part 1 . PART 1 concordance between cancer in humans and in experimental CHAPTER 3 animals chapter 3. Arsenic and metals 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 beryllium 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 arsenite in um(VI) compounds, and nickel and ic forms of arsenite and arsenate. drinking-water from 2 weeks before nickel compounds, 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 (Group 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 donor (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 carcinogens; there is suf- acid (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 lung, urinary bladder, and induced bronchiolo-alveolar carcino- nic via drinking-water or oral use of skin, as well as limited evidence for ma in animals that received prenatal arsenic-based drugs was considered cancer of the kidney, liver, 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. gallium 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 strain 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 gesta tion 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 arsenide 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 gallium arsenide 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 methylation 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 lead 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 lung cancer 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 carcinogen 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- malignant transformation in cells that volve sustained cytotoxicity, pos- do not methylate the metalloid, indi- Mechanisms of sibly from oxidative stress (Kitchin cating that neither methylation nor a carcinogenesis and Conolly, 2010), followed by cell methylated metabolite are required Although a unifying mechanis- proliferation and genomic instability.