Existing data on the oral carcinogenicity of nickel substances have been historically inconclusive, yet, the assessment of the oral carcinogenicity potential of nickel has serious scientific and regulatory implications. In a study by Heim et al. (2007), nickel sulfate hexahydrate was administered daily to rats by oral gavage for two years (104 weeks) at exposure levels of 10, 30 and 50 mg NiSO4•6H2O/kg. This treatment produced a statistically significant reduction in body weight of male and female rats, compared to controls, in an exposure-related fashion at 30 and 50 mg/kg/ day. An exposure-dependent increase in mortality was observed in female rats. However, daily oral administration of nickel sulfate hexahydrate did not produce an exposure-related increase in any common tumor type or an increase in any rare tumors. This study achieved sufficient toxicity to reach the Maximum Tolerated Dose (MTD) while maintaining a sufficiently high survival rate to allow evaluation for carcinogenicity. The study by Heim et al. (2007) demonstrates that nickel sulfate hexahydrate does not have the potential to cause carcinogenicity by the oral route of exposure. Data from this and other studies demonstrate that inhalation is the only route of exposure that might cause concern for cancer in association with nickel compound exposures.
Unlike other species of nickel, oral exposure to soluble nickel occurs from drinking water and food. Data from both human and animal studies show that absorption of nickel from food and water is generally low (1-30%), depending on the fasting state of the subject, with most of the nickel excreted in feces (Diamond et al., 1998). In humans, effects of greatest concern for ingested nickel are those produced in the kidney, possible reproductive effects, and the potential for soluble nickel to exacerbate nickel dermatitis following oral provocation.
Several researchers have examined the evidence of nephrotoxicity related to long-term exposures of soluble nickel in electroplating, electrorefining and chemical workers (Wall and Calnan, 1980; Sunderman and Horak, 1981; Sanford and Nieboer, 1992; Vyskocil et al., 1994). These workers not only would have been exposed to soluble nickel in their food and water, but also in the workplace air which they breathed. Wall and Calnan (1980) found no evidence of renal dysfunction among 17 workers in an electroplating plant. Likewise, Sanford and Nieboer (1992), in a study of 26 workers in electrolytic refining plants, concluded that nickel, at best, might be classified as a mild nephrotoxin. In the Sunderman and Horak study (1981) and the Vyskocil et al., study (1994), elevated markers of renal toxicity (e.g., ß2 microglobulin) were observed, but only spot urinary nickel samples were taken. The chronic significance of these effects is uncertain. In addition, nickel exposures were quite high in these workers (up to 13 mg Ni/m3 in one instance), and certainly not typical of most current occupational exposures to soluble nickel. Severe proteinuria and other markers of significant renal disease that have been associated with other nephrotoxicants (e.g., cadmium) have not been reported in nickel workers, despite years of biological monitoring and observation (Nieboer et al., 1984).
In regard to reproductive effects, there is some evidence in humans to indicate that absorbed nickel may be able to move across the placenta into fetal tissue (Creason et al., 1976; Casey and Robinson, 1978; Chen and Lin, 1998; Haber et al., 2000b). Because of this, the preliminary results from a study of Russian nickel refinery workers that purported to show evidence of spontaneous abortions, stillbirths, and structural malformations in babies born to female workers at that refinery deserved careful attention (Chashschin et al., 1994). Concerns about the reliability of the Chashschin et al. (994) study prompted a more thorough and well-conducted epidemiology study to determine whether the effects observed in the Russian cohort were really due to their workplace nickel exposures or to other confounders in the workplace and/or ambient environment. The investigation of the reproductive health of the Russian cohort was important for another reason. Specifically, the nickel refineries in this region are the only places worldwide where enough female nickel refinery workers exist to perform an epidemiological survey of reproductive performance compared to nickel exposure. In order to accomplish this task the researchers constructed a birth registry for all births occurring in the region during the period of the study. They also reconstructed an exposure matrix for the workers at the refineries so as to be able to link specific pregnancy outcomes with occupational exposures. The study culminated in a series of manuscripts by A. Vaktskjold et al. describing the results of the investigation. The study demonstrated nickel exposure was not correlated with adverse pregnancy outcome for 1) male newborns with genital malformations, 2) spontaneous abortions, 3) small-for-gestationalage newborns, or 4) musculosketal effects in newborns of female refinery workers exposed to nickel. These manuscripts showed no correlation between nickel exposure and observed reproductive impairment.
These are important results as spontaneous abortion in humans would most closely approximate the observation of perinatal lethality associated with nickel exposure in rodents. Further evidence that nickel exposure is not adversely affecting the reproduction of these women is provided by the lack of a “small-for-gestational- age” finding and also the lack of an association of male genital malformations with nickel exposure. Both of these findings are considered “sentinel” effects (i.e., sensitive endpoints) for reproductive toxicity in humans.
The work by Vaktskjold et al. (2006, 2007, 2008a, 2008b) is important in demonstrating that any risk of reproductive impairment from nickel exposure is exceedingly small. However, it should be noted that it is not possible to find women whose occupational nickel exposure persisted throughout their pregnancies until birth.
Generally, fetal protection policies require removal of pregnant women from jobs with exposures to possible reproductive toxicants. Therefore, it cannot be concluded that occupational exposure to nickel compounds during pregnancy presents no risk, only a risk that is exceedingly small.
With respect to animal studies, a variety of developmental, reproductive, and teratogenic effects have been reported in animals exposed mainly to soluble nickel via oral and parenteral administration (Haber et al., 2000b). However, factors such as high doses, relevance of routes of exposure, avoidance of food and water, lack of statistical significance, and parental mortality have confounded the interpretation of many of the results (Nieboer, 1997; Haber et al., 2000b). In the most recent and reliable reproductive study conducted to date, rats were exposed to various concentrations of nickel sulfate hexahydrate by gavage. In the 1-generation range finding study, evaluation of post-implantation/perinatal lethality among the offspring of the treated parental rats (i.e., number of pups conceived minus the number of live pups at birth) showed statistically significant increases at the 6.6 mg Ni/kg/day exposure level and questionable increases at the 2.2 and 4.4 mg Ni/kg/day levels. The definitive 2-generation study demonstrated that these effects were not evident at concentrations up to 1.1 mg Ni/kg/day soluble nickel and were equivocally increased at 2.2 mg Ni/kg/day soluble nickel. No nickel effects on fertility, sperm quality, estrous cycle and sexual maturation were found in these studies (NiPERA, 2000).
Allergic contact dermatitis is the most prevalent effect of nickel in the general population. Epidemiological investigation showed that 20% of young (15-34 years) Danish women and 10% of older (35-69 years) women were nickel-sensi- tized, compared with only 2-4% of Danish men (15-69 years) (Nielsen and Menné, 1992). The prevalence of nickel allergy was found o be 7-10% in previously published reports (Menné et al., 1989). EDTA reduced the number and severity of patch test reactions to nickel sulfate in nickel- sensitive subjects (Allenby and Goodwin, 1983).
Systemically induced flares of dermatitis have been reported after oral challenge of nickel-sensitive women with 0.5-5.6 mg of nickel as nickel sulfate administered in a lactose capsule (Veien, 1987). At the highest nickel dose (5.6 mg), there was a positive reaction in a majority of the subjects; at 0.5 mg, only a few persons responded with flares. Responses to oral doses of 0.4 or 2.5 mg of nickel did not exceed responses in subjects given placebos in double-blind studies (Jordan and King, 1979; Gawkrodger et al., 1986).
There are several reports on the effects of diets low or high in nickel, but it is still a matter of discussion whether naturally occurring nickel in food may worsen or maintain the hand eczema of nickel-sensitive patients, mainly because results from dietary depletion studies have been inconclusive (Veien and Menné, 1990). In a single- blind study, 12 nickel-sensitive women 74ere challenged with a supplementary high-nickel diet (Nielsen et al., 1990). The authors concluded that hand eczema was aggravated during the period (i.e., days 0-11) and that the symptoms thus were nickel-induced. However, it should be noted that in some subjects the severity of the eczema (i.e., the number of vesicles in the palm of the hand) varied markedly between day 14 or 21 before the challenge period and the start of the challenge period.
Oral hyposensitization to nickel was reported after six weekly doses of 5 mg of nickel in a capsule (Sjövall et al., 1987) and 0.1 ng of nickel sulfate daily for 3 years (Panzani et al., 1995). Cutaneous lesions were improved in eight patients with contact allergy to nickel after oral exposure to 5 mg of nickel weekly for 8 weeks (Bagot et al., 1995). Nickel in water (as nickel sulfate) was given to 25 nickel-sensitive women in daily doses of 0.01-0.04 mg/kg of body weight per day for 3 months after they had been challenged once with 2.24 mg of nickel (Santucci et al., 1988). In 18 women, flares occurred after the challenge dose, whereas only 3 out of 17 subjects had symptoms during the prolonged exposure period. Later, Santucci and coworkers (1994) gave increasing oral doses of nickel in water (0.01-0.03 mg of nickel per kg of body weight per day) to eight nickel-sensitive women for up to 178 days. A significant improvement in hand eczema was observed in all subjects after 1 month.
The Lowest Observed Adverse Effects Level (LOAEL) established after oral provocation of patients with empty stomachs was reported as 12 µg/kg of body weight (Nielsen et al., 1999). However, this study sought to evaluate exacerbation of hand eczema which positions these results as occurring in probably the most sensitive human population possible. This figure was similar to the dose found in a study by Hindsén et al. (2001), where a total dose of 1 mg (17 µg/kg of body weight) was reported to result in a flare-up of dermatitis in an earlier patch test site in two of ten nickel-sensitive patients. The dose of 12 µg/kg of body weight was considered to be the acute LOAEL in fasting patients on a 48-hour diet with reduced nickel content. A cumulative LOAEL could be lower, but a LOAEL in non-fasting patients is probably higher because of reduced absorption of nickel ions when mixed in food.
With respect to oral provocations of nickel dermatitis, it should be noted that nickel dermatitis via oral exposures only occurs in individuals already sensitized to nickel via dermal contact. The literature is not definitive with respect to the nickel concentration required to elicit a dermatitic response. However, collectively, studies suggest that only a minor number of nickel sensitive patients react to oral doses below 1.25 mg of nickel (~20 µg Ni/kg) (Menné and Maibach, 1987; Haber et al., 2000b). These doses are in addition to the normal dietary nickel intake (~160 µg Ni/day).
Conversely, oral exposure to nickel in non-nickelsensitized individuals has been shown to provide tolerance to future dermal nickel sensitization. Observations first made in animal experiments (Vreeburg et al., 1984) and correlations obtained from studies of human cohorts (van der Burg et al., 1986) led to the hypothesis that nickel hypersensitivity reactions may be prevented by prior oral exposure to nickel if long-term, low-level antigenic contact occurs in the non-sensitized organism. Studies that followed van der Burg’s initial observation of induced nickel tolerance in humans have repeatedly confirmed the occurrence of this phenomenon both in humans (Kerosuo et al., 1996; Todd and Burrows, 1989; van Hoogstraten et al., 1991a; van Hoogstraten et al., 1989; van Hoogstraten et al., 1991b) and animals (van Hoogstraten et al., 1992; van Hoogstraten et al., 1993). Suppression of dermal nickel allergic reactions can also be achieved in sensitized individuals (Sjövall et al., 1987).