Agency for Toxic Substances and Disease Registry
Case Studies in Environmental Medicine (CSEM) 

Cadmium Toxicity
How Does Cadmium Induce Pathogenic Changes?

Learning Objectives

Upon completion of this section, you will be able to

• discuss how cadmium induces pathogenic changes in the body.

Introduction

Depending on the route of exposure, cadmium has differing rates of absorption and varying health effects. Cadmium is a cumulative toxin. Its levels in the body increase over time because of its slow elimination. It accumulates chiefly in the liver and kidneys. However, it also accumulates in muscle and bone.

The principal organs affected by cadmium’s toxicity, both acutely and chronically, are the:

• kidneys,
• bone, and
• lungs.

The lungs can be damaged by acute inhalation exposures as well as suffering effects from more chronic occupational exposures. The kidneys can be damaged with both acute high-dose but more commonly, long-term chronic exposures. The bone disease that occurs with above average chronic exposures is thought to be secondary to cadmium’s effects on the kidney.

Target Organs

The chief organs acted upon by cadmium with its chronic toxic effects are

• kidneys, and
• bone

The lungs are a target organ in acute high-dose exposures to inhaled cadmium fumes.

Mechanisms of Toxicity

Cadmium is known to increase oxidative stress by being a catalyst in the formation of reactive oxygen species, increasing lipid peroxidation, and depleting glutathione and protein-bound sulfhydryl groups. Cadmium also can stimulate the production of inflammatory cytokines and downregulates the protective function of nitric oxide formation (Navas-Acien et al. 2004).

Genotoxicity

Cadmium expresses genotoxic activities in vitro in cells and in vivo in animals; and there is limited epidemiological evidence for in vivo human genotoxicity.

• An occupational study showed increased numbers of chromosomal aberrations in the lymphocytes of cadmium-exposed workers (NTP 2004).
• Cadmium has been found to cause chromosomal damage in animal experiments with subcutaneous administration (ATSDR 1999).
• Cadmium causes mutations, DNA strand breaks, chromosomal damage, cell transformation and impaired DNA repair in cultured mammalian cells (NTP 2004).
• Cadmium is known to modulate gene expression and signal transduction (Waisberg et al. 2003).

Carcinogenicity

There is sufficient evidence that cadmium metal and a number of cadmium compounds, such as cadmium chloride, oxide, sulfate, and sulfide, are carcinogenic in animals. Increased rates of testicular, prostate, and lung cancer in animals have been described (Sahmoun et al., 2005; ATSDR,1999).

Current classification of cadmium’s carcinogenicity by health agencies.

• EPA has classified cadmium as a Group B1 or “probable” human carcinogen.
• American Conference of Governmental Industrial Hygienists (ACGIH) considers cadmium a suspected human carcinogen.
• The World Health Organization’s (WHO) International Agency for Research on Cancer (IRAC) classifies cadmium as a known human carcinogen.
• The National Toxicology Program (NTP) has characterized cadmium as known to be a human carcinogen (NTP 2004).

Occupational cohort studies have suggested possible associations between chronic exposure to cadmium, particularly cadmium oxide, and cancers of the lung, prostate, and genitourinary system such as renal carcinoma. The strongest evidence for a linkage between occupational exposure to cadmium and cancer is that of lung cancer. This linkage is the reason cited by the IARC in 1993 for designating cadmium as a known human carcinogen and by the NTP for its characterization of cadmium as a known human carcinogen in 2000.

The most positive evidence for the IARC’s decision came from a series of studies of the “globe cohort” that showed a positive association between occupational cadmium exposure and lung cancer. However, there have been updated studies of that cohort and other evidence (Sorhan and Esmen 2004) since then as reviewed by Verougstraete et al. in 2003. These studies conclude that, to date the epidemiological evidence shows “a small increase in the relative risk of lung cancer in workers exposed to cadmium and cadmium compounds” (Verougstraete et al. 2003).

There is also a consensus that there is not enough evidence to definitely establish a link between cadmium exposure and renal and prostate cancer (Waalkes 2003; NTP 2004). There is no clinical or experimental evidence that background environmental exposures to cadmium causes cancer (Verougstraete et al. 2003).

Key Points

• Cadmium’s toxicity primarily affects the lungs and kidneys, with secondary effects on the skeletal system.
• Cadmium’s carcinogenic effects have been demonstrated in experimental animals; evidence in humans is somewhat less conclusive.

Progress Check