New views on the hypothesis of respiratory cancer risk from soluble nickel exposure; and reconsideration of this risk's historical sources in nickel refineries

Table 13 Selected neoplastic and non-neoplastic lung effects in 2 year inhalation studies of male and female F344/N rats and B6C3F₁ mice exposed to nickel subsulphide, nickel oxide and nickel sulphate hexahydrate [30–32]; and Wistar rats exposed to nickel metal powder [35]

	F344/N rats		B6C3F ₁ mice
Ni species, dose and lung effects	Male	Female	Male	Female
Nickel subsulphide:
Dose in % of MTD^{a, b}	(0, 15, 100)	(0, 15, 100)	(0, 50, 100)	(0, 50, 100)
Chronic active inflammation rate	(9/53, 53/53, 51/53)	(7/53, 51/53, 51/53)	(1/61, 52/59, 53/58)	(1/58, 46/59, 58/60)
Macrophage hyperplasia rate	(9/53, 48/53, 52/53)	(8/53, 51/53, 52/53)	(6/61, 57/59, 58/58)	(5/58, 57/59, 60/60)
Alveolar/bronchiolar adenoma or carcinoma rate	(0/53, 6/53, 11/53)	(2/53, 6/53, 9/53)^f	None	None
Nickel oxide:
Dose in % of MTD^c	(0, 25, 50, 100)	(0, 25, 50, 100)	(0, 25, 50, 100)	(0, 25, 50, 100)
Chronic inflammation rate	(28/54, 53/53, 53/53, 52/52)	(18/53, 52/53, 53/53, 54/54)	(0/57, 21/67, 34/66, 55/69)	(7/64, 43/66, 53/63, 52/64)
Alveolar/bronchiolar adenoma or carcinoma rate	(1/54, 1/53, 6/53, 4/52)^f	(1/53, 0/53, 6/53, 5/54)	None	(6/64, 15/66, 12/63, 8/64)
Nickel sulphate hexahydrate:
Dose in % of MTD^d	(0, 25, 50, 100)	(0, 25, 50, 100)	(0, 25, 50, 100)	(0, 25, 50, 100)
Chronic active inflammation rate	(14/54, 11/53, 42/53, 46/53)	(14/52, 13/53, 49/53, 52/54)	(1/61, 2/61, 8/62, 29/61)	(1/61, 7/60, 14/60, 40/60)
Macrophage hyperplasia rate	(7/54, 9/53, 35/53, 48/53)	(9/52, 10/53, 32/53, 45/54)	(6/61, 9/61, 35/62, 59/61)	(7/61, 24/60, 53/60, 59/60)
Neoplastic effects	None	None	None	None
	Wistar rats
Nickel metal:
Dose in % of MTD^e	(0, 25, 100)	(0, 25, 100)
Chronic inflammation rate	(14/50, 44/50, 41/50)	(16/50, 45/50, 45/54)
Neoplastic effects	None^g	None^g

^a MTD: Maximum Tolerated Dose. ^b MTD [Ni₃S₂/m³]: 0.73 mg (rats); 1.2 mg (mice). ^c MTD ["green" NiO/m³]: 2.0 mg (rats); 3.9 mg (mice).
^d MTD [NiSO₄.6H₂O/m³]: 0.11 mg (rats); 0.22 mg (mice). ^e MTD [Ni metal/m³]: 0.4 mg (rats). ^f Includes squamous cell carcinoma. ^g Oller et al. (2008) [35] concluded that the treatment of nickel metal powder administered by inhalation 6 h/day, 5 days/week over a two-year period did not produce an exposure-related increase in tumors anywhere in the respiratory tract, including the nose.