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occupational nickel exposure in humans, were determined to be the most appropriate for use in
developing a quantitative cancer risk assessment
Methodology
In the Ottolenghi et al. study, the low survival rate of the nickel subsulfide exposed group was
examined. Mortality was about the same during the first year of study between the control and the
nickel-exposed group but in the 76 th week when the first tumor was observed, the exposed group had
a 6% higher mortality rate (23% vs. 17% for controls). Taking this into account, the subsequent
mortality [(0.94 (exposed group mortality) – 0.23) × 208 (animals examined) = 148 animals] in the
nickel-exposed group due to tumors was 29/148 or approximately 20%. Based on these assumptions,
nearly all of the differences (0.32 – 0.06 = 0.26) in the survival between control animals (32%) and the
treated animals (6%) can be explained by lung tumor mortality. The animal data was adjusted for
continuous lifetime exposure [(979 µg/m 3 )(6/24 hr)(5/7 day)(78/110) = 122.8 µg/m 3 ]. This was used to
calculate the human equivalent exposure level using an inspiration rate of 20 m 3 /day and a 70 kg body
weight. The CDHS staff (CDHS, 1991) used a multistage model (GLOBAL86), fitted to adjusted data
from this inhalation bioassay to yield a maximum likelihood estimate of carcinogenic potency of 2 × 10 -4
(µg/m 3 ) -1 ) nickel subsulfide (or 28 × 10 -4 (µg Ni/m 3 ) -1 ). The upper 95% confidence limit of the estimated
carcinogenic potency is 28 × 10 -4 (µg/m 3 ) -1 nickel subsulfide [or 38 × 10 -4 (µg Ni/m 3 ) -1 ].
The risk quantification was also conducted using epidemiological data from worker studies. The
Ontario cohort study (Chovil et al., 1981; Roberts et al., 1984; Muir et al., 1985; ICNCM, 1990)
was determined to be the most appropriate for quantitative cancer risk assessment due primarily to the
fact that it was the only cohort study with exposure measurements available for a sufficiently early time
period. The West Virginia cohort (Enterline and Marsh 1982; ICNCM, 1990) was rejected for use in
the quantitative risk assessment due to the imprecision associated with the low SMR reported, which
could have been due to confounding factors. The Norwegian cohort (Magnus et al., 1982; Pedersen et
al., 1973) was deemed unsuitable for risk assessment due to the absence of nickel exposure data from
the refinery. The Welsh cohort (Doll et al., 1977; Peto et al., 1984; Breslow and Day, 1987; Kaldor
et al., 1986; ICNCM, 1990) was also not used in the quantitative risk assessment because exposure
measurements were not available for a relevant time period.
A relative risk model was chosen as the most appropriate method for linear extrapolation to low dose
lifetime exposure. The excess risk from nickel exposure among smokers was assumed to be the same
as among non-smokers. SMR values were plotted against cumulative exposure, and the slope of the
linear regression of the data was 9.22. The 95% confidence limit of the slope was 11.26. This upper
limit was corrected to 11.85 for the fraction of the study group lost to follow-up. The exposure was
adjusted for an equivalent lifetime exposure [(8 hr/24 hr) × (5 days/7 days) × (48 weeks/52 weeks)].
The excess relative risk estimate for lifetime exposure at 1 mg/m 3 was 5.04. Considering the
background lifetime mortality risk of 0.051 for Ontario at the time of the cohort study follow-up, the
upper bound for lifetime added risk for exposure to 1 mg/m 3 was 2.57 × 10 -1 (or 2.57 × 10 -4 (µg/m 3 ) -1 ).
The average of the unit risk is 2.1 × 10 -4 (µg/m 3 ) -1 (257 × 9.22/11.26) using the actual SMR rather the
upper confidence limit. Therefore, based on the human studies the range of unit risk is approximately
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