Review
Cadmium carcinogenesis

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Abstract

Cadmium is a heavy metal of considerable environmental and occupational concern. Cadmium compounds are classified as human carcinogens by several regulatory agencies. The most convincing data that cadmium is carcinogenic in humans comes from studies indicating occupational cadmium exposure is associated with lung cancer. Cadmium exposure has also been linked to human prostate and renal cancer, although this linkage is weaker than for lung cancer. Other target sites of cadmium carcinogenesis in humans, such as liver, pancreas and stomach, are considered equivocal. In animals, cadmium effectively induces cancers at multiple sites and by various routes. Cadmium inhalation in rats induces pulmonary adenocarcinomas, in accord with its role in human lung cancer. Cadmium can induce tumors and/or preneoplastic lesions within the rat prostate after ingestion or injection. At relatively high doses, cadmium induces benign testicular tumors in rats, but these appear to be due to early toxic lesions and loss of testicular function, rather than from a specific carcinogenic effect of cadmium. Like many other metals, cadmium salts will induce mesenchymal tumors at the site of subcutaneous (s.c.) or intramuscular (i.m.) injections, but the human relevance of these is dubious. Other targets of cadmium in rodents include the liver, adrenal, pancreas, pituitary, and hematopoietic system. With the exception of testicular tumors in rodents, the mechanisms of cadmium carcinogenesis are poorly defined. Cadmium can cause any number of molecular lesions that would be relevant to oncogenesis in various cellular model systems. Most studies indicate cadmium is poorly mutagenic and probably acts through indirect or epigenetic mechanisms, potentially including aberrant activation of oncogenes and suppression of apoptosis.

Introduction

Cadmium is a toxic transition metal of continuing occupational and environmental concern [1], [2], [3], [4]. Cadmium exposure leads to a variety of adverse effects [1], [2], [3], [4]. The extremely long biological half life of cadmium essentially makes it a cumulative toxin, so long past exposures could still result in direct toxic effects of the residual metal [1]. Unfortunately, there are no proven effective treatments for chronic cadmium intoxication [1]. The long residence time of cadmium is in part attributable to metallothionein (MT), a metal-binding protein that is induced at the transcriptional level by cadmium and tightly binds the metal [1], [3], [4]. Cadmium accumulates primarily in the liver and kidney where it is bound to MT, and it is felt that cadmium bound to MT is essentially detoxicated, at least temporarily, through this high affinity sequestration [1], [3]. The body has limited capacity to respond to cadmium exposure, as the metal cannot undergo metabolic degradation to less toxic species and is only poorly excreted, making long-term storage a viable option for dealing with this toxic element.

The toxic effects of cadmium often stem from interference with various zinc mediated metabolic processes, while zinc treatments frequently reduce or abolish the adverse effects of cadmium [1]. This might be viewed as molecular mimicry, as these two elements are closely located in the periodic table and favor similar bioligands. For instance, cadmium competes with zinc for binding to MT and blocks cellular zinc accumulation. Excess zinc can antagonize many of the adverse effects of cadmium, including tumor formation [4], indicating a mechanistic role for cadmium-zinc interaction in cadmium toxicity.

There are several sources of human exposure to cadmium, including employment in primary metal industries, production of certain batteries, some electroplating processes and consumption of tobacco products [5], [6]. Smoking tobacco is thought to double the life time body burden of cadmium in non-occupationally exposed persons. Environmental exposure to cadmium is also not uncommon [2]. The most frequently observed chronic toxic effect of the metal in humans is chronic nephropathy characterized by proximal tubular necrosis and proteinurea [1], [2], [3]. A debilitating osteoporosis has been associated with high levels of environmental cadmium, possibly produced in concert with nutritional deficiencies [1].

Cadmium has been designated a human carcinogen by the World Health Organization’s International Agency for Research on Cancer and the United States National Toxicology Program [5], [6]. Multiple studies have linked occupational exposure to cadmium with pulmonary cancer in humans [4], [5], [6]. Several studies indicate a role for cadmium in human prostatic [4], [5], [6] and renal [4], [5], [6], [7], [8], [9] cancers, while a few studies have associated cadmium exposure with human cancer of the liver, hematopoietic system, urinary bladder and stomach [4], [5], [6], [9]. There is some indication that cadmium might be important in pancreatic cancer [10], but this is yet to be established. The role of cadmium as a pulmonary carcinogen in occupationally exposed populations is largely the basis for its declaration by regulatory agencies as a human carcinogen [5], [6], while other target sites in humans, potentially including the prostate and kidney, are not definitively established [4], [5], [6], [7], [8], [9], [10].

On the other hand, cadmium is clearly an effective, multi-tissue animal carcinogen [4], [5], [6], [9], [11], [12]. In clear support of human data, rodent studies show that chronic inhalation of cadmium causes pulmonary adenocarcinomas [4], [5], [6], [9]. Cadmium can also cause prostatic proliferative lesions, including adenocarcinomas, after systemic or direct exposure in rats [4], [5], [6], [9], [11], [12]. Systemic exposure to cadmium can also induce lung tumors [9]. Other target tissues of cadmium carcinogenesis in rodents include repository injection sites, testes, adrenals, liver, kidneys, pancreas and the hemopoietic system [4], [5], [6], [9], [11], [12]. Treatments with zinc can modify cadmium carcinogenicity and prevents cadmium-induced injection site and testicular tumors while facilitating prostatic tumor formation [4], [9]. Zinc deficient diets increase the progression of testicular tumors but reduce the progression of prostatic tumors [4], [9]. There are definite species- and strain-related differences in sensitivity to cadmium carcinogenicity [4], [9].

The potential mechanism or mechanisms of cadmium carcinogenesis are unknown. Various cellular models have been developed to help define potential mechanisms. Relatively speaking, cadmium binds DNA in a weak fashion, indicating this is not a primary mode of action. Cadmium is not a redox active metal, although it does produce oxidative stress [1], which could indirectly result in attack on DNA, but this has not been absolutely established as a mechanism. Cadmium may well act as a epigenetic or indirectly geneotoxic carcinogen since it is, in general, poorly mutagenic [4], [9]. Potential contributing factors to cadmium oncogenicity include aberrant gene activation, suppressed apoptosis, and/or altered DNA repair. Additional work clearly is required to define the mode action of this important inorganic carcinogen. A more complete knowledge of mechanism would allow better assessment of the risk associated with this common environmental contaminant.

Section snippets

Cadmium metabolism

Metabolism of toxicant metals often is dictated by the essential elements they may mimic. Cadmium appears to mimic zinc and to a lesser extent calcium [1]. Cadmium absorption shows marked route dependency [1] as only ∼5% of an oral dose is absorbed by the gastrointestinal tract. Cadmium absorption from the lung is very high, with upwards of 90% of a dose being absorbed. There is a common pathway for absorption of cadmium and iron through the divalent metal transporter-1 (DMT-1) which accounts

Cadmium carcinogenesis in humans

Various regulatory agencies have concluded that there is adequate evidence that cadmium is a human carcinogen [5], [6]. This designation was largely prompted by repeated findings of a link between occupational cadmium exposure and lung cancer, as well as very strong data in rodents showing the pulmonary system as a target site after cadmium inhalation [1], [4], [9]. The lung is clearly the most definitive target site in humans. Multiple studies have also linked cadmium exposure to cancers of

Cadmium carcinogenesis in animals

Haddow et al. [17] provided the earliest suspicion that cadmium might be carcinogenic in rodents. They gave rats and mice either subcutaneous (s.c.) or intramuscular (i.m.) injections of rat liver ferritin which had been prepared by precipitation with cadmium [17], then a widely used method of protein precipitation. Subsequently, these animals developed malignant sarcomas at the site of injection [17]. At the time, although suspected, it was unclear if cadmium was the active agent in this

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

It is suspected that toxic metals, such as cadmium, often act by molecular/atomic mimicry of essential nutrient metals. In this fashion, cadmium may gain cellular access and disrupt normal cellular metabolism. An additional component of this mimicry is that excess essential element, when given with the toxic metal it mimics, can reduce or eliminate its toxicity. In this regard, the essential nutrient transition metal, zinc has a remarkable impact on cadmium carcinogenesis. In the lung, testes,

Possible mechanisms in rodent cancers induced by cadmium

No clear in vivo mechanisms of action for cadmium carcinogenesis have emerged, with the possible exception of the rodent testes (Fig. 1). Unfortunately, because of their nature and the requirement of high parenteral dose of cadmium to induce testicular tumors, it is doubtful that these benign neoplasia have much relevance to human cadmium exposure. The mechanism here appears to lie in the remarkable testicular necrosis induced by high doses of cadmium in rodents [4], [9], [21], a lesion never

Possible mechanisms defined in in vitro model systems of cadmium carcinogenesis

Many cellular model systems have been utilized to define the potential molecular events that are associated with the initiation phase of cadmium carcinogenesis. It should be kept in mind that there is, in general, a significant bias towards publication of positive results with in vitro work. This is not to say that work in vitro is invalid, just that negative results, that may have important bearing on defining mechanisms of carcinogenesis, are rarely published. There is also the tendency to

Summary

A clear carcinogenic potential for cadmium exists in both humans and rodents. Further efforts are necessary to define more precisely the risks of cancer from cadmium exposure and its target sites in humans. Molecular profiling of the events associated with cadmium carcinogenesis in model systems may allow development expression signatures of cadmium-induced cancers. This in turn may assist in molecular epidemiological studies that could enable a much more definitive linkage to be made between

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