Document km5G4oOZppa0JqK5JRpQGeK30

HEALTH AND SCIENCE COMMITTEE "7 .0 0 1 0 1 - ^ h ^ o o i 1984b). Effect ofCioy function in Fischerlation. Toxicol. Appl. itic hydrocarbons. In ' Toxicology (O. D. Vol. -B. 3rd rev. ed_, neuropathy. Ann. a . ' uaurt-Activity .mitiding Remarks. > to Workshop on the Boston. MA. ones. T. W,, HeatEsoicott, K., and .in ofthe significance nt> to man. In Re- jrbtwi (M. A. MehlThi --t and N. KPnn. Scientific. >. sso Ev *ns. J. B. t.tffasoline intoxi* L17-24. and aptued toxicology 10.563--570 < 1988) Experimental Evaluation of Haloalkanes and Li Gabriel L. Plaa ni'rancineni ie pharmacologic. Faculte dc medecine, Univenite dc Montreal. Montreal. Quebec. Canada H3C 3J7 Received November 6.1987: accepted November 18.1987 Experimental Evaluation ofHaloalkanes and Liver Injury. Plaa, G. L. (1988). Fundam. Appl. Toxicol. 10, 563-570. Potentiation of haloalkane-induced hepatotoxicity by ketones and ketogenic substances is used to illustrate questions that are raised when considering biological inter actions involving toxicants. The following characteristics ate considered: The effect ofthe poten tiator (ketone or ketogenic agent) on the dose-response characteristics of the haloalkane toxi cant; the recovery process of the potentiated tissue injury; dose-response characteristics of the potenbaton (minimally effective dosages); correlation of the potentiation with blood levels of the potentiator (threshold concentrations). The relative specificity ofthe haloalkanes for interac tion are discussed, as well as the potentiation of various fonas of hepatic injury (acute, chronic, neurogenic, and cholestatic). Enhanced bioactivation of the haloalkane toxicant is a major mrrhamsm of action for the potentiator; other posable contributing nMehaatsns, however, require consideration. Mixtures of haloalkanes, leading to enhanced livre injury, can also be potentiated by ketones, o 19t Soocr, ofToucaofy One of the purposes of this symposium is to discuss toxicological questions that are raised when considering biological interactions, iioioallcane-induced liver injury is an area that has benefited from a considerable amount of research interest; in recent yean, a number of studies are particularly helpful, since they specifically deal with interactive properties. The experimental material that will be used for illustrating various points is taken from ongoing work in our laboratory dealing with the potentiation of haloalkanefnduced hepatotoxicity by ketones and ketogenic substances. Our interest in the ketone potentiation phenomenon originated with the discovery that isopropanol potentiation of CCL and CHClj hepatotoxicity (Cornish and Adefuin, 1967; Traiger and Plaa, 1971) is actually me diated by acetone, the major metabolite of ` Presented at the 25th Annual Meeting of the Society ofToxicology, Match 1986, New Orleans, Louisiana. isopropanol (Traiger and Plaa, 1972; 1974). Later studies (Traiger and Bruckner, 1976; Hewitt et al,, 1980a; 1983c) showed that a number ofaliphatic ketones found in the oc cupational setting possess this property as well. The chlorocydic pesticide chloidecone, which contains a carbonyl group, is also a po tent potentiator of CHClj (Hewitt et ai,, 1979) and CO* (Curtis et ai., 1979). Further more, agents that are converted to ketones in vivo (ketogenic substances) or maneuvers leading to metabolic ketosis are also effective potentiators (Hewitt er al.. 1980b). Table 1 summarizes the list of ketone and ketogenic substances that possess these properties. CHARACTERISTICS OF THE POTENTIATION PHENOMENON One of the questions raised concerns the effects of the potentiator on the dose-re sponse characteristics of the toxicant Theo- 563 0272-0590/88 $' TO Owvmpv* >*** xtyafTmimlag). Airetaarnr vbxmmi 564 Gabriel l. plaa tablei Ketones or Ketogenic Substances Known to Potentiate Haloalkane Hepatotoxioty Ketones Keto|enic substances Acetone 2-Butanone(MEK) 2-Pentanone(MPK) 2-Hexanone (MnBK) 2.5-Hexanedione 4-Methyl-2- pentanone(MIBK) 4-Hydroxy-4-methyi- 2-pentanone 2-Heptanone (MaK) Chlordecone Isoprapanol l ,3-Butanediol /i-Hexane 4-Methy<-2-penunol Alloxan (diabetic state) Sueptozotocin (diabetic state) retically the potentiator could modify the dose-response curve three different ways. In Situation I the agent lowers the effective dose ofthe toxicant, but the response itself follows its normal course; the dose-response curve is shifted laterally to the left but remains paral lel to the one derived in nonpotentiated ani mals. Situation II would be where the agent does not modify the minimally effective toxic dose, but the response to the toxicant is exag gerated; the dose-response curve does not shift laterally, but its slope is increased (the curve rotates upward). Situation HI would be a combination of these two phenomena; the dose-response curve shifts laterally, but the dope increases. Decisions regarding the control of potenti ators in the environment depend largely on the effect of the agent on the dose-response relationships of the toxicant In Situation I, the no-effect level established for the toxicant when given alone is no longer applicable when exposure to this agent occurs in the presence ofthe potentiator, new safe-use con ditions need to be established. In Situation II, the no-effect level still applies, but the injury resulting from moderately effective levels is more severe. In Situation m, the no-effect level is no longer applicable, and the injury is more severe; new safe-use conditions need to be established. Our data indicate that the ketones which have been studied lower the threshold toxi cant level of the haloalkane required to pro duce hepatic injury. Thus, Situation I and possibly Situation III appear to best describe the phenomenon. With chlordecone and CHCI3 (Plaa and Hewitt, 1982a), evidence of a lateral shift of the dose-response relation ship was observed. However, the slope of the toxic response might also be increased (Situa tion III). Evidence supporting Situation II (no change in the minimally effective toxicant dosage) has not been observed. The effect of chlordecone on the hepatotoxic ED50 of CHG] is given in Table 2. It is evident that this potentiator markedly lowers the ED50 of CHClj. When enhanced injury results, one is inter ested in determining whether alterations in tissue repair are involved as this process can modify the overall duration as well as the se verity of the injury. With haloalkane hepatotoxicity, repair processes are initiated rapidly and the duration is dependent on the initial severity of the injury (Chaitoonneau et al.. 1985). The design of such experiments re quires that one use equitoxic conditions for such comparisons; the initial injury must comparable in both the potentiated and the nonpotentiated groups so that the recovery TABLE2 Chlordecone on Chloroform Median Effec tive Dosaoej (ED50 Values) for Induction of HEPATOTOXICTTY IN MALE MCE* ALTPientttmeat ED50* OCT- Potency ED50* too` Vehicle ChiordMOM 4} - Z35 (35-50)* (1*4-301) 13 u n (KMT) U^-TJ> (-3) - u (3J-12J) ChlonMwot (30 po) Emm 11 hr bdbn chlo roform rtiAllenpe (ZS-1000 *(/!& pot HipmnuurU] mmmti 24 hrhterchtaofeem. Ew* Ana EmiN Hnritt(l9E2a>. * EDJO (pl/k|) for NtwioR of(EMMALT tcovity, ' Vehicle EDM/chlORtaaM ED* ' EDSO <pi/k|) for drmn <dptaMtOCT activity. *ViiMinpeienihsenpHMMfoeWapRMeaclimiM. L;f|rt which t-hold toxi- to proK-iiion I and Voi describe ^-i'one and t:\idence of rei^tionijp- rhe lti..uairiion II (no if toxicant |*>.f effect of :ED50 of .mdent that Iof ED50 of .sei? ' *errati in loocess can tlrs the se;hepatotfd rapidly i ihe initial 3u et al.. nents reiuons for ust I an,, the trecovery Effectcnojj OF i.i ''"wtchlo*'s' lucutd Cai P*lin ;s HALOALKANES AND uver injury 565 process itself can be evaluated. This means that the response obtained in potentiated ani mals challenged with a small dose ofthe toxi cant is compared to the response obtained in nonpotentiated animals challenged with a larger dose of the toxicant; the severity of the initial injury should be the same (equitoxic), while the dosages of the toxicants differ. Our -ults with acetone, 2-hexanone, 2,5-hexanedione (Charbonneau et al.. 1985), or chlordecone (Charbonneau, 1982) potentia tion of CCU liver injury indicate that these ketones do not affect tissue repair. The time required to resolve the damage depends on the severity of the initial damage and is com parable to the time required for repair in ani mals challenged with an equitoxic dose of CG4 administered alone (Fig. 1). The dose-response relationships of the po tentiators is also of considerable interest. In all the cases that we have studied, each ketone exhibits a reproducible dose-dependent rela tionship. A "noneffective dosage" (NED) and a "minimally effective dosage" (MED) can be estimated (Plaa et al., 1982; Pilon et al. 1986a; Vezina etal., 1985), depending on the exposure conditions. With acetone, such val:es were established for both the oral and in halation route of administration (Charbon neau etal. 1986a). Furthermore, with l,3*butanediol, a ketogenic agent, the severity ofthe potentiation phenomenon correlates (Pilon et al., 1986a) with total ketone bodies result ing from the pretreatment (Fig. 2). An inter esting finding is that 2-hexanone also results in the appearance of circulating ketone bod ies (Pilon et al., 1986b). TOXICANT SPECIFICITY IN THE POTENTIATION PHENOMENON When encountering interactions the ques tion of specificity occurs. It is important to know if several toxicants are affected or ifthe Dhenomenon is restricted to only a few jrnts. Table 3 summarizes the haloalkanes investigated for the ketone potentiation phe- a) ALT vftJdM Fig. i. Effect of ketone potraoxnoo oa the am of re- covrey of CCU bepttotoudty. Groups of ns were treated with three different unite doregre of CCU [(O) 0.1 ml/kg, (A) 0.73 ml/kfc or () 1.0 ml/hg, po) end the peroenufe of animals exhibiting Uver injury (devaaon ofplasma ALT or OCT activity) anened24-130hr later. Other groups of rets were treated (1J nuaol/fci po) with () e-heune, (a) 2-hexanone. or(a) 24-fcannedtOM 18 hr before CCU chaiknfe (0.1 ml/kg pok the perweispi ofininuli mhihitini li nr injm j mi iiwteiil ilia reimi time periods. Rate of recovery of ketooe povenuated liw injury (ALT valure) was comparable to that huad with an equitoxic donee (0.73 or 1.0 ml/kg) of CCU given alone. Data from Charbonneau et aL (1915). nomenon (Traiger and Plaa. 1974; Plaa and Hewitt, 1982b; MacDonald et aL, 1982; Hewitt and Plaa, 1983). Potentiation is ob served with CCU. CHClj, 1,1,2-trichloroeth- ane, and 1,1-dichloroethylene. Thus, the phe nomenon is not limited to CCL, and CHG,, but no clear haloalkane relationship is evi dent There is a strong suggestion that weak hepatotoxic chlorinated alkanes are not con vened into potent hepatotoxicants by a previ ous exposure to ketones. With the bfominated derivatives, however, this conclusion is V <?v 566 Gabriel l. plaa , TOTAL KETOaC BOWES (unMl/mU Fra. 2. Correlation between severity ofpotentiated CCL-induced hepatotoxicity and plasma total ketooe body coocentiations. Rats were given 1.3-butanediol (0.1-9.0% in drinking water) for g days. Ob Day 7, they were challenged with CC1* (0.1 ml/kg, ip). Liver injury (elevation of plasma ALT activity) and ketone body concentrations were amrwri 24 hr later. Votical hatched area represents region of normal ketone body values in control rats. Horizontal shaded area represents region of normal plasma ALT activity tar control rata Data from Pilon et al. (1986a). not supported (Plaa and Hewitt, 1982b; Hew itt el al.. 1983d). Both acetone and chlordecone potentiation results in severe hepatotoxic responses when rats are challenged with dibromochloromethane or bromodichloromethane (Table 4); even brotnoform mildly potentiated by repetitive doses of chlordecone (Plaa and Hewitt, 1982b). The apparent difference between chlorinated and brominated analogues, when subjected to ke tone treatment, requires further investiga tion. TABLE 3 MECHANISMS OF ACTION Haloalkanes Tested for Potentiation by Ketones or Ketogenic Substances Haloulkaaa potentiated Carbon tetrachloride Chloroform 1,1,2-Trtchloroethane 1,1-Diehloroethylene Bromoform BromadichloroiDethaoe Dibromochloromethane Haloalkanes not potentiated 1,1.1 -Trichloroethane 1,1,2,2-Tetrachloroethane Trichloroethyiene (7) Tetrachloroethylene A cardinal consideration in interaction studies is the mechanism(s) of action in volved. Such knowledge permits predictions on conditions where the interaction might be observed. With CC1* and CHC1J( it is dear that these agents are activated by cytochrome P-450 to reactive toxic metabolites, which are responsible for the liver injury. Enhanced biotransfonnation ofCCL, and CHClj by ace tone, 2-hexanone, 2-butanone, and chiorde- cone occur both in vivo and in vitro (Sipes et HALOAUCANES and uver injury 567 TABLE 4 Action* and Chlordecone Potentiation op Bromomethane-Induced Hepatotoxictty* Pretreannent Challenge1 ALT activity OCT activity Vehicle Acetone Vehicle Acetone Vehicle Chtordecone Vehide Chlordecone BtCHClj BfCHClj BrjCHCl BtjCHCI BrCHClj BtCHCli BrjCHCl BfiCHCl 206 439$ 106 1306 76 2393 42 888 2.16 35.6 1.1 13.56 _ -- __ -- * Ketone was given tg hr before halotlkme ehnn Hep*totoxicity w** aliened (elevation ofptauna ALT or OCT activity) 24 hr after haknUcane daikngR Dau fern Flan and Hewitt (1982b) and Hewitt a at (1983d). * Withecetmef IS mmol/kg, po) pretrtamemdonge ofhatoallcaae cbadea^ was 025 ml/kg, po. With dilordeoone (30 mg/lcg, po) pcctreatment, doaa*e of haloalItane wai 0.30 mi/kfc pa aL, 1973; Branchflower and Pohl, 19*1; Cianflone et aL, 1980; Hewitt a aL. J983a,b). Hepatic glutathione levels, however, ate not markedly affected by the ketones (Hewitt et al., 1983b). Thus, enhanced bioactivation of these haloalkanes appears to be the major mechanism responsible for the potentiation phenomenon. A critical time-interval ousts for each ketone, during which subsequent challenge with the haloalkane results in po tentiation (Plat and Hewitt, 1982b). During this period we observe enhanced irreversible binding ofCHCVderived >4C to microsomal macromolecules (Hewitt et al., 1983b). With chlordecone this is particularly dramatic as potentiation of CHCU hepatotoxicity is still observed 20 days after pretreatment with a single dose ofchlordecone; this time interval correlates (Fig. 3) with the presence of en hanced covalent binding and persistent chlordecone tissue residues (Hewitt et al.. 1986b). While enhanced activation of the haloal kanes is a major mechanism of action, there are indications that other mechanisms may also be involved. With isopropanol (the pre cursor of acetone) potentiation, mitochon drial and lysosomal damage following CCU appears more severe than that produced by a larger dose of CCU given alone (Cote et al., 1974). Mehendale reported (Curtis et al., 1979) tint the lesion observed in animals treated with chlordecone and CCU differs from that seen with CCU alone. Recently, we demonstrated (Hewitt et al.. 1986c) that chlotdecone enhances CHClrderived 14C to mitochondria and that this pretreatment also enhances lysosomal fragility to osmotic stress. Thus, one needs to consider other mechanisms that might contribute to the overall potentiation phenomenon. CORRELATION WITH BLOOD LEVELS It is ofinterest to establish parameters that can be used to describe the existance of haz ardous exposure conditions between potenti ators and toxicants. We found that with ace tone, administered orally or by inhalation, there s an excellent correlation between the peak Hood concentration ofacetone and the severity of the potentiated CCU liver injury (Planer of, 1982;Charbonneau<raL 1986a). A threshold blood concentration exists, above which potentiation is observed. Fur thermore, when one takes into consideration the threshold Mood concentration, there is an excellent correlation between the adjusted area-under-curve-time (AUC) relationship and the severity of the potentiated damagu (Charbonneau et aL, 1986a). With 2-hexanone, the peak Mood concen tration i hr post-treatment correlates well with the administered doae (Pilon et aL, 1986b). However, AUC studies comparable to those performed with acetone have not been rtmpted. The rapid rata of Motrana- formatioa and the high lipid solubility of 2- hexanone suggest that such correlations would be fhr less favorable for the ketone. 568 GABRIEL L PLAA Flo. 3. Temporal relationship* of chlordecooe-potentiated CHQrinduced bepuouxidty (elevated plume ALT activity) with hepmic chloidecone concentration int/t liver) and w ntroCHGj Motmuformotion rate (pmoi "C/mg microsomal pmctn/mio). Tune is given in days (2-32) poo-chtateone administration (30 mg/kg. pot For the liver injury experiments, the CHG> chatagt (0-3 ml/kg, po) was administeredon the diypon-ddordecone treatment indicated; ALTactivity wasrammed 24 hrafterCHCU challenge. Data Grom Hewitt et aL (1986b). MIXTURES OF HALOALKANES OTHER FORMS OF LIVER INJURY Pessayre et al. (1982) demonstrated that trichloroethylene can aggravate CCl,-induced liver injury, and that mixtures ofthese two haloalkanes are more potent hepatotoxicants than the agents given singly. We ob served that acetone potentiates the bepatotoxicity of trichloroethylene-CCL mixtures (Chatbonneau et al.. 1986c) and has variable effects on the hepatotoxk effects of other haloalkane mixtures composed of CHC1), CCU, 1,1,1 -trichloroethane, 1,1.2-trichloroethane, tetrachioroethylene, 1,1,2,2-tetrachloroethane, or 1,1-dichloroethylene (Cbarbonneau et al., 1986b). An interesting finding is that with the trichloroethylene-CCU mix ture, the minimally effective potentiating dosage of acetone is considerably lower than that observed with CCU alone. The other ke tones have not been evaluated in the presence of mixtures. There is no doubt that ketones or ketogenic substances can potentiate the acute hepetonecrogenic properties of haloalkanes. Are other forms of chemically induced liver in jury so affected or b the potentiation limited to the acute ecrofenic response? Acetone given repetitively accelerates the appearance of cirrhosis produced by the subchronic administration of CCU (Charbonneau et al., 1986d). Thus, chronic lesions are also affected. Chemically induced diabetes poten tiates the acute liver injury produced by thioacetamide (El-hawxri and llaa, 1983) but not acetaminophen (Price and Jollow, 1982). Thus, not all acute forms of hepatotoxidty are affected. Chtordecouc enhances the cholestatic properties (diminution ofbile flow) of CCU (Curtis et aL, 1979), as does isopropanol (de Lamirande and Plat, 1981). Acetone and 2-hexanone enhance the cholestatic proper- I INJURY pkctogenic ther *o- -.re 1 liver inla limited |' Acetone ance fcbchronic fsneau et 1 are also F-ipo'en- ib>- -w I`'but not 1982). ^toxicity "the cho- |' How) 0f rj^panol Fnc and r Proper- HALOALKANES AND LIVER INJURY 569 ties ofCHClj (Hewitt etal.. 1986a). Thus, not r.!y necrogenic hepatotoxicants are affected. Pure cholestatic responses, in the absence of hepatocellular necrosis, are also potenti ated by ketones or ketogenic substances. 1,3Butanediol, 2-hexanone, and 4-methyl-2pentanone enhance the diminution in bile flow observed in rats after the administration of two experimental chemical models ofcho lestasis--injection of taurolithocholic acid or a manganese-bilirubin combination (de imirande and Plaa, 1981; Plaa and Ayotte, i985; Vezina et al,, 1985; Vezina and Plaa, 1986). Thus, it is clear that ketone potentia tion of liver injury is not restricted to the acute hepatonecrogenic effects ofhaloalkanes but also involves several different forms of liver injury. The importance of these other potentiations remains to be determined. REFERENCES Branchflower, R_ V., and Pom, L R_ (1981). Invo- tigatkm of the mechanism ofthe potenbauon ofchlo roform-induced hepatotoxidty and nephrotoxicity by methyl /rtutyl ketone. Toxical Appl Pharmacol. 61, 407-413. Clanfloni, D. J.. Hewitt, w. K. Villeneuve, d. C, and PLaa, O. L. (1980). Role ofbiotrarofonnaooii in the alterations ofchlorofbnn hepatotoxidty produced by Kepone and mirox. Tonal Appt. Pharmacol S3, 140-149. Charbonneau* M. (1982). Interaction cetone-hydro- orbuie halogene: evolution de fbepniotoxidte. Mi thesis, Umvetmte de Montreal. Montreal. Canada. Charbonneau, M.. BroocurJ- ou Souich, P, and Piaa, G. 1_ (1986a). Correiadoo between acetone-po tentiated CCL-induced liverinjury and Wood coocen* nations after inhalation or oral administration. Toxi col. Appt. Pharmacol 84,286-294. Charbonneau. M., Brodcur, J., and Piaa. G. L. (1986b). Influence of acetone on the severity of the li"*r i"jllfy *y h-in-is*-- Toxicoto- put 6,112. Charbonneau, M., Iltima, M_ Cirrt, M. G,, and Piaa, G. L. (1983). Temporal analysis of rat live- in jury following potentuuoo of orbon tetrachlorids hepatotoxidty with ketonic or ketogenic compounds. Toxicology iS, 93-112. Charbonneau. M., Oleskevkh, S., Brobeur, K and Piaa, G. L. (1986c). Acetone potentiaooo oftat liver injury induced by trichloroetbyiene<trbon tena- chloride mixtures. Fundam. Appt. Toxicol. 6, 634- 661. Charbonneau, M., Tuchweber, B.. and Plaa, G. L (1986d). Acetone potentiation of chronic liver injury induced by repetitive administration of carbon tetra chloride- Hepatology 6,694-700. Cornish. H. H., and adefuin, J. (1967). Potentiation of carbon tetrachloride toxicity by aliphatic alcohols. ,Arch. Environ. Health 14,237-240. C6ti M. G., Traiger. G. J., and Plaa. G. L (1974). Effect of isopropanol-ioduced potentiation of carbon tetrachloride on tat hepatic ultranructure. Toxicol. Appl. Pharmacol. 30,14-23. Curtis, L. R., Williams, w. L, and Mehendale. H. M. (1979). Potenttanon of the hepatotoxidty of carbon tetrachloride following preexposure to chlotdecone (Kepone) in the male raL Toxicol. Appl. PharmacoL SI, 283-293. oe Lamirande. E., and Plaa, G. I- (1981). 14-Butancdiol pretreatment on the choiestesis induced in rats by manganese-bilintbin combination, tauroltthocbolic acid, or a-napbtbyUsothiocyanate. Toxicol Appl. Pharmacol. 59,467-475. El-hawaRL A. M., and Plaa, G. I- (1983). Potentia tion of thiiwAtainirfe-iiirfnrgd hepetotoxictty in al loxan- and streptozotodn-diabetic rati. TaxicoL Leo. 17,293-300. HEwrrr. L. a., ayotte. P, and Plaa. G. L. (1986*). Modification in rat hepMobiliary fimctioR fallowing treatment with acetone, 2-butanooe. 2-hexanone, mirex or dtkwdeoone end subtequendy expored to chlo roform- Toxicol Appl Pharmacol 83,465-473. Hewttt, L. A- CAtui. Gw and Plaa, & L. (1986b). Temporal idarionthips batwnn biotramforautaon. detoxication and chionhcone potentieriou of chloro form-induced hepetoroxidty. Canod- J. Physiol Phar macol 64,477-462. Hewttt, L. A- Hewttt. W. R- an> Plaa. G. L. (1983a). Fractional bepmic locaHrerinn of CHG> in mice sad rats treated with chiordecooe or minx. Fun- dam. Appl Toxicol 3,489-493. Hewitt, L. A- Masson, SL, and Plaa. G. L (1986c). Evidence for the invofroment oftnftochondrin and ly sosomes in chlonlecooepotentiatioe ofCHO, hepato toxidty. Toxicologist i. 112. HEwrrr, W. R.. and Plaa, G. L. (1983). Doeedepen- dent modification of UnlichloroethylenB taxidty by acetone. Toxicol Lett. 14,143-152. Hewttt. L a, Vajjquette. G. and Plaa. G. L. (1983b). Correlation of biotrsnsfonnsaoo-detoxjcation parameters with 2-heaanonc, 2-biitancnr end acetone-potentiated ehtoreform hepniwnsiciiy. 7axicotogioi,99. Hewitt, W. R,, Brown, E M- and Plaa. G, L. (1983c). Relationship between the carbon ifcdeton length of ketonic solvents and potentiation ofchioro- 634 yOO 570 Gabriel l. plaa form-induced hepatotoxicity in tats. Toxicol. Lett. 16, 297-304. HHwrrr, W. R., brown, E. M., and Plaa. G. L. (1983d). Acetone-induced potentiation of trihalomethane toxicity in male rat*. Toxicol. Leu. 16, 283- ,296. HEwrrr, W. R_, Miyajima. R, CCfft M. G.. AND Plaa. G. L. (1979). Acute alteration of chloroform-induced bepato- and nephrotoxidty by nirex and KeponeToxtcot. Appl. Pharmacol 48, J09-J27. Hewttt, W, r,, Miyajima. R, CAte, M. G.. and Plaa, G. L. (1980a). Acute ilieranon ofchloroform-induced bepato- and nephrotoxidty by n-hexane. methyl rt-butyi ketone, and 2.5-hexindione. Toxicol. Appl. Phar macol. 53.230-248. Hewitt, w. R.. Miyajima, r, CAte. M. G.. and Plaa, G. U (1980b). Modification of Italoakane-induced hepatotoxicity by exogenous ketones and metabolic ketosis. Fed. Proc. 39,3118-3123. MacDonald. J. R, Gandout. a, J,, and Sipes, I. G. (1982). Acetone potentiation of 1,1.2-trichloroethane bepatotoxidty. Toxicol. Lea. 13,57-69. Pessayre, D,, Cobert. B.. Descatoire, V.. Deoott, C- Babany. G, Funck-Brentano. C- Delaporce. M., and Larxey. D. (1982). Hepatotoxidty of trvcfaloroethylene-caibon tetrachloride mixtures in rata Gastroenterology83,761-772. PtLON. D,, Brodeur, J, and Plaa. G. L (1986a). 1,3- Butanediol-inducedinaeaea in ketone bodies and ptN tennation of CQ, hepntosnxurity. Toxicology 40, 163-180. PtLON, D- Chareonneau. M.. Brodeur, j,, and Plaa, G. I- (1986b). Metabolites and ketone body production following methyl n-butyt ketone exposure es poreible indices of MaBK potenoanon of carton tetrachloride hepatotoxicity. Toxicol AppL Pharma col. 85,49-59. Plaa.0. L. and Ayotte.P.( 1985). Taurolithocbolateinducod inttahepatic 'Mi--potentiation by methyl isobutyl ketone end methyl n-butyl ketone in rata Toxicol Appl Pharmacol 80,228-234. Plaa, G. L.. and Hewttt, W. R. (1982a). Methodologi cal approaches for interaction studies: potentiation of haloalkine-induced bepatotoxidty. In Workshop on the Combined Effects ofXenobiotics, pp. 67-96. Natiottal Research ConnciL Publication No. 18978. Plaa, G. L, and Hewitt. W. R, (1982b). Potentiation of liver and kidney injury by ketones and ketogemc substances. In Adnmces in Pharmacology and Therapetaia II. VoL 5. Toxicology and Experimental Models (H. Yosinda. Y. Hagihata, and S. Ebashi Eds.), pp. 65-75. Pergamon. Oxford. Plaa. G. I-- Hewitt, w. r, du Souich. P.. Caiue. G- and Lock, S. (1982). Isopropanol and acetone potenBatson of carton tetrachlonde-induced hepatotox idty: Single versus repetitive ptetreatments in rats. J. Toxicol Environ. Health 4,235-230. Price, V. F., andJoslow, D. J. (1982). Increased redstanoe ofdiabetic iresto acetaminophen-induced hepatotoxirity. J. Phmmacot. Exp. Ther 220,304-313. Sites, l G., Strut, 8- Krishna, G,, Maunci, H. M., andGillette, J. R. (1973). Enhanced hepatic micro somal activity by pretreatment of tats with acetone or uopropanol. Proc. Sac. Exp. Biol. Med. 142,237-240. Trajgejl G. J., and Bruckner, ). V. (1976). The perndpenon of 2-fauaaone in 2-butanoMnducad poten tiation ofcarton wachlonde bepatotoxidty. J. Phar macol Exp. Ther. 196,493-300. Txajczr. G. J- and Plaa, G. L (1971). 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