These studies were undertaken to derive a lowest-observed-adverse-effect level (LOAEL) in the New Zealand White rabbit following a 91-day exposure to uranium (U, as uranyl nitrate hexahydrate, UN) in drinking water. Males were exposed for 91 days to UN in their drinking water (0.96, 4.8, 24, 120, or 600 mg UN/L). Subsequently, females were similarly exposed for 91 days (4.8, 24, or 600 mg UN/L). Control groups were given tap water (< 0.001 mg U/L). Regular observations were recorded, and urine was collected periodically. Four males showed evidence of Pasteurella multocida infection and were excluded from the study. Following the study, all animals were euthanized, and multiple hematological and biochemical parameters were determined. Necropsies were conducted, and histopathological examination was performed. The hematological and biochemical parameters were not affected in a significant exposure-related manner. Dose-dependent differences consisted of histopathological changes limited primarily to kidney. Changes in renal tubules were characteristic of uranium toxicity. Based on changes in the tubular nuclei, the 91-day LOAEL for males in this study is 0.96 mg UN/L drinking water. The females drank 65% more water than the males, yet appeared to be less affected by the exposure regimen, although they also developed significant tubular nuclear changes in their lowest exposure group, deriving a LOAEL of 4.8 mg UN/L. Tissue uranium residue studies suggested that pharmacokinetic parameters for the males and females differ, possibly accounting for the difference in observed sensitivity to UN. An adverse effect of P. multocida infection cannot be excluded.

This study was undertaken to examine the reversibility of renal injury in the male New Zealand White rabbit subsequent to a 91-day exposure to uranyl nitrate (UN) in drinking water, followed by various recovery periods. Specific pathogen-free (SPF) animals were exposed for 91 days to UN in their drinking water (24 or 600 mg UN/L). Control groups were given municipal tap water (< 0.001 mg U/L). Regular clinical observations were recorded, and urine was collected periodically. Recovery periods between the last UN exposure and termination were 0, 8, 14, 45, or 91 days. Following the study, all animals were anesthetized and terminated by exsanguination, and multiple hematological and biochemical parameters were determined. Necropsies were conducted, and histopathological examination was performed. Exposure-related histopathological changes were observed only at much higher doses than in our previous male rabbit study where non-SPF-free animals had been used. Minor increases in kidney to body weight ratios were observed in the high-dose groups following exposure and early recovery. Renal tubular injury with degenerative nuclear changes, cytoplasmic vacuolation, and tubular dilation was seen in the high-dose group, without consistent resolution even after 91 days recovery. Animals ingested approximately 33% more uranium per day in this study than did males in a comparable dose group in the previous study, yet their kidney tissue uranium residues were 30% lower. These results suggest that SPF rabbits are less sensitive to uranyl injury than the non-SPF animals. The lowest-observed-adverse-effect level is estimated to lie at or below 24 mg UN/L.