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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Int J Occup Environ Health. Author manuscript; available in PMC 2012 July 18.
Published in final edited form as:
PMCID: PMC3399253

Cadmium-induced Cancers in Animals and in Humans


Discovered in the early 1800s, the use of cadmium and various cadmium salts started to become industrially important near the close of the 19th century, rapidly thereafter began to flourish, yet has diminished more recently. Most cadmium used in the United States is a byproduct from the smelting of zinc, lead, or copper ores, and is used to manufacture batteries. Carcinogenic activity of cadmium was discovered first in animals and only subsequently in humans. Cadmium and cadmium compounds have been classified as known human carcinogens by the International Agency for Research on Cancer and the National Toxicology Program based on epidemiologic studies showing a causal association with lung cancer, and possibly prostate cancer, and studies in experimental animals, demonstrating that cadmium causes tumors at multiple tissue sites, by various routes of exposure, and in several species and strains. Epidemiologic studies published since these evaluations suggest that cadmium is also associated with cancers of the breast, kidney, pancreas, and urinary bladder. The basic metal cationic portion of cadmium is responsible for both toxic and cardinogenic activity, and the mechanism of carcinogenicity appears to be multifactorial. Available information about the carcinogenicity of cadmium and cadmium compounds is reviewed, evaluated, and discussed.

Keywords: cadmium, carcinogenicity, animal studies, environmental exposures, epidemiologic studies, public health, occupational exposures, cancer bioassays, extrapolation

Cadmium, discovered in 1817, was not used commercially until the end of the 19th century.1,2 An odorless, silver-white, blue-tinged malleable metal or grayish-white powder, cadmium in the environment occurs as eight stable and two radioactive isotopes.3 Almost all cadmium compounds have an oxidation state of +2. Cadmium is slowly oxidized in moist air but forms cadmium oxide fumes when heated.24 It is commercially available as powders, foils, ingots, slabs, sticks, and crystals. Commercially important cadmium salts include cadmium chloride, cadmium sulfate, and cadmium nitrate, and to a somewhat lesser extent, cadmium oxide and cadmium sulfide.3,4 Toxicology and carcinogenicity of cadmium and other metals, as well as environmental impacts,14,10,11 have been relatively well studied.39 Nonetheless, described herein are some alternative and more sensitive carcinogenesis bioassays. Our overview of cadmium 1) describes production, uses, and exposures, and toxicity data; 2) discusses human and animal carcinogenicity; and 3) comments on the importance of studies in experimental animals in identifying human carcinogens..

Production and Uses

Cadmium is a widely but sparsely distributed element found in the earth's crust at concentrations ranging from 0.1 to 1 ppm, primarily in association with zincores,4 ranking 67th in abundance among the 90 naturally occurring elements on earth.12 Though primarily found in zinc-containing ores, it is also found in lead and copper ores. The primary mineral form of the metal is greenockite or cadmium sulfide.12 Approximately 3 kilograms of cadmium are produced for each ton of zinc, or roughly 0.33%.5 U.S. production of cadmium began in 1907 and peaked in 1969 at 5,737 metric tons, but has declined in recent decades and was approximately 892 metric tons in 2006.3,13 Worldwide refinery production of cadmium in 2006 was 19,400 metric tons; China was the largest producer, followed by Japan, the Republic of Korea, and Kazakhstan. In 2003, the European Union adopted The Restriction of the Use of Hazardous Substances, which prohibits incorporation of cadmium and other heavy metals in most electrical and electronic equipment (including certain types of portable nickel-cadmium batteries) sold in the European Union after July 1, 2006. U.S. domestic consumption of cadmium metals has also declined due to environmental concerns, dropping about 14% between 2002 and 2006.13

The earliest use of cadmium, primarily as sulfide, was in paint pigments, in dental amalgams (minor amounts) in the early 1900s, and as a substitute for tin during World War II. Since World War II, almost all cadmium has been used in batteries, pigments, electroplating and coating, stabilizers for plastics and alloys. All uses except for batteries have declined in the late 20th century, and the major use for cadmium and cadmium compounds today is in battery manufacturing (81%). Cadmium use in batteries increased from 8% in 1970 to 75% in 2000.3 Cadmium also finds use in the green and blue phosphors in color TV tubes. Major uses for some specific compounds are as follows3,14:

  • Cadmium chloride—preparation of cadmium sulfide, dying and calico printing, electroplating, pigment manufacture, and vacuum tubes; previously used as a fungicide
  • Cadmium hydroxide—alkaline batteries
  • Cadmium nitrate—glass and porcelain colorant and photographic emulsions
  • Cadmium oxide—sliver zinc storage batteries, heat stabilizers for plastics and alloys
  • Cadmium sulfate—intermediate and electroplating
  • Cadmium stearate—lubricant and plastic stabilizer
  • Cadmium sulfide—pigment

Human Exposures

As with most naturally occurring chemicals, such as, for example, asbestos and benzene, humans play a significant role in creating concentrated sources of cadmium and releasing it into the environment through activities such as mining, smelting, and refining metal ores—zinc, lead, arsenic, cooper, chromium, and others.15 Cadmium is emitted from both stationary and mobile sources. Stationary sources likely to emit cadmium include secondary smelters, cement-manufacturing plants, cadmium-electroplating facilities, plants burning oil or coal, and sewage sludge incinerators. Mobile sources that emit cadmium include gasoline and diesel vehicles and particles resulting from tire wear. An emissions inventory compiled by the California Air Resources Board10 indicates that 16 to 18 tons/year of cadmium are emitted in California; stationary sources account for 80% or more of the cadmium emissions. Cadmium is also emitted airborne from fossil fuel burning, waste incineration, and steel production. Cadmium emissions from fossil fuel combustion and vehicles are projected to increase due to the expected increase in fuel use.

Soil and water near industrial areas or waste sites typically contain higher concentrations of cadmium. From these human activities, an estimated 4,000 to 13,000 tons of cadmium are released into the environment every year.12 According to the EPA toxic release inventory (TRI), total on- and off-site disposals or other releases of cadmium and cadmium compounds equal close to 5,000,000 pounds, with 80% from cadmium compounds16; clearly these figures serve as an indication of environmental and population exposures to cadmium, especially near cadmium operations. Cadmium present in soil from industrial emissions or other sources is selectively taken up by edible plants, resulting in levels much higher than those in the surrounding soils. Cadmium has also been shown to bio-concentrate in water plants and in fish. Of special concern are Mollusca and Crustacea; cadmium levels in crab may be as high as 30 to 50 parts per million.17

Primarily, however, exposures to cadmium and cadmium compounds occur in workplaces—mining, smelting, processing, product formulations, and battery manufacturing, whereas non-occupational exposures come from various foods and tobacco smoke.35 Occupational exposures to cadmium and cadmium compounds are mainly exposures to airborne dusts and fumes. The highest potential exposures occur in cadmium production and refining, nickel-cadmium battery manufacture, cadmium pigment manufacture and formulation, cadmium alloy production, mechanical plating, zinc smelting, soldering, and polyvinylchloride compounding. Although levels vary widely among the different industries, occupational exposures generally have decreased in the last two decades, largely together with decreased demand.15

Outside the occupational exposure setting, the main sources of cadmium in air are from zinc, lead, or copper smelters and from burning fossil fuels such as coal or oil and the incineration of municipal waste materials.3,5,12 On- and off-site disposal and dispersal represent a sizable source of cadmium exposure.16 Cadmium levels in some foods can be increased by the application of phosphate fertilizers or sewage sludge to farm fields.6 Smoking tobacco is an important source of cadmium exposure, with smokers having twice as much cadmium in their bodies as do nonsmokers. For nonsmokers, food is generally the largest source of non-occupational cadmium exposure. The average person in the United States consumes approximately 30 μg of cadmium per day in food; however, in cadmium-polluted areas intakes may reach several hundred micrograms.17 Approximately 3–10% of ingested cadmium is absorbed from the gastrointestinal system, whereas 50% of cadmium in inhaled smoke is absorbed into the bloodstream.18


Public awareness of cadmium's toxic effects rose with the post-World-War-II (1950) outbreak in Toyama Prefecture, Japan, of “itai-itai” disease, which was the first cadmium poisoning in the world. Itai-itai or “ouch-ouch” disease, so named from the painful screams due to severe pain in the joints and the spine, was caused by ingestion of runoff water containing cadmium released from mining companies in surrounding mountains.2,12,19 Farmers in the region used the runoff for irrigating rice paddies and other crops. Cadmium concentrated in the crops, and before long local women began to experience pain in bones and joints, eventually becoming so excruciating that they were bedridden. Cadmium interfered with calcium metabolism, leading to reduction in calcium levels and thus reduced density and strength of bones, often causing the weakened bones to break.12 In addition, kidney failure caused by cadmium poisoning was common. The mining companies were successfully sued for the damage. Itai-itai disease is one of the four major pollution-related diseases of Japan: 1) minamata disease—mercury poisoning; Chisso's chemical factory; 2) Niigata minamata disease (second minamata disease)—mercury poisoning; Showa Electrical Works; 3) Yokkaichi asthma—sulfur dioxide and nitrogen dioxide; air pollution in Yokkaichi; 4) itai-itai disease—cadmium poisoning; mining in Toyama Prefecture.

Short-term adverse effects of cadmium in humans through inhalational exposures from the environment consist mainly of effects on the lung, such as pulmonary irritation. Long-term inhalation or oral exposure to cadmium leads typically to build-up of cadmium in kidneys, and potential kidney disease.36 In the workplace, chronic inhalation and oral exposure of humans to cadmium results in adverse effects on the lung, including bronchiolitis and emphysema, and a build-up of cadmium in the kidneys, often resulting in kidney disease, including pro-teinuria, decrease in glomerular filtration rate, increased frequency of kidney stone formation, and cancer.35 In animals, longterm inhalation or oral exposure to cadmium results in harmful effects on the kidney, liver, lung, bone, immune system, blood, and nervous system.

Carcinogenicity—Experimental Animal Studies

Experimental animal studies demonstrate clearly that cadmium and cadmium compounds (referred to as cadmium) by multiple routes of exposure induce benign and malignant tumor formation at various sites in many species of experimental animals.3,4,79,2027 The earliest studies showing cadmium to be a carcinogen were bioassays conducted in the middle 1960s using the injection route of exposure,6,2833 a valid method for screening and identifying carcinogens.34 These findings of cadmium carcinogenicity predated the first accepted epidemiologic study, by Lemen et al. in 1976,35 of human lung and prostate cancers in cadmium workers.

Reported in 1983 by Takenaka et al.,36 the first non-injection cadmium cancer study showed unequivocal positive results (lung cancers) in rats exposed to cadmium chloride aerosol. Earlier oral exposure studies were reported negative, but these suffered from various inadequacies—incomplete experimental details, single exposures or low exposure levels, short exposure durations, inadequate overall length of experiment, too few animals, absence of concurrent controls, limited tissue sampling, and restricted histopathology. Length of experimental duration was the likely reason that Takenaka et al.36 but not Loser37 obtained positive carcinogenicity results.15,3840 That is, Loser37 conducted a two-year feeding study exposing Wistar rats to dietary levels of 0, 1, 3, 10, and 50 ppm cadmium chloride. “Cadmium administered orally was not associated with an increased incidence of total numbers of tumours or of any specific type of neoplasia, although the highest level tested resulted in adverse effects.” On the other hand, Takenaka et al.36 exposed groups of 40 male Wistar rats continuously (23 hours/day, 7 days/week) to cadmium chloride aerosols at cadmium concentrations of 0 (filtered air), 12.5, 25, and 50 μg/m3 for 18 months, and survivors were killed 13 months after the end of the inhalation experiments, at 31 months. The clear dose-related incidence of lung adenocarcinomas (often multiple) was 71% in the group exposed to 50 μg/m3, 53% in the group exposed to 25 μg/m3, and 15% in the group exposed to 12.5 μg/m3. None of the controls developed lung carcinomas. At the end of the experiment, the cadmium concentrations remaining in the lungs were relatively high, almost at the same level as those in the livers.

There were three major differences between the two studies: 1) aerosol (inhalation) versus dietary (oral) exposures to cadmium chloride; 2) 31 months (18 months exposure plus 13 months non-exposure) versus 24 months experimental duration; and 3) cumulative cadmium exposures were likely greater and more targeted (lung) with the aerosol route than with the dietary mode of exposure. Actually, Loser37 exposed animals to cadmium chloride longer than did Takenaka et al.,36 but for the latter the experiment went longer over all, perhaps allowing development of late-appearing tumors. We believe the key here regarding cadmium carcinogenesis and non-carcinogenesis is duration, as others have found this to be the case for toluene41,42 and xylene40,43 under like duration differences.3840 Takenaka et al.36 reported that in the highest-exposure group “the first lung carcinomas were noticed 23 months after beginning the experiment. During the following 4 months we found no lung carcinomas; however, after the 27th month 23 lung carcinomas occurred, which means an incidence of more than 90%. If we had killed the animals before the 27th month, we would surely have detected initial stages of lung cancer, but not so many macroscopically and microscopically clear tumors.”

However, this interpretation and clear differentiation becomes a bit complicated, since Waalkes and Rehm25 exposed male Wistar rats to diets containing 0, 25, 50, 100, or 200 ppm cadmium chloride for only 77 weeks, and animals at the higher exposure levels had increased incidences of leukemia (100 ppm), not dose-related, and interstitial cell tumors of the testes (200 ppm). The keen difference here is that exposure concentrations for detecting an effect were two to four times greater than those in earlier experiments.36,37 The Waalkes and Rehm study25 (oral exposure) also used a different route of administration than the study of Takenaka et al.36 (inhalation exposure), which may help to explain why the tumors were observed at different organ sites (leukemia and testicular tumors in the oral study and lung tumors in the inhalation study). In later drinking-water studies, Waalkes et al.23 reported a few rare tumors of the kidney in Noble (NBL/Cr) rats, and most significantly their “results indicate that oral cadmium can induce proliferative lesions in the prostate and kidney of the Noble rat. The finding of proliferative lesions of dorsolateral prostate in rats has presumed relevance to human prostate cancers.”

Over all, cadmium exposures of laboratory animals causes tumors of the hematopoietic system (leukemia and lymphoma), local sarcoma, and cancers of the adrenal gland, liver, lung, kidney, pancreas, pituitary, prostate, and testis.3,8 Even though cadmium penetrates the placenta and appears in breast milk, there appears to be no longterm cancer study using an inutero exposure design protocol. As cadmium mimics estrogen,44 and because children are exposed to cadmium via maternal exposures,45 interest in earlier exposure regimens, including in utero, should be considered to obtain a fuller understanding of cadmium carcinogenicity.7

Carcinogenicity—Human Epidemiological Studies

Regarding possible causal associations between cadmium exposures and human cancers, the International Agency for Research on Cancer (IARC) in February 1993 reviewed and evaluated the available epidemiologic findings and other relevant information on cadmium exposures and concluded there was sufficient evidence of carcinogenicity in humans for the carcinogenicity of cadmium and cadmium compounds.4 Their evaluation was based largely on occupational cohort studies of nickel-cadmium manufacturing, cadmium processing, cadmium-recovery plants, and copper-cadmium alloy plants. Most studies reported excess mortality from lung cancer among cadmium-exposed workers. Limitations included small numbers of long-term highly exposed workers, inadequate exposure assessment data, and potential confounding by cigarette smoking and exposures to other metals. For lung cancer, the IARC concluded that the dose–response relation for workers at a U.S. cadmium-recovery plant was unlikely to be confounded by cigarette smoking, and “the increase in lung cancer risk was unlikely to be explained by exposure to arsenic.” Other studies reported that risks of lung cancer were greater in highly exposed workers or that there were suggested trends with increased duration of employment or intensity of exposure. The IARC also noted that some studies (mainly earlier ones) reported excesses for prostate cancer.

Despite potential confounding, the IARC considered the totality of available information through early 1993 as being sufficient to place cadmium in its Group 1 category of evidence: “Cadmium and cadmium compounds are carcinogenic to humans.” Their conclusion was based on

  • sufficient evidence in humans for the carcinogenicity of cadmium and cadmium compounds,
  • sufficient evidence in experimental animals for the carcinogenicity of cadmium compounds, and
  • limited evidence in experimental animals for the carcinogenicity of cadmium metal.

The overall evaluation took into consideration that ionic cadmium causes genotoxic effects in a variety of eukaryotic cell types, including human cells.

In 2000, the National Toxicology Program (NTP)3 independently evaluated the available evidence and concluded “Cadmium and cadmium compounds are known to be human carcinogens based on sufficient evidence of carcinogenicity in humans, including epidemiological and mechanistic information that indicate a causal relationship between exposure to cadmium and cadmium compounds and human cancer.” The NTP concurred with the IARC's assessment that cohort studies showed an increased lung cancer risk among workers exposed to various cadmium compounds, and while they often were co-exposed to other agents, the increased risks of lung cancer were unlikely due to confounding factors. Additionally, the NTP stated that “Follow-up analyses for some of the cohorts has not definitely eliminated arsenic as a confounding factor but has confirmed that cadmium exposure is causally associated with elevated lung cancer risk under certain industrial exposure circumstances.”46,47

Regarding cadmium-associated prostate cancer, the NTP concurred with the IARC that the increases observed in earlier cohort studies were not confirmed in later studies. However, some case–control or ecologic studies suggest an association between cadmium exposure and cancer of the prostate.48,49 Epidemiologic studies have reported possible associations between cadmium exposures and cancers of the kidneys50; and of the urinary bladder.51

Since the NTP review, additional epidemiologic studies, reviews, and meta-analyses have evaluated cancer risks and exposures to cadmium compounds. Most have focused on cancers of the lung, prostate, pancreas, and kidney. Another study looked at cadmium exposure and breast cancer. Several of these are mentioned in brief.


In 2003, Verougstraete et al.52 reviewed the epidemiologic data on exposures to cadmium and lung and prostate cancers and concluded that the cohort studies (including the latest updates) consistently found an increased risk of lung cancer despite different exposure conditions, in different cadmium industries, and in different countries. Mentioned limitations were inconsistencies of exposure–response relationships and potential confounding by arsenic. Since that review, a further update of the U.K. nickel-cadmium factory reported an excess lung cancer mortality (standardized mortality ratio, SMR = 1.11, 95% confidence interval (CI) = 0.81–1.48; 45 observed deaths, for which the authors stated their study weakened the evidence for cadmium as a lung carcinogen.53 However, a later prospective population-based study of environmental exposures to cadmium demonstrated a positive association between 24-hour urinary cadmium levels (doubling of excretion) and both lung cancer (hazard ratio = 1.70, 95% CI = 1.13–2.57) and total cancer risk (hazard ratio = 1.31, 95 CI = 1.03–1.65) after adjusting for age, sex, and tobacco smoking.54 Significant findings were also found for an association between lung cancer and cadmium concentrations in the soil or living in a high-exposure area. Moreover, urinary cadmium excretion was a significant predictor of any cancer (hazard ratio = 1.28, 95% CI = 1.01–1.63) and lung cancer (hazard ratio = 1.60, 95% CI = 1.04–2.45) after adjusting for arsenic exposure . (Urinary arsenic excretion data were available for 26% of the population.) Use of urinary cadmium level to assess exposure alleviates some of the limitations of occupational cohort studies, such as misclassification of exposure and confounding from exposures to other agents or cigarette smoking, and thus strengthens the evidence for cadmium carcinogenicity. The urinary cadmium level is proportional to the cadmium body burden and is considered to be a sensitive dosimeter for lifetime exposure.55,56

Prostate gland

Although historically prostate cancer was the first cancer identified in association with exposure to cadmium,35 Verougstraete et al.52 suggested that their review of cohort studies (the same review as for lung studies discussed above) did not confirm the original findings of high-risk estimates for prostate cancer. Sahmoun et al.18 reviewed the literature for studies on prostate cancer and exposure to cadmium published between 1966 and 2002, and reported positive associations in three of four descriptive studies, five of ten case–control studies, and three of 11 cohort studies. From their collective findings, they decided the overall evidence of an association between exposure to cadmium and prostate cancer was either weakly positive or negative, but indicated that the studies were limited by potential exposure misclassification, which limits the ability to detect an effect. When they restricted their review to four cohorts of nickel-cadmium battery workers (who the authors stated had the highest and least ambiguous exposures), they calculated an elevated summary SMR of 1.26 (95% CI 0.83–1.84) for prostate cancer. A 1998 case–control study in southeast China with 297 male volunteers from a control area and two cadmium-polluted areas showed a clear dose–response relationship between cadmium exposure and the prevalence of abnormal prostate-specific antigen (PSA).57 These results indicate that chronic environmental cadmium exposure is associated with injuries to human prostate. Moreover, cadmium induces prostatic proliferative lesions and cancer in laboratory animals2023,25 and transforms human prostate cells in vitro,8 suggesting that more studies, with improved methods to access exposure, are needed. The available human studies have limited ability to detect an effect and thus reliance on animal findings strengthens the evidence of an association between cadmium exposure and cancer of the prostate in humans.


Since the IARC and NTP evaluations, there has been mounting evidence that cadmium may be associated with cancers at other sites, including kidney, pancreas, and breast. Il'yasova and Schwartz58 reviewed publications between 1966 and 2003 on exposures to cadmium and renal cancer and reported that three large (935 to 1,732 cases) case–control studies, from different geographic regions and using different methods to assess exposure, found increased risks for renal cancer from occupational exposures to cadmium, odds ratios (ORs) between 1.2 and 5. They identified four other studies with information about cadmium exposures: three had elevated but imprecise risk estimates (as evidenced by wide confidence intervals resulting from small numbers of exposed cases) and the fourth study did not report an increased risk. There is site concordance with animal studies and mechanistic or other data supporting the findings suggested by human studies. Because there is no apparent biological mechanism for excretion of cadmium, this metalloid accumulates in tissues, with the largest amounts deposited in kidneys (half-life in kidney cortex is 10 to 30 years) and liver, followed by the pancreas and lungs.5,17 Cadmium–metallothionein complexes accumulate in the proximal tubules in the kidney, and release of free cadmium is thought to produce renal tubular damage.5,17 Cadmium is an established cause of end-stage renal disease in humans.58,59


Schwartz and Reis5,17 proposed that cadmium exposure may present a risk for pancreatic cancer. A meta-analysis of studies published between 1966 and 1999 gave a pooled SMR of 1.62 (95 CI = 0.94–2.79) for three cohorts of male workers using the most recent reports giving numbers of observed and expected deaths from pancreatic cancer. However, a meta-analysis by Ojajärvi et al.60 did not show an elevated risk for cancer of the pancreas from cadmium exposure, based on two populations. (Cadmium was not the focus of their review, but was one of 23 chemicals or physical agents evaluated.) Additionally, Kriegel et al.61 measured serum cadmium levels of 31 newly diagnosed pancreatic cancer patients and 52 hospital comparison subjects from Mansoura, Egypt, and found significant differences in serum cadmium (mean ± SD 11.1 ± 7.7 ng/mL vs 7.1 ± 5.0 ng/mL). The OR for pancreatic cancer risk was significant for serum cadmium level, OR 1.12 (95% CI, 1.04–1.23) and farming, OR 3.25 (95% CI, 1.03–11.64) but not for age, sex, residence, or smoking status. From this pilot study, Kriegel et al.61 suggested that pancreatic cancer in the East Nile Delta region is significantly associated with the highest levels of serum cadmium and farming. As with cancer of the kidney, there is site concordance with animal studies and mechanistic or other data supporting the findings suggested by human studies for the pancreas. Cadmium causes trans-differentiation of pancreatic cells, increases synthesis of pancreatic DNA, and induces or regulates oncogenic activation of several proteins or tumor-suppressor proteins that are over-expressed in human pancreatic cancer.17


McElroy et al.62 reported in 2006 that cadmium exposures are associated with cancer of the breast. These authors carried out a population-based case–control study of 246 women, aged 20–69 years, with breast cancer and 254 age-matched controls. Cadmium levels in urine were measured and telephone interviews conducted to obtain information about known breast cancer risk factors. Women in the highest quartile of creatinine-adjusted cadmium level (≤ 0.58 μ/g) had twice the breast cancer risk of those in the lowest quartile (<0.26 μ/g; OR = 2.29, 95% CI 1.3–4.2) after adjusting for other breast cancer risk factors. Notably, there was a significant increase in risk with increasing cadmium level, P (trend) = 0.01. Nonetheless, McElroy et al.62 hedge a bit by concluding “whether increased cadmium is a causal factor for breast cancer or reflects the effects of treatment or disease remains to be determined.” No investigation of this target site in animal experiments on the effects of cadmium has been reported. However, there are other hormone-dependent cancers observed in animals, affecting the adrenal and pituitary glands, prostate, and testes, and evidence in rats indicates that cadmium at very low doses acts estrogenically in the uterus and mammary glands.44 Nagato et al.63 reported a positive association between urinary cadmium and serum testosterone levels after controlling for age and body index. Cadmium exposure may affect the mechanism that maintains the estrogen–androgen balance, and epidemiologic studies have shown that high testosterone levels have been associated with breast cancer risk.64

Urinary bladder

A new study was published while this publication was in proof; see note added in proof.

In contrast to the IARC and NTP evaluations, both of which have classified cadmium as a known human carcinogen, the U.S. Environmental Protection Agency has classified cadmium as a “probable” human carcinogen, indicating a lower level of concern.65 Further, in 1986 the California EPA under Proposition 65 listed cadmium and cadmium salts as known to the State to cause cancer, and “Based on available scientific information, a cadmium exposure level below which carcinogenic effects are not expected to occur cannot be identified.”66,67 This difference between the concordant evaluations by IARC and NTP and that of the EPA is significant with regard to:

  • regulatory categorization and enforcement levels of exposure,
  • occupational and environmental standard setting,
  • primary prevention initiatives, and
  • exposure-caused cancer victims' recourse.

The IARC and the NTP cited primarily cadmium-induced lung cancers as clearly demonstrating causation and incorporated mechanistic data in making their final evaluations. Recent studies suggest that cadmium may also be associated with cancers of the kidney, pancreas, and breast.

Mechanistic Considerations

Cadmium (i.e., cadmium or cadmium compounds) is poorly excreted and has a long biological half-life. Accumulating mainly in the liver and kidney, cadmium is bound to metallothionein (a metal-binding protein), which may serve to temporarily detoxify the metal.8

As discussed previously, cadmium causes cancers in experimental animals at many tissue sites, and thus it is likely that the mechanism of carcinogenicity is multi-factorial. Like other toxic metals, cadmium may act by molecular/atomic mimicry of essential nutrient metals; that is, it competes for binding at sites (specifically with a zinc finger motif) that are important in gene regulation, enzyme activity, or maintenance of genomic stability.8,68 Numerous studies have shown that zinc reduces the carcinogenic effect of cadmium at some sites (such as lung, testes and injection sites) but not all (such as prostate).8

In vitro, cadmium can transform a variety of cells, including human prostate epithelial cells, demonstrating its oncogenic properties.8 It has a wide spectrum of cellular and molecular effects, including both genetic and epigenetic, which could affect all stages in the carcinogenic process. Potential molecular and cellular mechanisms of cadmium that mediate carcinogenesis have been reviewed extensively in the last several years8,68,69 and thus will be discussed only briefly.

Most of the reviews have concluded that cadmium is weakly genotoxic.4,7,8,69 Cadmium causes genetic damage in cultured mammalian cells but is not mutagenic in bacteria. Cadmium compounds are co-mutagens in mammalian cells when combined with genotoxic agents.69 Cadmium also causes genetic damage (micronuclei, sister chromatid exchanges, and single-strand breaks) in experimental animals exposed by intraperitoneal injection but not in inhalational studies.52 Verougstraete et al.52 reviewed studies that evaluated cytogenetic effects in humans exposed occupationally and environmentally to cadmium. These authors concluded that the reported results of the human studies were conflicting and no definite conclusion could be reached. A contemporary study of workers exposed to cadmium, cobalt, and lead reported a positive correlation between cadmium concentrations in air and blood and DNA damage (single-strand breaks).70

Waisberg and colleagues stated, “Various studies have shown that cadmium carcinogenicity seems to be crucially mediated by the production of reactive oxygen species.” Cadmium induces the production of hydroxyl radicals, superoxide anions, nitric oxide, and hydrogen peroxide. It also increases lipid peroxidation levels in the liver and liver mitochondria in rats, and in cultured rat hepatocytes. Cadmium is not a Fenton metal, and induces reactive oxygen species by indirect mechanisms.69

In experimental systems, cadmium induces many biochemical changes, including aberrant gene expression and signal transduction, E-cadherin (protein important in (3-catenin signaling pathway and possibly tumor invasion) dysfunction, inhibition of DNA methylation, disruption of DNA repair, and cell death.69 Cadmium modifies the expression of several genes related to carcinogenesis, including intermediate early-response genes such as c-fos, c-jun, and c-myc; stress-response genes such as metallothonein, and heat-shock genes; genes controlling glutathione and related proteins; and transcription and translation factors.69 At low, non-cytotoxic concentrations, cadmium inhibits DNA repair including mismatch repair, nucleotide-excision repair, and base-excision repair. Inhibition of DNA repair in combination with increased oxidative stress causes DNA damage, cell cycle arrest, mutagenesis, and genomic instability, leading to cancer or cell death.68

Cadmium-induced biochemical changes may play roles in all stages of carcinogenicity (initiation, promotion, and progression). For example: 1) induction of oxidative stress in combination with decreased DNA repair can lead to DNA damage, and gene mutation, resulting in preneoplastic lesions; 2) aberrant gene expression and signaling in combination with inhibition of DNA methylation induces proto-oncogenes, resulting in cell proliferation; and 3) E-cadherin dysfunction disrupts cell adhesion and causes tumor progression.69

Cadmium also affects apoptosis. In cultured cells, exposure to cadmium causes an increase in apoptotic cells in a concentration-related matter. In some experimental systems, the increase in cell death is associated with increased p53 protein and mRNA levels, whereas in other cell lines, cadmium-induced apoptosis is p53-independent and related to reactive oxygen production. However, the induction of apoptosis is probably not protective against malignant transformation, because some studies have found that only a small fraction of cadmium-treated cells undergo apoptosis and the remaining cells may acquire apoptotic resistance.69 Moreover, cadmium-transformed cells such as prostate, epithelial, or rat liver or cadmium-adapted cells (lung cells) acquire resistance to apoptosis.69,71,72 Apoptotic resistance allows for the accumulation of critical mutations, or preneoplastic or early neoplastic cells.8,69

Calepa Risk Due to Atmospheric Cadmium

Hazards posed by atmospheric cadmium to residents of California were estimated by applying the unit risk estimate to cadmium concentrations measured in the state. The upper-bound excess lifetime cancer risk from atmospheric concentrations of cadmium in California has been estimated to be 30 per million. Near emission sources of cadmium, the upper-bound estimated excess lifetime cancer risk from 24-hour-per-day exposure to an average of 40 ng/m3 of cadmium is 480 per million persons exposed. These are health-conservative estimates; the actual risks may lie below these values. The CalEPA Board10,66,67 thus finds:

  • cadmium is an animal carcinogen with epidemio-logic evidence of carcinogenicity in humans;
  • there is not sufficient available scientific evidence to support the identification of a threshold exposure level for cadmium; and
  • cadmium is an air pollutant which, because of its carcinogenicity, may cause or contribute to an increase in mortality and an increase in serious illness, and poses a hazard to human health.


Like many other carcinogens, cadmium and cadmium compounds have long been known to cause cancers in laboratory animals, and are another example of chemicals first identified as being carcinogenic in animals and only subsequently in humans.15,7375 In fact, nearly 25–30% of known human carcinogens were first discovered in long-term bioassays in animals.15,74 This phenomenon typically results from an increasing debate regarding whether chemical carcinogenesis bioassay findings are relevant and validated to predict human cancer risks.76,77 The overwhelming majority of governmental and nongovernmental organizations support and endorse the biologic concept that animal bioassay results are the most reasonable and reliable means to identify likely human carcinogens.3 The endorsement from the IARC/WHO states: “In the absent of adequate data on humans, it is biologically plausible and prudent to regard agents and mixtures for which there is sufficient evidence in experimental animals as if they presented a carcinogenic risk to humans.”73

As one example whereby convincing animal carcinogenicity data have been repudiated, the editor of Science wrote two editorials in the 1990s78,79 criticizing us for declaring 1,3-butadiene as a unique and dangerous carcinogen. Others view this industrial hazard differently.80,81 We found this industrial chemical caused multiple cancers in only 60 weeks at and below (650 and 1,250 ppm)82 the then OSHA workplace standard (1,000 ppm); in further more definitive experiments the lowest exposure (6.5 ppm) tested was also considerably carcinogenic.83,84 OSHA eventually lowered its occupational exposure standard to 1 ppm, which is not likely to prevent completely further excess cancers in workers since every exposure level yet tested causes significant cancers in animals.84 Subsequently, of course, leukemias (also seen in animals) were found in butadiene workers,8588 and this is another example whereby animal evidence was disregarded, trumping worker safety. The NTP declared butadiene a human carcinogen in 2000,87 but the IARC, after much debate and controversy, retained its classification of “probably carcinogenic to humans.”8994 IARC will reevaluate the carcinogenicity data of 1,3-butadiene in June 2007.

In addition to butadiene, other animal carcinogens have also been impugned.95 “Questionable assessments involving liver cancer in B6C3F1 mice include the risks posed by trichloroethylene, perchloroethylene, methylene chloride, butadiene, and phenobarbital.”96 Certainly none of these chemicals caused liver tumors in mice only, and all of them (with the possible exception of phenobarbital) have now been evaluated and judged scientifically to be likely or known carcinogens to humans (e.g., TCE97). These among others are examples of likely carcinogenic hazards ignored until cancers occur in workers.98

As significant and further support of the biologically credible animal-to-human correlation, all known human carcinogens that have been evaluated experimentally are also carcinogenic to animals, and target sites are similar to a fault.99,100 Does this mean that all chemicals causing cancer in animals should be regulated or banned? No, all carcinogens are not equally potent carcinogenically, nor do all represent similar carcinogenic hazards to humans. As with most biology, there are gradations of adverse effects, and these must be evaluated accordingly.15,101,102

Epidemiologic findings of cancers in humans exposed to cadmium and cadmium compounds are supported by studies in experimental animals demonstrating that cadmium and cadmium compounds induce benign and malignant tumor formation by multiple routes, at various exposure concentrations, and at various and diverse sites in different species of experimental animals. Cadmium-inhalation–exposed animals develop lung cancers. As has been further supported and confirmed using other routes of exposures in animals, intra-tracheal exposure to cadmium also caused lung tumors; oral exposure caused leukemia and tumors of the testes, prostate, pituitary, and kidney; and subcutaneous exposure caused lymphoma, local sarcomas (also observed in other types of injection studies), and tumors of the prostate, testes, lung, liver, pancreas, pituitary, and adrenal gland.3,8,23 Route of exposure gently impacts “sites” of chemical carcinogenic activity, and has relatively little effect regarding the finding of carcinogenicity.103

In humans, cadmium and cadmium compounds are causally associated with cancers, mainly of the lung, with suggestive evidence for cancers of the breast, pancreas, kidney, and prostate (although the strength of the evidence for the latter site appears to have decreased in recent studies). Of these sites, only breast has not been investigated or observed in animals. Once again, concordance between animals and humans is upheld, and points to other sites in humans that may be prone to cadmium-associated cancers. Moreover, Sanner and Dybing104 found good agreement between hazard characterization for cadmium (lifetime cancer of 10–3) based on epidemiologic studies and animal experiments.

To reiterate, cadmium and cadmium salts were shown to cause cancer first in laboratory animals and only subsequently in humans. As in the case of butadiene (and others), the prudent course of action for operations involving exposures to cadmium and cadmium compounds would have been to take the collective results from animals seriously and act accordingly and more rapidly in the highest principled interests of public and worker health.105,106 The initial failure to find cancer in humans might reflect simply a lack of looking for other cancers in workers in cadmium industries. Epidemiologic studies of occupational exposures are likely to be spurred by clear evidence of carcinogenicity in animals.107 Moreover, occupational epidemiologic studies are often limited in their abilities to detect an effect because of poor exposure assessment, small numbers of exposed cases, and confounding by exposures to other agents. Also, individuals may be exposed to cadmium from non-occupational sources, such as food and cigarette smoking; therefore, occupational studies usually do not measure cumulative exposures to cadmium. The use of biomarkers to measure cadmium exposure, such as urinary cadmium excretion and blood or serum cadmium levels, may help address some of these limitations. As discussed above, three recent studies using exposure biomarkers have shown a positive association between cadmium exposure and cancer risks (lung, breast or pancreatic). Although epidemiology is the best means to unequivocally identify human carcinogens, as Hill has said, “All scientific work is incomplete—whether it be observational or experimental. All scientific work is liable to be upset or modified by advancing knowledge. That does not confer upon us a freedom to ignore the knowledge we already have, or to postpone the action that it appears to demand at a given time.”108

Fundamentally there is no convincing evidence to suggest that mechanisms thought to account for the multi-organ carcinogenicity of cadmium (and other chemical carcinogens) in experimental animals would not also operate in humans. Correlations between species exist, with first evidence being observed in animals. Thus, further reductions in allowable workplace and environmental exposures to cadmium and cadmium compounds should be actively pursued. This proposed action of occupational surveillance of adverse health effects and cancer and exposure reduction is especially relevant for developing countries.109115 Only by preventing, minimizing, or eliminating exposures to known and suspected chemical carcinogens will there be a significant lessening in the number of these workplace and environmental cancers and their attendant suffering.116119

Urinary bladder

Kellen et al.120 conducted a case–control study in Belgium, one of the most important cadmium-producing countries worldwide, to assess an association between blood cadmium levels and risk of urinary bladder cancer. Blood cadmium reflects current exposure rather than whole-body burdens, while urinary cadmium reflects total burden.5 Blood cadmium levels were measured in 172 urinary bladder cancer cases and 359 population controls. Bladder cancer risk increased with increasing levels of blood cadmium (Ptrend < 0.001), and the risk was greater than eightfold in the highest tertile of blood cadmium levels after adjusting for sex, age, and occupational exposure to PAHs or aromatic amines (OR = 8.3, 95% CI = 5.0–13.8). The OR decreased somewhat after further adjustment for cigarette smoking but was still significant (OR = 5.3, 95% CI = 3.3–9.9). This study supports the findings from an earlier case–control study (that was reviewed by NTP), which reported an association between occupational exposure to cadmium and bladder cancer risk.51 These epidemiologic findings are further supported mechanistically by studies showing that cadmium malignantly transforms human urothelial cells.121 Additionally, Sens et al.122 reported that tumor heterotransplants produced by these cadmium-transformed cells were epithelial in character and had features consistent with those expected of undifferentiated transitional-cell carcinomas of the urinary bladder.


The authors thank John Bucher and Rajendra Chhabra for reviewing the paper and presenting useful comments and interesting interrogations. Our continuing gratitude to Joe LaDou and Sandy Love-grove for their years of unyielding devotion to public and occupational health, especially their activist regards for protecting workers in developing countries.


1. Hiatt V, Huff J. The environmental impact of cadmium: an overview. Int J Environ Studies. 1975;7:277–85.
2. Hammons AS, Huff J, Braunstein HM, et al. ORNL/EIS-106 and EPA-600/ 1-78-026. Oak Ridge, TN: Oak Ridge National Laboratory; 1978. Review of the environmental effects of pollutants: IV. Cadmium; p. 274.
3. NTP. Report on Carcinogens. 11th. U.S. Department of Health and Human Services, Public Health Service, National Toxicology Program; 2004. Cadmium and cadmium compounds; pp. III-42–44.
4. IARC. Beryllium, cadmium, mercury, and exposures in the glass manufacturing industry. Working Group views and expert opinions, Lyon, France, 9–16 February 1993. Vol. 58. IARC Monogr Eval Carcinog Risks Hum; 1993. Cadmium and cadmium compounds; pp. 41–117. [PubMed]
5. ATSDR. Toxicological Profile for Cadmium. Agency for Toxic Substances and Disease Registry; 1999. p. 434.
6. Huff J. Evaluation of the carcinogenicity of cadmium and certain cadmium compounds. Proc 2nd Int Cadmium Conf, 1980; Cannes, France. Metal Bulletin, London; 1980. pp. 207–10.
7. Waalkes MP. Cadmium carcinogenesis in review. J Inorg Biochem. 2000;79:241–4. [PubMed]
8. Waalkes MP. Cadmium carcinogenesis. Mutat Res. 2003;533:107–20. [PubMed]
9. Waalkes MP, Coogan TP, Barter RA. Toxicological principles of metal carcinogenesis with special emphasis on cadmium. Crit Rev Toxicol. 1992;22:175–201. [PubMed]
10. ARB, Air Resources Board, State of California. Staff Report: Initial Statement of Reasons for Proposed Rulemaking. PublicHearing to Consider the Adoption of a Regulatory AmendmentIdentifying Cadmium as a Toxic Air Contaminant. Agenda Item No.: 87- 2-1. Scheduled for Consideration: January 22, 1987. Release Date: December 5, 1986. <>.
11. Corrill LS, Huff JE. Occurrence, physiologic effects, and toxicity of heavy metals—arsenic, cadmium, lead, mercury, and zinc—in marine biota: an annotated literature collection. Environ Health Perspect. 1976;18:181–217. [PMC free article] [PubMed]
12. Dartmouth. Center for Environmental Health Sciences; Hanover, NH: [Accessed November 2006]. Toxic Metals Research Program. <>.
13. USGS. Minerals Information. Mineral Commodities Summaries. Cadmium US Geological Survey. 2006 <>.
14. HSDB. Hazardous Substances Data Bank, National Library of Medicine; Nov, 2006. Cadmium Compounds. <>.
15. Huff J. Value, validity, and historical development of carcinogenesis studies for predicting and confirming carcinogenic risks to humans. In: Kitchin K, editor. Carcinogenicity Testing, Predicting, & Interpreting Chemical Effects. New York: Marcel Dekker; 1999. pp. 21–123.
16. EPA. TRI On-site and Off-site Reported Disposed of or Otherwise Released (in pounds), for Facilities in All Industries, for All Chemicals, U.S. [Accessed November 2006];2004 <>.
17. Schwartz GG, Reis IM. Is cadmium a cause of human pancreatic cancer? Cancer Epidemiol Biomarkers Prev. 2000;9:139–45. [PubMed]
18. Sahmoun AE, Case LD, Jackson SA, Schwartz GG. Cadmium and prostate cancer: a critical epidemiologic analysis. Cancer Invest. 2005;23:256–63. [PubMed]
19. Kagawa J. Atmospheric pollution due to mobile sources and effects on human health in Japan. Environ Health Perspect. 1994;102(suppl):93–9. [PMC free article] [PubMed]
20. Achanzar WE, Diwan BA, Liu J, Quader ST, Webber MM, Waalkes MP. Cadmium-induced malignant transformation of human prostate epithelial cells. Cancer Res. 2001;61:455–8. [PubMed]
21. Goyer RA, Liu J, Waalkes MP. Cadmium and cancer of prostate and testis. Biometals. 2004;17:555–8. [PubMed]
22. Waalkes MP, Anver M, Diwan BA. Carcinogenic effects of cadmium in the Noble (NBL/Cr) rat: induction of pituitary, testicular, and injection site tumors and intraepithelial proliferative lesions of the dorsolateral prostate. Toxicol Sci. 1999;52:154–61. [PubMed]
23. Waalkes MP, Anver MR, Diwan BA. Chronic toxic and carcinogenic effects of oral cadmium in the Noble (NBL/Cr) rat: induction of neoplastic and proliferative lesions of the adrenal, kidney, prostate, and testes. J Toxicol Environ Health A. 1999;58:199–214. [PubMed]
24. Waalkes MP, Rehm S. Chronic toxic and carcinogenic effects of cadmium chloride in male DBA/2NCr and NFS/NCr mice: strain-dependent association with tumors of the hematopoietic system, injection site, liver, and lung. Fundam Appl Toxicol. 1994;23:21–31. [PubMed]
25. Waalkes MP, Rehm S, Perantoni AO, Coogan TP. IARC Sci Publ. 1992. Cadmium exposure in rats and tumours of the prostate; pp. 391–400. [PubMed]
26. Waalkes MP, Rehm S, Sass B, Ward JM. Induction of tumours of the haematopoietic system by cadmium in rats. IARC Sci Publ; 1992. pp. 401–4. [PubMed]
27. Heath JC, Daniel MR, Dingle JT, Webb M. Cadmium as a carcinogen. Nature. 1962;193:592–3. [PubMed]
28. Gunn SA, Gould TC, Anderson WA. Cadmium-induced interstitial cell tumors in rats and mice and their prevention by zinc. J Natl Cancer Inst. 1963;31:745–59. [PubMed]
29. Gunn SA, Gould TC, Anderson WA. Effect of zinc on cancerogenesis by cadmium. Proc Soc Exp Biol Med. 1964;115:653–7. [PubMed]
30. Gunn SA, Gould TC, Anderson WA. Comparative study of interstitial cell tumors of rat testis induced by cadmium injection and vascular ligation. J Natl Cancer Inst. 1965;35:329–37. [PubMed]
31. Haddow A, Roe FJ, Dukes CE, Mitchley BC. Cadmium neoplasia: sarcomata at the site of injection of cadmium sulphate in rats and mice. Br J Cancer. 1964;18:667–73. [PMC free article] [PubMed]
32. Kazantzis G, Hanbury WJ. The induction of sarcoma in the rat by cadmium sulphide and by cadmium oxide. Br J Cancer. 1966;20:190–9. [PMC free article] [PubMed]
33. Roe FJ, Dukes CE, Cameron KM, Pugh RC, Mitchley BC. Cadmium neoplasia: testicular atrophy and Leydig cell hyperplasia and neoplasia in rats and mice following the subcutaneous injection of cadmium salts. Br J Cancer. 1964;18:674–81. [PMC free article] [PubMed]
34. Tomatis L. Comment on methodology and interpretation of results. J Natl Cancer Inst. 1977;59:1341–2. [PubMed]
35. Lemen RA, Lee JS, Wagoner JK, Blejer HP. Cancer mortality among cadmium production workers. Ann NY Acad Sci. 1976;271:273–9. [PubMed]
36. Takenaka S, Oldiges H, Konig H, Hochrainer D, Oberdorster G. Carcinogenicity of cadmium chloride aerosols in W rats. J Natl Cancer Inst. 1983;70:367–73. [PubMed]
37. Loser E. A 2 year oral carcinogenicity study with cadmium on rats. Cancer Lett. 1980;9:191–8. [PubMed]
38. Haseman J, Melnick R, Tomatis L, Huff J. Carcinogenesis bioassays: study duration and biological relevance. Food Chem Toxicol. 2001;39:739–44. [PubMed]
39. Huff J. Chemicals studied and evaluated in long-term carcinogenesis bioassays by both the Ramazzini Foundation and the National Toxicology Program: in tribute to Cesare Maltoni and David Rall. Ann NY Acad Sci. 2002;982:208–30. [PubMed]
40. Soffritti M, Belpoggi F, Minardi F, Maltoni C. Ramazzini Foundation cancer program: history and major projects, life-span carcinogenicity bioassay design, chemicals studied, and results. Ann NY Acad Sci. 2002;982:26–45. [PubMed]
41. Huff J. Absence of carcinogenic activity in Fischer rats and B6C3F1 mice following 103-week inhalation exposures to toluene. Int J Occup Environ Health. 2003;9:138–46. [PubMed]
42. Soffritti M, Belpoggi F, Padovani M, Lauriola M, Esposti DD, Minardi F. Life-time carcinogenicity bioassays of toluene given by stomach tube to Sprague-Dawley rats. Eur J Oncol. 2004;9:91–102.
43. Maltoni C, Ciliberti A, Pinto C, Soffritti M, Belpoggi F, Menarini L. Results of long-term experimental carcinogenicity studies of the effects of gasoline, correlated fuels, and major gasoline aromatics on rats. Ann NY Acad Sci. 1997;837:15–52. [PubMed]
44. Johnson MD, Kenney N, Stoica A, et al. Cadmium mimics the in vivo effects of estrogen in the uterus and mammary gland. Nat Med. 2003;9:1081–4. [PubMed]
45. Schoeters G, Den Hond E, Zuurbier M, et al. Cadmium and children: exposure and health effects. Acta Paediatr. 2006;95(suppl):50–4. [PubMed]
46. Sorahan T, Lancashire RJ. Lung cancer mortality in a cohort of workers employed at a cadmium recovery plant in the United States: an analysis with detailed job histories. Occup Environ Med. 1997;54:194–201. [PMC free article] [PubMed]
47. Sorahan T, Lister A, Gilthorpe MS, Harrington JM. Mortality of copper cadmium alloy workers with special reference to lung cancer and non-malignant diseases of the respiratory system, 1946–92. Occup Environ Med. 1995;52:804–12. [PMC free article] [PubMed]
48. Garcia Sanchez A, Antona JF, Urrutia M. Geochemical prospection of cadmium in a high incidence area of prostate cancer, Sierra de Gata, Salamanca, Spain. Sci Total Environ. 1992;116:243–51. [PubMed]
49. van der Gulden JW, Kolk JJ, Verbeek AL. Work environment and prostate cancer risk. Prostate. 1995;27:250–7. [PubMed]
50. Kolonel LN. Association of cadmium with renal cancer. Cancer. 1976;37:1782–7. [PubMed]
51. Siemiatycki J, Dewar R, Nadon L, Gerin M. Occupational risk factors for bladder cancer: results from a case–control study in Montreal, Quebec, Canada. Am J Epidemiol. 1994;140:1061–80. [PubMed]
52. Verougstraete V, Lison D, Hotz P. Cadmium, lung and prostate cancer: a systematic review of recent epidemiological data. J Toxicol Environ Health B Crit Rev. 2003;6:227–55. [PubMed]
53. Sorahan T, Esmen NA. Lung cancer mortality in UK nickel-cadmium battery workers, 1947–2000. Occup Environ Med. 2004;61:108–16. [PMC free article] [PubMed]
54. Nawrot T, Plusquin M, Hogervorst J, et al. Environmental exposure to cadmium and risk of cancer: a prospective population-based study. Lancet Oncol. 2006;7:119–26. [PubMed]
55. Nordberg GR, Nordberg M. Biological monitoring of cadmium. In: Clarkson TW, Friberg I, Nordberg G, Sager PR, editors. Biological Monitoring of Toxic Metals. New York: Plenum Press; 1988. pp. 151–68.
56. Paschal DC, Burt V, Caudill SP, et al. Exposure of the U.S. population aged 6 years and older to cadmium: 1988–1994. Arch Environ Contam Toxicol. 2000;38:377–83. [PubMed]
57. Zeng X, Jin T, Jiang X, Kong Q, Ye T, Nordberg GF. Effects on the prostate of environmental cadmium exposure—a cross-sectional population study in China. Biometals. 2004;17:559–65. [PubMed]
58. Il'yasova D, Schwartz GG. Cadmium and renal cancer. Toxicol Appl Pharmacol. 2005;207:179–86. [PubMed]
59. Jarup L. Cadmium overload and toxicity. Nephrol Dial Transplant. 2002;17(2):35–9. [PubMed]
60. Ojajarvi IA, Partanen TJ, Ahlbom A, et al. Occupational exposures and pancreatic cancer: a meta-analysis. Occup Environ Med. 2000;57:316–24. [PMC free article] [PubMed]
61. Kriegel AM, Soliman AS, Zhang Q, et al. Serum cadmium levels in pancreatic cancer patients from the East Nile Delta region of Egypt. Environ Health Perspect. 2006;114:113–9. [PMC free article] [PubMed]
62. McElroy JA, Shafer MM, Trentham-Dietz A, Hampton JM, Newcomb PA. Cadmium exposure and breast cancer risk. J Natl Cancer Inst. 2006;98:869–73. [PubMed]
63. Nagata C, Nagao Y, Shibuya C, Kashiki Y, Shimizu H. Urinary cadmium and serum levels of estrogens and androgens in postmenopausal Japanese women. Cancer Epidemiol Biomarkers Prev. 2005;14:705–8. [PubMed]
64. Key T, Appleby P, Barnes I, Reeves G. Endogenous sex hormones and breast cancer in postmenopausal women: reanalysis of nine prospective studies. J Natl Cancer Inst. 2002;94:606–16. [PubMed]
65. EPA. Cadmium Compounds. Hazard Summary. [Accessed November 2006]; Created April 1992; revised January 2000. <>.
66. OEHHA. Chemicals Known to the State to Cause Cancer or Reproductive Toxicity. Safe Drinking Water and Toxic Enforcement Act of 1986. Office of Environmental Health Hazard Assessment. California Environmental Protection Agency; Sacramento, CA: 2005. [Accessed November 2006]. <>.
67. OEHHA. Public Health Goal for Cadmium in Drinking Water, Pesticide and Environmental Toxicology Branch. Office of Environmental Health Hazard Assessment. California Environmental Protection Agency; Feb, 2006.
68. Bertin G, Averbeck D. Cadmium: cellular effects, modifications of biomolecules, modulation of DNA repair and genotoxic consequences (a review) Biochimie. 2006;88:1549–59. [PubMed]
69. Waisberg M, Joseph P, Hale B, Beyersmann D. Molecular and cellular mechanisms of cadmium carcinogenesis. Toxicology. 2003;192:95–117. [PubMed]
70. Hengstler JG, Bolm-Audorff U, Faldum A, et al. Occupational exposure to heavy metals: DNA damage induction and DNA repair inhibition prove co-exposures to cadmium, cobalt and lead as more dangerous than hitherto expected. Carcinogenesis. 2003;24:63–73. [PubMed]
71. Hart BA, Potts RJ, Watkin RD. Cadmium adaptation in the lung—a double-edged sword? Toxicology. 2001;160:65–70. [PubMed]
72. Qu W, Fuquay R, Sakurai T, Waalkes MP. Acquisition of apoptotic resistance in cadmium-induced malignant transformation: specific perturbation of JNK signal transduction pathway and associated metallothionein overexpression. Mol Carcinog. 2006;45:561–71. [PubMed]
73. IARC. Cobalt in hard metals and cobalt sulfate, gallium arsenide, indium phosphide and vanadium pentoxide. IARC Monogr Eval Carcinog Risks Hum. 2006 Jun;86:1–294. [PubMed]
74. Huff J. Chemicals and cancer in humans: first evidence in experimental animals. Environ Health Perspect. 1993;100:201–10. [PMC free article] [PubMed]
75. Tomatis L. The predictive value of rodent carcinogenicity tests in the evaluation of human risks. Annu Rev Pharmacol Toxicol. 1979;19:511–30. [PubMed]
76. Farland WH, Rodan B, Preuss P. Which drugs cause cancer? Cancer bioassays. Against. BMJ. 2005;331:E389–91. [PubMed]
77. Knight A, Bailey J, Balcombe J. Animal carcinogenicity studies: 1. Poor human predictivity. Altern Lab Anim. 2006;34:19–27. [PubMed]
78. Abelson PH. Exaggerated carcinogenicity of chemicals. Science. 1992;256:1609. [PubMed]
79. Abelson PH. Chemicals: perceptions versus facts. Science. 1994;264:183. [PubMed]
80. Landrigan PJ. Carcinogenicity of butadiene. Science. 1992;257:1330–1. [PubMed]
81. Rall DP. Carcinogenicity of butadiene. Science. 1992;257:1330. author reply 31. [PubMed]
82. Huff JE, Melnick RL, Solleveld HA, Haseman JK, Powers M, Miller RA. Multiple organ carcinogenicity of 1,3-butadiene in B6C3F1 mice after 60 weeks of inhalation exposure. Science. 1985;227:548–9. [PubMed]
83. Melnick RL, Huff J, Chou BJ, Miller RA. Carcinogenicity of 1,3-butadiene in C57BL/6 x C3H F1 mice at low exposure concentrations. Cancer Res. 1990;50:6592–9. [PubMed]
84. Melnick RL, Huff JE. IARC Sci Publ. 1993. 1,3-Butadiene induces cancer in experimental animals at all concentrations from 6.25 to 8000 parts per million; pp. 309–22. [PubMed]
85. Matanoski GM, Santos-Burgoa C, Schwartz L. Mortality of a cohort of workers in the styrene–butadiene polymer manufacturing industry (1943–1982) Environ Health Perspect. 1990;86:107–17. [PMC free article] [PubMed]
86. Melnick RL, Huff J, Matanoski GM. Carcinogenicity of 1,3-butadiene. Lancet. 1992;340:724–5. [PubMed]
87. NTP. Report on Carcinogens. 11th. U.S. Department of Health and Human Services, Public Health Service, National Toxicology Program; 2004. 1,3-Butadiene; pp. III-37–39.
88. Santos-Burgoa C, Matanoski GM, Zeger S, Schwartz L. Lymphohematopoietic cancer in styrene–butadiene polymerization workers. Am J Epidemiol. 1992;136:843–54. [PubMed]
89. Huff J. IARC monographs, industry influence, and upgrading, downgrading, and under-grading chemicals: a personal point of view. Int J Occup Environ Health. 2002;8:249–70. [PubMed]
90. Huff J. Industry influences IARC carcinogenesis evaluations. Int J Occup Environ Health. 2003;9:83–4. [PubMed]
91. Infante PF. Safeguarding scientific evaluations by governmental agencies: case study of OSHA and the 1,3-butadiene classification. Int J Occup Environ Health. 2005;11:372–7. [PubMed]
92. Sass JB. Industry efforts to weaken the EPA's classification of the carcinogenicity of 1,3-butadiene. Int J Occup Environ Health. 2005;11:378–83. [PubMed]
93. Tomatis L. The IARC monographs program: changing attitudes towards public health. Int J Occup Environ Health. 2002;8:144–52. [PubMed]
94. IARC. 1,3-Butadiene. (IARC Monogr Eval Carcinog Risks Hum).Re-evaluation of some organic chemicals, hydrazine, and hydrogen peroxide. 1999;71(Pt 1):109–225. [PubMed]
95. Axelson O, Balbus JM, Cohen G, et al. Re: Regulatory Toxicology and Pharmacology. Int J Occup Environ Health. 2003;9:386–9. author reply 89-90. [PubMed]
96. Abelson PH. Health risk assessment. Regul Toxicol Pharmacol. 1993;17:219–23. [PubMed]
97. Huff J, Melnick R, Tomatis L, LaDou J, Teitelbaum D. Trichloroethylene and cancers in humans. Toxicology. 2004;197:185–7. [PubMed]
98. Moure-Eraso R. Primary prevention and precaution in hazard identification in the NIEHS/NTP: body in the morgue approach. Public Health Rep. 2002;117:564–73. [PMC free article] [PubMed]
99. Huff J. Chemically associated respiratory carcinogenesis in rodents and humans. In: Waalkes MP, Ward JM, editors. Carcinogenesis. New York: Raven Press; 1994. pp. 199–214.
100. Huff J. Chemicls causally associated with cancers in humans and in laboratory animals: a perfect concordance. In: Waalkes MP, Ward JM, editors. Carcinogenesis. New York: Raven Press; 1994. pp. 25–37.
101. Fung VA, Barrett JC, Huff J. The carcinogenesis bioassay in perspective: application in identifying human cancer hazards. Environ Health Perspect. 1995;103:680–3. [PMC free article] [PubMed]
102. Fung VA, Huff J, Weisburger EK, Hoel DG. Predictive strategies for selecting 379 NCI/NTP chemicals evaluated for carcinogenic potential: scientific and public health impact. Fundam Appl Toxicol. 1993;20:413–36. [PubMed]
103. Waalkes MP, Infante P, Huff J. The scientific fallacy of route specificity of carcinogenesis with particular reference to cadmium. Regul Toxicol Pharmacol. 1994;20:119–21. [PubMed]
104. Sanner T, Dybing E. Comparison of carcinogen hazard characterization based on animal studies and epidemiology. Basic Clin Pharmacol Toxicol. 2005;96:66–70. [PubMed]
105. Melnick RL, Kamel F, Huff J. Declaring chemicals “not carcinogenic to humans” requires validation, not speculation. Environ Health Perspect. 2003;111:A203–4. [PMC free article] [PubMed]
106. Tomatis L, Huff J. Evolution of cancer etiology and primary prevention. Environ Health Perspect. 2001;109:A458–60. [PMC free article] [PubMed]
107. Tomatis L, Huff J. Evolution of research on cancer etiology. In: Coleman WB, Tsongalis GJ, editors. The Molecular Basis of Human Cancer: Genomic Instability and Molecular Mutation Neoplastic Transformation. Totowa, NY: Humana Press; 2002. pp. 189–201.
108. Hill AB. The environment and disease: association or causation? Proc R Soc Med. 1965;58:295–300. [PMC free article] [PubMed]
109. Castleman B. Global corporate policies and international “double standards” in occupational and environmental health. Int J Occup Environ Health. 1999;5:61–4. [PubMed]
110. Castleman BI. Controversies at international organizations over asbestos industry influence. Int J Health Serv. 2001;31:193–202. [PubMed]
111. Castleman BI, Lemen RA. The manipulation of international scientific organizations. Int J Occup Environ Health. 1998;4:53–5. [PubMed]
112. Epstein SS, Ashford N, Castleman B, Mazzocchi A, Young QD. The crisis in U.S. and international cancer policy. Epidemiol Prev. 2003;27:175–7. [PubMed]
113. LaDou J. Occupational health in industrializing countries. Occup Med. 2002;17:349–54. iii. [PubMed]
114. LaDou J. International occupational health. Int J Hyg Environ Health. 2003;206:303–13. [PubMed]
115. LaDou J. World Trade Organization, ILO conventions, and workers' compensation. Int J Occup Environ Health. 2005;11:210–1. [PubMed]
116. Tickner JA. Commentary: barriers and opportunities to changing the research agenda to support precaution and primary prevention. Int J Occup Med Environ Health. 2004;17:163–73. [PubMed]
117. Tomatis L, Melnick RL, Haseman J, Barrett JC, Huff J. Alleged misconceptions' distort perceptions of environmental cancer risks. Faseb J. 2001;15:195–203. [PubMed]
118. Grandjean P. Implications of the precautionary principle for primary prevention and research. Annu Rev Public Health. 2004;25:199–223. [PubMed]
119. Tomatis L, Huff J, Hertz-Picciotto I, et al. Avoided and avoidable risks of cancer. Carcinogenesis. 1997;18:97–105. [PubMed]
120. Kellen E, Zeegers MP, Hond ED, Buntinx F. Blood cadmium may be associated with bladder carcinogenesis: the Belgian case–control study on bladder cancer. Cancer Detect Prev. 2007;31:77–82. [PubMed]
121. Somji S, Zhou XD, Garrett SH, Sens MA, Sens DA. Urothelial cells malignantly transformed by exposure to cadmium (Cd(+2)) and arsenite (As(+3)) have increased resistance to Cd(+2) and As(+3)-induced cell death. Toxicol Sci. 2006;94:293–301. [PubMed]
122. Sens DA, Park S, Gurel V, Sens MA, Garrett SH, Somji S. Inorganic cadmium- and arsenite-induced malignant transformation of human bladder urothelial cells. Toxicol Sci. 2004;79:56–63. [PubMed]