INTRODUCTION

Cobalt is a transition element and a component of more than 70 naturally occurring minerals. It is often combined with other metals to make metal alloys or cemented carbides for a variety of medical or commercial applications; some cobalt compounds are used as pigments or in electronic devices. People can be exposed to cobalt or its compounds in workplaces that use or produce cobalt, from cobalt-containing orthopedic joint replacements that release cobalt ions from wear and tear, and from the environment. Exposure to cobalt from food and water is generally limited.

METHODS

The National Toxicology Program (NTP) evaluated evidence for human exposure, cancer studies in humans and experimental animals, mechanisms of carcinogenesis, and other relevant information, including evaluating study quality, integrating the evidence across studies, and integrating evidence across data streams (mechanistic, animal, and human data). Using established criteria, NTP reached conclusions on the strength of evidence for the carcinogenicity of cobalt from cancer studies in experimental animals and humans, and the final listing recommendation was reached by applying the Report on Carcinogens (RoC) listing criteria to the body of evidence.

RESULTS AND DISCUSSION

The physicochemical properties, toxicokinetics, mechanistic data, and other relevant data for cobalt and cobalt compounds were used to identify and compare the chemical and biological properties and events that are relevant to cobalt-induced carcinogenicity to determine if a group listing for cobalt and cobalt compounds that release cobalt ions in vivo was warranted.

CANCER STUDIES IN EXPERIMENTAL ANIMALS

NTP concluded that there was sufficient evidence of carcinogenicity in animals based on its review of 16 rodent carcinogenicity studies. Exposure of experimental animals to cobalt metal or cobalt compounds (both water-soluble and poorly water-soluble compounds) caused tumors in rats and/or mice through several different routes of exposure and at several different tissue sites. Inhalation exposure to cobalt metal or cobalt sulfate caused lung tumors in rats and mice as well as tumors of the pancreas (male rats only), the adrenal gland (male and female rats for cobalt metal and female rats for cobalt sulfate), and the hematopoietic system (female rats exposed to cobalt metal only). Intratracheal instillation of cobalt oxide also caused lung tumors in rats. In addition, local injection of rats with cobalt or cobalt compounds at various anatomic locations caused tumors at the injection sites, including intraperitoneal or intramuscular injection of poorly water-soluble cobalt oxide, subcutaneous injection of water-soluble cobalt chloride, and intramuscular or intrathoracic injection of cobalt metal or nanoparticles.

MECHANISTIC DATA

The key events related to toxicity and carcinogenicity of cobalt and cobalt compounds are thought to include cellular uptake of cobalt, intracellular release of cobalt ions from particles, and immediate and downstream biological responses related to the proposed modes of action. These events are applicable to all cobalt forms that release cobalt ions in vivo, including water-soluble and poorly water-soluble particles. The biological responses include inhibition of DNA repair, genotoxicity, generation of reactive oxygen species resulting in oxidative damage, and stabilization of hypoxia-inducible factor 1α, a protein that increases the expression of genes that promote survival of cells that receive less oxygen.

HUMAN CANCER STUDIES

NTP concluded that the data available from studies in humans were inadequate to evaluate the relationship between human cancer and exposure to cobalt and cobalt compounds that release cobalt ions in vivo. Although increased risks of lung cancer were found in most of the five cohort studies, it is unclear that the excess risks were due to exposure specifically to cobalt, because of potential confounding from exposure to known carcinogens or other study limitations.

NTP HAZARD CONCLUSION AND SIGNIFICANCE

The conclusion of the cancer hazard evaluation was that cobalt and cobalt compounds that release cobalt ions in vivo should be listed as in the RoC. The Secretary of Health and Human Services approved the listing of cobalt compounds that release cobalt ions in vivo in the 14th RoC. The rationale for the listing was sufficient evidence of carcinogenicity from experimental animals and evidence from studies on mechanisms of carcinogenesis that indicate that the release of cobalt ions is a key event for cobalt-induced carcinogenicity.