-cis,trans-3-(2,2-dichlorovinyl)-2,2-

dimethylcyclopropanecarboxylate], an insectide, Nehez et al. (2000) administered 

cypermethrin to outbred male Wistar rats (30 days old) by gavage for 4 weeks, five times 

per week, at 5.54, 11.08, or 22.16 mg/kg b.w. (1/100, 1/50, or 1/25 LD50) alone or in 

combination with 10 mg/kg lead acetate at the 1/100 and 1/50 LD50 dose levels. 

Following treatment, animals were sacrificed, and bone marrow cells were obtained from 

the femur. Twenty metaphases from 10 animals per group were evaluated for the number 

of aberrant cells, numerical aberrations (chromosome number under or over 42), and 

structural aberrations (gaps, iso gaps, breaks, iso breaks, chromatid exchange, acentric 

fragments, dicentric and ring chromosomes, deletions, and translocations). Exposure to 

lead acetate significantly increased the frequencies of aberrant cells (18% vs. 5.5% for 

vehicle control; P < 0.01) and numerical chromosomal aberrations (16% vs. 6% for 

vehicle control; P < 0.05) but did not affect the frequency of structural chromosomal 

aberrations (1% in control and exposed groups). The combination of cypermethrin and 

lead acetate significantly increased the frequency of aberrant cells (21.5% at a 

cypermethrin concentration of 5.54 mg/kg; P < 0.01; 25% at a cypermethrin 

concentration of 11.08 mg/kg; P < 0.001) over that in vehicle-treated cells (10%). The 

frequency of numerical aberrations was not significantly increased by cypermethrin and 
05/08/03 RoC Background Document for Lead and Lead Compounds 

141 

lead acetate in combination. However, the frequency of structural chromosomal 

aberrations was significantly increased (7.0% at a cypermethrin concentration of 5.54 

mg/kg; P <0.05; 11.5% at a cypermethrin concentration of 11.08 mg/kg; P < 0.001). The 

authors concluded that the co-administration of lead increased the genotoxic effect of 

cypermethrin (see Table 5-5). 

Table 5-5. Genotoxicity of lead compounds to mammals in vivo

End point Results Species Compound Concentrationa Reference 

Reproductive genotoxicity studies 

SCE 

fetuses 

dams 

– 

+ 

ICR Swiss Webster 

mice: pregnant 

mice exposed and 

genotoxicity 

measured in 

maternal bone 

marrow and fetal 

liver and/or lung 

cells 

lead nitrate 

100, 150, 200 

mg/kg b.w. 

150, 200 mg/kg 

b.w. 

Nayak et al.

1989 

NORs 

fetuses 

dams 

– 

+ 

ICR Swiss Webster 

mice: pregnant 

mice exposed and 

genotoxicity 

measured in 

maternal bone 

marrow and fetal 

liver and/or lung 

cells 

lead nitrate 

100, 150, 200 

mg/kg b.w. 

150, 200 mg/kg 

b.w. 

Nayak et al.

1989 

Chromosomal 

aberrations 

fetuses 

dams 

+ 

+ 

ICR Swiss Webster 

mice: pregnant 

mice were exposed 

and genotoxicity 

was measured in 

maternal bone 

marrow and fetal 

liver and/or lung 

cells 

lead nitrate 

100 mg/kg b.w. 

100, 150, 200 

mg/kg b.w. 

Nayak et al.

1989 

Fetal resorptions in 

unexposed females 

mated with leadexposed males 

– male NMRI mice 

exposed before 

breeding 

lead chloride 1.33 g/L in water Kristensen et 

al. 1993 

Sperm morphology – male White New 

Zealand rabbits 

lead acetate 0.25, 0.5 mg/kg 

b.w. 

Willems et al.

1982b

Abnormal chromatin 

structure in sperm 

+ Cynomolgus 

monkey sperm 

cells 

lead acetate 50, 100, 500, 2,000 

μg/kg b.w. 

Foster et al.

1996 
05/08/03 RoC Background Document for Lead and Lead Compounds 

142 

End point Results Species Compound Concentrationa Reference 

Animal genotoxicity studies 

DNA fragmentation + 

(both doses) 

male albino 

Sprague-Dawley 

rat kidney cells 

lead acetate 117 mg/kg (1 dose) 

78 mg/kg (3 

doses) 

Robbiano et 

al. 1999 

Chromosome loss or 

nondisjunction 

– Drosophila 

melanogaster 

lead nitrate 200 ppm in corn 

meal-agar substrate 

Ramel and 

Magnusson 

1979b

Structural 

chromosomal 

aberrations or 

chromatid gaps 

+ 

aberrations 

– gaps 

C57B1 mouse bone 

marrow 

lead acetate 0.5% in food Deknudt and 

Gerber 1979b

Structural 

chromosomal 

aberrations or 

chromatid gaps 

– aberrations 

+ gaps 

A/sw mouse 

leukocytes 

lead acetate 1% in food Muro and 

Goyer 1969b

Structural 

chromosomal 

aberrations or 

chromatid gaps 

– aberrations 

+ gaps 

female C57B1 

mouse bone 

marrow 

lead acetate 0.50%, 1% in food Jacquet et al.

1977b

Structural 

chromosomal 

aberrations or gaps 

+ Sprague-Dawley 

rat bone marrow 

lead acetate 10.4, 51.8, 77.6, 

103.5 mg/kg b.w. 

Tachi et al.

1985b

Chromosomal 

aberrations 

+ male Wistar rats 

bone marrow 

lead acetate 10 mg/kg b.w. Nehez et al.

2000 

Structural 

chromosomal 

aberrations or gaps 

+ Cynomolgus 

monkey 

lymphocytes 

lead acetate 1.5, 6, 15 mg/day 

in water 

Deknudt et al.

1977b

Structural 

chromosomal 

aberrations or gaps 

+ Cynomolgus 

monkey 

lymphocytes 

lead acetate 1, 5 mg/day Jacquet and 

Tachon 1981b

Micronucleus 

formation 

+ Sprague-Dawley 

rat bone marrow 

lead acetate 10.4, 51.8, 77.6, 

103.5 mg/kg b.w. 

Tachi et al.

1985b

Micronucleus 

formation 

+ 

(both doses) 

male albino 

Sprague-Dawley 

rat kidney cells 

lead acetate 117 mg/kg (1 dose) 

78 mg/kg (3 doses) 

Robbiano et 

al. 1999 

Micronucleus 

formation 

+ Swiss albino 

mouse bone 

marrow 

lead nitrate 0.625, 1.25, 2.5, 5, 

10, 20, 40, 80 

mg/kg b.w. 

Jagetia and 

Aruna 1998 

Micronucleus 

formation 

– C57BL/6 x 

C3H/He F1 mice 

lead acetate 125, 250, 500, 

1,000 mg/kg b.w. 

Bruce and 

Heddle 1979b

Micronucleus 

formation 

– male rabbit bone 

marrow 

erythrocytes 

lead acetate 0.25, 0.5 mg/kg 

b.w. 

Willems et al.

1982b

SCE – male rabbit 

peripheral blood 

lymphocytes 

lead acetate 0.25, 0.5 mg/kg 

b.w. 

Willems et al.

1982b
05/08/03 RoC Background Document for Lead and Lead Compounds 

143 

End point Results Species Compound Concentrationa Reference 

SCE + male Swiss albino 

mouse bone 

marrow 

lead nitrate 10, 20, 40 mg/kg 

b.w. 

Dhir et al.

1993 

Cellular 

proliferation 

– male Swiss albino 

mouse bone 

marrow 

lead nitrate 10, 20, 40 mg/kg 

b.w. 

Dhir et al.

1993 

a

The concentration reported is the dose level at which treatment-related effects were observed. 

b

Not reviewed in text; source: ATSDR 1999. 

5.4.2.3 Human genotoxicity studies 

Summary of ATSDR review 

ATSDR (1999) reviewed genotoxicity studies of humans exposed to lead in vivo (mainly 

from occupational studies) published through 1994 and concluded that although the 

results were somewhat contradictory, they did suggest that lead might have an effect on 

chromosomes. Occupational exposure to lead was associated with increased mitotic 

activity or effects on cell division. Most, but not all, studies reported higher frequency of 

chromosomal aberrations in workers exposed to lead, and mixed results were reported for 

SCE. ATSDR noted that a common problem in these occupational studies was the 

possibility of confounding by occupational co-exposures. These studies and others 

published since 1994 (discussed below), are summarized in Table 5-6. 

Current studies 

Rajah and Ahuja (1995) examined the in vivo genotoxic effects of smoking and 

occupational lead exposure in printing press workers. The study population contained 29 

males, including 13 printing-press workers and 16 individuals from the general 

population. Previous studies had indicated that atmospheric lead levels from the printing 

press were three times as high as background levels. A questionnaire was used to obtain 

data on age; duration of lead exposure; smoking; alcohol, coffee, and drug consumption; 

and recent illnesses. The subjects were divided into four groups: nonsmoking controls 

(N = 9), smoking controls (N = 7), lead-exposed nonsmokers (N = 7), and lead-exposed 

smokers (N = 6). Mitotic index and SCE were determined in peripheral blood 

lymphocytes. Lead-exposed smokers had the lowest mitotic index (0.78), compared with 

smoking controls (1.24) and lead-exposed nonsmokers (1.26); however, significance 

testing was not reported for the difference between lead-exposed smokers and smoking 

controls. The lead-exposed nonsmokers also had a significantly (P < 0.05) lower mitotic 

index than did nonsmoking controls. Smokers in the control and lead-exposed groups had 

significantly (P < 0.05) higher frequencies of SCE than did the nonsmoking controls 

(5.66 ± 1.52/cell for smoking controls, 5.37 ± 2.53/cell for lead-exposed smokers, and 

3.22 ± 0.47/cell for nonsmoking controls). The frequency of SCE in the lead-exposed 

nonsmokers (3.75 ± 0.58/cells) did not differ significantly from that in the non-smoking 

controls (3.22 ± 0.47/cell). The authors concluded that the combination of smoking and 

lead exposure increased the frequency of SCE and inhibited mitosis, but that lead 

exposure did not appear to increase genotoxic damage beyond that caused by smoking 

alone. [The ability to separate the effects of lead from those of smoking or to evaluate 

any possible interactions between lead and smoking was limited by small numbers in 
05/08/03 RoC Background Document for Lead and Lead Compounds 

144 

each exposure category (N = 6 or 7) and by the lack of quantitative information on 

smoking and lead exposure. Individuals smoking 10 or more cigarettes per day for more 

than a year were considered smokers; thus, the “smoker” groups included both light and 

heavy smokers, and it is not known whether the degree of smoking was similar between 

the lead-exposed smokers and the smoking controls.] 

Vaglenov et al. (1997) correlated micronucleus formation in lead smelter workers with 

lead air concentrations at the work site, blood lead levels, employment period, and 

smoking habits. A total of 73 male workers were grouped by occupation: millers (N = 

23), assembly workers (N = 21), plate-stacking workers (N = 20), and formation workers 

(N = 9). Controls were 23 males from administration and maintenance staff of the same 

plant who were never in direct occupational contact with lead. The total exposed group 

and controls also were subdivided into smokers and nonsmokers. The frequency of 

micronucleated cells per 1,000 binucleated lymphocytes was measured in peripheral 

blood lymphocytes. The mean concentration of lead in the air at the work sites was 0.7 ± 

0.5 mg/m3

 for mill workers, 0.38 ± 0.3 mg/m3 for assembly workers, 0.23 ± 0.2 mg/m3 

for plate-stacking workers, and 0.19 ± 0.1 mg/m3

 for formation workers. The mean air 

lead concentration for controls at the same factory was 0.06 ± 0.02 mg/m3. 

Mean blood lead concentrations for 65 of the 73 workers were over the “dangerous” level 

of 1.92 μmol/L [40 μg/dL], which is associated with biological effects. Elevated 

micronucleus frequencies were observed in lead-exposed workers from the four groups, 

and micronucleus frequency was correlated with external exposure (air lead 

concentrations) and internal exposure (blood lead levels). The micronucleus frequencies 

per 1,000 binucleated cells for the groups were 51.1 for mill workers, 46.5 for assembly 

workers, 37.3 for plate-stacking workers, and 35.2 for formation workers, for an average 

of 44.0 for the lead-exposed group, compared with 20.1 for the control group. The 

number of cells containing micronuclei also was significantly higher in the lead-exposed 

group than in the control group. For the whole group, analysis of variance showed that 

lead exposure, but not age and smoking, was correlated with micronucleus formation. 

The genotoxic effect was linearly dependent (P < 0.001) on the internal exposure, 

supporting an association between lead exposure and micronucleus formation. 

Micronucleus frequency did not differ significantly (P > 0.05) between lead-exposed 

smokers and nonsmokers, but did differ significantly between the control-group smokers 

and nonsmokers. [Strengths of this study include quantitative assessment of lead 

exposure (both external and internal); larger numbers of smoking (44) and nonsmoking 

(29) lead-exposed workers; evaluation of effects of different variables, such as smoking, 

age, and lead exposure; greater power to detect an effect, due to the high lead-exposure 

levels; and the finding of an exposure-response relationship. Limitations included the 

small number of controls and small subsets of smoking (10) and nonsmoking (13) 

controls and the lack of reported quantitative information on smoking habits.] 

Bilban (1998) analyzed the incidence of cytogenetic damage in peripheral blood 

leukocytes of miners working in a lead and zinc mine in Slovenia (N = 120 males; 52% 

smokers), housewives living in the immediate vicinity of the mine, but not occupationally 

exposed (control group 1: N = 57 females; 17% smokers), and an independent control 

group (control group 2: N = 100; 86 males, 14 females; 58% smokers). Workers were 
05/08/03 RoC Background Document for Lead and Lead Compounds 

145 

exposed to metals, including lead, cadmium and zinc, and radon. The blood lead 

concentration in the lead-exposed miners averaged 28 μg/dL, but 16% of these miners 

had blood lead concentrations greater than 40 μg/dL (the permissible value recommended 

by the World Health Organization in 1980). The blood lead concentration in the control 

groups averaged 7.2 μg/dL. Peripheral blood leukocytes were examined for structural 

chromosomal aberrations, SCE, and micronucleus formation. 

The frequencies of chromosomal aberrations, SCE, and micronuclei were significantly 

higher in the miners than in the control groups. The mean percentages of cells with 

chromosomal aberrations were 4.09% (21,600 cells examined) in miners, 1.43% (11,400 

cells) in control group 1, and 1.88% (20,000 cells) in control group 2. The mean 

frequencies of SCE were 7.97 per cell (5,800 cells examined) in miners, 6.17 (2,850 

cells) in control group 1, and 6.63 (3,050 cells) in control groups 2. The frequency of 

micronucleated cells was 13.00 ± 3.55 per 500 cytokinesis cells (60,000 cells examined) 

for miners and 6.40 ± 2.12 (29,000 cells) in control group 2. Blood lead concentration 

and years worked in the mine were significantly correlated (P = 0.012). SCE frequency 

was significantly dependent on blood lead concentration (P = 0.001), as well as smoking. 

Chromosomal aberrations, but not SCE, were significantly dependent on radiation dose 

(radon). Moreover, smoking and the frequency of micronucleated cells were 

significantly correlated (P = 0.001). The purpose of this study was to detect cytogenetic 

damage in the miners; the authors cautioned that it was not possible to separate the 

individual effects of the different occupational exposures, as well as any effects from 

smoking. [The strongest evidence of lead-induced cytogenetic damage probably was for 

SCE, because SCE frequency depended on blood lead levels and not on radon dose. 

Strengths of this study include larger numbers of exposed workers, measurements of 

blood lead levels and other occupational exposures, and smoking information. 

Limitations include the lack of a relevant control group (that is, workers not exposed to 

lead) and the lack of analysis to control for confounders (occupational or lifestyle).] 

Donmez et al. (1998) examined SCE frequencies in 32 male workers in a lead and zinc 

powder-producing factory in Turkey. The controls were 20 male sugar-refinery workers 

matched for age, smoking habits, and alcohol consumption. Metal-exposed workers had 

statistically significant higher blood lead levels than the controls (P < 0.0001), but the 

differences in blood zinc levels between groups were not significant (P > 0.05). 

Peripheral blood lymphocytes were evaluated for SCE; for each subject, the frequency of 

SCE was determined in 30 metaphases. The frequency of SCE was significantly higher in 

lead- and zinc-exposed subjects (P < 0.01) than in the controls (mean SCE per cell = 8.55 

in exposed subjects vs. 7.55 in controls), and was significantly higher in nonsmoking 

lead- and zinc-exposed subjects than in nonsmoking controls (P < 0.01). SCE frequency 

also was significantly higher (P < 0.01) in control smokers than in control non-smokers 

(8.74 vs. 7.16). [Strengths of this study included matching of controls by age, smoking, 

and alcohol consumption, which minimized possible confounding by these variables. 

Although the study population was small, significant differences were observed; 

however, the further stratification of the small number of workers and controls into 

smokers and non-smokers could result in spurious associations.] 
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146 

Vaglenov et al. (1998) monitored the genotoxic effects of lead in 22 male workers from a 

starter-battery plant in Bulgaria who were heavily exposed to lead (0.45 ± 0.5 mg/m3

 lead 

in air at the workplace, which exceeded the threshold limit value of 0.1 mg/m3). Two 

control groups were included: an internal control group of 19 male workers from the 

same plant without direct lead exposure (control group 1) and an external control group 

of 19 male workers from the administrative staff of another factory in the same town 

(control group 2). A questionnaire was used to obtain data on smoking and alcohol 

consumption habits. Blood lead levels were 0.88 ± 0.03 μmol/L [18.23 ± 0.62 μg/dL] for 

control group 2, 1.33 ± 0.08 μmol/L [27.56 ± 1.66 μg/dL] for control group 1, and 2.94 ± 

2.15 μmol/L [60.92 ± 44.55 μg/dL] for the lead-exposed workers. 

The frequency of micronucleated cells per 1,000 binucleated lymphocytes was 

determined from peripheral blood lymphocytes. The lead-exposed workers had a higher 

frequency of micronucleated cells (61.95 ± 3.31) and larger numbers of binucleated cells 

containing one or more micronuclei (53.09 ± 2.36) than did the internal controls (26.47 ± 

2.71 micronuclei and 23.74 ± 2.34 binucleated cells containing micronuclei) or the 

external controls (19.68 ± 2.14 micronuclei and 18.84 ± 2.09 binucleated cells containing 

micronuclei). [Strengths of this study were good exposure assessment of lead (both air 

concentrations and blood levels were measured) and the lack of any apparent 

occupational exposure to other genotoxic agents. Limitations included the small number 

of subjects and the lack of exposure-response analyses; however, the numbers may have 

been too small for the latter.] Although the authors assessed and reported smoking 

(cigarettes per day) for each individual, they did not appear to use this information in 

their analyses. The lead-exposed group included a higher percentage of smokers (77%) 

than did either control group 1 (58%) or control group 2 (63%), but the average cigarettes 

per day in the lead-exposed group (13.2) was intermediate between the averages for the 

two control groups (11.1 for control group 1 and 15.7 for control group 2). [Percent 

smokers and average cigarettes per day were calculated from data reported in the 

publication. Because micronucleus formation was two- to three-fold higher in the leadexposed workers than in the control groups, and the difference in smoking between the 

exposed and control groups did not appear to be substantial, it seems unlikely that 

smoking confounded these results.] 

To explore the possible relationship between lead exposure and DNA damage and 

oxidative stress in Chinese secondary lead smelter workers, Ye et al. (1999) correlated 

DNA damage as measured by the comet assay with concentrations of blood lead, urinary 

lead, and urinary α-aminolevulinic acid. Malondialdehyde (MDA) concentrations and 

superoxide dismutase (SOD) activity in plasma also were determined. Information was 

obtained by questionnaire concerning gender, age, duration of work, job type, cigarette 

smoking, and alcohol consumption. Heparinized blood and urine were obtained from 66 

secondary lead smelter workers (41 male and 25 female) (46 used for the comet assay) 

and 28 controls (18 male and 10 female). Subjects were divided into four groups based on 

blood lead concentrations (< 13, 13 to 27, 27 to 37, and > 37 μg/dL). SOD activity and 

MDA concentrations were significantly higher in females in the three highest blood lead 

groups than in the lowest blood lead group, and SOD activity was higher in males with 

the highest blood lead levels; smoking and alcohol consumption did not significantly 
05/08/03 RoC Background Document for Lead and Lead Compounds 

147 

affect MDA concentrations or SOD activity. A positive correlation was observed between 

the blood lead concentration and DNA damage, which was statistically significant 

(P < 0.05) for blood lead concentrations greater than 27 μg/dL. Amounts of DNA 

damage differed significantly between lead-exposed workers with the same smoking 

levels or alcohol consumption but different lead levels, except for nonsmokers and the 

low-lead-exposure group. DNA damage also increased with increasing smoking levels at 

the same blood lead levels. [Strengths of this study were the finding of an exposureresponse relationship between lead exposure and DNA damage and attempts to separate 

genotoxic effects of lead exposure from those of cigarette smoking. Another strength was 

measurement of MDA concentrations and SOD activity, which are markers of oxidative 

stress; elevated levels were consistent with potential mechanisms of lead-induced DNA 

damage. A potential limitation of the study was the stratification of a small number of 

subjects on many different variables (i.e., gender, smoking status, and lead exposure), 

resulting in very small numbers in each subgroup, which can yield spurious results.] 

Restrepo et al. (2000) investigated the relationship between lead exposure and DNA 

damage and repair in 43 Colombian battery-factory workers and 13 controls who were 

not occupationally exposed to lead. Individuals completed a questionnaire on smoking 

habits, age, and medical and occupational histories. Workers were highly exposed to 

lead; 74% of the exposed workers exhibited clinical symptoms of lead toxicity, including 

headache, abdominal colic, metallic taste, and paresthesia. The average blood lead 

concentration of the lead-exposed workers (98.5 ± 25.3 μg/dL) was much higher than that 

of the non-exposed group (5.4 ± 3.6 μg/dL). Lead-exposed workers and controls were 

subdivided into four groups according to classification of their blood lead concentrations 

by Colombia’s National Institute of Health: (1) lower than 40 μg/dL (normal), (2) 41 to 

80 μg/dL (acceptable), (3) 81 to 120 μg/dL (excessive), and (4) greater than120 μg/dL 

(dangerous). [The normal blood lead group consisted of the 13 controls, who had blood 

levels of less than 15 μg/dL.] Approximately 70% of the workers had blood lead levels 

classified as excessive or dangerous. DNA damage was measured by the comet assay, 

using whole blood, and DNA repair capacity was assessed by measuring DNA damage 

before and after in vitro exposure of the cells to X rays, after various incubation times. A 

statistically significant (P < 0.05) difference in both the level of basal DNA damage 

(before irradiation) and level of DNA damage induced by X radiation was observed 

between the lowest and highest categories of lead exposure. Multiple regression analysis, 

in which variables included length of employment, age, and blood lead concentrations, 

showed that lead concentration was the main factor contributing to sensitization to 

genotoxic damage (that is, the difference in DNA damage before and immediately after 

irradiation). No significant differences in DNA repair capacity (as measured by DNA 

damage following incubation after irradiation) among the different blood level groups 

were observed. The comet assay under alkaline conditions mainly detects single-strand 

breaks, whereas X rays induced both single- and double-strand breaks; thus, repair of 

double-strand breaks was not measured in this study. Only 9% of the population smoked, 

and the authors stated that smoking habits had no effect on DNA damage. [Strengths of 

this study included measurement of blood lead concentration and the ability to control for 

smoking.] 
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148 

Wu et al. (2002) evaluated SCE frequencies in 57 lead-exposed workers and 30 workers 

not occupationally exposed to lead (controls) at a storage-battery manufacturer in 

Taiwan. Blood lead levels were measured, and lead-exposed workers were divided into a 

high-blood-level group (≥ 15 μg/dL; mean = 32.5 μg/dL; N = 23) and low-blood-level 

group (< 15 μg/dL; mean = 9.3 μg/dL; N = 34). The mean blood lead level in controls 

was 4.2 μg/dL. Zinc protoporphyrin also was measured and was significantly higher in 

both the high- and low-blood-level groups than in controls. [As discussed in Section 2, 

zinc protoporphyrin is a biomarker of effect, arising from the disturbance of heme 

synthesis by lead.] SCE, high-SCE frequency cells (HFCs) and DNA–protein crosslinks 

were measured by fluorescence spectrophotometry in peripheral blood lymphocytes 

collected from the subjects. An HFC was defined as a cell having a SCE frequency over 

the median 95% value from the 19 nonsmoking control subjects. SCE frequencies and 

percentages of HFCs and DNA–protein crosslinks were significantly higher in the highblood-level group (6.1 SCEs/cell, 11% HFC, and 1.5% crosslinks) than in the controls 

(5.2 SCEs/cell, 3% HFC, and 1.0% crosslinks). Moreover, frequencies of SCE and 

percentages of HFCs and DNA–protein crosslinks also were significantly higher in both 

smoking and nonsmoking workers with high blood lead levels than in smoking and 

nonsmoking controls. Multiple linear regression analysis showed that smoking and blood 

lead levels but not age and gender were significantly associated with the percentage of 

DNA–protein crosslinks and SCE frequency. [A strength of this study was the use of 

multiple linear regression models to adjust for age, gender, and smoking.] 
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Table 5-6. Genotoxicity of lead compounds in vivo in humans 

End point Results 

Blood lead 

levela 

(μg/dL) Exposure (country) Reference 

Chromosomal 

aberrations in peripheral 

blood lymphocytes 

+ 37.7 lead-exposed workers Schwanitz et al.

1970b,c Schwanitz et 

al. 1975b,c 

Chromosomal 

aberrations in peripheral 

blood lymphocytes 

+ 38 to 64 storage-battery plant workers 

(Italy) 

Forni et al. 1976b

Chromosomal 

aberrations in peripheral 

blood lymphocytes 

+ > 50 lead-exposed smelter workers 

(Sweden) 

Nordenson et al. 1978b

Chromosomal 

aberrations in peripheral 

blood lymphocytes 

+ 38 to 96 storage-battery plant workers 

(Iraq) 

Al-Hakkak et al. 1986b

Chromosomal 

aberrations in peripheral 

blood lymphocytes 

+ 22 to 48 storage-battery plant workers 

(China) 

Huang et al. 1988b,d

Chromosomal 

aberrations (also 

significantly dependent 

on radiation dose) in 

peripheral blood 

lymphocytes 

+ 27.9 lead and zinc mine workers, 

also exposed to metals and 

radon 

(Slovenia) 

Bilban 1998 

Chromosomal 

aberrations in peripheral 

blood lymphocytes 

+/– 40 to > 120 shipyard workers 

(Scotland) 

O'Riordan and Evans 

1974b

Chromosomal 

aberrations in peripheral 

blood lymphocytes 

– average 48.7 lead smelter workers 

(Finland) 

Maki-Paakkanen et al.

1981b

Chromosomal 

aberrations in peripheral 

blood lymphocytes 

– > 30 children living near lead plant 

(Germany) 

Bauchinger et al.

1977b

Chromosomal 

aberrations 

– NA lead manufacturing industry 

(The Netherlands) 

Schmid et al. 1972b,c 

Chromosomal 

aberrations in peripheral 

blood lymphocytes 

– 40 volunteers who ingested lead 

acetate (49 days) 

(The Netherlands) 

Bijlsma and de France 

1976e,f

SCE in peripheral blood 

lymphocytes 

+ 22 to 48 storage-battery plant workers 

(China) 

Huang et al. 1988b,d

SCE in peripheral blood 

lymphocytes (exposureresponse with blood 

lead levels) 

+ 27.9 lead and zinc mine workers, 

also exposed to metals and 

radon 

(Slovenia) 

Bilban 1998 
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End point Results 

Blood lead 

levela 

(μg/dL) Exposure (country) Reference 

SCE in peripheral blood 

lymphocytes 

+ 13.81 lead and zinc powder factory 

(Turkey) 

Donmez et al. 1998 

SCE in peripheral blood 

lymphocytes 

High-SCE-frequency 

cells 

+ 

+ 

32.5 battery manufacturer 

(Taiwan) 

Wu et al. 2002 

SCE in peripheral blood 

lymphocytes 

+/–g

 average 48.7 lead smelter workers 

(Finland) 

Maki-Paakkanen et al.

1981b

SCE in peripheral blood 

lymphocytes 

+/–h

 29 to 75 storage-battery plant workers 

(Denmark) 

Grandjean et al. 1983b

SCE in peripheral blood 

lymphocytes 

– 29 to 63 children living near lead 

smelter 

(Italy) 

Dalpra et al. 1983b

SCE in peripheral blood 

lymphocytes 

– NA battery factory workers 

(Mexico) 

Leal-Garza et al.

1986b

SCE in peripheral blood 

lymphocytes 

– NR printing-press workers 

(India) 

Rajah and Ahuja 1995 

Micronuclei in 

peripheral blood 

leukocytes 

+ 67.55 lead smelter workers 

(Bulgaria) 

Vaglenov et al. 1997 

Micronuclei in 

peripheral blood 

leukocytes 

+ 27.9 lead and zinc mine workers, 

workers also exposed to metals 

and radon 

(Slovenia) 

Bilban 1998 

Micronuclei in 

peripheral blood 

leukocytes 

+ 60.92 starter-battery plant 

(Slovenia) 

Vaglenov et al. 1998 

Micronuclei in blood 

lymphocytes 

+ 40 metal-powder producing 

workers (lead, zinc, cadmium) 

(Turkey) 

Hamurcu et al. 2001 

DNA-protein crosslinks 

in peripheral blood 

lymphocytes 

+ 32.5 battery manufacture workers 

(Taiwan) 

Wu et al. 2002 

DNA damage (comet 

assay) in peripheral 

blood lymphocytes 

significant relationship 

at blood levels > 27 

μg/dL 

+ four groups: 

< 13 

13 to 27 

27 to 37 

> 37 

lead smelter workers 

(secondary) 

(China) 

Ye et al. 1999 
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151 

End point Results 

Blood lead 

levela 

(μg/dL) Exposure (country) Reference 

DNA damage (comet 

assay) in peripheral 

blood lymphocytes 

basal level 

sensitivity to X rays 

+ 

+ 

41 to >120 battery factory workers 

(Colombia) 

Restrepo et al. 2000 

DNA damage (comet 

assay) 

+ 39 battery factory workers 

(Italy) 

Fracasso et al. 2002 

DNA repair capacity 

(comet assay) after 

exposure to X rays in 

peripheral blood 

lymphocytes 

– 41 to > 120 battery factory workers 

(Colombia) 

Restrepo et al. 2000 

Higher mitotic activity 

in peripheral blood 

lymphocytes 

+ 40 volunteers who ingested lead 

acetate (49 days) 

(The Netherlands) 

Bijlsma and de France 

1976b,e

Decrease in mitotic 

index in peripheral 

blood lymphocytes 

+ NR printing press workers 

(India) 

Rajah and Ahuja 1995 

Increased mitotic 

activity 

+ NA lead-exposed workers 

(Germany) 

Schwanitz et al.

1970b,c 

Effects on cell division + NA (not available) Sarto et al. 1978b,c 

a

NA = not available; NR = not reported. 

b

Not reviewed in text; source: ATSDR 1999. 

c

Foreign-language publication, not reviewed here; results are those reported by ATSDR 1999. 

d

Incorrectly listed in ATSDR (1999) as environmentally exposed children and as reporting negative results 

for SCE; no papers by Huang and genotoxicity in environmentally exposed children were found. 

e

Incorrectly listed in ATSDR (1999) as Bulsma. 

f

Study was reviewed in ATSDR (1999) (see mitotic index), but chromosomal aberrations were not 

reported. 

g

SCE frequency was higher in lead-exposed smokers than in non-exposed smokers, but not higher in leadexposed nonsmokers than control non-smokers. 

h

ATSDR (1999) also reported a slight positive correlation with duration but not level of exposure. 

5.5 Summary 

Lead induced chromosomal aberrations in most studies in plants and in mammals (in 

vitro and in vivo) and DNA damage and fragmentation in mammals (in vivo; conflicting 

results were observed in in vitro studies) and cell-free systems (in the presence of 

hydrogen peroxide) and inhibited DNA and RNA polymerase in cell-free systems and 

mammalian cells (in vitro). Conflicting results were observed for SCE and micronucleus 

induction in mammalian studies (in vitro and in vivo). Lead was not mutagenic in 

bacteria, and conflicting results were observed in mammalian in vitro systems. 

Conflicting results may reflect differences in the model systems employed, the end points 
05/08/03 RoC Background Document for Lead and Lead Compounds 

152 

used to determine genotoxicity, and the lead compounds employed. In studies of humans 

occupationally exposed to lead, there is evidence to suggest that lead damages 

chromosomes or DNA; most studies were positive for induction of micronuclei, 

chromosomal aberrations, and DNA damage. Studies on SCE and studies in humans 

exposed environmentally to lead gave conflicting results. Studies in humans sometimes 

are difficult to evaluate, because little information is given on how the populations were 

selected for study and because of potential exposure to compounds from occupational or 

environmental sources that may act in conjunction with lead to increase its genotoxic 

potential. Likewise, personal habits such as cigarette smoking and alcohol consumption 

affect the genotoxic properties of various compounds, including lead. However, many of 

the more recent studies either controlled for smoking or reported an exposure-response 

relationship, suggesting that the genotoxic effects were due to lead exposure. Although 

lead(II) forms stable complexes with the nitrogenous bases and phosphate groups of 

purified DNA, it is unlikely that lead compounds are directly genotoxic. However, 

several mechanisms exist by which lead compounds could indirectly alter DNA 

replication, fidelity, and repair, resulting in genotoxicity. 
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153 

6 Other Relevant Data 

This section is divided into three subsections: (1) absorption, distribution, and excretion 

of lead in humans, (2) other toxic effects of lead compounds, and (3) mechanistic studies 

relevant to lead carcinogenicity. In all subsections, the majority of the discussion focuses 

on human studies, since these are extensive. 

6.1 Absorption, distribution, and excretion of lead in humans 

6.1.1 Inorganic lead 

6.1.1.1 Absorption 

Inorganic lead can be absorbed by inhalation of fine particles and by ingestion. Before 

lead is absorbed by the lungs, a fraction of the inhaled lead is deposited in the respiratory 

tract. In adults, the rate of deposition of airborne lead is approximately 30% to 50%. This 

rate is dependent on the size of the particles and the ventilation rate of the individual. 

Smaller particles (< 1 μm) have been shown to have greater deposition and absorption 

rates than larger particles (ATSDR 1999). 

Ingestion of inorganic lead results in gastrointestinal (GI) absorption in humans and 

rodents. Although GI absorption is influenced by chemical species, no inorganic lead 

compound studied to date is completely unavailable, as demonstrated in studies of rats by 

Dieter et al. (1993). GI absorption of lead also is age-dependent in humans and rodents. It 

is estimated that young children absorb 4 to 6 times more lead than do adults. Dietary 

constituents, also may influence GI absorption, as shown in Table 6-1. Deficiencies in 

iron, calcium, and zinc appear to increase the GI absorption of lead, while a high-protein 

diet appears to reduce absorption (Hammad et al. 1996). 

Lead also can be absorbed through the skin, as demonstrated by a study in which 4.4 mg 

of lead (as lead acetate or lead nitrate) was applied to the skin under a covered plastic 

patch on the forearms of human subjects; 1.3 mg of lead was not recovered from washing 

of the skin and was detected in sweat, blood, and urine within 6 hours of the application 

(Stauber et al. 1994). 
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Table 6-1. Effects of nutritional elements on gastrointestinal lead absorption in 

animals 

Element Species Index of effect Interactive effect 

Calcium rat lead in tissues and severity of 

effect at low levels of dietary 

calcium 

low dietary calcium (0.1%) increases 

lead absorption and severity of effects 

Calcium rat lead retention calcium deficiency increases retention 

Calcium rat lead in tissues at high levels of 

dietary calcium during 

pregnancy 

high dietary calcium reduces release of 

lead from bone 

Calcium pig lead in tissues at low levels of 

dietary calcium 

low dietary calcium increases lead 

absorption 

Calcium horse lead in tissues at low levels of 

dietary calcium 

low dietary calcium increases lead 

absorption 

Calcium lamb lead in tissues at low levels of 

dietary calcium 

low dietary calcium increases lead 

absorption 

Calcium chick lead absorption and retention calcium deficiency increases lead 

absorption and retention 

Iron rat tissue levels and relative toxicity 

of lead 

iron deficiency increases lead absorption 

and toxicity 

Iron rat lead absorption in everted 

duodenal sac preparation 

reduction in intubated iron increases lead 

absorption; increased levels decrease 

lead uptake 

Iron rat in utero or milk transfer of lead 

in pregnant or lactating rats 

iron deficiency increases both in utero 

and milk transfer of lead to sucklings 

Iron mouse lead retention iron deficiency has no effect on lead 

retention 

Protein rat body lead retention low dietary protein either reduces or 

does not affect lead retention in various 

tissues 

Protein rat tissue levels of lead casein diet increases lead uptake, 

compared with soybean meal 

Protein rat lead uptake by tissues both low and high dietary protein 

increase lead absorption 

Milk 

components 

rat lead absorption lactose-hydrolyzed milk does not 

increase lead absorption, but ordinary 

milk does 

Milk 

components 

rat lead absorption lactose in diet increases lead absorption, 

compared with glucose 

Zinc rat lead absorption low-zinc diet increases lead absorption 

Zinc rat lead transfer in utero and in milk 

during lactation 

low-zinc diet of mother increases lead 

transfer in utero and in maternal milk 

Zinc rat tissue retention low-zinc diet increases brain lead levels 

Sources: Fullmer 1997 (chick), ATSDR 1999 (all others). 
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6.1.1.2 Distribution and PBPK models 

The mean-life of lead in blood is approximately 30 days. In blood, lead is partitioned 

between red cells and plasma. The relationship between whole-blood lead and plasma 

lead is linear at lower concentrations, but at higher concentrations, levels in plasma are 

higher than would be expected based on a linear relationship (Manton et al. 2001) (see 

Figure 6-1). 

Source: ATSDR 1999. 

Figure 6-1. Curvilinear relationship of human serum lead to blood lead 

Note: Crosshatched area represents several overlapping data points. 

Extensive physiologically based pharmacokinetic (PBPK) modeling has been conducted 

on inorganic lead in both adults and children (O'Flaherty 1993, 1995). The skeleton is a 

major compartment for inorganic lead deposition in mammals; between 75% and 90% of 

the body burden of lead is found in bones and teeth. In humans, bone lead levels 

gradually increase over the lifespan, as demonstrated in a series of autopsy and biopsy 

studies by Aufderheide et al. (1992). The half-life of lead in bone depends on bone type; 

it is estimated that the half-life of lead in cortical bone may be as long as 25 years 

(Marcus 1985). For this reason, analyses of teeth and bone provide an integrated 

biomarker of previous lead exposure, which has been used in several important studies of 

lead toxicity in both children and adults. Lead also is transferred across the placenta and 
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156 

is excreted in breast milk. Some evidence indicates that the fetus accumulates lead in 

both the skeleton and soft tissue (ATSDR 1999). 

6.1.1.3 Mobilization 

Skeletal lead can be mobilized under normal and pathophysiological conditions that 

affect bone mineral metabolism. For example, lead is mobilized from the skeleton during 

pregnancy and lactation, as demonstrated in a series of elegant studies using stable 

isotope analysis to distinguish skeletal lead from environmental lead in Australian 

women (Gulson et al. 1997). In women, lead also is released from bone stores at 

menopause (Silbergeld et al. 1988), which can result in significant elevations of blood 

lead that may be associated with increases in blood pressure and other toxic effects 

(Hertz-Picciotto and Croft 1993). Pathophysiological conditions that favor bone 

resorption, such as Paget’s disease, hypothyroidism, and prolonged bed rest, also increase 

blood lead concentrations; this occurrence has been interpreted as a redistribution of bone 

lead into blood (Silbergeld et al. 1993). 

Mobilization of maternal lead during pregnancy was studied in female Sprague-Dawley 

rats (Buchet et al. 1977). Treatment regimens included controls (group 1), rats given 1 

mg/L of lead as lead nitrate in drinking water for 150 days before mating, over gestation, 

and for three weeks after parturition (group 2), rats given 1 mg/L lead in drinking water 

for 150 days before mating, discontinued on day 1 of pregnancy (group 3), and rats given 

1 mg/L lead in drinking water for 150 days, but discontinued 50 days before mating 

(group 4). On day 21 after delivery, lead concentrations and free porphyrins were 

measured in blood and various tissues. The results are summarized in Table 6-2. It was 

concluded that lead stored in the organism could be mobilized during gestation. 

Lead also has been measured in a variety of tissue samples in humans. In one study 

investigating levels of inorganic chemicals in brain tumors, Al-Saleh and Shinwari (2001) 

measured concentrations of lead, as well as cadmium and mercury, in samples of tumors 

from 23 patients with malignant and 21 patients with benign brain tumors who were 

undergoing treatment at a Saudi Arabian hospital. Lead levels were somewhat higher in 

malignant than in benign tumors (0.65 vs. 0.61 μg/g); however, the authors noted that 

these concentrations were much higher than reported for brain tissue in a non-Saudi 

population. In addition, the lack of any biomarker surveyed in nondiseased tissue or other 

indices of cumulative lead exposure and the absence of a true control group for 

comparison preclude reliable inference from this study. 
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Table 6-2. Mobilization of lead during gestation in Sprague-Dawley rats 

Concentration of lead 

on day 31 after delivery 

Concentration of free 

porphyrins in brain 

on day 31 after delivery 

Exposure group Blood (μg/L) Brain (ng/mg of protein) (ng/mg of protein) 

Group 1 (controls) 

Mothers 30 0.5 1.0 

Offspring 20 0.02 0.8 

Group 2 (exposed before mating, over gestation, and after parturition) 

Mothers 18 0.2 0.7 

Offspring 9 0.02 0.7 

Group 3 (exposed before mating) 

Mothers 11 0.2 0.9 

Offspring 6 0.02 0.8 

Group 4 (exposed until 50 days before mating) 

Mothers 49 0.7 1.6 

Offspring 36 0.23 1.1 

Source: Buchet et al. 1977. 

6.1.1.4 Excretion 

Excretion of lead does not depend on the route of exposure (ATSDR 1999). Dietary lead 

excreted in the feces includes both lead that was not absorbed by the GI tract and lead 

that was excreted in the bile. The major routes of excretion of absorbed lead are urinary 

and biliary clearance, and excretion of lead in the feces generally is greater than excretion 

in the urine. In rats, fecal excretion of lead due to biliary clearance may still exceed 

urinary excretion even for lead administered i.v. Excretion in rats, dogs, and mice is a 

multiphasic process. In rats, excretion of lead following i.v. administration is biphasic, 

with half-lives of 21 hours for the fast phase and 280 hours for the slow phase. In dogs, a 

triphasic process with half-lives of 12, 184, and 4,951 days has been reported. The 

terminal phase of the biphasic elimination curve observed for mice had a half-life of 110 

days. In humans, the total excretion rate may be lower in infants than in adults, resulting 

in retention of a larger percentage of the total amount of lead absorbed. 

6.1.2 Organic lead compounds 

Organic lead compounds are toxicokinetically distinct from inorganic lead compounds in 

terms of absorption and distribution. Eventually, organic lead compounds are dealkylated 

by hepatic metabolism and stored in the body as inorganic lead. Owing to their greater 

lipophilicity, organic lead compounds are rapidly partitioned into soft tissues, as 

demonstrated by average lead levels in major viscera (i.e., lung, brain, liver, kidney, 

spleen, and heart tissue) of approximately 7 to 100 mg/kg in rats and 7 to 30 mg/kg in 
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158 

dogs following inhalation exposure to lethal doses of tetraethyl lead (12 to 46 mg/m3) or 

tetramethyl lead (4 to 63 mg/m3

) (Davis et al. 1963). 

It has been shown that inhalation of TEL results in much higher levels of lead in the brain 

than does exposure to inorganic lead. Boudene et al. (1977) exposed 40 female Wistar 

rats to an aerosol of gasoline containing 0.6 g/L of tetraethyl lead and enhanced with 

organic 210Pb chelated with dibenzoylmethane. Animals were placed in a box and 

breathed the gasoline aerosol for 30 to 45 minutes. Lead was rapidly cleared from the 

lungs, with less than 10% remaining after 48 hours. Six days after exposure, 40% of the 

dose was eliminated in the feces and 15% in the urine; 40% was fixed in the bones, 4% 

was distributed among soft tissues, and 1% remained in the lungs. In another inhalation 

study (nose-only exposure), 203Pb-labelled TEL was administered over 40 to 60 minutes 

(Morgan and Holmes 1978). Approximately 20% to 25% of lead particulates generated 

from engine exhaust was deposited in the lungs of 12 male albino rats, and at least half of 

the deposited lead was absorbed, with a half-life of less than one hour. Less than 2% 

remained in the lungs after 7 days. 

Organic lead compounds also have been shown to be rapidly and extensively absorbed 

through the skin of rats and rabbits (ATSDR 1999). One study showed that 0.75 mL of 

TEL applied to the abdominal skin of rabbits resulted in 1.06 mg of lead being detected 

in the carcass after 0.5 hours and 4.41 mg after 6 hours of exposure. However, these 

measurements did not include the contents of the intestinal tract, which were 

inadvertently discarded. Following dermal application of 0.75 mL of TEL to three other 

rabbits, 7.9 to 9.3 mg of lead was detected in the carcasses after 4 hours of exposure 

(Kehoe and Thamann 1931). 

Excretion of organic lead differs from that of inorganic lead (see Section 6.1.1.4, above). 

A major route of elimination of inhaled tetraalkyl lead compounds is exhalation (ATSDR 

1999). 

6.2 Other toxic effects of lead compounds 

The toxicity of lead compounds to humans has been extensively studied. For the last 100 

years, considerable attention has been focused on the neurotoxic effects of lead 

compounds in young children, following reports of the exposure of children to lead-based 

house paint. Because of the very large amount of published literature on lead toxicity, this 

section will provide only a brief review, with references to major reviews and 

government documents. 

Human exposure to lead is regulated in the occupational and non-occupational 

environments (see Section 2.9 and Appendix A for lists of lead regulations). Several end 

points of concern have been associated with human exposure to lead and lead 

compounds; end points identified in adults, children, and/or fetuses include (but are not 

limited to) neurotoxicity, nephrotoxicity, hematoxicity and anemia, reproductive toxicity, 

developmental toxicity, and cardiovascular toxicity. The end points are discussed briefly 

below. 
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159 

6.2.1 Neurotoxicity 

By the 1930s, it was increasingly recognized that exposure to lead compounds (inorganic, 

lead carbonate based, and lead chromate and oxide pigments) was a frequent cause of 

encephalopathy in children. Under conditions of chronic exposure, the neurotoxic effects 

of exposure to lead in paint included loss of speech, seizures, and coma (McKhann 1932). 

Children who survived these severe events frequently were retarded intellectually and in 

their motor skills (Silbergeld 1997). Reviews of several large prospective studies of 

children’s neurocognitive and behavioral development reached a consistent conclusion 

that “subencephalopathic” exposures to inorganic lead, i.e., at doses associated with 

blood lead levels as low as 10 μg/dL, are significantly associated with poor outcomes in 

neurocognitive and behavioral development and with impairments in attention, hearing, 

and school attainment (ATSDR 1999, Silbergeld 1997). 

Although the CNS toxicity of lead in children became the critical end point in pediatrics, 

inorganic lead compounds also can affect both CNS and peripheral nervous system (PNS) 

function in adults. Neurotoxic manifestations depend on both dose and duration of 

exposure. High levels of exposure cause disabling impairments in PNS function, 

described as “painter’s wrist” or “foot drop” in the 18th and 19th centuries, as well as 

profound mental changes and cognitive impairments, which were observed in workers in 

lead industries in the 19th century. In the 1920s, when production of TEL began in the 

United States, cases of acute psychosis and hallucinations in workers were reported. 

Some recent reviews (Stewart et al. 2002, Kamel et al. 2002) have suggested that adult 

lead exposure may be associated with increased risks of neurodegenerative disease in 

aging, specifically, amyotrophic lateral sclerosis and dementias. 

6.2.2 Nephrotoxicity 

The renal toxicity of lead has been well described for over 100 years. Acute 

nephrotoxicity has been described in lead-intoxicated children (Loghman-Adham 1997). 

The evidence in both humans and experimental animals indicates that thresholds exist for 

lead nephropathy. In rodents, proximal tubular injury occurs at blood lead levels of 

60 μg/dL. Observations in humans indicate that blood lead levels greater than 60 μg/dL 

for up to 12 years are required for nephropathy. Increased risk of end-stage renal failure 

has been reported in lead workers long after cessation of exposure. 

6.2.3 Hematoxicity and anemia 

Lead inhibits the biosynthesis of heme through highly specific interactions with one of 

the rate-limiting enzymes in this pathway, ALAD. As a consequence of this effect, levels 

of some heme precursors are elevated (by feedback deregulation), and heme levels are 

decreased (Silbergeld 1987). These effects have been widely used as biomarkers for lead 

exposure, but they also represent toxic effects of lead and may play a role in target organ 

responses. Inhibition of heme production, along with toxic effects on globin synthesis and 

erythrocyte integrity, is associated with anemia at high levels of exposure (> 40 μg/dL). 
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160 

6.2.4 Reproductive toxicity 

Lead is toxic to sperm and can alter endocrine function in adults. Decreases in 

spermatologic parameters were reported in men exposed to inorganic lead compounds in 

battery plants and were associated with blood lead levels as low as 40 μg/dL, which are 

well within current occupational standards; in some cases, these deficits were ameliorated 

when lead exposure and blood lead levels were reduced (Sallmen 2001). No specific 

effects of lead have been reported on female reproduction; however, lead is toxic to fetal 

development, and these effects sometimes are misinterpreted as effects on pregnant 

women or women of childbearing age. 

6.2.5 Developmental toxicity 

Lead crosses the placenta and is accumulated in fetal organs, including the brain. High 

exposure to inorganic lead can induce intrauterine death and stillbirth. At lower levels, 

prenatal exposure to lead, indicated by cord blood lead level obtained at parturition, is 

associated with a range of adverse effects, including decreased growth in stature and 

delays in early infant development. If no further elevated lead exposure occurs after birth, 

development generally, but not always, normalizes, as demonstrated in longitudinal 

studies in which the subjects were enrolled prior to birth (Bellinger et al. 1992). 

6.2.6 Cardiovascular toxicity 

Several studies have reported significant associations between blood lead level and blood 

pressure in adult men and women (Hertz-Picciotto and Croft 1993, ATSDR 1999). In 

both of the NHANES surveys (II and III) of lead exposure and health status in the United 

States, blood lead level was positively associated with blood pressure, in a dose-related 

fashion. It was estimated that the effects of lead exposure on blood pressure contribute 

significantly to risks of hypertensive heart disease and stroke in the U.S. population. 

6.2.7 Other effects in rodents 

It is important to note that all of these toxic effects of lead described in human 

populations have been observed in rodent models at similar blood lead levels. Lead 

induces both PNS and CNS toxicity; affects CNS development in young animals, 

resulting in impaired learning performance and hyperactivity; inhibits heme biosynthesis; 

affects intrauterine growth; affects auditory-evoked responses; impairs reproductive 

function in males; and induces hypertension. 

6.3 Mechanisms of lead carcinogenesis 

Knowledge of the mechanisms by which metals cause cancer remains uncertain, even for 

those metals for which the evidence of human carcinogenicity is considered adequate. At 

high concentrations, lead can bind to DNA and change its conformation (Smirnov and 

Shafer 2000), break nucleic acids (Brown et al. 1983, Wedrychowski et al. 1986), and 

induce cell proliferation, measured by increased mitotic indices or increased thymidine 

incorporation (Calabrese and Baldwin 1992). However, the exposure levels used in these 

studies are well above the levels associated with other severe toxic effects of lead, 

including tissue damage and cytotoxicity. Because lead can cause tumors in experimental 
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161 

animals at exposure levels that are not associated with tissue damage (Waalkes et al.

1995), these events probably are not relevant to mechanisms of carcinogenesis. 

6.3.1 Possible mechanisms of genotoxicity and carcinogenicity 

Even though lead has been intensely studied for many years, the mutagenic, clastogenic, 

and carcinogenic properties of lead and lead compounds are not well understood. IARC 

(1980, 1987) has determined that there is sufficient evidence to conclude that lead and 

inorganic lead compounds cause cancer in experimental animals, but that sufficient 

evidence in humans is lacking. Several possible mechanisms have been examined to 

better understand the carcinogenic properties of lead and the conditions required for this 

effect. These include mitogenesis, chronic nephropathy, effects on gene transcription, and 

various indirect mechanisms of genotoxicity. 

6.3.1.1 Mitogenesis 

Increased cell proliferation (40-fold) was noted in the proximal tubular epithelium of 

adult female Sprague-Dawley rats following a single i.p. injection of lead acetate at 40 

mg/kg b.w. No renal pathology was noted in lead-exposed rats. A similar increase in the 

mitotic index (45-fold) was observed in the proximal and distal epithelium of the renal 

cortices of adult female CD-1 mice given a single dose of lead acetate at 5 mg/kg b.w. As 

in the rat study, no detectable microscopic lesions were observed in the renal tubules 

(Choie and Richter 1972). A similar proliferative mitogenic response, but of lesser 

magnitude, was observed in the liver of adult male Wistar rats following administration 

of a single dose of lead acetate at 100 μmol/kg b.w. Lead acetate caused a significant 

enlargement of the liver, with a 30-fold increase in DNA synthesis as measured by 

labeled thymidine incorporation (Columbano et al. 1983). In this context, several other 

studies were conducted to determine whether mitogen-induced cell proliferation in the 

liver supported the formation of foci. 

A series of studies used diethylnitrosamine to initiate hepatocytes in male Wistar rats 

(Columbano et al. 1990, Ledda-Columbano et al. 1992, Coni et al. 1993a, 1993b). 

Regenerative mitogenesis was stimulated by partial hepatectomy and carbon 

tetrachloride, whereas proliferative mitogenesis was stimulated by i.v. injection of 100 

μmole/kg of lead nitrate and other mitogenic chemicals. Both types of treatment induced 

cell proliferation primarily within zone 1, produced a similar labeling index (65% to 

70%), and stimulated serum growth factors capable of inducing DNA synthesis in 

primary hepatocyte cultures. However, the initiated hepatocytes did not respond to lead 

nitrate but did respond to regenerative mitogenic stimuli. Therefore, DNA synthesis alone 

apparently is not a sufficient condition for cancer development. Some possible 

explanations include differences in the genes involved in the growth signal transduction 

and growth factors induced, elimination of altered hepatocytes by apoptosis during 

regression after proliferative mitogenesis, or differences in the subpopulation of cells 

responding (ploidy state). 

Coni et al. (1993b) provided evidence of differences in patterns of mRNA expression for 

growth factors following regenerative mitogenesis and proliferative mitogenesis. 

Following partial hepatectomy or carbon tetrachloride administration, increased 
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162 

expression of c-fos, c-jun, and c-myc were noted; however, following lead nitrate 

administration, only expression of c-jun increased. Furthermore, studies by LeddaColumbano et al. (1994) demonstrated that a single injection of lead nitrate induced a 

rapid increase in tumor necrosis factor-α (TNF-α). Inhibition of TNF-α resulted in an 

inhibition of liver cell proliferation, suggesting that TNF-α is involved in triggering 

proliferative mitogenesis in the liver. This finding is in contrast to observations on 

regenerative mitogenesis, in which the primary growth factors involved are hepatocyte 

growth factor, transforming growth factor-α, and transforming growth factor-β

(Kinoshita et al. 1989, Lindroos et al. 1991). These studies suggest that proliferative 

mitogenesis induced by chemical exposure, unlike regenerative mitogenesis, does not 

have a significant role in initiation or promotion of hepatocarcinogenesis. Although the 

mechanism by which lead induces renal tumors in rodents has not been established, 

mitogenesis may be a contributing factor. Furthermore, marked differences in organspecific susceptibility to this response are consistent with observations of renal but not 

liver tumors in animals (Calabrese and Baldwin 1992). 

6.3.1.2 Nephropathy 

Because the kidney is a frequent target for lead-induced cancer, studies have been 

undertaken to test the hypothesis that renal cancers are a consequence of renal pathology 

due to lead exposure. Goyer (1993) reviewed several current issues in regard to lead 

toxicity, including nephropathy and cancer. As described above, the toxic effects of lead 

on the kidney in both humans and experimental animals begin with morphologic changes 

in tubular endothelial cells, which may slowly progress to a chronic irreversible 

nephropathy after years of heavy exposure (Fowler 1993). The role of nephrotoxicity in 

renal carcinogenesis remains unclear. In rodents, progression from acute reversible 

nephropathy to chronic irreversible nephropathy to renal adenocarcinoma has been 

demonstrated; however, the evidence in humans is less clear. No evidence indicates that 

lead induces male-specific nephropathy or hyaline-droplet nephropathy. As noted in 

Section 4, lead can induce tumors in female and male mice, as well as rats, and at 

exposures that do not induce frank renal toxicity. 

A characteristic histologic finding of early or acute lead-induced nephropathy is the 

appearance of intranuclear inclusion bodies in renal proximal tubule cells (VicenteOrtega et al. 1996). These bodies contain lead complexed with acidic proteins, which 

may include human lead-binding protein or similar proteins; in this complex, lead is 

bound in a nondiffusible form (Moore and Goyer 1974, Saryan and Zenz 1994). Inclusion 

bodies are thought to represent a defense mechanism by which the cytoplasmic 

concentrations of lead are lowered. Furthermore, since they are excreted in the urine, 

inclusion bodies would provide the kidneys with a method for eliminating surplus lead 

without destroying the viability of the tubular lining cells (Saryan and Zenz 1994). Few 

or no nuclear inclusion bodies are observed in chronic lead nephropathy (ATSDR 1999). 

The presence of intranuclear inclusion bodies in the kidney is used as a primary 

biomarker of effect for lead (ATSDR 1999). 

Following in vivo lead exposure, lead inclusion bodies commonly are found in the 

cytoplasm and the nuclei of osteoclasts, but not of other bone cells (Pounds et al. 1991). 
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163 

These inclusion bodies may contain high-affinity binding proteins and may sequester 

lead, but also may indicate a potential for modulation of gene expression. High-affinity 

cytosolic lead-binding proteins also have been identified in the kidneys and brain. These 

high-affinity zinc- and lead-binding proteins are thought to moderate the inhibition of 

ALAD by lead through chelation of lead and donation of zinc; these proteins 

subsequently translocate lead to the nucleus, where it may influence gene expression. In 

the rat kidney, the high-affinity lead-binding protein was found in intranuclear inclusion 

bodies and was associated with nuclear chromatin. Similar lead-binding proteins have 

been found in human kidney, liver, and brain cytosol. In rats, the brain lead-binding 

protein is not the same as that found in the kidney and is developmentally regulated. Only 

traces of this protein were detected in neonatal rats, but protein concentrations increased 

to adult levels within 2 weeks; the increased protein levels also resulted in increased 

resistance to lead-induced encephalopathy. Development of this resistance is 

hypothetically related to the formation of lead-protein inclusion bodies in the astroglia, 

which, as they mature, develop the ability to sequester lead (ATSDR 1999). 

6.3.1.3 Clastogenicity 

Exposure of mice to lead causes chromosomal damage (Winder and Bonin 1993, Johnson 

1998). More recently, Valverde et al. (2002) administered lead to mice by inhalation at a 

concentration of 0.0068 μg/cc (equivalent to 6.8 mg/m3) for 60 minutes twice per week; 

they reported induction of DNA damage, detectable by electrophoresis, in many organs, 

including liver, kidney, brain, and lung. Yuan and Tang (2001) reported detection of 

DNA damage in the comet assay in the second and third generations of mice exposed to 

lead in drinking water at 1 or 0.25 mg/L. Consistent with these findings in experimental 

systems, researchers have reported chromosomal aberrations, micronuclei, and increased 

SCE in studies of lead-exposed workers (Gebhart 1984, Johnson 1998). However, these 

effects were not found consistently and generally were reported in occupational cohorts 

(Vaglenov et al. 2001) with blood lead levels in excess of the current OSHA standard 

(30 μg/dL). 

6.3.1.4 DNA repair 

The strongest evidence that lead may be permissive rather than initiating in its 

carcinogenic effects comes from studies of co-exposures to lead and directly genotoxic 

agents. As discussed in Section 5.3.1, lead in vitro can increase mutations in cells 

exposed to UV radiation (Hartwig 1994), X rays (Fischer and Skreb 2001), or the 

chemical mutagen N-methyl-N ́-nitrosoguanidine (Roy and Rossman 1992). Similar in 

vivo interactions between lead and sensitivity to genotoxic agents were suggested by 

Restrepo et al. (2000), who exposed lymphocytes from battery workers to X rays in vitro. 

These effects may be due to lead’s ability to decrease the accuracy of DNA polymerase 

and the fidelity of RNA synthesis. As reported by Zelikoff et al. (1988), lead affects 

DNA synthesis fidelity in CHO V79 cells. Hartwig et al. (1990) reported that lead 

interferes with repair of UV-induced DNA damage in vitro, which appears to be the same 

mechanism by which several toxic heavy metals act to prevent closure of single-strand 

DNA breaks (Snyder et al. 1989). 
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6.3.1.5 Oxidative damage 

A general mechanism for metal toxicity involves generation of free radicals, either 

through depletion of cellular antioxidants, such as glutathione, or production of ROS 

(Klein et al. 1991). Lead has been shown to increase hydrogen peroxide production in 

cells (Ariza et al. 1998, Yang et al. 1999) (see Sections 5.3.1 and 5.4). In the presence of 

exogenously added hydrogen peroxide, lead increases the formation of the DNA adduct 

8-OHdG (Yang et al. 1999). Fracasso et al. (2002) reported that significantly elevated 

levels of DNA breaks in lymphocytes of lead-exposed battery plant workers were 

significantly and positively correlated with ROS production and negatively correlated 

with glutathione levels. In addition, both the increase in ROS and the decrease in 

glutathione levels differed significantly between lead-exposed and unexposed controls. 

Another mechanism of adduct formation may involve δ-aminolevulinic acid, the heme 

precursor whose levels are elevated by lead exposure through feedback disinhibition of 

the enzyme ALA synthase (Silbergeld 1987). ALA can generate free radicals (HermesLima et al. 1991) and has been shown to cause oxidative damage to DNA in CHO cells in 

vitro through the formation of 8-OHdG (Yusof et al. 1999). The role of oxidative damage 

to DNA in human lead toxicity also is supported by a recent study of 7,8-dihydro-9-

oxoguanine adducts in lymphocytes collected from persons exposed environmentally to 

metals, including lead, chromium, cadmium, and nickel (Merzenich et al. 2001). 

6.3.1.6 DNA-binding proteins 

Lead is known to bind to several DNA-binding proteins, including protamines and 

histones, as well as transcription regulators such as stimulatory protein-1 and 

transcription factor IIA (Hanas et al. 1999, Petering et al. 2000, Zawia et al. 2000, 

Quintanilla-Vega et al. 2000, Silbergeld et al. 2000). In fact, many, if not all, zincbinding nuclear proteins probably also can bind lead, and thus potentially dysregulate 

gene expression, as first suggested by Sunderman and Barber (1988). The critical role of 

zinc in conferring appropriate conformational structure has been well demonstrated for 

the zinc finger proteins, many of which are transcription regulators, such as the 

glucocorticoid receptor (O'Halloran 1993, Searles et al. 2000). Quintanilla-Vega et al. 

(2000) reported that lead could bind at a sulfhydryl and a nonsulfhydryl site to human 

protamine (HP2), a DNA-associated protein that regulates the condensation of sperm 

DNA. Several lines of evidence, including spectroscopy, nuclear magnetic resonance, and 

circular dichroism analysis, indicate that protein configuration is changed when lead is 

bound (Quintanilla-Vega et al. 2000, Razmiafshari et al. 2001). When HP2 is bound to 

lead, its subsequent binding to consensus sequences in DNA is significantly reduced 

(Quintanilla-Vega et al. 2000, Silbergeld et al. 2000). 

Because one of the functions of protamines and histones, analogous somatic-cell nuclear 

proteins, is to protect DNA (Mirsky and Silverman 1972), genetic material may become 

more vulnerable to damage from other sources in the presence of lead-containing 

protamines or histones. Liang et al. (1999) reported that when nickel or copper was 

bound to HP2 in place of zinc, single- and double-strand DNA breakage increased, as 

well as oxidative damage to both purine and pyrimidine bases of DNA. These authors 

suggested that the DNA damage induced in the presence of HP2 and metals was related 
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165 

to interactions of HP2 with DNA, as well as to the redox properties of HP2–metal 

complexes. 

6.3.1.7 Tumor suppressor proteins 

A final potential mechanism for lead carcinogenicity involves its interactions with tumorsuppressor proteins, at the pre- and post-translational level. The tumor-suppressor protein 

p53 is a zinc-binding protein. It has been shown that when p53 is exposed to cadmium, 

the protein is structurally altered, with functional consequences similar to those resulting 

from mutation of the p53 gene (Hainaut and Milner 1993, Hainaut and Mann 2001). 

Other proteins related to tumorigenesis have been identified in studies of gene 

expression. Although these analyses were undertaken to identify novel targets related to 

lead neurotoxicity, some of the results are relevant to mechanisms of carcinogenicity. 

Bouton et al. (2001) undertook a broad analysis of lead-induced alterations in gene 

expression, using immortalized rat astrocytes exposed to 10 μM lead acetate or 10 μM 

sodium acetate (as control). Extensive controls were run to ensure reproducibility of the 

results. In the Clontech array (which contains a set of 418 genes), expression of 48 genes 

was upregulated and expression of 12 genes was downregulated. For instance, lead 

exposure downregulated expression of the gene for the tumor suppressor DCC (deleted in 

colon cancer) precursor protein. In the InCyte microarray (which included 282 genes also 

represented on the Clontech array), expression of 34 genes was upregulated and 

expression of 18 genes was downregulated. Among these, lead significantly affected the 

expression of genes for zinc-binding transcription factors (not further identified). In a 

more limited analysis of gene expression in astrocytes, Li and Rossman (2001) reported 

that exposure of glioma cells in culture to lead (at concentrations as low as 100 μM) 

resulted in downregulation of expression of the gene for thrombospondin 1, which has 

been considered to be a tumor-suppressor protein. These data suggest the importance of 

further research on the interaction of lead with expression of genes involved in 

tumorigenesis. 

6.3.2 Indirect mechanisms 

Glutathione transferase P (GST-P) is increased in rat kidney and liver following exposure 

to lead, and overproduction of GST-P is known to be a marker for hepatocarcinogenesis 

in the rat (Suzuki et al. 1996). These effects offer a possible explanation for the ability of 

lead to induce cancer without being a potent direct-acting mutagen (Johnson 1998). 

Oberley et al. (1995) demonstrated marked induction of specific GST isoforms in 

specific kidney cell types in female Sprague-Dawley rats and their pups following 

chronic administration of lead acetate in drinking water. Increases in GSTs preceded 

irreversible renal damage; however, the authors concluded that the observed renal 

damage was not related to neoplastic events. In another study, Daggett et al. (1998) 

determined that glutathione depletion and oxidative stress were not responsible for 

changes in the production of GSTs in rat kidney or liver. Sprague-Dawley rats were 

injected with lead acetate at 114 mg/kg b.w. and examined at 0.5, 1, 3, 6, and 12 hours 

after the injection. Two other exposure groups received injections on three successive 

days and were examined at 72 hours and 7 days after the first injection. Lead exposure 

resulted in increased levels of most GSTs in the kidney but decreased levels of most 

GSTs in the liver. GST-P1 was the only subunit increased in the liver. GST increases in 
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166 

the kidney were independent of glutathione depletion or malondialdehyde (MDA) 

production. MDA was used as a marker for lipid peroxidation. In contrast, increased 

GSTP1 in the liver did correlate with glutathione depletion and MDA production. 

Histopathological effects were noted in the kidneys but not in the liver. Although these 

observations suggest an adaptive response to lead toxicity, they do not indicate that 

oxidative stress is a primary mechanism of toxicity. One possible explanation is that lead 

reduces the activity of glutathione in the kidney without depleting it (Daggett et al. 1998). 

6.4 Summary 

Lead absorption in humans and laboratory animals is affected by age, the chemical form 

of lead, and minerals in the diet (e.g., iron, calcium, and zinc). Inorganic lead can be 

absorbed by inhalation of fine particles and by ingestion. In adults, the rate of deposition 

of airborne lead in the respiratory tract is approximately 30% to 50% and is dependent on 

the size of the particles and the ventilation rate of the individual. Ingestion of inorganic 

lead results in GI absorption in humans. GI absorption declines with age, with children 

absorbing 4 to 6 times more lead than adults. Dietary deficiencies in iron, calcium, and 

zinc increase lead absorption and retention, whereas a high-protein diet appears to reduce 

absorption. Lead also can be absorbed through the skin. After absorption, lead is 

distributed to blood plasma, nervous system, and soft tissues. In humans, the relationship 

between whole-blood lead and plasma lead levels is linear at lower concentrations, but at 

higher concentrations, levels in plasma are higher than would be expected based on a 

linear relationship. 

The skeleton is a major compartment for inorganic lead, as approximately 75% to 90% of 

the lead body burden is found in bones and teeth. In humans, bone lead levels gradually 

increase over the lifespan. The half-life of lead in bone depends on bone type. Lead 

analyses of teeth and bone provide an integrated biomarker of previous lead exposure. 

Lead also is transferred across the placenta and is excreted in breast milk. Some evidence 

indicates that the fetus accumulates lead in both the skeleton and soft tissue. Skeletal lead 

can be mobilized under normal conditions, such as pregnancy, lactation, and menopause, 

and under pathophysiological conditions, including Paget’s disease, hypothyroidism, and 

prolonged bed rest; this mobilization affects bone mineral metabolism and increases 

blood lead concentrations. 

Excretion of lead does not depend on the route of exposure. Dietary lead excreted in the 

feces includes both lead that was not absorbed by the GI tract and lead that was excreted 

in the bile. The major routes of excretion of absorbed lead are urinary and biliary 

clearance, and excretion of lead in the feces generally is greater than excretion in the 

urine. In humans, the total excretion rate for lead may be lower in infants than in adults, 

resulting in retention of a larger percentage of the total amount of lead absorbed. 

The toxic effects of lead include neurotoxicity, nephrotoxicity, hematoxicity and anemia, 

and reproductive, developmental, and cardiovascular effects. These end points have been 

identified in adults, children, and/or fetuses. Lead exposure was a frequent cause of 

encephalopathy in children. Chronic exposure of children to lead in paints resulted in 

neurotoxic effects including loss of speech, seizures, and coma. Children who survived 

these severe events frequently were retarded intellectually and in their motor skills. In 
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167 

adults, lead is a potent neurotoxin affecting the CNS and the PNS, with neurotoxic 

manifestations dependent on dose and duration of exposure. Recently, reviews have 

suggested that adult lead exposure may be associated with increased risks of 

neurodegenerative disease in aging, specifically, amyotrophic lateral sclerosis and 

dementias. Acute nephrotoxicity has been described in lead-intoxicated children. 

Exposure to lead also results in anemia and hematopoietic disturbances. Additionally, 

lead is toxic to sperm and can alter endocrine function in adults. Lead crosses the 

placenta and is accumulated in fetal organs, including the brain. Several studies have 

reported positive exposure-related associations between blood lead level and blood 

pressure in adult men and women. It was estimated that the effects of lead exposure on 

blood pressure contribute significantly to risks of hypertensive heart disease and stroke in 

the U.S. population. It is important to note that all these toxic effects of lead described in 

human populations have been observed in rodent models at similar blood lead levels. 

The mechanisms leading to the carcinogenic effects of lead are not understood. Lead 

compounds do not appear to be directly genotoxic but may cause genetic damage through 

several indirect mechanisms. These include inhibition of DNA synthesis and repair, 

oxidative damage, and interaction with DNA-binding proteins and tumor-suppressor 

proteins. Interference with DNA synthesis and repair has been suggested as one possible 

explanation for the genotoxic and co-mutagenic properties of lead. 

It has been suggested that cell proliferation may play a role in lead’s induction of renal 

cancer; however, the mechanisms have not been established. Although exposure to lead 

also induces cell proliferation in the liver, the data suggest that the liver is not as 

susceptible as the kidneys to the carcinogenicity of this effect. No studies have associated 

liver tumors with lead exposure, and several studies have shown that lead-induced 

proliferative mitogenesis does not promote the formation of liver foci or nodules from 

initiated hepatocytes, as observed during regenerative mitogenesis. An association of 

renal adenocarcinoma with cystic nephropathy has been suggested but is uncertain. 
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Appendix A: Lead Regulations 
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200 
05/08/03 RoC Background Document for Lead and Lead Compounds 

A-1 

Table A-1. CPSC regulations 

Regulatory citation Regulatory action 

16 CFR 1303 - PART 1303 - BAN OF LEADCONTAINING PAINT AND CERTAIN CONSUMER 

PRODUCTS BEARING LEAD-CONTAINING 

PAINT. 1978. 

Bans paint or any other similar surface coating that 

contains more than 0.06% lead. 

The regulations in this table have been updated through the 2001 Code of Federal Regulations 29 CFR, 

July 1, 2001. 

Table A-2. EPA regulations 

Regulatory citation Regulatory action 

40 CFR 50 – PART 50 – NATIONAL PRIMARY AND 

SECONDARY AMBIENT AIR QUALITY 

STANDARDS. Promulgated: 36 FR 22384, 11/25/71. 

U.S. Codes: 42 U.S.C. 7409, 7601(a). 

National primary and secondary ambient air quality 

standards for lead and its compounds, measured as 

elemental lead, are 1.5 μg/m3

, maximum arithmetic 

mean averaged over a calendar quarter. 

40 CFR 60 - PART 60, SUBPART L - STANDARDS 

OF PERFORMANCE FOR SECONDARY LEAD 

SMELTERS. Promulgated: 42 FR 37937, 7/25/77. U.S. 

Codes: 42 U.S.C. 7401-7601. 

Standards for particulate matter for secondary lead 

smelters are: < 50 mg/dscm (0.022 gr/dscf) for blast 

(cupola) or reverberatory furnace and < 20% 

opacity. 

40 CFR 60 - PART 60, SUBPART P - STANDARDS 

OF PERFORMANCE FOR PRIMARY COPPER 

SMELTERS. Promulgated: 41 FR 2338, 1/15/76. U.S. 

Codes: 42 U.S.C. 7401-7601. 

Standards for particulate matter have been set for 

primary copper smelters. 

40 CFR 60 - PART 60, SUBPART R - STANDARDS 

OF PERFORMANCE FOR PRIMARY LEAD 

SMELTERS. Promulgated: 41 FR 2340, 1/15/76. U.S. 

Codes: 42 U.S.C. 7401-7601. 

Standards for particulate matter for secondary lead 

smelters are: < 50 mg/dscm (0.022 gr/dscf) for blast 

furnace, dross reverberatory furnace, or sintering 

machine discharge, < 20% opacity, and < 0.065% 

by volume sulfur dioxide. 

40 CFR 60 - PART 60, SUBPART CC - STANDARDS 

OF PERFORMANCE FOR GLASS 

MANUFACTURING PLANTS. Promulgated: 36 FR 

24877, 12/23/77l U.S. Codes: 42 U.S.C. 7401-7601. 

Standards for particulate matter have been set for 

glass manufacturing plants. 

40 CFR 60 - PART 60, SUBPART KK - STANDARDS 

OF PERFORMANCE FOR LEAD-ACID BATTERY 

MANUFACTURING PLANTS. Promulgated 47 FR 

16573, 4/16/82. U.S. Codes: 42 U.S.C. 7401-7601. 

Standards for lead are: < 0.40 mg/m3 of exhaust 

(0.000176 gr/dscf) for grid casting facilities, <1 

mg/m3

 of exhaust (0.00044 gr/dscf) for paste mixing 

facilities or three-process operation facilities, <5.0 

mg/kg lead feed (0.010 lb/ton) for lead oxide 

manufacturing facilities, < 4.50 mg/m3

 of exhaust 

(0.00198 gr/dscf), 1.0 mg/m3

 of exhaust (0.00044 

gr/dscf) for any other lead-emitting operation, 0% 

opacity for affected facilities other than leadreclamation facilities, < 5% opacity for lead 

reclamation facilities. 
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40 CFR 60 - PART 60, SUBPART VV - STANDARDS 

OF PERFORMANCE FOR EQUIPMENT LEAKS OF 

VOC IN THE SYNTHETIC ORGANIC CHEMICALS 

MANUFACTURING INDUSTRY (SOCMI), 

Promulgated 48 FR 48335, 10/18/83. U.S. Codes: 42 

U.S.C. 7401-7601. 

Standards of performance have been set for 

equipment leaks for facilities in the Synthetic 

Organic Chemicals Manufacturing Industry 

producing tetraethyl lead and tetramethyl lead. 

40 CFR 60 - PART 60, SUBPART NNN - 

STANDARDS OF PERFORMANCE FOR VOC 

EMISSIONS IN THE SYNTHETIC ORGANIC 

CHEMICALS MANUFACTURING INDUSTRY 

(SOCMI) DISTILLATION OPERATIONS, 

Promulgated 55 FR 26942, 6/29/90. Codes: 42 U.S.C. 

7401-7601. 

Standards of performance have been set for VOC 

emissions for facilities in the Synthetic Organic 

Chemicals Manufacturing Industry, distillation 

operations, producing tetraethyl lead and 

tetramethyl lead. 

40 CFR 60 - PART 60, SUBPART NNN - 

STANDARDS OF PERFORMANCE FOR VOC 

EMISSIONS IN THE SYNTHETIC ORGANIC 

CHEMICALS MANUFACTURING INDUSTRY 

(SOCMI) REACTOR PROCESSES, Promulgated 58 

FR 45962, 8/31/93. Codes: 42 U.S.C. 7401-7601. 

Standards of performance have been set for VOC 

emissions for facilities in the Synthetic Organic 

Chemicals Manufacturing Industry, reactor 

processes, producing tetraethyl lead and tetramethyl 

lead. 

40 CFR 63 - PART 63, SUBPART RRR - NATIONAL 

EMISSION STANDARDS FOR HAZARDOUS AIR 

POLLUTANTS FOR SOURCE CATEGORIES. 

Promulgated: 57 FR 61992, 12/29/92. U.S. Codes: 42 

U.S.C. 7401 et seq.1. 

Hazardous waste incinerators must not discharge 

lead and cadmium > 240 g/dscm, combined 

emissions, corrected to 7% oxygen. 

 40 CFR 80 - PART 80, SUBPART A - DEFINITION. 

Promulgated 38 FR 1255, 1/10/73, as amended at 38 FR 

33741, 12/6/73; 42 FR 25732, 5/19/77. U.S. Codes: 42 

U.S.C. 7414, 7545, and 7601(a). 

Definition of unleaded gasoline is < 0.05 g of lead 

per gallon and < 0.005 g phosphorus/gallon. 

40 CFR 80 - PART 80, SUBPART B - CONTROLS 

AND PROHIBITIONS. Promulgated 38 FR 1255, 

1/10/73, as amended at 6/26/96. U.S. Codes: 42 U.S.C. 

7414, 7545, and 7601(a). 

No person shall sell gasoline with > 0.05 g of lead 

per gallon. 

40 CFR 80 - PART 80, SUBPART D - 

REFORMULATED GASOLINE. Promulgated 59 FR 

7813, 2/16/94. U.S. Codes: 42 U.S.C. 7414, 7545, and 

7601(a). 

Reformulated gasoline may not contain lead. 

40 CFR 80 - PART 80, SUBPART G - DETERGENT 

GASOLINE. Promulgated 59 FR 54706, 11/1/94. U.S. 

Codes: 42 U.S.C. 7414, 7545, and 7601(a). 

Detergent gasoline must meet the requirements 

outlined, including the definition of unleaded 

gasoline. 

40 CFR 80 - PART 80, APPENDIX B - TEST 

METHODS FOR LEAD IN GASOLINE. Promulgated 

38 FR 1255, 1/10/73. U.S. Codes: 42 U.S.C. 7414, 7545, 

and 7601(a). 

Test methods have been established for lead in 

gasoline. 

40 CFR 86 - PART 86, SUBPART F - EMISSION 

REGULATIONS FOR 1978 AND LATER NEW 

MOTORCYCLES; TEST PROCEDURES. Promulgated 

42 FR 1137, 1/5/77. U.S. codes: 42 U.S.C. 7401 - 

7671q. 

For leaded fuel, the lead content shall not exceed 

0.1 g of lead per gallon. 
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40 CFR 116 - PART 116 - DESIGNATION OF 

HAZARDOUS SUBSTANCES. Promulgated: 43 FR 

10474, 03/13/78. U.S. Codes: 33 U.S.C. 1251 et seq. 

Lead acetate, lead arsenate, lead chloride, lead 

fluoroborate, lead fluoride, lead iodide, lead nitrate, 

lead stearate, lead salt, lead sulfate, lead sulfide, and 

lead thiocyanate are classified as hazardous 

substances. 

40 CFR 117 – PART 117 – DETERMINATION OF 

REPORTABLE QUANTITIES FOR HAZARDOUS 

SUBSTANCES. Promulgated: 44 FR 50776, 08/29/79. 

U.S. Codes: 33 U.S.C. 1251 et seq., as amended by the 

Clean Water Act of 1977. 

Discharges to water of amounts equal to or greater 

than the Reportable Quantity (RQ) must be reported 

to EPA. RQs for environmental releases of lead 

acetate, lead chloride, lead fluoborate, lead fluoride, 

lead iodide, lead nitrate, lead stearate, lead sulfate, 

lead sulfide, and lead thiocyanate are 10 lb (4.54 

kg). The RQ for lead arsenate is 1 lb (0.454 kg). 

40 CFR 136 - GUIDELINES ESTABLISHING TEST 

PROCEDURES FOR THE ANALYSIS OF 

POLLUTANTS. Promulgated: 55 FR 33442, 8/15/90. 

U.S. Codes: 33 U.S.C. 1251, et seq., as amended by the 

Clean Water Act of 1977. 

Established test methods for the identification of 

lead. 

40 CFR 141 - PART 141, SUBPART E - SPECIAL 

REGULATIONS, INCLUDING MONITORING 

REGULATIONS AND PROHIBITION ON LEAD 

USE. Promulgated: 52 FR 20674 6/2/87, as amended at 

65 FR 2002, 1/12/00. U.S. Codes: 42 U.S.C. 300 g-6(e). 

All plumbing shall be lead-free. The definition of 

lead-free is: solder and flux must contain ≤ 0.2% 

lead; pipes and pipe fittings must contain ≤ 8.0% 

lead. 

40 CFR 141 - PART 141, SUBPART I - NATIONAL 

PRIMARY DRINKING WATER REGULATIONS, 

CONTROL OF LEAD AND COPPER. Promulgated: 56 

FR 26548, 6/7/91. U.S. Codes: 42 U.S.C. 300f, g, and j. 

To protect a safe drinking water supply, a treatment 

technique that includes corrosion control, source 

water treatment, lead service line replacement, and 

public education has been set for lead. An action 

level of 0.015 mg/l has been established for lead; 

this action level is exceeded if the concentration of 

lead in > 10% of the tap water samples is > 0.015 

mg/L. 

40 CFR 141 - PART 141, SUBPART Q - PUBLIC 

NOTIFICATION OF DRINKING WATER 

VIOLATIONS. Promulgated: 65 FR 26035, 5/4/00. U.S. 

Codes: 42 U.S.C. 300f, g, and j. 

Public water systems must notify the public for 

violations of maximum contaminant levels or 

treatment techniques for all regulated contaminants, 

including lead. 

40 CFR 258 - PART 258 - CRITERIA FOR 

MUNICIPAL SOLID WASTE LANDFILLS. 

Promulgated 56 FR 51016, 10/9/91. U.S. Codes: 33 

U.S.C. 1345(d)(e); 42 U.S.C. 6902(a), 6907, 6912(a), 

6944, 6945(c), 6949a(c). 

Lead is considered a hazardous inorganic compound 

in municipal solid waste landfills. A maximum 

contaminant level (MCL) of 0.05 mg/L has been set 

for lead. 

40 CFR 261 - PART 261 - IDENTIFICATION AND 

LISTING OF HAZARDOUS WASTES. Promulgated: 

46 FR 4619, 1981 with numerous amendments. U.S. 

Codes: 42 U.S.C. 6905, 6912(a), 6921, 6922, and 6938. 

Solid wastes containing lead are subject to 

notification requirements and the constituent 

maximum concentration of lead in any composite 

wastewater sample is 0.15 mg/L. 

40 CFR - PART 264, SUBPART CC - AIR EMISSION 

STANDARDS FOR TANKS, SURFACE 

IMPOUNDMENTS AND CONTAINERS. Promulgated 

56 FR 62927, 12/6/94. U.S. Codes 42 U.S.C. 6906, 

6912, 6922-6925, 6937, 6938. 

The Sisterville Plant in West Virginia shall monitor 

for lead. 
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40 CFR - PART 264, SUBPART EE - HAZARDOUS 

WASTE MUNITIONS AND EXPLOSIVES 

STORAGE. Promulgated 62 FR 6652, 2/12/97. U.S. 

Codes 42 U.S.C. 6906, 6912, 6922-6925, 6937, 6938. 

Lead must be monitored for in groundwater. 

40 CFR 266 - PART 266, SUBPART H - 

HAZARDOUS WASTE BURNED IN BOILERS AND 

INDUSTRIAL FURNACES. Promulgated 56 FR 7208, 

2/21/91 and 64 FR 53075, 9/30/99. 42 U.S.C. 1006, 

2002(a), 3004, 3014, 6905, 6906, 6912, 6922, 6924, 

6925, 6937. 

Reference air concentrations have been set for 

release of lead from hazardous waste burned in 

boilers and industrial furnaces as follows: lead = 

0.00009 mg/L, tetraethyl lead = 0.0000001 mg/L. 

40 CFR 266 - PART 266, SUBPART M - MILITARY 

MUNITIONS. Promulgated 62 FR 6654, 2/12/97. 42 

U.S.C. 1006, 2002(a), 3004, 3014, 6905, 6906, 6912, 

6922, 6924, 6925, 6937. 

Military munitions wastes containing lead must be 

stored as hazardous wastes. 

40 CFR 268 - PART 268 - LAND DISPOSAL 

RESTRICTIONS. Promulgated 51 FR 40638. 42 U.S.C. 

6905, 6912(a), 6921, 6924. 

Lead is listed as a hazardous waste restricted from 

land disposal. 

40 CFR 300 - PART 300, SUBPART L - NATIONAL 

OIL AND HAZARDOUS SUBSTANCES 

POLLUTION CONTINGENCY PLAN; 

INVOLUNTARY ACQUISITION OF PROPERTY BY 

THE GOVERNMENT. Promulgated 62 FR 34602, 

6/26/97. U.S. Codes: 42 U.S.C. 9605 and 

33.U.S.C.1321(d). 

Provides procedures for responding to discharges of 

oil and hazardous substances. In the hazard ranking 

system, lead has a human toxicity factor value of 

10,000. 

40 CFR 302 – PART 302 – DESIGNATION, 

REPORTABLE QUANTITIES, AND 

NOTIFICATION. Promulgated: 50 FR 13474, 04/04/85. 

U.S. Codes: 42 U.S.C. 9602, 9603, and 9604; 33 U.S.C. 

1321 and 1361. 

This part designates RQs for lead acetate, lead 

subacetate, lead chloride, lead fluoborate, lead 

fluoride, lead iodide, lead nitrate, lead phosphate, 

lead stearate, lead sulfate, lead sulfide, lead 

thiocyanate, and tetraethyl lead are 10 lbs (4.54 kg). 

The RQ for lead arsenate is 1 lb (0.454 kg). 

40 CFR 372 – PART 372 – TOXIC CHEMICAL 

RELEASE REPORTING: COMMUNITY RIGHT-TOKNOW. Promulgated: 53 FR 4525, 02/16/88; 1/16/01. 

U.S. Codes: 42 U.S.C. 11023 and 11048. 

Toxic release information is collected for lead to 

inform the general public and the communities 

surrounding covered facilities about releases of 

toxic chemicals, to assist research, and to aid in the 

development of regulations, guidelines, and 

standards. The reporting threshold for lead and lead 

compounds was lowered to 100 lbs (1/16/01). 

40 CFR 401 – PART 401 – GENERAL PROVISIONS. 

Promulgated: 39 FR 4532, 02/01/74. U.S. Codes: 33 

U.S.C. 1251, 1311, 1314 (b) and (c), 1316 (b) and (c), 

1317 (b) and (c) and 1326(c); 86 Stat. 816 et seq.; Pub. 

L. 92-500. 

Lead and lead compounds are classified as toxic 

pollutants under the Clean Water Act. 

40 CFR 414 - PART 414 - ORGANIC CHEMICALS, 

PLASTICS, AND SYNTHETIC FIBERS. Promulgated 

52 FR 42568, 11/5/87, as amended at 57 FR 41844, 

9/11/92. U.S. codes: 33 U.S.C. 1311, 1314(b)(c)(e), 

1316(b)(c), 1317(b)(c), 1318, and 1361. 

Effluent limitation guidelines have been set for 

tetraethyl lead and tetramethyl lead for organic 

chemicals, plastics, and synthetic fiber 

manufacturers. 
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40 CFR 415 - PART 415, SUBPART AR - 

INORGANIC CHEMICALS MANUFACTURING 

POINT SOURCE CATEGORY, LEAD MONOXIDE 

PRODUCTION SUBCATEGORY. Promulgated 47 FR 

28278, 6/29/82. U.S. codes: 33 U.S.C. 1311, 

1314(b)(c)(e), 1316(b)(c), 1317(b)(c), 1318, and 1361. 

Effluent limitation guidelines have been set for lead 

for inorganic chemicals manufacturers. 

40 CFR 420 - PART 420 - IRON AND STEEL 

MANUFACTURING POINT SOURCE CATEGORY. 

Promulgated 47 FR 23284, 5/27/82. U.S. codes: 33 

U.S.C. 1311, 1314(b)(c)(e), 1316(b)(c), 1317(b)(c), 

1318, and 1361. 

Effluent limitation guidelines have been set for lead 

for iron and steel manufacturers. 

40 CFR 421 - PART 421 - NONFERROUS METALS 

MANUFACTURING POINT SOURCE CATEGORY, 

SUBPART G - PRIMARY LEAD SUBCATEGORY. 

Promulgated 49 FR 8790, 3/8/84. U.S. codes: 33 U.S.C. 

1311, 1314(b)(c)(e), 1316(b)(c), 1317(b)(c), 1318, and 

1361. 

Effluent limitation guidelines have been set for lead 

for nonferrous metals manufacturers. 

40 CFR 423 - PART 423 - STEAM ELECTRIC 

POWER GENERATING POINT SOURCE 

CATEGORY. Promulgated 47 FR 52304, 11/19/82. 

U.S. codes: 33 U.S.C. 1311, 1314(b)(c)(e), 1316(b)(c), 

1317(b)(c), 1318, and 1361. 

Effluent limitation guidelines have been set for lead 

for steam electric power generating manufacturers. 

40 CFR 455 - PART 455 - PESTICIDE CHEMICALS, 

SUBPART A - ORGANIC PESTICIDE CHEMICALS 

MANUFACTURING SUBCATEGORY. Promulgated 

43 FR 17776, 4/25/78. U.S. codes: 33 U.S.C. 1311, 

1314(b)(c)(e), 1316(b)(c), 1317(b)(c), 1318, and 1361. 

Effluent limitation guidelines have been set for lead 

for organic pesticide manufacturers. 

40 CFR 461 - PART 461 - BATTERY 

MANUFACTURING, POINT SOURCE CATEGORY, 

SUBPART C - LEAD SUBCATEGORY. Promulgated 

49 FR 9134, 3/9/84. U.S. codes: 33 U.S.C. 1311, 

1314(b)(c)(e), 1316(b)(c), 1317(b)(c), 1318, and 1361. 

Effluent limitation guidelines have been set for lead 

for battery manufacturers. 

40 CFR 464 - PART 464 - METAL MOLDING AND 

CASTING POINT SOURCE CATEGORY. 

Promulgated 50 FR 45247, 10/30/85. U.S. codes: 33 

U.S.C. 1311, 1314(b)(c)(e), 1316(b)(c), 1317(b)(c), 

1318, and 1361. 

Effluent limitation guidelines have been set for lead 

for metal molding and casting manufacturers. 

40 CFR 468 - PART 468 - COPPER FORMING POINT 

SOURCE CATEGORY. Promulgated 48 FR 36957, 

8/15/83. U.S. codes: 33 U.S.C. 1311, 1314(b)(c)(e), 

1316(b)(c), 1317(b)(c), 1318, and 1361. 

Effluent limitation guidelines have been set for lead 

for copper forming manufacturers. 
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40 CFR 471 - PART 471 - NONFERROUS METALS 

FORMING POINT SOURCE CATEGORY, SUBPART 

A - LEAD-TIN-BISMUTH FORMING 

SUBCATEGORY, SUBPART F - TITANIUM 

FORMING SUBCATEGORY, SUBPART G - 

URANIUM FORMING SUBCATEGORY, SUBPART 

J - METALS POWDERS SUBCATEGORY. 

Promulgated 48 FR 36957, 8/15/83. U.S. codes: 33 

U.S.C. 1311, 1314(b)(c)(e), 1316(b)(c), 1317(b)(c), 

1318, and 1361. 

Effluent limitation guidelines have been set for lead 

for metals powders, titanium forming, uranium, and 

lead-tin-bismuth forming manufacturers. 

40 CFR 503 - PART 503 - STANDARDS FOR THE 

USE AND DISPOSAL OF SEWAGE SLUDGE. 

Promulgated 58 FR 9387, 2/19/93. U.S. Codes: 33 

U.S.C. 1345 (d) and (e) and 33 U.S.C. 1251 et seq. 

The following standards have been set for lead in 

sewage sludge applied to the land, placed on a 

surface disposal site, or fired in a sewage sludge 

incinerator: ceiling concentration = 840 mg/kg; 

cumulative pollutant loading rate = 300 kg/hectare; 

annual loading rate = 15 kg/hectare/365 days. 

40 CFR 745 - PART 745 - LEAD-BASED PAINT 

PREVENTION IN CERTAIN RESIDENTIAL 

STRUCTURES. Promulgated 61 FR 9085, 3/6/96. U.S. 

Codes: 15 U.S.C. 2605, 2607, 2681-2692 and 42 U.S.C. 

4852(d). 

A seller must disclose to the purchaser any leadbased paint in a home for sale; paint used in home 

renovations must not contain lead ≥ 1.0 mg/cm2

 or ≥

0.5% by weight; a pamphlet on the health hazards of 

lead must be provided to the homeowner. Amended 

3/6/01: Dust-lead hazard consists of lead ≥ 40 μg/ft2 

on floors or 250 μg/ft2 on interior window sills. 

Soil-lead hazard consists of lead ≥ 400 ppm (μg/g) 

in play area, or average of 1,200 ppm in bare soil. 

The regulations in this table have been updated through the 2001 Code of Federal Regulations 40 CFR, 

July 1, 2001 

Table A-3. FDA regulations 

Regulatory citation Regulatory action 

21 CFR 73 - PART 73 -LISTING OF COLOR 

ADDITIVES EXEMPT FROM CERTIFICATION. 

Promulgated: 42 FR 15643, 03/22/77. U.S. Codes: 21 

U.S.C. 321, 341, 342, 343, 348, 351, 352, 355, 361, 362, 

371, 379e. 

Concentration limits for lead in various color 

additives used in foods, drugs, cosmetics, and 

medical devices may not exceed 5–70 ppm. The 

concentration of lead acetate may not exceed 0.6% 

(weight to volume) in hair coloring for scalp use 

only. 

21 CFR 74 - PART 74 - LISTING OF COLOR 

ADDITIVES SUBJECT TO CERTIFICATION. 

Promulgated: 42 FR 15654, 03/22/77. U.S. Codes: 21 

U.S.C. 321, 341, 342, 343, 348, 351, 352, 355, 361, 362, 

371, 379e. 

Concentration limits for lead in various color 

additives used in foods, drugs, cosmetics, and 

medical devices may not exceed 10–40 ppm. 
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21 CFR 109 - PART 109 - UNAVOIDABLE 

CONTAMINANTS IN FOOD FOR HUMAN 

CONSUMPTION AND FOOD-PACKAGING 

MATERIAL. Promulgated: 42 FR 52819, 09/30/77. 

U.S. Codes: 21 U.S.C. 321, 336, 342, 346, 346a, 348, 

371. 

A conspicuous stick-on label shall be on the surface 

of ornamental or decorative ceramics clearly visible 

to consumers that states one of the following 

messages: "Not for Food Use. May Poison Food," 

"Not for Food Use. Glaze contains lead. Food Use 

May Result in Lead Poisoning," and "Not for Food 

Use-Food Consumed from this Vessel May be 

Harmful," 

21 CFR 109 and 509 - PARTS 109 and 509 - ACTION 

LEVELS FOR POSIONOUS OR DELETERIOUS 

SUBSTANCES IN HUMAN FOOD AND ANIMAL 

FEED. Compliance Policy Guide 545.450 

Action levels for lead in ceramicware are: flatware 

= 3.0 μg/mL leaching solution, small hollowware 

(other than cups and mugs) = 2.0 μg/mL leaching 

solution, large hollowware (other than pitchers) = 

1.0 μg/mL leaching solution, cups and mugs = 0.5 

μg/mL leaching solution, pitchers = 0.5 μg/mL 

leaching solution. 

21 CFR 109 and 509 - PARTS 109 and 509 - ACTION 

LEVELS FOR POSIONOUS OR DELETERIOUS 

SUBSTANCES IN HUMAN FOOD AND ANIMAL 

FEED. Compliance Policy Guide 545.500 

Action levels for silver-plated hollowware are: 

product intended for use by adults = 7 μg/mL 

leaching solution, product intended for use by 

infants and children = 0.5 μg/mL leaching solution. 

21 CFR 189 - PART 189 - SUBSTANCES 

PROHIBITED FROM INDIRECT ADDITION TO 

HUMAN FOOD THROUGH FOOD-CONTACT 

SURFACES. Promulgated: 60 FR 33109, 06/27/95. U.S. 

Codes: 21 U.S.C. 321, 342, 348, 371. 

Food packaging must not contain lead solder. 

21 CFR 584 - PART 584 - FOOD SUBSTANCES 

AFFIRMED AS GENERALLY RECOGNIZED AS 

SAFE IN FEED AND DRINKING WATER OF 

ANIMALS. Promulgated: 61 FR 43453, 08/23/96. U.S. 

Codes: 21 U.S.C. 321, 342, 348, 371. 

Amorphous fumed hydrophobic silica or 

precipitated hydrophobic silica may be used as an 

anticaking/free-flow agent in vitamin preparations 

for animal feed provided that lead concentration do 

not exceed 10 ppm. 

The regulations in this table have been updated through the 2001 Code of Federal Regulations 21 CFR, 

April 1, 2001. 

Table A-4. OSHA regulations 

Regulatory citation Regulatory action 

29 CFR 1910 - PART 1910.1025, SUBPART Z - 

TOXIC AND HAZARDOUS SUBSTANCES. 

Promulgated 60 FR 52856, 10/11/95, as amended 

numerous times. U.S. codes: 29 U.S.C. 653, 655, 657. 

Establishes permissible exposure limit (PEL) for 

lead of 50 μg/m3

 as an 8-hour time-weighted 

average (TWA). Action level of 30 μg/m3 TWA, 8-

hour workday. Initiates exposure monitoring, 

medical surveillance, and training and education. 

29 CFR 1910 - PART 1910.1200, SUBPART Z - 

HAZARD COMMUNICATION. Promulgated 59 FR 

17479, 4/13/94; 59 FR 65947, 12/22/94; and 61 FR 

5507, 2/13/96. U.S. codes: 29 U.S.C. 653, 655, 657. 

Requires that the hazards of all chemicals produced 

or imported are evaluated, and that information 

concerning their hazards is transmitted to employers 

and employees. Hazard communication programs 

are to include container labeling and other forms of 

warning, material safety data sheets and employee 

training. 
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29 CFR 1910 - PART 1910.1450, SUBPARAT Z - 

OCCUPATIONAL EXPOSURE TO HAZARDOUS 

CHEMICALS IN LABORATORIES. Promulgated 61 

FR 5507, 2/13/96. U.S. codes: 29 U.S.C. 653, 655, 657. 

Establishes requirements for laboratory use of 

hazardous chemicals, including initial exposure 

determination, development of a chemical hygiene 

plan, employee information and training, and other 

requirements. 

29 CFR 1926 - PART 1926, SUBPART D - 

OCCUPATIONAL HEALTH AND 

ENVIRONMENTAL CONTROLS. Promulgated 57 FR 

26627, 5/4/93, as amended numerous times. U.S. codes: 

40 U.S.C. 333, 29 U.S.C. 653, 655, 657. 

Establishes PEL for lead of 50 μg/m3

 as an 8-hour 

TWA in construction. Action level of 30 μg/m3 

TWA, 8-hour workday. Initiates exposure 

monitoring, medical surveillance, and training and 

education. 

The regulations in this table have been updated through the 2001 Code of Federal Regulations 29 CFR, 

July 1, 2001.