Ka. Keller et al., INHALATION TOXICITY STUDY OF A HALOALKENE DEGRADANT OF SEVOFLURANE, COMPOUND A(PIFE), IN SPRAGUE-DAWLEY RATS, Anesthesiology, 83(6), 1995, pp. 1220-1232
Background: Under certain circumstances in the clinical setting, conta
ct of the anesthetic sevoflurane with a CO2 absorbant (e.g., soda lime
, Baralyme) leads to the formation of a degradant designated as pentaf
luoroisopropenyl fluoromethyl ether (PIFE; Compound A). Previous studi
es have shown that the kidney is the primary target organ for toxicity
in the rat. This study was designed to determine the impact of PIFE o
n rat renal histology correlated with functional changes. The findings
are discussed in terms of probable mechanism of action and relevance
to humans. Methods: Male and female Sprague-Dawley rats were exposed t
o 0, 30, 61, 114, or 202 ppm PIFE for a single 3-h period via nose-onl
y inhalation. Rats were observed daily for behavioral changes or exter
nal physical signs of toxicity (i.e., lacrimation, dyspnea, piloerecti
on, etc.) and body weights were recorded at 6, 4, and 1 day preexposur
e and 1, 3, 7, and 13 days postexposure. Animals were evaluated for he
matologic, clinical chemistry and/or urinalysis changes immediately po
stexposure and/or at 1, 4, and 14 days postexposure. Rats were killed,
subjected to a macroscopic postmortem examination, and evaluated for
histopathologic changes in all major tissues and organs at 1, 4, and 1
4 days postexposure. Results: Labored breathing was observed in 3 of t
he 20 and 2 of the 20 rats in the 114 ppm and 202 ppm groups, respecti
vely, during the 3-h exposure period. No significant reductions in bod
y weight gain were noted during the 2-week study period. Clinical chem
istry evaluations revealed Increases in blood urea nitrogen and creati
nine 1 day postexposure in males and females exposed to 202 ppm PIFE.
Changes in urinary glucose, protein and N-acetyl-beta-glucoaminidase/c
reatinine were evident one day postexposure in males and females expos
ed to 202 ppm and in males exposed to 114 ppm PIFE. Most values were w
ithin normal ranges by 4 or 14 days postexposure. No drug-related alte
rations in hematolologic parameters were noted. Evidence of olfactory
epithelial degeneration and desquamation in the nasal turbinates was n
oted at 4 days postexposure in male and female rats exposed to 202 ppm
PIFE. Concentration-dependent renal tubular necrosis and tubular cell
hyperplasia, in the corticomedullary border, were observed In males a
nd females exposed to 114 and 202 ppm PIFE. The severity of tubular ne
crosis in both males and females was considered minimal to slight at t
he 114 ppm exposure concentration and slight to moderate at the 202 pp
m exposure. Both the numbers of affected animals and severity were red
uced over time. The most marked changes in serum and urine chemistry w
ere associated with the animals described as having moderate renal nec
rosis. Male rats appeared more susceptible to nephropathy than female
rats. There were no other PIFE-related histopathologic findings. Concl
usions: The renal histopathologic findings in this study are consisten
t with those reported In previous acute studies hn rats after PIFE adm
inistration. Functional changes in the kidney, as evidenced by serum c
hemistry and urinalyses, were observed at exposure concentrations that
induced morphologic alterations.