Chemical speciation of workplace nickel exposures is critical because nickel-containing substances often differ in toxicological properties. Exposure matrices based on leaching methods have been used to ascertain which chemical forms of nickel are primarily associated with adverse respiratory effects after inhalation. Misjudgments in the relative proportion of each of the main fractions of nickel in workplace exposures could translate into possible misattributions of risk to the various forms of nickel. This preliminary study looked at the efficiency of the first step of the Zatka leaching method for accurately assessing the ‘water-soluble’ fraction of several substances present in nickel production operations, compared to leaching in synthetic lung fluid. The present results demonstrate that for nickel sulfate or chloride, the current Zatka solution is adequate to assess the ‘water-soluble’ fraction. However, when sparingly water-soluble compounds like nickel carbonates or water-insoluble substances like nickel subsulfide and fine metallic nickel powders are present, the first step of the Zatka method can greatly over estimate the amount of nickel that could be released in pure water. In contrast, the releases of nickel from nickel carbonate, nickel subsulfide, and nickel metal powders in pure water are consistent with their releases in synthetic lung fluid, indicating that deionized water is a better leaching solution to estimate the biologically relevant ‘water-soluble’ nickel fraction of workplace exposures. Exposure matrices relying mostly on the Zatka speciation method to estimate the main forms of nickel need to be re-evaluated to account for any possible misattributions of risk.