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ARU6-0OO6 g ) FUNDAMENTAL AND AFFUED TOXICOLOGY 4. 972-976 (1984) Cholestyramine-Enhanced Fecal Elimination of C arbon-14 in Rats after Administration of Ammonium [14C]Perfluorooctanoate or Potassium [14C]Perfluorooctanesulfonate Ja m es D . J o h n so n ,1 Sh eila J. G ibson, a n d R o b e r t E. O ber H iker Laboratories. Inc.. 3M Center. Building 270-3S-05. St. Paul. M innesota 55144 Cholestyramine-Enhanced Fecal Elimination of Caibon-I4 in Rats after Administration of Ammonium [l4C]Perftuoroocunoate or Potassium (l4C]Perfluorooctanesulfonate. Johnson, J. D - Gibson, S. J-. and Ober, R. E. (1984). Fundam. AppL Toxicol. 4, 972-976. After a smile intravenous dose of ammonium (" Qperfiuoroocunoate Q'*C]PFO, 13.3 mtOcg) or of potassium ["Qperfluorooctanesulfonate (['*C]PFOS, 3.4 mg/kg) to rats, cholestyramine fed daily as a 4% mixture in feed was shown to increase the total carbon-14 eliminated via feces and to decrease liver concentration of carbon-14. Rats were fed cholestyramine in feed for 14 days after administration of [l4C]PFO and for 21 days after administration of [,4C]PFOS. Control rats were administered radiolabeled fluorochemical but were not treated with choles tyramine. Cholestyramine treatment increased mean cumulative carbon-14 elimination in feces by 9.8-fold for rats administered [>4C]PF0 and by 9.5-fold for rats administered ["CJPFOS. After (" CJPFO, a mean of 4% of the dose of carbon-14 was in liver of cholestyramine-treated rats at 14 days versus 7.6% in control rats; after [l4C]PFOS, 11.3% of the dose was in Ever at 21 days versus 40.3% in control rats. After administration of other radiolabeled compound, ( i plasma and red blood cell carbon-14 concentrations, which were relatively lower *" liver I concentrations, were also significantly reduced by cholestyramine treatment e in* Soday of 1 1 Toeotoo* The anion o f perfluorooctanoic add has been found in the serum o f manufacturing plant workers (U bel et ai.. 1980). Toxirity studies in anim als have been reported (Griffith and Long, 1980). In view o f the slow elim ination and the presence o f the compound in plant workers' serum , a means o f enhandng elim ination was sought In addition, since both am monium perfluorooctanoate and potas sium perfluorooctanesulfonate are com m er cial products and intermediates o f products, the possibility o f affecting the elim ination o f perfluorooctanesulfonate was also o f interest. Cholestyram ine, an agent approved for use in humans to lower cholesterol blood levels, is an anion exchange resin which has been used to prom ote fecal excretion o f the pesti cide chlordecone (Kepone) in rats (Cohn et 1To whom all correspondence should be addressed. a i. 1978). Since both perfluorooctanoic ad d and perfluorooctanesulfonic add are prepared as salts and exist as anions at physiologic pH, they would be expected to com plex with cholestyramine in vivo. Although Pastoor el ai. (1983) investigated cholestyramine in mice and rats and found no enhanced elim ination o f carbon-14 with a single 1000-mg/kg c . se o f cholestyramine given at 24 hr after a 10mg/kg oral dose o f am m onium [l4C]perfluorooctanoate, the usual application o f cholestyramine adm inistered to enhance elim ination o f xenobiotics is with repeated doses. In the study reported here, we inves tigated the effect o f cholestyram ine adminis tered in feed for several days on the rate of fecal elim ination o f carbon-14 after either a subtoxic intravenous dose o f am m oc ra ( l4C]perfluorooctanoate ([l4C]PFO) or pouissium (u C)perfluorooctanesulfonate ([14C]PFOS). 0272-0590/84 S3.00 UM kr UmSocmi; wtTwwHc Al Italia of naraawiioii in n, tan* nMMO 972 Not-r.e- Thi* matenol may be proteetec by f.or-v..-!it law (Tille 17 u S Cocci. 0000 +c 4 mat. diet were S is at prep the I |r c ] m ine . weigh An ~3o-: *taboli J 7 4 hr had b -dostni j*as sint "liters i | Tea r. -from 3 (fiw ai x Purina 3,-ndiom /.doses > j average follows kg and amine tr Sam; fleeted a: ?days aft ' i ,4q P F anesthet ^drawing red btoo- Liver wa t until an: Samp. }plasma \ ^Sver wer j**ter to jthe horn' -combust; Joxidixer.' 'concentr . Counting *an auton calibrate! 974 JOHNSON. GIBSON. AND OBER t FlC. 1. Cumulative excretion of total carbon-14 in feces after a single intravenous dose of potassium [" Qperfluorooctancsulfonate fl,4CJPFOS). Mean dose o f (,4C]PFOS: cholestyramine treated, 3.4 mg/kg (O): control 3.5 mg/kg (). Total cumulative percentage excreted in feces: cholestyramine treated, 7S.8 A 5.0, control, 8.0 A 0.8. Fro. [ " Qp< contro contro': ) tigation o seats 4 and 8% o f the dose for cholestyramine- D ISC U S SIO N ther comp treated and control..rats, respectively. The laboratory mean carbon-14 concentration o f plasma and The carbon-14 present in rat liver after '.ch rom atog red blood cells with cholestyramine treatment administration o f (,4qPFO S or [14C]PFO is feces and is significantly less than the mean concentra probably in the form o f anions. (The pK* of ability o f px tion in controls. these compounds is < 1 .0 .) Thorough inves- .o f the lite pound is 1 TABLE 1 itration o f Effect of Cholestyramine Treatment on Concentration of Carbon-14 in Ra t Ltver, Plasma, and Ren Blood Cells after a Single Intravenous Dose of Potassium [" CJPerfluorooctanesulfonate* (I^qPFOS) or Ammonium [,4C}-Perfluorooctanoate* fl,4C]PFO) :2 to 3 wee fact that ci .fecal elim i: Carbon-14 concentration' fold sugges Treatment group Liver Plasma Red blood cells rterohepatic j [ ' 4q P F O . [,4qP FO S Cholestyramine-treated (21 days) Controls 9.4 1.6` 35.6 5.6 0.9 A 0.1 ` 6.9 A 0.6 0.3 * 0 .1 ` 1.8 0.4 exchange r r ienhanced i [,4q P F O 1 [,4q P F 0 Cholestyramine-treated (14 days) Controls 12.1 A 2.1* 22.3 A 6.2 5.1 A \ J * 14.7 6.8 1.8 A 0.7* 4.2 A 2.4 feed m ost : "7 :the prorflur . the lum en * Each rat received 1.13 mg l'*QPFOS; mean dose: cholestyramine-treated rats, 3.4 mg/kg; control rats. 3.5 mg/kg. -H ` Each rat received 4.2 mg ['*]PFO, mean dose: cholestyramine-treated rats. 13.3 mg/kg; control rats 5 - .have found f& olestyrar mg/kg. * 'arc very di *Concentration is expressed as ng eq of radiolabeled compound/g of tissue or ml of fluid. ` Significantly different from control values (p < 0.05). 72 .chloric aci. tures o f r 000075 976 JOHNSON. GIBSON. AND OBER "FUNDAME? remaining in the liver. This difference is most likely due to small additive losses in collection o f the m any urine and feces samples as well as the sm all but cum ulative error in not correcting for com bustion recovery in the many sam ples (>95% ). Since the experimen tal conditions for cholestyramine-treated and control rats were identical with respect to the dosing, sam ple collection, and analyses, the less than 100% recovery o f carbon-14 (urine, feces, and liver) was judged to not affect the results or conclusion. Overall, the data support possible utility o f cholestyram ine in promoting the excretion o f perfiuorooctanoate and perfiuorooctanesulfonate in hum ans. ACKNOWLEDGMENTS The author* gratefully acknowledge the synthesis of ammonium (l4C)pexfiuorooctanoaie and potassium [,4CJperfiuorooctaaesulfonate by F. E. Befar or Commercial Chemicals Division. 3M, and the typing of this manuscript by K. F. Gibson and J. E. Wain of Riker Laboratories. REFERENCES Boylan, J. J,, Egle, J. I_ and Guzeuan, P. S. (1978). Cholestyramine: Use as a new therapeutic approach for chlordecone (Kepone*) poisoning. Science (Washupon. D.CJ 199, 893-895. Cohn, w . j , Boylan, J. J,, Lanke, R. v ,, Fawss. M. W,, Howell, J. R-, and Guzeuan, P. S. (1978). Treatment of chlordecone (Kepone*) toxicity with cholestyramine. N. ErtgL J. Med. 298, 243-278. Griffith, F. D,, and Long, J. E. (1980). Animal toxicity studies with ammonium perfiuorooctan -e. J. Amer. Ind. Hyg. Assoc 41, 576-583. Pastoor, T. P , Kjnzler, K. w ,, and Kennedy, G. L. Jr. (1983). The effect of cholestyramine on elimination of ammonium perfiuorooctanoate from the blood of rats and mice. Toxicologist 3,82. Ubel, F. a^ Sorenson, S. D,, and Roach, D. e. (1980). Health status of plant workers exposed to fluorochemicals--A preliminary report. /. Amer. Ind. Hyg. Assoc 41, $84-589. * V ir s * Depart. K El es ) SIT hi 3E * 3 F ass ' r avt 8 pv. *V * to t tho. coir etre in tl w ach & Vitamin a Kids) have mopreventiv tfects in th< ten sive lite 1 and ph2 ginoids m c perim ents, tfbrts to det I retinoids !tod different [ tossful (see L z Mention of tocific equipm. *?n*nty by thr i it imply ap: w* may be suit * To whom al 000076