Review
Nickel carcinogenesis

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Abstract

Human exposure to highly nickel-polluted environments, such as those associated with nickel refining, electroplating, and welding, has the potential to produce a variety of pathologic effects. Among them are skin allergies, lung fibrosis, and cancer of the respiratory tract. The exact mechanisms of nickel-induced carcinogenesis are not known and have been the subject of numerous epidemiologic and experimental investigations. These mechanisms are likely to involve genetic and epigenetic routes. The present review provides evidence for the genotoxic and mutagenic activity of Ni(II) particularly at high doses. Such doses are best delivered into the cells by phagocytosis of sparingly soluble nickel-containing dust particles. Ni(II) genotoxicity may be aggravated through the generation of DNA-damaging reactive oxygen species (ROS) and the inhibition of DNA repair by this metal. Broad spectrum of epigenetic effects of nickel includes alteration in gene expression resulting from DNA hypermethylation and histone hypoacetylation, as well as activation or silencing of certain genes and transcription factors, especially those involved in cellular response to hypoxia. The investigations of the pathogenic effects of nickel greatly benefit from the understanding of the chemical basis of Ni(II) interactions with intracellular targets/ligands and oxidants. Many pathogenic effects of nickel are due to the interference with the metabolism of essential metals such as Fe(II), Mn(II), Ca(II), Zn(II), or Mg(II). Research in this field allows for identification of putative Ni(II) targets relevant to carcinogenesis and prediction of pathogenic effects caused by exposure to nickel. Ultimately, the investigations of nickel carcinogenesis should be aimed at the development of treatments that would inhibit or prevent Ni(II) interactions with critical target molecules and ions, Fe(II) in particular, and thus avert the respiratory tract cancer and other adverse health effects in nickel workers.

Introduction

Nickel,1 discovered and named by Cronstedt in 1751, is the 24th element in order of natural abundance in the earth’s crust. It is widely distributed in the environment. Natural sources of atmospheric nickel include dusts from volcanic emissions and the weathering of rocks and soils. Natural sources of aqueous nickel derive from biological cycles and solubilization of nickel compounds from soils. Global input of nickel into the human environment is approximately 150,000 metric tonnes per year from natural sources and 180,000 metric tonnes per year from anthropogenic sources, including emissions from fossil fuel consumption, and the industrial production, use, and disposal of nickel compounds and alloys [1], [2].

Major deposits of nickel ores, either oxidic or sulfidic are located in Australia, Canada, Cuba, Indonesia, New Caledonia, and Russia. Readers are referred to monographs and reviews for detailed discussions of the metallurgy, chemistry, environmental chemistry, biochemistry, toxicology, and biological monitoring of nickel [1], [2], [3], [4], [5], [6], [7], [8], [9], [10], [11], [12].

The high consumption of nickel-containing products inevitably leads to environmental pollution by nickel and its derivatives at all stages of production, utilization, and disposal. Human exposure to nickel occurs primarily via inhalation and ingestion and is particularly high among nickel metallurgy workers [1]. In addition, implantation of nickel-containing endoprostheses and iatrogenic administration of nickel-contaminated medications (e.g., albumin, radiocontrast media, hemodialysis fluids) leads to significant parenteral exposures [13], [14], [15], [16], [17] and wearing or handling of jewelry, coins, or utensils that are fabricated from nickel alloys or that have nickel-plated coatings may result in cutaneous nickel absorption [18]. In industrialized regions and large cities, atmospheric nickel concentrations are related to fly-ash from burning fossil fuels in power plants and automobiles and may reach 120–170 ng/m3 as compared to 6–17 ng/m3 in suburban areas [19]. Cigarette smoking can further increase inhaled nickel [20]. Another source of human nickel exposure is dietary where some foods, especially plant foods, may contain well over 1 mg Ni/kg [2], [5].

Occupational exposure to nickel occurs predominantly in mining, refining, alloy production, electroplating, and welding. In 1990, the International Committee on Nickel Carcinogenesis in Man suggested that respiratory cancer risks are primarily related to exposure to soluble nickel concentrations above 1 mg/m3 and to exposure to less soluble forms at concentrations above 10 mg/m3 [1]. The Committee was unable, however, to determine with confidence the level at which nickel exposure becomes a substantial hazard. Approximately 2% of the work force in nickel-related industries are exposed to airborne nickel-containing particles in concentrations ranging from 0.1 to 1 mg/m3 [1], [5].

Exposure to nickel compounds can produce a variety of adverse effects on human health. Nickel allergy in the form of contact dermatitis is the most common reaction. Although the accumulation of nickel in the body through chronic exposure can lead to lung fibrosis, cardiovascular and kidney diseases, the most serious concerns relate to nickel’s carcinogenic activity which is reviewed below in more detail in regard to its human epidemiology, experimental animal models, and postulated molecular mechanisms.

Section snippets

Carcinogenic effects in humans

The propensity of nickel workers to develop cancers of the nasal cavities was first reported by Bridge in 1933. In 1937, Baader described 17 nasal and 19 lung cancer cases among workers of the same Welsh refinery. By 1949, these numbers increased to 47 nasal cancers and 82 lung cancers (diagnosed between 1923 and 1948), and cancers at both locations were proclaimed in Great Britain as industrial diseases among some classes of nickel refinery workers [2], [21], [22]. During the decades since

Carcinogenic effects in experimental animals

Following the findings of Baader of respiratory tract cancer in nickel workers, published in 1937, Campbell [34] reported that chronic inhalation of nickel dust caused a two-fold increase of lung tumor incidence in mice. Since that time, numerous bioassays in experimental animals have yielded positive results for nickel compounds with low or no aqueous solubility (e.g., Ni(OH)2, Ni3S2, NiO) following inhalation or parenteral administration. Carcinogenesis of soluble nickel compounds (e.g.,

In vitro transformation of cells

Ni compounds are not mutagenic in the S. typhimurium and E. coli test systems [80]. This may be due to efficient metal uptake/export control systems which protect microorganisms against Ni(II) overload [81]. Nonetheless, as shown by Pikalek and Necasek [82], Ni(II) chloride at higher, relatively toxic concentrations (36–50 mg/l), was markedly mutagenic in a strain of Corynebacterium sp. 887 (hom).

In contrast to its weak mutagenicity in microbial cells, nickel efficiently transforms human and

Uptake, distribution, and retention of nickel

The marked differences in the carcinogenic activities of various nickel compounds most likely reflect the differences in their uptake, transport, distribution and retention, and ultimately—the capacity to deliver Ni(II) ions to specific cells and target molecules. This, in turn, strongly depends on the physical and chemical properties of such molecules. Our knowledge of these factors is sketchy, but nonetheless, it allows for explaining at least some of the epidemiologic and experimental

Nickel carriers

At the physiological pH range, the strength of Ni2+ interactions with proteins depends on the type of amino acid residues, their positions relative to each other, and their accessibility in the protein molecule. Under certain conditions, deprotonated peptide nitrogen may also coordinate Ni2+ ions. In concordance with the highest relative affinity for Ni2+ of free histidine (thanks to imidazole nitrogen) and cysteine (the sulfhydryl group) and their small peptides (e.g., carnosine, anserine,

Mechanistic considerations

Since there is no convincing evidence of a direct mutagenic Ni(II)–DNA “adduct” formation in cells exposed to nickel compounds, current hypotheses on the mechanisms of nickel carcinogenesis consider the reported genetic and epigenetic effects of Ni(II) as indirect results of Ni(II) binding to various other molecular components of the cell, including chromatin proteins. Owing to that, the competition of Ni(II) with essential divalent metal cations for common cellular ligands and binding sites

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