Cadmium carcinogenesis in review

doi:10.1016/S0162-0134(00)00009-X

Journal of Inorganic Biochemistry

Volume 79, Issues 1–4, 30 April 2000, Pages 241-244

https://doi.org/10.1016/S0162-0134(00)00009-X Get rights and content

Abstract

Cadmium is an inorganic toxicant of great environmental and occupational concern which was classified as a human carcinogen in 1993. Occupational cadmium exposure is associated with lung cancer in humans. Cadmium exposure has also, on occasion, been linked to human prostate cancer. The epidemiological data linking cadmium and pulmonary cancer are much stronger than for prostatic cancer. Other target sites for cadmium carcinogenesis in humans (liver, kidney, stomach) are considered equivocal. In rodents, cadmium causes tumors at several sites and by various routes. Cadmium inhalation in rats results in pulmonary adenocarcinomas, supporting a role in human lung cancer. Prostate tumors and preneoplastic proliferative lesions can be induced in rats after cadmium ingestion or injection. Prostatic carcinogenesis in rats occurs only at cadmium doses below those that induce chronic degeneration and dysfunction of the testes, a well-known effect of cadmium, confirming the androgen dependency of prostate tumors. Other targets of cadmium in rodents include the testes, adrenals, injection sites, and hematopoietic system. Various treatments can modify cadmium carcinogenesis including supplemental zinc, which prevents cadmium-induced injection site and testicular tumors while facilitating prostatic tumors. Cadmium is poorly mutagenic and probably acts through indirect mechanisms, although the precise mechanisms remain unknown.

Introduction

Cadmium is a toxic transition (‘heavy’) metal of continuing occupational and environmental concern with a wide variety of adverse effects [1]. Cadmium has an extremely long biological half-life that essentially makes it a cumulative toxin [1]. To date there are no proven effective treatments for chronic cadmium intoxication [1]. Cadmium accumulates primarily in the liver and kidney where it is bound to metallothionein (MT), a low molecular weight metal binding protein thought to detoxify the metal through high affinity sequestration [1]. The toxic effects of cadmium often stem from interference with various zinc mediated metabolic processes, and zinc treatments frequently reduce or abolish the adverse effects of cadmium [1]. There are several sources of human exposure to cadmium, including employment in primary metal industries and consumption of tobacco products [2].

Cadmium has been designated a human carcinogen by the International Agency for Research on Cancer and the US National Toxicology Program [2], [3] and is clearly a potent, multi-tissue animal carcinogen [4], [5]. Occupational exposure to cadmium is associated with lung cancers in humans, while other sites, potentially including the prostate, are not definitively established [2], [3], [4], [5]. Rodent studies have shown that chronic inhalation of cadmium causes pulmonary adenocarcinomas [4], [5], [6], in clear support of human data [2], [3]. Cadmium can also cause prostatic proliferative lesions, including adenocarcinomas, after systemic or direct exposure [7], [8], [9], [10]. Other target tissues of cadmium carcinogenesis in animals include injection sites, adrenals, testes, and the hemopoietic system [2], [3], [4], [5], [8]. Certain treatments modify cadmium carcinogenicity, including administration of zinc, which prevents cadmium-induced injection site and testicular tumors while facilitating prostatic tumor formation [10]. Diets deficient in zinc increase the progression of testicular tumors [11] but reduce the progression of prostatic tumors [8]. There are definite species and strain-related differences in sensitivity to cadmium carcinogenicity. The potential mechanism or mechanisms of cadmium carcinogenesis are unknown but may well involve non-genotoxic or indirectly genotoxic events since cadmium is, in general, a poor mutagen [5]. Such events could include enhanced proliferation, depressed apoptosis, and/or altered DNA repair.

Section snippets

Cadmium metabolism

Cadmium metabolism has several unique facets [1], [12] and absorption of cadmium shows marked route dependency. Only about 5% of a given dose of cadmium is absorbed from the gastrointestinal tract while cadmium absorption from the lung is very high, with as much as 90% of a dose deposited in the deep lung being absorbed. Once absorbed, cadmium is rapidly cleared from the blood and concentrates in various tissues.

Cadmium in the liver and kidney usually make up the bulk of the total body burden

Cadmium carcinogenesis in humans

The International Agency for Research on Cancer and the US National Toxicology Program [2], [3] have both concluded that there is adequate evidence that cadmium is a human carcinogen. This designation as a human carcinogen was prompted primarily by repeated findings of an association between occupational cadmium exposure and lung cancer, as well as very strong rodent data which included the pulmonary system as a target site [2], [3]. Thus, the lung is the most definitively established site of

Cadmium carcinogenesis in animals

The earliest suspicion that cadmium might be carcinogenic in rodents came from the 1961 study of Haddow et al. [14] who gave either subcutaneous (sc) or intramuscular (im) injections of ferritin which had been prepared from rat liver by cadmium precipitation. They subsequently found malignant tumors at the site of injection in rats and mice [14]. It was unclear at that time if cadmium was the carcinogenic agent, but it was suspected [14]. These results prompted further investigations and

Modification of the carcinogenic response to cadmium in rodents; some mechanistic considerations

Zinc can have an important impact on cadmium carcinogenesis. In several tissues, including the lung, testes, and at the injection site, zinc treatments reduce cadmium carcinogenesis [2], [3], [4], [5]. In this regard calcium and magnesium are relatively ineffective in reducing the carcinogenic effects of cadmium compared to zinc [2], [3], [4], [5]. This selective antagonism by zinc of the carcinogenic effects of cadmium at so many different target sites could point to a basic mechanism of

Possible mechanisms in cadmium carcinogenesis

Although cadmium can produce genotoxic and mutagenic events, these generally require high doses [4], [5], [27]. Cadmium will not form stable DNA adducts and, since cadmium is not a redox active metal, indirect oxidative DNA damage is unlikely as a primary carcinogenic mechanism. Thus, epigenetic non-genotoxic or indirect genotoxic mechanisms may apply. Such mechanisms could include aberrant gene expression resulting in stimulation of cell proliferation or blockage of apoptosis. Both these

Summary and conclusions

The carcinogenic potential of cadmium is clearly established in humans and experimental animals. Further efforts are warranted in the epidemiology of cadmium in order to determine more precisely the risks and target sites in humans. The mechanisms of cadmium carcinogenesis remain unknown. However, the mechanisms appear to be related in some undefined way to zinc metabolism because of the pronounced effects that zinc can have on cadmium carcinogenesis in many experimental systems. As yet there

Abbreviations

MT	metallothionein
sc	subcutaneous
im	intramuscular

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Cadmium carcinogenesis in review

Abstract

Introduction

Section snippets

Cadmium metabolism

Cadmium carcinogenesis in humans

Cadmium carcinogenesis in animals

Modification of the carcinogenic response to cadmium in rodents; some mechanistic considerations

Possible mechanisms in cadmium carcinogenesis

Summary and conclusions

Abbreviations

Fundam. Appl. Toxicol.

Toxicol. Appl. Pharmacol.

Fundam. Appl. Toxicol.

Fundam. Appl. Toxicol.

Toxicology

Toxicol. Appl. Pharmacol.

Toxicol. Appl. Pharmacol.

Toxicology

Toxicol. Lett.

Toxicol. Appl. Pharmacol.

J. Natl. Cancer Inst.