Carcinogenicity assessment of water-soluble nickel compounds

Abstract

IARC is reassessing the human carcinogenicity of nickel compounds in 2009. To address the inconsistencies among results from studies of water-soluble nickel compounds, we conducted a weight-of-evidence analysis of the relevant epidemiological, toxicological, and carcinogenic mode-of-action data. We found the epidemiological evidence to be limited, in that some, but not all, data suggest that exposure to soluble nickel compounds leads to increased cancer risk in the presence of certain forms of insoluble nickel. Although there is no evidence that soluble nickel acts as a complete carcinogen in animals, there is limited evidence that suggests it may act as a tumor promoter. The mode-of-action data suggest that soluble nickel compounds will not be able to cause genotoxic effects in vivo because they cannot deliver sufficient nickel ions to nuclear sites of target cells. Although the mode-of-action data suggest several possible non-genotoxic effects of the nickel ion, it is unclear whether soluble nickel compounds can elicit these effects in vivo or whether these effects, if elicited, would result in tumor promotion. The mode-of-action data equally support soluble nickel as a promoter or as not being a causal factor in carcinogenesis at all. The weight of evidence does not indicate that soluble nickel compounds are complete carcinogens, and there is only limited evidence that they could act as tumor promoters.

Unrecognized risks of nickel-related respiratory cancer among Canadian electrolysis workers

“…An additional selection bias could, of course, be detrimental. We found neither an explanation for the loss of data nor any review to discuss the problem [searching in the US EPA 1986 health assessment document (45), the IARC 1990 mongraph (1), the Toxicology Excellence for Risk Assessment (TERA) toxicological review of soluble nickel salts prepared in 1999 (30), and the review sponsored by nickel producers in 2009 (19)]. …”

“…Data on soluble nickel in the CCCR copper electrolyte were hard to find, and -notably -provided neither in any of the relevant epidemiological reports from 1971-1992 (13,29,32,43) nor in the 1992 industrial hygiene report from the refinery (34) or reviews of nickel-related cancer conducted since the 1970s (1,13,19,30,(44)(45)(46). We found relevant data in books on chemistry and metallurgy printed between 1930 and 1960 (40-42).…”

“…The apparent diverging results across cohorts with assumed similar exposures, especially the comparison of the Norwegian and Canadian experiences, have been the basis of a reoccuring argument over whether soluble nickel should be regarded as carcinogenic, even throughout the last decade (19,30,31). The ICNCM discussed the difference in risk in 1990 but was not able to fully explain the observation (13).…”

“…The argument continued after 1990 in articles, information, and reviews sponsored by nickel producers (17)(18)(19), despite additional epidemiological evidence of carcinogenicity from the UK, Finland, and Norway (20)(21)(22)(23)(24)(25).…”

Hypothesis-based weight of evidence: A tool for evaluating and communicating uncertainties and inconsistencies in the large body of evidence in proposing a carcinogenic mode of action—naphthalene as an example

“…Epidemiology data are lacking To our knowledge, there are no cohort or case-control studies of naphthalene and cancer risk� There are only a few reports of individual cancer cases with prior naphthalene exposure (Griego et al�, 2008)� These include four smokers with laryngeal cancer among naphthalene purification workers in East Germany and 23 colon cancer cases, half of whom reported taking a treatment containing naphthalene (Griego et al�, 2008)� In no case can the cancer be definitively attributed to naphthalene� Also, none of these cancers occurred in the lung or nose� Exposure to polycyclic aromatic hydrocarbons (PAHs) in general has been associated with a modest increase in lung cancer risk (Bosetti et al�, 2007), but it is unclear if any of this risk is attributable to naphthalene� In contrast, to our knowledge, no studies have examined risks of nasal cancer from PAHs� It is conceivable that this is because nasal cancer is extremely rare, which makes it difficult to study epidemiologically, but nasal cancer has been studied and found to be associated with other environmental and occupational exposures in epidemiological studies (e�g�, insoluble nickel, see Goodman et al�, 2009)� Were PAHs in general, and naphthalene in particular, associated with nasal cancer risk, it certainly could have been studied� Even though the chances of a statistically significant association is low (owing to nasal cancer's low background rate), any occurrence of this rare cancer would have been notable� Yet, it has never been noted� Although this lack of evidence does not definitively show that naphthalene is not associated with nasal cancers in humans, it is certainly suggestive� Current in vitro data for naphthalene activity in humans Buckpitt and Bahnson (1986) showed that naphthalene is metabolized to its epoxide (as measured by presence of the dihydrodiol) in microsomal fractions of human lung tissue at about 3% the rate observed in rodents� Recombinant human lung CYP2F1 has been shown to metabolize naphthalene to its epoxide metabolite in human lymphoblastoid cells at very low rates Lanza et al�, 1999), and CYP2F1 mRNA has been identified in human respiratory tissue, but results in much lower expression than CYP2F4 in rats Raunio et al�, 1999;Ding and Kaminsky, 2003)� Currently, no studies have examined the involvement of CYP2F1 in the activation of naphthalene to its epoxide in actual human lung tissue, i�e�, in the presence of other CYPs and metabolic and detoxifying enzymes (GSH S-transferase, EH, and DD) in the human lung� It is important to point out that the naphthalene concentrations used in the bioassays exceeded the maximum tolerable dose (MTD) (North et al�, 2008), where nearly 100% chronic inflammation occurred in both rats and mice and in both sexes at all doses, indicating that cytotoxicity occurred at all doses� Although this does not in itself constitute proof, especially given the high exposure concentrations, these data suggest that cytotoxicity played a significant role in the observed naphthalene-induced tumor formation in both species� Therefore, since the concentrations used in these bioassays were about 3000-fold greater than naphthalene levels measured in ambient air (Griego et al�, 2008), low-dose extrapolation of these data to concentrations human...…”