Results from animal and preliminary exposure studies have called into question whether the 5 mg/m38-hour time-weighted average threshold limit value (TLV) for zinc oxide fume is sufficient to protect workers against metal fume fever. The objectives of this study were to determine the clinical effects of exposures to low concentrations of zinc oxide and to ascertain whether these exposures elevated circulating levels of specific cytokines, which could account for the symptoms of the metal fume fever syndrome.Thirteen resting naive subjects inhaled, on separate days, air and 2.5 and 5 mg/m3of furnace-generated zinc oxide fume for 2 hours. Subjects recorded symptoms and temperature and had blood drawn before and after each exposure. The mean (± SE) maximum rise in oral temperature at 6 to 12 hours after exposure was 1.4 ± 0.3°F after 5 mg/m3, compared with 0.6 ± 0.5°F after air exposure (P < 0.05). Mean temperature was also elevated after exposure to 2.5 mg/m3zinc oxide (1.2 ± 0.3°F). In a parallel fashion, plasma levels of interleukin 6 (IL-6), a pyrogen, were significantly elevated after exposure to 5 mg/m3zinc oxide. Mean IL-6 values (pg/mL) at pre-exposure and at 3 and 6 hours post-exposure were 1. 9 (± 0.6), 2.8 (± 0.7), and 2. 9 (± 0.6), respectively, on the air day and 1.6 (± 0.6), 4.4 (± 1.2), and 6.4 (± 1.1) on the 5 mg/m3zinc oxide day. Zinc oxide exposure did not significantly affect plasma levels of tumor necrosis factor. Total symptom scores peaked 9 hours after the 5 mg/m3zinc oxide exposure. Myalgias, cough, and fatigue were the predominant symptoms reported. Inhalation of zinc oxide for 2 hours at the current TLV of 5 mg/m3produces fever and symptoms along with elevation in plasma IL-6 levels.