Yokoyama, K., S. Araki, H. Aono, and K. Murata. 1998. Calcium disodium ethylenedia-minetetraacetate-chelated lead as a predictor for subclinical lead neurotoxicity: Follow-up study on gun-metal foundry workers. Int. Arch. Occup. Environ. Health 71(7):459-464.
Yu, C.C., J.L. Lin, and D.T. Lin-Tan. 2004. Environmental exposure to lead and progression of chronic renal diseases: A four-year prospective longitudinal study. J. Am. Soc. Nephrol. 15(4):1016-1022.
Zhu, M., E.F. Fitzgerald, K.H. Gelberg, S. Lin, and C. Druschel. 2010. Maternal lowlevel lead exposure and fetal growth. Environ. Health Perspect. 118(10):1471-1475.
On the basis of nonhuman experimental evidence, lead and lead compounds have been recognized as probably or likely to be carcinogenic in humans by several authoritative organizations, including the International Agency for Research on Cancer (IARC 2006), the National Toxicology Program (NTP 2004, 2011), and the US Environmental Protection Agency (EPA 2012). In this chapter, in addition to human studies, the committee relied on evidence from animal cancer bioassays and mechanistic studies in evaluating the evidence supporting a causal link between lead and cancer, as has been done by IARC, NTP, and EPA. Several lead compounds have been used in animal and mechanistic studies, but the committee considered all inorganic forms of lead to be applicable to this review.
A number of animal experiments have demonstrated the carcinogenicity of inorganic lead, mostly in the kidney (renal-cell carcinoma), but cancer at other sites has been reported, including brain tumors (gliomas), lung cancer, and cancers of the hematopoietic system. Lead also has genotoxic potential. Relatively low concentrations of lead in vitro (less than 1 μM) have caused mutations in mammalian cells in a dose-dependent manner, possibly through the generation of reactive oxygen species. Lead inhibits the repair of DNA damage caused by ultraviolet light and x rays and so potentially increases the genotoxicity of other agents. It stimulates lipid peroxidation and may increase free radicals through its inhibition of the enzyme delta-aminolevulinic acid dehydratase (ALAD). Lead also induces micronuclei and increases chromosomal aberrations in mammalian studies, although typically at higher doses than in occupational studies. In addition to genotoxicity, lead increases cell proliferation in the absence of cytotoxicity (IARC 2006). Thus, lead may contribute to carcinogenicity through a variety of mechanisms.
The committee reviewed the human, animal, and mechanistic evidence on lead carcinogenicity, first by the reviewing the evaluations of IARC (2006), NTP (2011), and EPA (2012). The NTP Monograph on Health Effects of Low-Level Lead (NTP 2012) reviewed in Chapter 4 did not include cancer end points. Through literature searches, the committee also identified relevant recent studies
International Agency for Research on Cancer 2006 Monograph
On the basis of sufficient evidence from experimental animal studies and limited evidence on humans, IARC (2006) classified inorganic lead compounds as “probably carcinogenic to humans” (Group 2A). The evidence presented in the IARC report consisted of results of human studies of exposed workers and environmentally exposed groups, results of experimental animal studies, and other relevant data. Except for two studies of the second National Health and Nutrition Examination Survey (NHANES II), human studies have relied primarily on comparisons of exposed workers who had blood lead levels (BLLs) mostly over 40 μg/dL. Those studies provided evidence of “no or a slight excess of lung cancer”, a 30-50% excess risk of stomach cancer, a two-fold increase in renal cancer, and a risk of glioma. One concern regarding the stomach-cancer findings was the use of external referent populations and the potential differences in dietary habits and Helicobacter pylori prevalence (see also Ward et al. 2010). Because of the crude exposure classification used in the studies and because effects of confounding could not be ruled out, IARC did not conclude the epidemiologic evidence sufficient to support a causal association. Instead, IARC found that “there is limited evidence in humans for the carcinogenicity of inorganic lead compounds” (IARC 2006, p. 377). However, IARC found the evidence from animal studies sufficient for lead acetate, lead subacetate, lead chromate, and lead phosphate and noted that “extensive experimental evidence shows that various water-soluble and insoluble lead compounds can induce kidney tumours in rodents” and that a study showed they “can occur in the absence of lead-induced nephropathy” (p. 374). It further highlighted the ability of lead to be an effective promoter of organic renal carcinogens.
National Toxicology Program 2011 Report on Carcinogens
The 2004 and 2011 editions of the NTP Report on Carcinogens list lead and lead compounds as “reasonably anticipated to be human carcinogens” (NTP 2011, p. 251). The document supporting the NTP deliberation is the Report on Carcinogens Background Document for Lead and Lead Compounds (NTP 2003). NTP concluded that the epidemiologic evidence linking cancer with lead was strongest for lung and stomach cancer. It noted, however, that evidence
from human studies was limited by the crude measures of exposure and had the disadvantage of inadequate control for confounding variables (smoking in the case of lung cancer and H. pylori infections and socioeconomic status in the case of stomach cancer) and for coexposure to arsenic. NTP’s overall “reasonably anticipated” finding was based on animal evidence; it noted that lead compounds caused tumors in several species of experimental animals, at several different tissue sites, and by several different routes of exposure. NTP noted that benign and malignant renal tumors were most frequently associated with lead exposure and that brain tumors (gliomas), lung cancer, and cancers of the hematopoietic system were also seen in some studies. It emphasized the experiment in mice that showed that gestational and postpartum exposure of dams produced renal lesions, including adenocarcinomas, in offspring. Although the overall conclusion was that the mechanisms by which lead causes cancer were not understood, NTP noted that lead compounds can cause genetic damage through several mechanisms, including inhibition of DNA synthesis and repair, oxidative damage, and interaction with DNA-binding proteins and tumor-suppressor proteins.
Environmental Protection Agency 2012 Integrated Science Assessment for Lead (Second External Review Draft)
The EPA (2012) Integrated Science Assessment for Lead (Second External Review Draft) notes that there is “likely a causal relationship” between lead exposures and cancer. Studies highlighted by EPA included ones that had not been included in its 2006 air quality criteria document for lead and emphasized studies of overall cancer mortality and lung, brain, breast, renal, and other cancers. Human evidence on cancer mortality was found to be mixed, including results from more recent studies of lung cancer. Brain-cancer studies demonstrated stronger effects among particular genotypes. EPA reviewed hypothesis-generating studies in which biomonitored concentrations of lead in urine, blood, or tissue in people that did or did not have particular types of cancer were compared. For example, lead concentrations were highest in tissues adjacent to renal tumors and were higher in cases than in controls (Cerulli et al. 2006). However, a number of limitations were noted in the studies. Similarly, human evidence on other cancers was found to be weak or inconsistent with earlier findings. Nevertheless, findings from mechanistic studies and animal studies were found to be strongly supportive of the carcinogenic potential of lead.
Table 5-1 presents the occupational and environmental epidemiologic studies that the committee believed to be most relevant for evaluating cancer risks posed by lead on DOD firing ranges.
TABLE 5-1 Key Human Studies of the Carcinogenic Effects of Lead
|Cancer Type||Population Characteristics||BLL or Other Measures||Effect Estimate||Why Study Is Relevant to DOD||Reference|
|Overall cancer mortality||NHANES II, mortality study (n = 3,592), 203 cancer deaths, average 13.3 y of followup||≤9.8 μg /dL 9.9-12.9 μg/dL 13.0-16.9 μg/dL ≥17.0 μg/dL||Reference RR = 1.24 (95% CI: 0.66, 2.33) RR = 1.33 (95% CI: 0.57, 3.09) RR = 1.50 (95% CI: 0.75, 3.01) p trend = 0.16.||Measured BLL in range lower than current OSHA standard, but higher than current population level||Jemal et al. 2002|
|NHANES III, mortality study (n = 9,757), 1988-1994||<5 μg/dL 5-9 μg/dL ≥10 μg/dL||Reference RR = 1.44 (95% CI: 1.12, 1.86) RR = 1.69 (95% CI: 1.14, 2.52) p trend <0.01.||Measured BLL.||Schober et al. 2006|
|NHANES III, using data with BLL <10 μg/dL||≤1.93 μg/dL 1.94-3.62 μg/dL ≥3.63 μg/dL||HR = 1.00
HR = 0.72 (95% CI: 0.46, 1.12)
HR = 1.10 (95% CI: 0.82, 1.47)
p trend = 0.101
|—||Menke et al. (2006)|
|Normative Aging Study (n = 868)||—||No association with cancer mortality.||Bone lead exposure was measured cumulatively.||Weisskopf et al. 2009|
|Women (65-87 y old) enrolled in Study of Osteoporotic Fractures in two US research centers (n = 533)||<8 μg/dL or ≥8 μg/dL||No association with cancer mortality.||—||Khalil et al. 2009|
|Male (n = 1,423) and female (n = 3,102) printing-industry workers||—||Pancreatic-cancer mortality (SMR = 2.3; 95% CI: 1.46, 3.68)||No confounding by other workplace carcinogens.||Ilychova and Zaridze 2012|
|Renal cancer||Nested case-control study of male smokers in Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study||<2.50 μg/dL 2.50-3.31 μg/dL 3.31-4.66 μg/dL >4.66 μg/dL||Renal-cell carcinoma: Reference OR = 1.1 (95% CI: 0.6, 2.0) OR = 1.8 (95% CI: 1.0, 3.6) OR = 2.0 (95% CI: 1.0, 3.9) p trend = 0.022||Measured BLL within range of interest.||Southard et al. 2012|
EPA (2012) reported on studies of associations between BLL and overall cancer mortality. Because cancer is a collection of diseases only some of which may be influenced by a particular environmental agent, this approach tends to bias findings toward the null. Studies of the association between BLL and overall cancer mortality are equivocal: few studies support the link between lead exposure and mortality, and many do not. A study of the NHANES III population, for which subjects were matched to the National Death Index, reported that those who had BLLs at a baseline of 5-10 μg/dL were 1.44 times as likely to die from cancer-related causes (95% confidence interval [CI]: 1.12, 1.86) as those who had BLLs under 5 μg/dL, and those who had BLLs of 10 μg/dL or higher were 1.69 times as likely to die from cancer-related causes (95% CI: 1.14, 2.52) as the referent group (Schober et al. 2006). Although the study adjusted for important confounders, such as smoking, it did not consider exposure to other known carcinogens, such as arsenic, which may correlate with lead exposure in the general population. A study of the same population but restricted to subjects who had BLLs under 10 μg/dL found no significant association (Menke et al. 2006); by design, this study had lower statistical power because of a reduced sample size and reduced exposure range. Similarly, a study that used the NHANES II population did not find statistically significant associations, although a weak trend between lead exposure and mortality was reported (Jemal et al. 2002). Studies of other populations have yielded negative findings. The study by Weisskopf et al. (2009), which used the Normative Aging Study population, found no association between lead exposure and cancer mortality, even when bone lead concentration was used as a measure of cumulative exposure. It is possible that the Weisskopf et al. study was subject to survivor bias if those who had the highest exposures died before the bone lead evaluations or if only the healthiest among those who had the highest exposures survived. Finally, a study by Khalil et al. (2009) did not find an association between lead exposure and mortality when it used data on women (65-87 years old) enrolled in the Study of Osteoporotic Fractures. Although the aforementioned studies have the weakness of using overall cancer mortality as the end point, which means that deaths from cancers that may be affected by lead exposure are combined with deaths from cancers that are not so affected, they have the strength of adjusting for several confounders, given their population-based nature (in contrast with studies of workers only).
Cancer-mortality studies of specific cancer types have greater relevance because the measures of effect in potentially affected sites are not diluted by those in unaffected sites. A recent study focused on mortality from specific cancer types found significant associations with lead exposure. Ilychova and Zaridze (2012) reported that risk of renal-cancer and pancreatic-cancer mortality had a two-fold increase (standardized mortality ratio [SMR] for renal cancer = 2.2, 95% CI: 1.1, 4.07; SMR for pancreatic cancer = 2.3, 95% CI: 1.46, 3.68) in exposed workers compared with the referent population Although studies that compared
exposed workers with the referent population are typically confounded by other work-related exposures, the study authors note that this particular study of printing workers was not subject to such bias in that the major work exposure was to lead and no other carcinogens (such as organic solvents) were used in the workplace.
Studies of the association between lead and renal cancer were noted in the IARC and NTP evaluations. Evidence of lead effects on renal cancers has been growing in the last decade, and a recent well-conducted study has added supporting evidence of the link. Using data from a nested case-control study of male smokers in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study, Southard et al. (2012) estimated a two-fold increase in the odds of renal cancer (95% CI: 1.0, 3.9) when comparing the 4th quartile (over 4.6 μg/dL) with the 1st quartile (under 2.5 μg/dL) of BLL at baseline. Cases included subjects wo had a diagnosis of renal-cell carcinoma at least 5 years after enrollment and at least 2 months after whole-blood draw. Controls were matched on age at randomization (± 7 years), whole-blood draw date (± 20 days in the same season), pack-years of smoking, and time to followup. In their case-control study, Boffetta et al. (2011) also showed an increased risk in those who were ever occupationally exposed to lead compared with unexposed subjects (OR = 1.55; 95% CI: 1.09, 2.21). Strengths of the study included adjustment for other metals and confounders. The association between lead exposure and renal-cancer mortality previously mentioned (Ilychova and Zaridze 2012) also supports an association between lead and renal cancer; the risk was two-fold greater (SMR = 2.2; 95% CI: 1.1, 4.07) in printing workers as in the referent population.
Evidence of links between lead exposure and lung cancer relies on studies that compared exposed workers with a referent population (based on either country or regional cancer rates). In a meta-analysis of eight studies that compared exposed workers with their referent populations, Steenland and Boffetta (2000) found an association between lead exposure and lung cancer. In six of the eight studies, the average BLLs of exposed workers were over 40μg/dL; one study reported only air concentrations (the geometric mean of respirable dust concentrations measured with personal samplers was 48 μg/m3). Steenland and Bofetta (2000) estimated a 14% higher cancer risk (meta-analysis relative risk [RR] = 1.14; 95% CI: 1.04, 1.25) in comparing exposed workers with their referent population. The study of Jones et al. (2007) also found an increased risk in exposed workers compared with their referent population (RR = 1.54; 90% CI:
1.14, 2.08). However, those studies controlled inadequately for confounders, such as smoking or asbestos exposure, because information on the unexposed (general) population that served as the comparison group was not available. Another study of occupationally exposed adults compared with their referent populations did not show significant associations between lead exposure and lung cancer (Rousseau et al. 2007) and was able to adjust for important confounders (OR = 1.1; 95% CI: 0.7, 1.7); however, the confidence bounds in this study did not preclude the finding of the degree of association reported by Jones et al. (2007). Although weak in their design, lung-cancer studies lend support to the existence of a link between lead exposure and lung cancer.
Brain and Nervous System Cancers
Since the early study of Anttila et al. (1996) reported a significant association between lead exposure and brain cancers in occupationally exposed workers compared with their referent population, at least six studies have examined this association. van Wijngaarden and Dosemeci (2006) used a job-exposure matrix to classify participants in the National Longitudinal Mortality Study into exposure categories based on intensity and duration. The hazard rate for mortality comparing those with high probability and intensity of exposure with those who were not exposed was 2.3 (95% CI: 1.3, 4.2). On the basis of a case-control study, Rajaraman et al. (2006) found a significant increase in meningioma risk associated with cumulative lead exposure (OR = 12.8; 95% CI: 1.4, 120.8 for highest-exposure group vs a referent group); the association was seen in those with the ALAD2 allele. The case-control study of Bhatti et al. (2009) also found an increased risk of meningioma (OR = 1.1; 95% CI: 1.0, 1.2). Results of multiple human studies now support a link between lead exposure and nervous system cancers.
Experiments in rats in the late 1950s and early 1960s found that lead caused renal tumors. Lead salts were and are used to administer lead in animal experiments. Carcinogenesis studies used lead forms of varied solubility, such as lead phosphate (insoluble, +2 valence) and lead subacetate and acetate (soluble, +2 valence), each of which induced renal tumors in animal experiments. Various routes of exposure were used (gavage, drinking water, feed, lactational and placental exposure, injection, and subcutaneous injection). Each of the experiments has limitations—for example, studies often examined only the kidneys)—and none followed the design of the standard carcinogenesis bioassay that is used today by the NTP. Nonetheless, as a whole they demonstrate that lead is a carcinogen in mice and rats. Table 5-2 shows tumor dose-response data on renal tumors in some of the rodent studies.
TABLE 5-2 Dose-Response Data on Renal Tumors from Some Oral Studies in Rodents
|Lead Exposure||Study Duration (wk)||Sex||Dose Rates (mg/kg-day)a||Tumor Incidence||Reference|
|Lead acetate in drinking water||76||Male||0, 130||0/10, 13/16||Koller et al. 1985|
|Lead acetate in feed||104||Male||0.12, 0.2, 0.72, 2.5, 5.6, 22, 45, 84||0/20, 0/100, 0/50, 0/50, 0/50, 5/50, 10/20, 16/20||Azar et al. 1973|
|104||Female||0.15, 0.25, 0.9, 3.1, 7.1, 27, 56, 105||0/20, 0/100, 0/50, 0/50, 0/50, 0/50, 0/20, 7/20|
|Lead acetate in drinking water||104||Male||0, 2.0, 10, 40||0/55, 0/42, 5/52, 24/41||Fowler and Lipsky 1999|
|Lead subacetate in feed (low dose)||126||Male||0, 15||0/14, 5/16||van Esch et al. 1962|
|126||Female||0, 18||0/15, 6/16|
|Lead subacetate in feed (high dose)||104||Male||0, 146||0/13, 6/13|
|104||Female||0, 183||0/13, 7/11|
|Lead subacetate in feed||78||Male||0, 146||0/30, 13/29||Kasprzak et al. 1985|
|Lead subacetate in feed||99||Male||0, 146||1/20, 31/40||Mao and Molnar 1967|
|Lead subacetate in feed||104||Male||0, 44||0/19, 6/20||van Esch and Kroes 1969|
Source: Adapted from CalEPA (2002).
Of male Wistar rats that received 1% lead acetate in their diet for 1 year, 88% developed renal carcinoma (Boyland et al. 1962). Another experiment with Wistar rats that were fed lead subacetate in the diet found renal tumors in both the high-dose (1%) and low-dose (0.1%) groups (van Esch et al. 1962). Several later experiments in Wistar rats exposed via the diet to either lead subacetate or lead acetate also observed renal tumors (Mao and Molnar 1967; Zawirska and Medras 1968, 1972; Ito et al. 1971; Ito 1973; Waszynski 1977); many of these included observations of renal carcinoma. Renal tumors were also observed in different rat strains. For example, Sprague Dawley rats that received 1% lead
subacetate in the diet had renal tumors, and the incidence was increased in animals that also received calcium (Kasprzak et al. 1985). In male and female Fischer 344 rats that received lead acetate in the diet (Fears et al. 1989), both sexes were affected; the male was more sensitive. Lead acetate in the diet (1%) induced tumors in male CD Sprague Dawley rats (Oyasu et al. 1970). The latter studies also examined lead in combination with other carcinogens and found no carcinogenic interactions. Drinking-water studies in male Sprague Dawley rats (Koller et al. 1985) and male Fischer rats (Fowler and Lipsky 1999) also observed lead-induced renal tumors.
Renal tumors were induced in two experiments with subcutaneous injection of lead phosphate in albino rats (Zollinger 1953; Balo et al. 1965) and in an experiment that used both subcutaneous and intraperitoneal injection in albino Chester Beatty rats (Roe et al. 1965).
Dietary calcium was observed to increase the effectiveness of lead in drinking water in causing renal tumors in Wistar rats (Bogden et al. 1991). A 1-year inhalation study that included a group of rats that were exposed to lead oxide did not observe lung tumors and found only one treated animal that had a renal tumor (Monchaux et al. 1997). Standard carcinogenicity studies in rats usually have a duration of 2 years, so this shorter study may have precluded the observation of late-occurring tumors. Hyperplastic and squamous metaplastic foci of the alveolar region were found in hamsters that received intratracheal administration of lead oxide, and lead oxide showed a cocarcinogenic effect with benzo[a]pyrene (Kobayashi and Okamoto 1974).
In one study that was not well described (for example, the strain and age of the rats were not provided), groups of 50 rats of each sex were given diets that contained lead acetate at 10, 50, 100, or 500 ppm for 2 years (Azar et al. 1973). Groups of 20 animals that received 1,000 or 2,000 ppm were added in a second experiment. In males, 10% of the animals in the 500-ppm group, 50% in the 1,000-ppm group, and 80% in the 2,000-ppm group developed renal tumors. The 500-ppm group had an average BLL of 77.8 μg/dL.
In mice, renal tumors have been induced by lead acetate in the diet (van Esch and Kroes 1969). A significant dose-related trend in renal proliferative lesions (atypical hyperplasia, adenoma, and adenocarcinoma) was observed in male and female offspring of B6C3F1 mice that were exposed to lead in drinking water while pregnant and after birth (Waalkes et al. 1995).
Renal tumors were not observed in Syrian Golden hamsters that were fed lead acetate for up to 2 years (van Esch and Kroes 1969).
Pulmonary adenomas were induced in Strain A/Strong mice given intraperitoneal injections of lead; kidneys were not examined in these studies (Stoner et al. 1976; Shimkin et al. 1977). In studies in Strain A mice, intraperitoneal injections of lead subacetate increased the incidence of pulmonary tumors (Poirier et al. 1984).
There is consistent and strong evidence that lead causes benign and malignant renal tumors in animals; tumors at additional sites have also been observed in some animal studies. Findings of renal tumors after exposure by multiple routes suggest that the kidney is a target for any route that results in increased BLLs. The finding of renal cancers in offspring of dams that were exposed to lead raises concerns about exposures of women of reproductive age. Animal studies have not clearly demonstrated lung-cancer risk, but lead exposure by inhalation has been inadequately studied. Mechanistic studies have provided supporting evidence of the potential carcinogenicity of lead. Some studies showed tumor induction at concentrations that were not cytotoxic and thus supported mechanisms at micromolar concentrations. Human studies have provided more limited evidence. Although it was not emphasized in the recent EPA review draft, there is additional epidemiologic evidence on both renal and brain cancers. These conclusions are consistent with the overall conclusions presented in the NTP, IARC, and EPA draft reports.
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