part 1. PART 1

concordance between in humans and in experimental CHAPTER 3 animals

chapter 3. and Michael P. Waalkes

Arsenic and arsenic compounds as a contaminant of drinking-water adult offspring in C3H/HeNCr mice together with various metals, spe- (IARC, 2004). The most prevalent (two studies) and CD1 mice (IARC, cifically including and source of human exposure to ar- 2012). In addition, in a study of CD1 beryllium compounds, cadmium senic is now drinking-water, where mice with “whole-life” exposure to and cadmium compounds, chromi- it is found primarily as the inorgan- multiple levels of sodium in um(VI) compounds, and and ic forms of arsenite and . drinking-water from 2 weeks before , were re-evalu- Inorganic arsenic can be metabolized breeding (male and female mice), ated in IARC Monographs Volume by most mammals to form trivalent during gestation and lactation (fe- 100C (IARC, 2012) as carcinogenic and pentavalent methylated metab- male mice), and after weaning until to humans ( 1). The most re- olites through specific methyltrans- age 2 years (offspring, both sexes), cent earlier evaluations appeared ferases, with S-adenosylmethionine bronchiolo-alveolar carcinoma oc- in Volume 84 (IARC, 2004) for ar- as the methyl (IARC, 2004, curred in a dose-related fashion senic, Volume 58 (IARC, 1993) for 2012). Questions remain about the in both male and female offspring beryllium and cadmium, and Volume relative contribution of the inorganic (Tokar et al., 2011). In CD1 mice, in 49 (IARC, 1990) for chromium and and the methylated arsenic species utero exposure via maternal con- nickel. to the overall carcinogenic potential sumption of sodium arsenite in drink- Arsenic and arsenic of exposure to arsenic. Arsenic and ing-water during gestation with or compounds arsenic compounds in drinking-water without subsequent dimethylarsinic are human ; there is suf- (DMA(V)) in drinking-water of Carcinogenicity ficient evidence in humans for can- the offspring throughout adulthood Early on, exposure to inorganic arse- cer of the , urinary bladder, and induced bronchiolo-alveolar carcino- nic via drinking-water or oral use of skin, as as limited evidence for ma in animals that received prenatal arsenic-based drugs was considered cancer of the , , and pros- arsenite alone, DMA(V) alone, or the carcinogenic to the skin in humans, tate (IARC, 2004, 2012). combination of prenatal arsenite and and exposure to inorganic arsenic In rodents, transplacental arsenic DMA(V) (Tokar et al., 2012a). In CD1 via inhalation in occupational set- exposure via maternal consumption mice, in utero exposure to arsenic via tings was evaluated as carcinogenic of sodium arsenite in drinking-wa- maternal consumption of monometh- to the lung in humans (IARC, 1973). ter during gestation induced bron- ylarsinous acid (MMA(III)) in drink- Arsenic was most recently assessed chiolo-alveolar carcinoma in the ing-water produced bronchiolo-alveolar

Part 1 • Chapter 3. Arsenic and metals 31 carcinoma in male offspring as cal hyperplasia) of the lung epitheli- In multiple studies in rodents, in- adults, but not in a dose-related um. The role of the separate moieties organic arsenic or DMA(V) given in fashion (Tokar et al., 2012b). Multiple of the inhaled compound (i.e. drinking-water or by the transplacen- intratracheal instillations of inorgan- and arsenic) in the carcinogenic re- tal route had initiating, promoting, or ic arsenic produced lung tumours sponse could not be defined by this co-carcinogenic activity in the skin, in hamsters (three studies) (IARC, one study in rodents, and it was con- kidney, and urinary bladder with oth- 2012). In adult A/J mice, oral cluded that either moiety alone or er, non-arsenic-based compounds sodium arsenate increased the size some combination of both could be (IARC, 2004, 2012). Multiple studies and multiplicity of lung tumours in humans have found oral arsenic active (IARC, 2006). (male mice), and oral DMA(V) in- exposure to be carcinogenic to the There is limited evidence that the creased the incidence and multiplici- skin and urinary bladder, and there liver is a target site for the carcino- ty of lung tumours (IARC, 2012). Oral is limited evidence that the kidney genic effects of arsenic and arsenic exposure to DMA(V) increased the is a target site in humans (IARC, compounds in humans (IARC, 2012). incidence of lung tumours in Ogg−/− 2004, 2012). It is difficult to assess In rodents, multiple studies showed mice, which cannot repair certain the relevance to humans of rodent that in utero exposure to arsenic via types of oxidative DNA damage, but studies that use multiple agents, one maternal consumption of sodium not in Ogg+/+ mice (IARC, 2012). of which is an arsenic compound of Multiple studies in humans have arsenite in drinking-water during concern. found oral arsenic exposure to be gesta­tion induced hepatocellular Overall, the target sites for which carcinogenic to the urinary bladder, carcinoma in the adult offspring of there is sufficient evidence in humans typically producing transitional cell C3H/HeNCr mice (two studies) and for the carcinogenicity of arsenic and carcinoma (IARC, 2004, 2012). Most CD1 mice (IARC, 2012). In addition, arsenic compounds include the uri- oral exposure in humans would in- in a study of CD1 mice with “whole- nary bladder and the lung, and there volve inorganic arsenic as the prima- life” exposure to multiple levels of are multiple concordant rodent stud- ry form. Multiple studies in rodents sodium arsenite in drinking-water ies for these two sites (IARC, 2012). show that chronic oral exposure to (see above), hepatocellular carci- The skin is also a target site in hu- DMA(V) causes transitional cell car- noma occurred in a dose-related mans for inorganic arsenic and arse- cinoma of the urinary bladder in adult fashion in both male and female off- nic compounds, but in rodents there rats, but not in mice (IARC, 2012). spring (Tokar et al., 2011). In CD1 is insufficient evidence that inorganic DMA(V) exposure can be from the mice, in utero exposure via maternal arsenic or arsenic compounds acting drinking-water or the feed. Exposure consumption of sodium arsenite in alone can cause cancer of the skin to inorganic arsenic has not been drinking-water during gestation with (IARC, 2012). There is limited evi- shown to be carcinogenic to the uri- dence that the liver is a target site for or without subsequent DMA(V) in nary bladder in rodents; the reasons the carcinogenic effects of arsenic the drinking-water of the offspring for this are not clear. and arsenic compounds in humans, throughout adulthood induced hepa­ Gallium is considered and sufficient evidence that the liv- tocellular carcinoma in animals that carcinogenic to humans, based er is a target site in rodents (IARC, received prenatal arsenite alone largely on one robust study in ro- 2012). There is limited evidence that or the combination of prenatal ar- dents together with ancillary evi- the kidney is a target site in humans senite and DMA(V). The combined dence (IARC, 2006). Chronic inhala­ (IARC, 2012), and one recent study treatment produced hepatocellular tion of induced lung in mice provided evidence that can- bronchiolo-alveolar adenoma or carcinoma at a significantly higher cer of the kidney can be induced by carcinoma in a dose-related fashion rate than prenatal arsenite alone or a combination of inorganic arsenic in female F344 rats, but not in male DMA(V) alone (Tokar et al., 2012a). (prenatal) and DMA(V) in adulthood rats or male or female B6C3F1 mice In CD1 mice, in utero exposure to (Tokar et al., 2012a). There is limited (IARC, 2006, 2012). Male rats ex- arsenic via maternal consumption of evidence that the prostate is a tar- posed to gallium arsenide did show MMA(III) in drinking-water produced get site in humans, and there are no dose-related increases in the num- hepatocellular carcinoma in male off- studies in rodents showing increased ber of pre-neoplastic lesions (atypi- spring as adults (Tokar et al., 2012b). incidence of prostate cancer after

32 exposure to inorganic arsenic or same tumour type induced in rats plification, altered DNA arsenic compounds (IARC, 2012). by chronic oral exposure to DMA(V) (epigenetic effects), or aneuploidy Inorganic arsenic can cause lung (IARC, 2012). Some researchers may cause alterations in gene ex- cancer in humans after inhalation or believe that the rat is a poor model pression that to genomic in- PART 1

ingestion, but there are no studies for studying arsenic toxicology in hu- stability and cellular transformation. CHAPTER 3 showing development of mans, because the toxicokinetics of The metabolism of inorganic arsenic in rodents after inhalation exposure arsenic are dramatically different as by methylation may contribute to its (IARC, 1973, 2012). In fact, an ade- a result of sequestration of arsenic in epigenetic effects, because the ar- quate inhalation study in rodents with the blood of rats (Carter et al., 2003; senic methylation pathway overlaps inorganic arsenic has never been Aposhian et al., 2004). However, for with DNA methylation by consump- performed, presumably because the DMA(V) and cancer of the urinary tion of S-adenosylmethionine as the agent had already been declared a bladder, there is clear site concor- common methyl donor (Brocato and human and rodent re- dance between humans and rats. For Costa, 2013). However, it is notewor- search resources were directed bladder tumours induced by DMA(V) thy that inorganic arsenic can cause elsewhere. in the rat, the mechanism may in- in cells that volve sustained , pos- do not methylate the , indi- Mechanisms of sibly from oxidative stress (Kitchin cating that neither methylation nor a and Conolly, 2010), followed by cell methylated metabolite are required Although a unifying mechanis- proliferation and genomic instability. for a cell to acquire a malignant phe- tic hypothesis for arsenic-induced Specific methylated forms of arsenic notype after exposure to inorganic carcinogenesis may seem reason- may be involved in the sustained cy- arsenic (Kojima et al., 2009). Thus, able, it is important to emphasize totoxicity (Cohen et al., 2007). cell-specific, complex, multifaceted that given the multitude of toxic Inorganic arsenic and methyl- mechanisms are likely to be opera- events at the subcellular level seen ated arsenic metabolites generally tive with arsenic (Kitchin and Conolly, with inorganic arsenic and arsenic show weak activity as . 2010; Tokar et al., 2010). compounds (e.g. oxidative stress, Low-dose exposure to inorganic ar- Another important issue with altered DNA repair, altered DNA senic can increase the number of mechanistic implications is the methylation, gene amplification, and mutations resulting from genomic strong evidence that cancer can altered growth factors), it is likely that instability, perhaps through produc­ develop long after elevated arsenic multiple mechanisms are operative tion of reactive species, exposure ends. For instance, a re- in arsenic-induced carcinogenesis and cells that methylate inorganic cent study on a human population (Kitchin and Conolly, 2010; Tokar arsenic show much more oxidative in measured rates of cancer et al., 2010; Hartwig, 2013). These DNA damage than cells that poorly of the bladder and lung in individ- multiple mechanisms are probably methylate the metalloid during in vi­ uals who were highly exposed to linked, at least in part, to the quali- tro malignant transformation (Kojima inorganic arsenic in drinking-water ties of specific target tissue (e.g. high et al., 2009). MMA(III) may be one of during 1958–1970 but drank low-ar- oxygen tension in the lung might fa- the most deleterious arsenic methyl- senic water thereafter. These sub- vour oxidative stress, in contrast with ation products, although the number jects still showed very high risks of the situation in the bladder) (Kitchin of tumour end-point studies is very cancer even 40 years after the high and Conolly, 2010). The target tis- limited (only one study). The main exposures ended (Steinmaus et al., sue-specific toxicokinetics of arsenic cascade of mechanisms leading to 2013). Similarly, the mouse transpla- are likely to be key and may dictate carcinogenesis for inorganic arsenic cental model demonstrated that brief that multiple toxic events combine and arsenic compounds after expo- exposure to inorganic arsenic may into a target-specific carcinogenic sure to low concentrations could in- result in tumours in adulthood (IARC, mechanism (Kitchin and Conolly, clude the rapid induction of oxidative 2012). Given the time lag between 2010). DNA damage and inhibition of DNA arsenic exposure and development In humans, arsenic causes tran- repair, followed by changes in DNA of cancer, the operative mechanisms sitional cell carcinoma of the urinary methylation patterns, aneuploidy, would appear not to require concur- bladder (IARC, 2012), which is the and gene amplification. Gene am- rent high tissue levels of arsenic.

Part 1 • Chapter 3. Arsenic and metals 33 In discerning mechanisms of ar- inorganic carcinogens, beryllium of cadmium chloride and cadmium senic-induced carcinogenesis by produces oxidative stress, which both induced primarily bron- use of in vitro model systems, the can lead to damage in DNA or oth- chiolo-alveolar carcinoma. consideration that arsenic adverse- er key biomolecules and then pro- Multiple studies in rodents have ly alters many cellular physiological duce gene activation and . established that various water-sol- functions is critical; studies have The cytotoxicity of beryllium in the uble and insoluble cadmium com- frequently been carried out with lev- lung may result in compensatory pounds can produce soft tissue els of arsenic that would be highly cell proliferation, along with chron- sarcomas after repository injections unrealistic in vivo. Another common ic inflammation. The inflammatory (IARC, 1993, 2012). Studies that issue with in vitro arsenic studies is processes induced by beryllium produced injection-site tumours that many use short time frames, and could contribute to the formation of have provided some evidence of the very early responses to arsenic do reactive oxygen species, precipitate carcinogenic potential of cadmium, not necessarily reflect in vivo expo- cell turnover, and activate or disrupt but there is no concordance with sures or take into account the adap- pulmonary cell signalling pathways. any specific target site in humans. tive capacities towards arsenic that Beryllium can decrease DNA repair Prostatic proliferative lesions can be are generally observed in vivo. and recombination. The impairment produced in rats after oral adminis- of DNA repair by beryllium togeth- tration or subcutaneous injection of Beryllium and beryllium er with increased mitotic signalling cadmium chloride. compounds may cooperate to induce error-prone Overall, cadmium and cadmium cell proliferation (Beyersmann and Carcinogenicity compounds are carcinogenic to hu- Hartwig, 2008). The mechanisms of mans and target the lung after inha­ There is sufficient evidence in hu- beryllium-induced carcinogenesis lation (IARC, 2012). Lung mans that beryllium and beryllium are probably complex, multifacet- have been repeatedly produced in compounds cause lung cancer ed, and interactive, as with other rodents by either inhalation or in- (IARC, 2012). In rats, inhalation of metals that are human carcinogens tratracheal instillations of cadmium beryllium , beryllium sulfate, (Beyersmann and Hartwig, 2008; compounds. There is limited evi- or beryl ore dust produced bronchi- Kitchin and Conolly, 2010; Tokar dence in humans for prostate and olo-alveolar carcinoma, and intratra- et al., 2010; Brocato and Costa, renal carcinogenesis with cadmium cheal instillation of beryllium metal, 2013; Koedrith et al., 2013). or cadmium compounds. In rodents, beryllium hydroxide, or beryllium prostatic proliferative lesions can be produced bronchiolo-alveolar Cadmium and cadmium induced by cadmium, but there is no carcinoma. compounds concordant evidence in rodents for Overall, for inhaled beryllium and the kidney. beryllium compounds, the lung is the Carcinogenicity one identified cancer target site in Mechanisms of There is sufficient evidence in hu- carcinogenesis humans, a response that has been mans that cadmium and cadmium repeatedly duplicated in rodent mod- compounds cause lung cancer, with Cadmium-induced carcinogenesis els (IARC, 2012). positive associations between rel- may be attributable to various mech­ evant exposure and cancer of the anisms (Beyersmann and Hartwig, Mechanisms of kidney and prostate (IARC, 2012). In 2008; Brocato and Costa, 2013; carcinogenesis rodents, there is sufficient evidence Hartwig, 2013; Koedrith et al., Multiple, related mechanisms are for the carcinogenicity of cadmium 2013). Direct interaction of cadmi- likely to be operative in beryllium-in- and cadmium compounds (IARC, um with DNA appears to be limited, duced carcinogenesis (IARC, 2012). 2012). In rats, inhalation of cadmium and cadmium is a weak . Although beryllium is inactive or chloride, , cadmium Cadmium can perturb DNA repair weakly positive as a mutagen, chro- sulfide, or cadmium sulfate pro- and affect tumour suppressor pro- mosomal aberrations and aneu­ duced bronchiolo-alveolar carcino- teins, potentially causing genomic ploidy can occur in vivo in rodents ma or squamous cell carcinoma of instability and chromosomal damage. at non-toxic doses. Like many other the lung, and intratracheal instillation Altered DNA methylation patterns

34 and disrupted signal transduction 2012), and therefore the combination lated scarring (confluent fibrosis) and processes have been observed after of data from male and female ani- chronic inflammatory changes indic- exposure to cadmium; these factors mals may be problematic. Male rats ative of high tissue burdens of the could potentially contribute to aber- chronically exposed by inhalation to test agent and local . PART 1

rant cell growth, but their role in cad- sodium dichromate developed lung Many studies have demonstrat- CHAPTER 3 mium-induced carcinogenesis is un- tumours in one study, although the ed carcinogenic activity for various clear. Cadmium can induce reactive Working Group for that Monograph chromium(VI) compounds in ro- oxygen species, but this would be an cautioned about small group sizes dents, such as production of soft indirect effect and its precise role in in that study (IARC, 1990). Nasal tissue sarcomas after repository in- cadmium-induced carcinogenesis papilloma occurred after chronic jections (IARC, 1990, 2012). Studies is not completely defined. Specific inhalation of in that produced injection-site tumours mechanisms of lung carcinogenesis female mice in one study (IARC, have provided some evidence of the after exposure to cadmium have not 1990). Various compounds of chro- carcinogenic potential of chromium been elucidated fully. As with the oth- mium(VI), including calcium chro- (VI), but there is no concordance er inorganic human carcinogens, the mate, strontium chromate, and zinc with any specific target site in hu- mechanisms of cadmium-induced chromate, produced local squamous mans. Sodium dichromate dihydrate carcinogenesis are probably multi- cell carcinoma in rats when the test in drinking-water caused adeno- faceted (Beyersmann and Hartwig, agent was first mixed with cholester- carcinoma of the small intestine in 2008; Brocato and Costa, 2013; ol and then used to fill or coat stain- mice and squamous cell carcinoma Koedrith et al., 2013). less steel wire baskets that were of the oral mucosa and tongue in subsequently surgically implanted rats (National Toxicology Program, Chromium(VI) compounds via tracheotomy into the bronchus 2008), but these tissues are not (IARC, 1990). The coated basket considered cancer target sites in hu- Carcinogenicity acts as a point of release for the mans. Given the response and the There is sufficient evidence in hu- test agent. Implantation of a basket rarity of these tumours in rodents mans for the carcinogenicity of chro- containing cholesterol alone caused and the potential for oral exposure of mium(VI) compounds, which cause notable squamous metaplasia (7% humans to chromium(VI), these sites cancer of the lung (IARC, 1990, of controls) and bronchial inflamma- deserve additional focus in epidemi- 2012). Most of the epidemiological tion (89% of controls), indicating that ological studies. data come from occupational set- chronic, not agent-related, irritation is The lung is a target site for the tings that would involve inhalation as involved with this model even without carcinogenic effects of chromi­ the primary route of exposure. Also, a test agent. Although the tumours um(VI) compounds in humans positive associations have been ob- induced by this technique of expo- (IARC, 1990, 2012). From inhalation served between exposure to chro- sure via implantation of a wire basket studies in rats and mice, there is mium(VI) compounds and cancer of were histologically defined as bron- sufficient evidence that chromi- the nose and nasal sinuses (IARC, chiolar squamous cell carcinoma, um(VI) induces lung tumours, al- 2012). In rodents, there is sufficient their relevance to human lung can- though all the available studies are evidence for the carcinogenicity of cer induced by inhalation of chromi- considered to have some limita- chromium(VI) compounds (IARC, um(VI), or in fact by any other agent, tions (IARC, 1990). Lung tumours 1990, 2012). Calcium chromate in- has not been rigorously validated. produced by surgically implanting duced lung tumours (adenomas) in Repeated weekly intratracheal instil- stainless steel wire baskets con- mice, but only when data from male lations of calcium chromate or sodi- taining chromium(VI) compounds and female groups were combined um dichromate in male and female in cholesterol into the bronchus (Nettesheim et al., 1971). The sex rats produced bronchiolo-alveolar of rats, like injection-site tumours, of a test animal is considered by carcinoma and squamous cell carci- probably reflect carcinogenic activ- IARC as a quantitative aspect of a noma in one study (Steinhoff et al., ity, but the relevance of this expo- tumour end-point study that poten- 1986). The authors noted that the sure technique in modelling tumours tially affects the outcome in terms of chromium(VI)-induced tumours co- produced in humans by inhalation of chemically induced tumours (IARC, existed with extensive treatment-re- chromium(VI) compounds requires

Part 1 • Chapter 3. Arsenic and metals 35 further validation. Repeated in- reductants, various toxic intermedi- lung, whereas intratracheal instilla- tratracheal instillations of certain ates, including radicals of chromium, tion of nickel oxide, nickel subsulfide, chromium(VI) compounds can oxygen, and , are likely to be or metallic nickel caused squamous produce malignant lung tumours generated, and they can react with cell carcinoma of the lung. In sev- (Steinhoff et al., 1986). There is key biomolecules relevant to carcino- eral well-performed experiments, limited evidence that the nose or the genesis (IARC, 2012; Hartwig, the inhalation of various nickel com- nasal sinuses are target sites for the 2013; Proctor et al., 2014). Some pounds, both water-soluble and in- carcinogenic effects of chromium(VI) chromium(VI) reductants undergo soluble, including metallic nickel (in in humans (IARC, 2012), and one Fenton-type reactions to produce rats), nickel sulfate (in rats and mice), study in mice showed nasal papillo- hydroxyl radicals, which attack DNA. and nickel subsulfide (in mice) did mas induced by inha­lation of chromi- Chromium(VI) can stimulate forma- not cause lung tumours. Oral expo- um(VI) (IARC, 2012). tion of superoxide and sure to nickel sulfate did not cause Generally speaking, chromium(VI) in vitro. Chromium(VI) metabolites tumours in rats or mice. compounds do show concordance can be directly genotoxic, and the Various water-soluble and insol- between humans and rodents for the metal also causes inflammation and uble nickel compounds and metal- established target site in humans, stimulates tumour growth pathways lic nickel produced various types of the lung, on the basis of: (i) two pos- in cell culture systems. Aneuploidy sarcomas in rats, mice, or hamsters itive inhalation studies in rodents, has been observed after exposure when administered by repository both with noted limitations (IARC, to chromium(VI). Significant DNA injections (subcutaneous, intramus- 1990); (ii) lung tumours induced in methylation changes could be a con- cular, intraperitoneal, etc.) (IARC, rodents by repeated intratracheal in- tributing factor in chromium(VI)-in- 2012). Studies that produced in- stillations; and (iii) activity in a rodent duced carcinogenesis, particularly in jection-site tumours have provided model with surgical implantation of the lung (Brocato and Costa, 2013). some evidence of the carcinogenic wire baskets containing chromi­ As with other inorganic human car- potential of nickel and nickel com- um(VI) compounds into the bronchus cinogens, it is likely that multiple, pounds, but there is no concor- to produce lung tumours. However, probably interactive, mechanisms dance with any specific target site in additional state-of-the-art studies in are operative in chromium(VI)-in- humans. experimental animals with inhaled duced carcinogenesis, including There are multiple studies in chromium(VI) compounds appear to DNA damage, oxidative stress, and rodents that recorded increased be needed. A high-quality, contem- aneuploidy, which lead to the acqui- pheochromocytoma of the adrenal porary tumour end-point inhalation sition of a malignant phenotype. medulla after inhalation of nickel study in rodents would add great- compounds, including metallic nickel ly to the understanding of chromi- Nickel and nickel compounds and nickel subsulfide (IARC, 2012). um(VI)-induced carcinogenesis and These studies might imply the sys- Carcinogenicity could be designed to significantly aid temic bioavailability of inhaled nickel in elucidation of the mode of action of There is sufficient evidence that compounds, although there are no this compound (Proctor et al., 2014). mixtures of nickel compounds and concordant data concerning the ad- Such a study is lacking, presumably metallic nickel cause cancers of renal gland as a target of nickel-in- because the agent had already been the lung, nose and nasal cavity, duced carcinogenesis in humans. declared a human carcinogen and and paranasal sinuses in humans Overall, for nickel and nickel com- rodent research resources were di- (IARC, 2012). Epidemiological stud- pounds, target site concordance ex- rected elsewhere. ies provided evidence for induction ists between the human lung and the of lung cancer by specific nickel rodent lung for various nickel com- Mechanisms of compounds, including water-soluble pounds and metallic nickel. There carcinogenesis and insoluble substances. In rats, are no data in rodents on cancers of In terms of general mechanisms, inhalation of nickel oxide, nickel sub- the nose, nasal cavity, and parana- during in vitro conversion of chromi- sulfide, or nickel carbonyl caused sal sinuses that would be concordant um(VI) to chromium(III) by cellular bronchiolo-alveolar carcinoma of the with data in humans.

36 Mechanisms of carcinogens, it is likely that multiple, for the metals that are human car- carcinogenesis potentially interdependent, complex cinogens (i.e. beryllium, cadmium, mechanisms are operative in nick- chromium(VI), and nickel) (IARC, The nickel ion Ni(II) is considered to 2012). However, this scenario is not el-induced carcinogenesis. PART 1 be the ultimate carcinogenic species likely to be entirely true for the met- CHAPTER 3 in nickel-induced carcinogenesis Comparative mechanisms alloid arsenic and its compounds. Of (Beyersmann and Hartwig, 2008; of the inorganic human all the inorganic human carcinogens, IARC, 2012). Water-soluble and carcinogens inorganic arsenic alone can undergo poorly water-soluble nickel com- conjugative biotransformation with- pounds both enter the cell and reach Among arsenic compounds and met- in the host. Methylation of inorganic the nucleus, although the soluble als that are human carcinogens, only arsenic generally produces mon- compounds do this by ion channels chromium(VI) seems to have the omethylarsenic (MMA) forms and and transporters, whereas the poorly ability to interact with DNA directly, then dimethylarsenic forms, but this soluble compounds are taken up by at least when it undergoes intracel- process is not complete in most peo- phagocytosis. After phagocytosis, lular reduction, and to act as a direct ple (Melak et al., 2014). Incomplete methylation can result in the forma- particulate nickel compounds grad- genotoxin. Chromium(VI) does show tion of very toxic, monomethylated ually release nickel ions, making human-to-rodent target site con- arsenic metabolites, like MMA(III). them available for interaction with cordance with respect to the lung, Recent data in humans indicate key biomolecules. An increased lev- although up-to-date inhalation stud- that an increased MMA level, as a el of nickel in the nucleus is evident ies in rodents would greatly aid in percentage of total urinary arsenic, after exposure to water-soluble or defining the mechanisms of chromi- strongly correlates with cancer of um(VI)-induced carcinogenesis (see insoluble nickel compounds. Nickel the lung and bladder in a population compounds are weakly mutagenic above; Proctor et al., 2014). With the in northern Chile exposed to envi- in mammalian cells but induce DNA inorganic human carcinogens other ronmental inorganic arsenic (Melak damage, chromosomal aberrations, than chromium(VI), direct induction et al., 2014). This indicates that arse- and micronuclei in vitro and in vivo. of DNA damage is not a key mechan- nic metabolites generated by incom- Both water-soluble and insoluble ism. All the metals that are human plete methylation are associated with nickel compounds induce malignant carcinogens seem to be able to increased carcinogenic risk after ex- cell transformation in vitro. However, cause oxidative stress (Beyersmann posure to inorganic arsenic. delayed mutagenicity and chromo- and Hartwig, 2008; Hartwig, 2013), Stimulation of inflammation is also somal instability have been observed mostly by indirect means. This may common among the group of inor- ganic human carcinogens. The role long after treatment of cells with nick- contribute to their carcinogenic po- of inflammation in carcinogenesis el. Nickel compounds induce epige- tential because the resulting oxi- may be secondary, through provi- netic changes, including alteration in dative species could attack DNA. sion of oxidants or radical species DNA methylation patterns and mod- Arsenic, cadmium, chromium, and produced by oxidation. ification of histones (Brocato and nickel can have epigenetic effects on Definitive mechanisms have not Costa, 2013). An inflammatory com- DNA that alter critical gene expres- been established for any inorganic ponent is also thought to contribute sion and promote the acquisition of human carcinogen. These agents to nickel-induced carcinogenesis. a malignant phenotype (Brocato and are best considered to be multi- Direct effects of nickel on DNA are Costa, 2013). faceted, interrelated, and complex probably limited, but oxidative stress With respect to carcinogenesis carcinogens. For the inorganic car- and oxidative DNA damage have induced by inorganic chemicals, it cinogens with multiple target sites, been found after nickel exposure. is generally accepted that the ionic there is a strong possibility that the As with the other inorganic human species is the most active species mechanism is target site-specific.

Part 1 • Chapter 3. Arsenic and metals 37 References

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