home edit2 whole TSD November 2002 PDF format - OEHHA

Table 1: Lung cancer risks in four cohort studies (from US EPA, 1986)
Study
Number of
subjects
Lung
cancer
deaths
Lung cancer
SMR
90% confidence
limits(CI)
W. Virginia 1855 8 1.12 0.56, 2.02 8.5
Ontario 495 37 8.71 6.49, 11.45 1.4
Wales 967 145 5.28 4.58 – 6.03 1.2
Norway 2247 82 3.73 3.08, 4.48 1.3
* Note: the (SMR-1) is an estimate of excess relative risk
Ratio of upper
CI of (SMR-1)
to (SMR-1) *
The Ontario cohort study was determined to be the most appropriate for quantitative cancer risk
assessment (CDHS, 1991). The main reason for choosing this cohort was that it was the only cohort
with actual measurements of exposure associated with a relevant causal period with sufficient latency
(available from 1948 on which is the most relevant period for the lung cancer deaths ascertained
between 1963 and 1978).
Animal Studies
At the time that the CDHS (1991) report “Health Risk Assessment for Nickel” was written, inhalation
exposure cancer bioassays had only examined insoluble forms of nickel for their carcinogenic potential.
Likewise, only soluble forms of nickel had been evaluated by oral administration. Evidence of
carcinogenic potential following inhalation exposure has been shown for nickel subsulfide (Ni 3 S 2 ) and
suggested for nickel carbonyl. Inhalation exposure to metallic nickel resulted in very poor survival which
was too short to properly evaluate carcinogenicity. Many rats exposed to metallic nickel by inhalation
developed squamous metaplasia and peribronchial adenomatoses (Hueper and Payne, 1962).
Exposure to metallic nickel by intratracheal instillation produced a significant increase in lung tumor
incidence. Pott et al. (1987) administered nickel powder in a total intratracheal dose of 6 or 9 mg
Ni/animal to female Wistar rats. Following treatment, animals were maintained for up to an additional
2.5 years. The lung tumor incidence in the saline control, 6 mg Ni (0.3 mg Ni × 20), and 9 mg Ni (0.9
mg × 10) treatment groups were 0%, 26% and 25%, respectively. The results from the nickel oxide
(NiO) studies assessing the carcinogenicity of nickel oxide following inhalation exposure are negative in
hamsters (Wehner et al., 1975, 1981) and inconclusive in rats (Takenaka et al., 1985; Glaser et al.,
1986; Horie et al., 1985). These studies were also plagued by very poor survival rates. Intratracheal
instillation of nickel oxide resulted in lung tumor induction. Female Wistar rats received a total dose of 0,
50, or 150 mg Ni/animal. Animals were maintained for an additional 2.5 years. The lung tumor
incidence in the saline control, 50 (5 mg Ni × 10) and 150 mg Ni (15 mg Ni × 10) were 0%, 27% and
32%, respectively (Pott et al., 1987).
Two studies produced positive results in evaluating the pulmonary tumorgenicity of nickel subsulfide,
one utilizing inhalation exposure (Ottolenghi et al., 1974) and the other, intratracheal administration. In
the Ottolenghi et al. study 122 male and 104 female Fischer-344 rats were exposed to 0.97 mg/m 3
nickel subsulfide via inhalation for 78-80 weeks (6 hours/day, 5 days/week). The control group, 120
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