Scientific basis for an air quality standard for nickel

Report no. 99/53: The health effects due to nickel exposure are reviewed in this document for the purposes of understanding the scientific basis for an Air Quality Standard (AQS). The report provides an overview of two approaches for deriving a nickel AQS by presenting both a threshold/safety factor and a linear non-threshold approach. Using a threshold/safety factor approach with a lowest observed-adverse-effect-level (LOAEL) of 1000 mg Ni/m3 for soluble nickel compounds based on the occupational epidemiology data, exposure limits of 0.6 mg Ni/m3 for soluble nickel compounds and6 mg Ni/m3 for less soluble compounds (e.g., oxidic and sulfidic compounds), as an annual average, are justified on scientific grounds. Use of a single value of 0.6 mgNi/m3 (annual average) is recommended since it would be protective for both solubleand less soluble nickel compounds.

By contrast, exposure limits derived using the animal and human data and a linear non-threshold approach are approximately an order of magnitude lower and range from 0.01-0.03 mg Ni/m3 (annual average) for both soluble and insoluble compounds. In general, nickel compounds are not acutely toxic. However, nickel is a proven sensitizer; therefore nickel compounds should be regarded as potential sensitizers. The primary hazard associated with exposure to certain nickel compounds is the ability to adversely affect the respiratory system and to produce respiratory cancers.

This effect is consistent between animals and humans. Oral exposures do not appear to result in the biological activities exhibited by the inhalation route. Because inhalation is the most pertinent exposure route for an AQS and inhalation is the most toxic route for nickel compounds, inhalation-related health effects (excluding nickelcarbonyl) and the bio availability of the relevant forms of these compounds to relevant target tissues are considered most appropriate. In particular, the critical effect associated with nickel exposure, for the purposes of setting an ambient air standard,is respiratory cancer. The choice of human versus animal data sets for deriving a nickel AQS does not strongly influence the final recommended value. However, the choice of extrapolation method (i.e., a threshold/safety factor versus linear non-threshold approach) has an impact on the recommended AQS value.

A common weakness of both approaches is that the characteristics of nickel exposures in animal and human studies are qualitatively different from exposures present in ambient air. Specifically, the strongest respiratory cancer associations identified in the human and animal studies are with sulfidic and oxidic nickel; sulfidic nickel is not likely to be detected in ambient air while nickel oxide may be present up to a maximum of 8%. Overall, the weight of the evidence strongly supports the use of a threshold/safety factor approach for deriving a scientifically justified and defensible AQS for nickel. Factors that support the use of the threshold/safety factor approach include the following:

• the existence of a NOAEL for pulmonary inflammation of 130 mg Ni/m3 (nickel dust) derived from inhalation studies,
• the lack of carcinogenic response in the absence of pulmonary inflammation,
• the presence of good evidence for an empirical threshold for lung and nasal cancer in epidemiology studies of occupationally exposed groups,
• the presence of a NOAEL for pulmonary carcino genesis of approximately 100 mgNi/m3 observed in recent rodent studies conducted with three nickel compounds administered by inhalation, the relevant route of exposure,
• no evidence of genotoxicity in in vivo studies conducted by the inhalation route of exposure in humans and rodents.

Although the finding of genotoxicity from in vitro studies of nickel compounds may support the use of a default linear non-threshold approach, the combined weight of the evidence suggests that this would likely produce an unduly conservative AQS value.Accordingly, a value of 0.6 mg Ni/m3 (annual basis) is recommended as an AQS for nickel to protect the general public against carcinogenic and other potential hazardous effects associated with exposure to both soluble and less soluble nickel compounds. This value is derived from the threshold/safety factor approach.