The authors examined the acute and subacute toxicity of the low-osmolality nonionic radiographic contrast agent, ioversol. The median lethal dose (LD50) of ioversol administered intravenously to mice, rats, rabbits, and dogs was more than 12 g I/kg, which exceeds the maximal anticipated clinical dose by at least tenfold. When the acute intravenous toxicity of 35% I, wt/vol, ioversol was compared with 35% I, wt/vol, iohexol and 37% I, wt/vol, iopamidol in mice, no significant differences in LD50 values or general toxicity were found. Ioversol also was administered via intrathecal routes to rats, dogs, and monkeys. In a comparative study, acute intracisternal injections of 35% I, wt/vol, ioversol in rats demonstrated far less toxicity than 35% I, wt/vol, iohexol and 37% I, wt/vol, iopamidol, a result that may be due to the increased hydrophilic tendency of ioversol relative to iohexol and iopamidol. Acute intracisternal injections of 43% I, wt/vol, ioversol, 35% I, wt/vol, iohexol, and 37% I, wt/vol, iopamidol into dogs at 160 or 240 mg I/kg, demonstrated comparable, but only minimal, toxicity. Monkeys given lumbar intrathecal injections of ioversol tolerated 60 mg I/kg well with no resulting arachnoiditis. Subacute toxicity studies involving 4-week daily intravenous injections (0.2, 0.8, and 3.2 g I/kg/day) in rats and dogs showed ioversol to be well tolerated. The signs of toxicity included a reversible renal cytoplasmic tubular vacuolation in the rat at high doses and a reversible hepatocyte vacuolation in the dog at the same high dose. However, clinical chemistry tests showed no signs of renal or hepatic dysfunction, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)