Genetic and epigenetic mechanisms in metal carcinogenesis and cocarcinogenesis: nickel, arsenic, and chromium Nickel (Ni), arsenic (As), and chromium (Cr) are toxic metals that have been shown to increase cancer risk in humans. Chronic exposure to Ni(II), Cr(VI), or inorganic arsenic (iAs) has been linked to increased cancer incidence. Recent studies have shown that the carcinogenic risks associated with chromate and iAs exposures are higher than previously thought, leading to changes in federal standards for ambient and drinking water levels. The genotoxic effects of Cr(VI) and iAs are influenced by their intracellular metabolism, which creates reactive intermediates and byproducts. Toxic metals can activate stress-signaling pathways that contribute to cancer development. Ascorbate (vitamin C) can act as either a strong enhancer or suppressor of toxic responses in human cells. In addition to genetic damage via oxidative and nonoxidative mechanisms, metals can cause significant changes in DNA methylation and histone modifications, leading to epigenetic silencing or reactivation of gene expression. In vitro genotoxicity experiments and recent animal carcinogenicity studies support the idea that metals can act as cocarcinogens in combination with nonmetal carcinogens. Cocarcinogenic and comutagenic effects of metals are likely due to their ability to interfere with DNA repair processes. Overall, metal carcinogenesis requires the formation of specific metal complexes, chromosomal damage, and activation of signal transduction pathways promoting survival and expansion of genetically/epigenetically altered cells. Nickel is a toxic and carcinogenic metal that is used in various industrial applications. It is known to cause respiratory symptoms, cardiovascular and kidney diseases, and allergic dermatitis. Nickel carcinogenic activity is likely through nongenotoxic mechanisms. The toxicity and carcinogenicity of Ni(II) depend on its intracellular dose, which is a function of the physicochemical properties of particular nickel compounds. Nickel compounds can induce tumors in various animal models and are classified as human carcinogens. Epigenetic changes, including changes in DNA methylation and histone modifications, are primary events in nickel carcinogenesis. Nickel exposure can lead to the inactivation of gene expression through DNA hypermethylation and changes in histone acetylation. Nickel exposure also activates hypoxic signaling pathways, which may contribute to the development of cancer. Nickel can act as a cocarcinogen by enhancing the effects of other carcinogens. Arsenic is an environmental contaminant that can cause various types of cancer, including lung, skin, respiratory, liver, and bladder cancers. Arsenic exposure can lead to increased cellular proliferation, apoptosis, and genetic and epigenetic changes. Arsenic can act as a cocarcinogen by enhancing the effects of other carcinogens. Arsenic exposure can lead to changes in DNA methylation and histone modifications, which may contribute toGenetic and epigenetic mechanisms in metal carcinogenesis and cocarcinogenesis: nickel, arsenic, and chromium Nickel (Ni), arsenic (As), and chromium (Cr) are toxic metals that have been shown to increase cancer risk in humans. Chronic exposure to Ni(II), Cr(VI), or inorganic arsenic (iAs) has been linked to increased cancer incidence. Recent studies have shown that the carcinogenic risks associated with chromate and iAs exposures are higher than previously thought, leading to changes in federal standards for ambient and drinking water levels. The genotoxic effects of Cr(VI) and iAs are influenced by their intracellular metabolism, which creates reactive intermediates and byproducts. Toxic metals can activate stress-signaling pathways that contribute to cancer development. Ascorbate (vitamin C) can act as either a strong enhancer or suppressor of toxic responses in human cells. In addition to genetic damage via oxidative and nonoxidative mechanisms, metals can cause significant changes in DNA methylation and histone modifications, leading to epigenetic silencing or reactivation of gene expression. In vitro genotoxicity experiments and recent animal carcinogenicity studies support the idea that metals can act as cocarcinogens in combination with nonmetal carcinogens. Cocarcinogenic and comutagenic effects of metals are likely due to their ability to interfere with DNA repair processes. Overall, metal carcinogenesis requires the formation of specific metal complexes, chromosomal damage, and activation of signal transduction pathways promoting survival and expansion of genetically/epigenetically altered cells. Nickel is a toxic and carcinogenic metal that is used in various industrial applications. It is known to cause respiratory symptoms, cardiovascular and kidney diseases, and allergic dermatitis. Nickel carcinogenic activity is likely through nongenotoxic mechanisms. The toxicity and carcinogenicity of Ni(II) depend on its intracellular dose, which is a function of the physicochemical properties of particular nickel compounds. Nickel compounds can induce tumors in various animal models and are classified as human carcinogens. Epigenetic changes, including changes in DNA methylation and histone modifications, are primary events in nickel carcinogenesis. Nickel exposure can lead to the inactivation of gene expression through DNA hypermethylation and changes in histone acetylation. Nickel exposure also activates hypoxic signaling pathways, which may contribute to the development of cancer. Nickel can act as a cocarcinogen by enhancing the effects of other carcinogens. Arsenic is an environmental contaminant that can cause various types of cancer, including lung, skin, respiratory, liver, and bladder cancers. Arsenic exposure can lead to increased cellular proliferation, apoptosis, and genetic and epigenetic changes. Arsenic can act as a cocarcinogen by enhancing the effects of other carcinogens. Arsenic exposure can lead to changes in DNA methylation and histone modifications, which may contribute to