Document xj2LdZ4ZeB0zqJxR34Zpvm9Zm

JOURNAL OF APPLIED TOXICOLOGY, VOL. 11(1), 51-60 (1991) CUSTOMER COPY Complies with Cop4ght craw Servo Effects of Short-term Oral Dosing of Polychlorotrifluoroethylene (PolyCI ) on the Rhesus Monkerk( Christopher E. Jones, Michael B. Ballinger, David,11. Mattie --and Nicholas J. DelRaso Toxic Hazards 45433-6573i 4K t1arr Armstrong AcrospLe Medieal Res Labotarecy, a u.-.\Patterson AFB, OH Constanc'e-Seckel=and Allen Vhegai_ .. itSI TN-hoologySecvice-s-Corpotil,Ull, RH-Woodman Dr7Sutre-12, Daytou, 6H , Keywords: polyCTFE; aircraft hydraulic fluid; toxicity; peroxisome proliferation. Polychlorotrifluoroethylene (polyCTFE--primarily oligomers with 3-4 monomer units), a non-flammable hydraulic fluid for aircraft, was given daily for 15 days by oral gavage to four Rhesus monkeys at a concentration of 0.725 g kg- '. The administered dose was at a level that had caused toxicity in rats. Steadyslate blood and liver concentrations reached were the same in both species. In monkeys, polyCTFE did not cause the electrolyte, serum protein, liver enzyme and anemic disturbances previously seen in rats. Liver sections taken at 15 days, analyzed for palmitoyl Co-A beta-oxidation rates or by electron microscopy, showed no significant indication of peroxisotnal proliferation. An increased blood urea nitrogen (BUN) at 15 days was the only clinical pathological abnormality seen in both monkeys and rats. Previously unobserved effects were increased triglycerides and glycogen depletion. INTRODUCTION Chlorotrifluoroethylene (CTFE, CAS no. 79-38-9) is a gaseous fluoroalkene used in the production of fluoropolymers. Polychlorotrifluoroethylene (polyCTFE, CAS no. 9002-83-9) is the base stock for a nonflammable hydraulic fluid for aircraft.' It contains CTFE oligomers blended to a viscosity of 3.1 cSt using primarily three (trimer) and four (tetramer) monomeric units. All future US Air Force hydraulic systems operating at or above 8000 psi must be able to use polyCTFE.2 In rats, the primary toxicity seen as a result of exposure to the vapor of monomer CTFE was nephrotoxicity.3-6 Gad et al.6 did see an increase in liver weights, but there were no other indicators that the liver is a target organ. Rats exhibited increased water intake and decreased urinary osmolalities even when exposed to a single exposure of CTFE, suggesting histopathological changes in the renal tubules. Microscopic examination at necrospy revealed necrosis that was primarily localized in the pars recta of the proximal tubule.'" There was, however, regeneration of the tubule epithelial cells by day 3 and full regeneration within 2 weeks.4 Potter et a1.4 and Buckley et al.5 found a * The animals used in this study were handled in accordance with Athneimprainlsc,ipplreespsatraetdedbyinththeeCGomuidmeitftoere tohne CCaarree aanndd UUssee ooff LLaabboorraattoorryy Animals of the Institute of Research Council, DHHS, Laboratory Animal Resources, National National Institute of Health Publication 8p6o-r2ti3o,n19o8f5t,haisndstuthdey AwnaismcaolnWduecltfeadre uAncdterofD1o9D66,coanstraamctennduemd.beAr F33615-85-C-0532. t Author to whom correspondence should be addressed. 0260-437X/91/010051-10$05.00 1991 by John Wiley & Sons, Ltd. dose-related increase in urinary lactate dehydrogenase (LDH), blood urea nitrogen (BUN) and serum creatinMe at all inhalation exposure levels above 100 ppm, suggesting that the plasma clearance ability is affected. All these parameters returned to normal rapidly, even in animals receiving multiple exposures. Inorganic fluoride, a probable metabolite of CTFE and a known renal toxin, was measured both as an indicator of metabolism and of toxic effect. There was a dose-related increase in inorganic fluoride in blood and urine, but again levels returned to baseline, although more slowly in repeated exposure experiments than in single exposure experiments.45 Clayton' conducted repeated exposure experiments that suggest a species-specific toxicity. In guinea pigs exposed to 300 ppm for 6 h per day, 5 days per week, less than 18 exposures produced death. In a study using dogs involving stepped exposures from 15 to 150 ppm, exposures of 50 ppm resulted in hematological changes, such as leukopenia, erythrocytosis, granulocytopenia and elevated plasma cholesterol. When the exposures were increased to 150 ppm, neurological disturbances were observed in the dog. Rabbits exposed to 250 ppm for 6 h per day for up to 110 days showed hypochronic anemia, a reduction of hemoglobin concentrations, a reduction in red blood cell count and leukopenia. Sex might also be a factor in the toxicity of CTFE. A dose--response effect was evident in both sexes, with males being more sensitive.6 A dose--response effect was most noticeable in causing an increase in both the absolute and relative liver weights in males. Although females were affected, males had a dose--response effect, significant differences in weight gain, urine creatinine and urine fluoride, and histopathological changes. Received 24 May 1990 Accepted (revised) 2 October 1990