The conclusions of the inhalation studies recently published by US National Toxicology Program (NTP 1996b, c and a) were: Nickel subsulfide; clear evidence of carcinogenic activity in male an female rats, nickel oxide;
some evidence of carcinogenic activity in male an female rats, and nickel sulfate hexahydrate; no evidence of carcinogenic activity in male an female rats.
The present document will address the lack of alveolar/bronchiolar neoplasms in the rats exposed to nickel sulfate hexahydrate and discuss whether this compound would have been expected to induce tumours if the tumour inducing potency of the sulfate were the same as that of the subsulfide or oxide. The document is based on NTP (1996b), NTP (1996c), NTP (1996a) and Dunnick et al. (1995).
Exposure levels of the nickel compounds
Table 7.5.1 shows the exposure levels of the nickel compounds used in the 2-year carcinogenicity studies. The nickel concentration at the highest level of nickel sulfate hexahydrate corresponds to the low dose with nickel subsulfide. The nickel concentration at the next higher dose of nickel subsulfide (which was the highest dose used) is nearly 7 times higher than the nickel concentration at the highest dose of nickel sulfate hexahydrate. The nickel level at the lowest exposure concentration of nickel oxide was almost 5 times higher than the nickel concentration at the highest exposure level of nickel sulfate hexahydrate.
Table 7.5.1 Exposure levels of nickel compounds or nickel in 2-year rat studies and mean bodyweight of the exposed male and female rats in per cent of that found in the control groups
Dose Nickel sulfate
hexahydrate (22.3% nickel)
(mg/m3)
Nickel subsulfide (73.3% nickel)
(mg/m3)
Nickel oxide (76.6% nickel)
(mg/m3) Low dose Compound
Nickel Mean body weight (per cent of controls) (males, females)
0.125 0.03 99, 97
0.15 0.11 98, 96
0.62 0.5 100, 96 Medium dose Compound
Nickel Mean body weight (per cent of controls) (males, females)
0.25 0.06 101, 97
1 0.73 85, 78
1.25 1.0 95, 92 High dose Compound
Nickel Mean body weight (per cent of controls) (males, females)
0.5 0.11 98, 94
-
- 2.5
2.0 93, 90
Survival of rats exposed to nickel sulfate, nickel subsulfide, and nickel oxide were in general similar to those of the controls. The final mean body weights of the exposed rats relative to the controls are included in the table 1.
The relative mean bodyweights at the highest doses used for the rats exposed to nickel sulfate were 98% and 94% for the males and females, respectively, for nickel subsulfide the mean bodyweight was 85% and 78% for males and females, respectively, and for nickel oxide the mean bodyweights were 93% and 90% for males and females, respectively, compared to the untreated controls.
Increase in lung weights
Lung weights in exposed animals were greater than controls, and this was considered to be related to inflammatory lung reactions that occurred in response to nickel exposure. Table 7.5.2 shows the increase in lung weights after 7-months. The results at 7-months were used since the exposure increase in lung weights were greater during the first 7 months than during the subsequent 8 months. The average of the absolute lung weights in the male and female controls, respectively, were used in the calculation of the increase in lung weights. No significant increase (P 0.01) in the lung weights were found among the rats exposed to nickel sulfate. The lung
R312_0807_hh_chapter0124567 weights of the rats exposed to nickel subsulfide were significantly increased in all groups. The lung weights were also significantly increased among the rats exposed to the medium and high dose of nickel oxide. At 15-months the lung weights in the exposure nickel sulfate rats was 33-41% higher than in the controls; the high-exposure lung weight in the nickel subsulfide rats was 300% higher than controls; in the nickel oxide studies the high-exposure lung weight in rats was 86-94% higher than controls.
The finding that the lung weights increased more in the nickel subsulfide and nickel oxide exposed rats than in the nickel sulfate exposed animals correlated with a more severe inflammatory response in the lungs after exposures to the first two substances (Dunnick et al., 1995).
Table 7.5.2. Increase in lung weight after 7-months
INCREASE IN LUNG WEIGHT (g)
DOSE Nickel sulfate
hexahydrate
Nickel subsulfide Nickel oxide
Low dose Male
Female -
- 0.63*
0.52* 0.10
0.08 Medium dose Male
Female -
- 1.73*
1.36* 0.71*
0.42*
High dose Male
Female 0.14
0.22 -
- 0.84*
0.55*
*Significant (P = 0.001) Lung nickel burden
Analysis of the nickel lung burden data showed a considerable accumulation of nickel in the lungs of the nickel oxide exposed animals (Table 7.5.3). Thus, at the same level of nickel exposure, the lung nickel burden in the nickel oxide exposed animals was about 20 times higher than in the nickel subsulfide-treated animals. On the other hand, the lung nickel burden in the nickel subsulfide exposed animals was 6 times higher than that found in the nickel sulfate exposed rats at the same nickel exposure level. The nickel lung burden reflects the half-life of the compounds in the rat lung. Thus, the half-life of nickel oxide is approximately 120 days while nickel subsulfide has a half-life of 5 days and nickel sulfate of 1 - 3 days.
Table 7.5.3. Nickel lung burden after 7-months
NICKEL LUNG BURDEN (μg nickel/g lung)
DOSE Nickel sulfate
Hexahydrate
Nickel subsulfide Nickel oxide
Low dose Male
Female -
- 6
6 175
173 Medium dose Male
Female -
- 9
9 388
477 High dose Male
Female 1
1 -
- 701
713
R312_0807_hh_chapter0124567
Lung tumour induction
Table 7.5.4. Total number of lung adenomas and carcinomas. The number of animals available in each group for evaluation of tumours varied between 52 and 54.
ADENOMA/CARCINOMAS COMBINED
DOSE Nickel sulfate
hexahydrate Nickel subsulfide Nickel oxide Control Male
Female Sum
1A 1 2
1 1 2
1 1 2 Low dose Male
Female Sum
0 0 0
6 6 12
1 1 2 Medium dose Male
Female Sum
1 0 1
11 9 20
6 6 12 High dose Male
Female Sum
3 1 4
-
- 4
5 11
AThe average of the controls in the three groups has been used
There was a significant dose-related increase in adenoma/carcinomas combined both in male and female rats exposed to nickel subsulfide (Table 7.5.4). There was a significant increase in adenoma-/carcinomas combined both in male and female rats exposed to the two highest doses of nickel oxide.
The number of tumours at the two highest doses were similar. There was no significant increase of lung tumours in rats exposed to nickel sulfate hexahydrate. No lung tumours was found in the low dose groups, one carcinoma was found among the males in the medium dose groups, and two adenomas and one carcinoma was found among the males and one adenoma among the females in the high dose groups.
Number of tumours as a function of nickel-exposure, increase in lung weight, and nickel lung burden
Fig. 7.5.1 shows the number of lung adenoma/carcinomas combined in male/female rats combined as a function of the Ni-exposure in rats exposed to nickel sulfate, nickel subsulfide, and nickel oxide. The results clearly demonstrate that nickel subsulfide is significantly more potent in inducing lung tumours than nickel oxide and nickel sulfate. On the other hand, it would not be expected that nickel sulfate should induce lung tumours at the doses tested if it had the same tumour inducing potency as nickel oxide.
R312_0807_hh_chapter0124567
The number of lung tumours as a function of increase in lung weight are shown in Figs 7.5.2 and 7.5.3. Both among the males and females the number of tumours are directly proportional to the increase in lung weight. No increase in lung weight was found among the rats exposed to the low and medium dose of nickel sulfate. The