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1984b). Effect ofCl0y function in Fischerlation. Toxicol. Appl. itic hydrocarbons. In ' Toxicology (G. D. Vol. 2B, 3rd rev. ed., -miropathy. Ann. m ! uciure-Actmty i including Remarks, i to Workshop on the Boston. MA. j>es. T. w,, Heat, ESDICOTT, K., AND mi of the significance vrity to man. In Reerbt<n\ (M. A. Mehl. Thi -v and N. K. Pnn, Scientific, i. ssd Es ans. J, B. of gasoline intoxi** 117-34. t'-Ty"T-' TO: health and science committee FROM: THOMAS A.""cORTII!A y., * v- ,, AND applied toxicology 10,563-570 (1988)1 DATE: MAY 19MT27B86 Experimental Evaluation of Haloalkanes and I Gabriel L. Plaa Departement depharmacologie. Facuite de medecine, Universite de Montreal, Montreal. Quebec, Canada H3C3J7 ReceivedNovember6,1987; acceptedNovember IS, 1987 Experimental Evaluation ofHaloalkanes and Liver Injury. Plaa, G. L. (1988). Fundam. Appl. Toxicol. 10,563-570. Potentiation of haloalkane-induced hepatotoxidty by ketones and ketogenic substances is used to illustrate questions that are raised when considering biological inter actions involving toxicants. The following characteristics are considered: The effect ofthe poten tiator (ketone or ketogenic agent) on the dose-response characteristics of the baloalkane toxi cant; the recovery process of the potentiated tissue injury; dose-response characteristics of the potentiators (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 ofvarious forms ofhepatic injury (acute, chronic, neuogenic, and cholestatic). Enhanced bioactivation of the halnaiieane toxicant is a major mechanism of action for the potentiator; other possible contributing mechanisms, however, require consideration. Mixtures of haloalkanes, leading to enhanced liver injury, can also be potentiated by ketones, e 19ts Soocty ofT<uxx*i(y. One of the purposes of this symposium is to discuss toxicological questions that are raised tadien considering biological interactions, nuioalkane-induced liver injury is an area that has benefited from a considerable amount of research interest; in recent years, 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 haloalkaneinduced hepatotoxidty by ketones and keto genic substances. Our interest in the ketone potentiation phenomenon originated with the discovery that isopropanol potentiation of CCL and CHClj hepatotoxidty (Cornish and Adefuin, 1967; Traiger and Plaa, 1971) is actually me diated by acetone, the major metabolite of 1 Presented at the 25th Annual Meeting of the Society ofToxicology, March 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 pestidde chlordecone, which contains a carbonyl group, is also a po tent potentiator of CHClj (Hewitt et al,, 1979) and CCL (Curtis et al,, 1979). Further more, agents that are converted to ketones in vivo (ketogenic substances) or maneuvers leading to metabolic ketosis are also effective potentiators (Hewitt et 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 S3.00 GaMOfKC 1911 by UMSocmyorrowcokw- A a^li ofnrpfoducooa in ay faun iwrr ad. sL 040A3A 564 GABRIEL L PLAA TABLE 1 Kctones or Khtogenic Substances Known to Potentiate Haloalkane Hefatotoxictty Ketones Ketogenic substances Acetone 2-Butanone (MEK) 2-Pentanone (MPK) 2-Hexanone (MnBK) 2,5-Hexanedione 4*Methyl-2- pentanone (MIBK) 4-Hydrojcy-4-methyl- 2-pentanone 2-Heptanone (MAK) Chlordecone Isopropanol 1.3-Butanediol n-Hexane 4-MethyLZ-penttnol Alloxan (diabetic state) Streptozococin (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 III would be a combination of these two phenomena; the dose-response curve shifts laterally, but the slope 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 CHOj (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 bepatotoxic ED50 of CHO3 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 hepatotoxirity, repair processes are initiated rapidly and the duration is dependent on the initial severity of the injury (Chaibonneau 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 CHlorotorm Median Effec tive Dosages (ED50 Values) 10* Induction of Hepatotoxioty in Male Mice* Pieueatmeot ALTED50* fwicy twtio* OCTED50* Potency ntio' Vehicle Chlordecone 43 (35-50)* 13 (10-17) mm 34 (U-7J) 235 014-301) 2* (20-43) 8.3 (5.3-12.8) * Chlordecone (50 mi/kg. po) admmincrat IS hr before chlo roform chellenpe (2.5-1000 *l/tfc po). Hnwomrioty iweMrri 24 hr after chloroform. Data 6m Ptao od Hewitt (1982a). * ED30 0U/k|) for ekvetjoo ofpiano* ALT activity. ' Vehicle EDSO/chlonieme ED50. * ED50 MAC) for etevuioo ofptam OCTMivity. ' Vilues m percntheses irpnjAut the 9W confidence limits. L,nes "hich Lihold toxiL_^d to pro..iion I and describe V^v'one and t;\idence of ; rehtion>op- `he jtion II (no -.< toxicant f>.e effect of ED50 of Indent that |:ieED50of l.nei* *'*ertrati in (rrocess can : os the se ts hepatocrd rapidly t ihe initial iu et al., rments re lations for ran- ust l an,, the ' recovery effeccnoN of 8.3 '5-3-12.8) p*hrt ls. HALOALKANES and liver 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 ofthe 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 CCU 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 et al., 1985), depending on the exposure conditions. With acetone, such val ues were established for both the oral and in halation route of administration (Chaibonneau etal. 1986a). Furthermore, with 1,3-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 etal., 1986b). TOXICANT SPECIFICITY IN THE POTENTIATION PHENOMENON When encountering interactions the ques tion of specificity occurs. It is important t know if several toxicants are affected or ifth Dhenomenon is restricted to only a fe J-nts. Table 3 summarizes the haloalkane investigated for the ketone potentiation ph< a) ALT vakiM Fig. 1. Effect ofketone potentiation on the rate ofre covery of CCL, hepntotoxidty. Groups of rats were noted with three different single dmyr of CCL ((O) 0.1 ml/kg, (A) 0.75 ml/kg, or (O) 1.0 ml/kg. poj and the percentage of animals exhibiting liver injury (elevation ofplasma ALTorOCT activity) assessed 24-120 hr later. Other groups ofiats were treated (15 mmol/k& po) with ()n-hexane,(A)2-bexanone,or(a)2,5-hexanedione 18 hr before CCL challenge (0.1 ml/ltg, po): the percentage ofanimals exhibiting liverinjury was asaeaedatthesame time periods. Rate of recovery of ketone-potentiated liver injury (ALT values) was comparable to that found with an equitoxic dosage (0.75 or 1.0 ml/kg) of CCL given alone. Data from Charbonneau a aL (1985). nomenon (Traiger and Plaa, 1974; Plaa and Hewitt, 1982b; MacDonald et al., 1982; Hewitt and Plaa, 1983). Potentiation is ob served with CCU, CHC13, 1,1,2-trichloroethane, and 1,1 -dichloroethylene. Thus, the phe nomenon is not limited to CCU and CHC13, but no clear haloalkane relationship is evi dent There is a strong suggestion that weak hepatotoxic chlorinated alkanes are not con verted into potent hepatotoxicants by a previ ous exposure to ketones. With the brominated derivatives, however, this conclusion is SL 040*36 566 GABRIEL L. PLAA 1000 O CCU-CHMXINMO < 0.1 MJkQ ) o.-CH<uiCNaeo r0.*321 * 3 < , TOTAL KETONE BOOKS (umoUmO Fig. 2. Correlation between severity ofpotentiated CCL-induced hepatotoxicity and plasma total ketone body concentrations. Rats were given 1,3-butansdioi (0.1-9.M in drinking water) for 8 days. On Day 7, they were challenged with CCL (0.1 ml/kg, ip). Liverinjury (elevation ofplasma ALT activity) and ketone body concentrations were assessed 24 hr later. Vertical hatched area represents region of normal ketone body values in control rats. Horizontal shaded area represents region of normal plasma ALT activity for control rats. Data from Pilon et al. (1986a). not supported (Plaa and Hewitt, i 982b; Hew itt et al.. 1983d). Both acetone and chlordecone potentiation results in severe hepatotoxic responses when rats are challenged with dibromochloromethane or bromodichloromethane (Table 4); even bromoform is 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 Haloalkanes Tested for Potentiation by Ketones or Ketogenic Substances Haloalkanes potentiated Haloalkanes not potentiated Carbon tetrachloride Chloroform l, 1.2-Trichloroethane 1,1-Dichloroetbylene Bromoform Bromodkhloromethane Dibromochloromethane 1,1,1-Trichloroethane 1,1,2,2'Tetrachloroethane Trichloroethylene (?) Tetrachloroethylene MECHANISMS OF ACTION 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 CCl* and CHClj, it is clear that these agents are activated by cytochrome P-450 to reactive toxic metabolites, which are responsible for the liver injury. Enhanced biotransformation ofCC1 and CHClj by ace tone, 2-hexanone, 2-butanone, and chlorde cone occur both in vivo and in vitro (Sipes et lent > *. Bn nr u tan o`" Cl Th. ttrdand taiofce*tsiiga- tN *=actic in- Actions ,=|ght be : a clear ^ciirome `'chare ^nced ace- h SiPes HALOALKANES AND LIVER INJURY 567 TABLE 4 Acetone and Chlordecone Potentiation of Bromomethane-Induced Hepatotoxictty' Pretreatment Challenge5 ALT activity OCT activity Vehicle Acetone Vehide Acetone Vehicle Chlordecone Vehicle Chlordecone BtCHCU BiCHCIj BrjCHCl BrjCHCl BrCHClj BiCHCIi BrjCHCl BrjCHCl 206 4398 106 1306 76 2393 42 888 116 35.6 l.l 13-56 _ -- _ -- * Ketone was given 18 hr before haloalkane challenge. Hepatotoxicity was assessed (elevation ofplasma ALT or OCT activity) 24 hr after haloalkane challenge. Data from PUaand Hewitt (1982b)and Hewitt aal. (1983d). ` With acetone (13 mmol/kg, po) pretreatment. dosage ofhaloalkane challenge was 0.23 ntl/kg, pa With chlordccone (30 mg/ltg, po) pretreatment, dosage of haloal kane was 0.30 ml/kf. po. al.. 1973; Branchflower and Pohl, 1981; Cianflone et al.. 1980; Hewitt et aL, I983a,b). Hepatic glutathione levels, however, aie 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 exists for each ketone, during which subsequent challenge with the haloalkane results in po tentiation (Plaa and Hewitt, 1982b). During this period we observe enhanced irreversible binding of CHGrdenved 14C to microsomal macromolecules (Hewitt et al., 1983b). With chlordecone this is particularly dramatic as potentiation of CHCI3 hepatotoxicity is still observed 20 days after pretreatment with a single dose of chlordecone; 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 CCl* appears more severe than that produced by a larger dose of CCl* given alone (Cote et al., 1974). Mehendale reported (Curtis et al., 1979) that the lesion observed in animals treated with chlordecone and CCL, differs from that seen with CCU alone. Recently, we demonstrated (Hewitt et al., 1986c) that chlordecone enhances CHGy-derived 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 is an excellent correlation between the peak Mood concentration ofacetone and the severity of the potentiated CCL, liver injury (PlaaetaL, 1982; Charbonneau et al., 1986a). A threshold blood concentration exists, above which potentiation is observed. Fur thermore, when one takes into consideration the threshold blood concentration, there is an excellent correlation between the adjusted area-under-curve-time (AUQ relationship and the severity of the potentiated damage (Charbonneau et al., 1986a). With 2-hexanone, the peak blood concen tration 1 hr post-treatment correlates well with the administered dose (Pilon et al., 1986b). However, AUC studies comparable to those performed with acetone have not been attempted. The rapid rate of biotrans formation and the high lipid solubility of 2hexanone suggest that such correlations would be far less favorable for the ketone. SL 040438 568 GABRIEL L. PLAA I Fic. 3. Temporal relationships of chlordecone-poientiated CHClj-induced bepatotoxicity (elevated plasma ALT activity) with hepatic chlordecone concentration (>ig/g liver) and in ribwCHCli biotransformadon rate (pmol ,4C/mg miaosomal protein/min). Time is given in days (2-32) post-chiordeconc administration (30 mg/kg, po). For the liver injury experiments, the CHCl, challrwge (0J ml/kg, po) was administeted on the day post'Chlordecone treatment indicated; ALT activity wasaanssed 24 hrafter CHO) challenge. Dam from Hewitt erni. (1986b). MIXTURES OF HALOALKANES OTHER FORMS OF UVER INJURY Pessayre et al. (1982) demonstrated that trichloroethylene can aggravate CCU-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 hepatotoxicity of trichloroethylcne-CCU mixtures (Charbonneau et al., 1986c) and has variable effects on the hepatotoxic effects of other haloalkane mixtures composed of CHC13, CCU, 1,1,1 -trichloroethane, 1,1,2-trichloroethane, tetrachloroethylene, 1,1,2,2-tetrachloroethane, or l, 1 -dichloroethylene (Char bonneau etal., 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 hepatonecrogenic properties of haloalkanes. Are other forms of chemically induced liver in jury so affected or is the potentiation limited to the acute nccrogenic 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-hawari and Plaa, 1983) but not acetaminophen (Price and Jollow, 1982). Thus, not all acute forms of hepatotoxicity are affected. Chlordecone enhances the cho lestatic properties (diminution ofbile flow) of CCU (Curtis et al,, 1979), as does isopropanol (de Lamirande and Plaa, 1981). Acetone and 2-hexanone enhance the cholestatic proper- SL 040439 |:vjury rletogenic (he:' -*0nes. -.re ! liver in- M limited F Acetone arance b-hchronic fiaeau et 5 ate also f-s poten cy 'but not 1982). b<oxicity * `he chohtlow) of [rropanol `'one and f"' Proper- HALOALKANES and liver injury 569 ties ofCHCU (Hewitt et al.. 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 of cho lestasis--injection of taurolithocholic acid or a manganese-bilirubin combination (de tmirande and Plaa, 1981; Plaa and Ayotte, 1985; 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 Pohl. L. R. (1981). Inves tigation ofthe mechanism ofthe potentiation ofchlo roform-induced hepatotoxidty and nephrotoxicity by methyl n-butyl ketone. Toxicol Appi. Pharmacol 61, 407-413. Cianflone, D. J., Hewitt, w. IL. Villeneuve, D. G, and Plaa, G. L. (1980). Role ofbiotnms/bnuanon in the alterations ofchloroform hepatotoxidty produced by Kepone and mirex. Toxicol Appi. Pharmacol. 53, 140-149. CharbonneaU, M. (1982). Interaction cetone-hydrocarbure halogene: evolution de rhepntotoxicite. M.S. thesis, Universite de Montreal, Montreal. Canada. CharbonneaU. M., Brodeur,.J, du Souich, P., and Plaa, G. L. (1986a). Correlation between acetone-po tentiated CCL-induced liver injury and Mood concen trations alter inhalation or oral administration. Taxicol. Appi Pharmacol 84,286-294. CharbonneaU, M., Brodeur, J., and Plaa, G. L. (1986b). Influence of acetone on the seventy of the liverinjury induced by haioalkane mixtures. Toxicolo gist 6, 112. CharbonneaU, M,, Iuima, M- Cflri, M. G., and Plaa, G. L. (1985). Temporal analysis of rat liver in jury following potentiation of carbon tetrachloride hepatotoxidty with ketonic or ketogenic compounds. Toxicology 35,95-112. CharbonneaU, M., Oleskevich, S,, Brodeur. J,, and Plaa, G. L. (1986c). Acetone potentiation of rat liver injury induced by trichloroethylene-carbon tetra chloride mixtures. Ftmdam. Appi. Toxicol. 6, 654661. 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. CflTE, M. G,, Traiger. G. J., and Plaa, G. L (1974). Effect of isopropanol-induced potentiation of carbon tetrachloride on rat hepatic ultrastructure. Toxicol. Appi. Pharmacol. 30, 14-25. Curtis, L. R., Williams, w. l_, and Mehendale, H. M. (1979). Potentiation of the hepatotoxidty of carbon tetrachloride following preexposure tochlordeconc (Kepone) in the male rau Toxicol Appi. Pharma col. 51,283-293. DE Lamirande. E., and Plaa, G. L. (1981). 1,3-Butanediol pretreatment on the cholestasis induced in rats by manganese-bilirubin combination, taurolitho cholic add, or a-naphthylisothiocyanate. Toxicol. Appi Pharmacol. 59,467-475. El-Hawari, A. M., and Plaa, G. L. (1983). Potentia tion of thioacetamide-induced hepatotoxidty in al loxan- and stieptozotodn-diabctic rats, Toxicol Lett 17,293-300. Hewitt, L. A., Ayotte, P,, and Plaa, G. I- (1986a). Modification in rat hepatobiliary function following treatment with acetone, 2-butanone, 2-hexanooe, mi rex or chlortiecone and subsequently exposed to chlo roform. Toxicol Appi Pharmacol 83.465-473. Hewitt, L. A., CailuL G,, and Plaa, G. L. (1986b). Temporal relationshipB between biotransfonnatson, detoxication and chlordecone potentiation ofcfaioroform-induced hepatotoxidty. Canad. J. Physiol Phar macol 64,477-482. Hewitt, L. a., Hewitt, W. r,, and Plaa, G. L. (1983a). Fractional hepatic localization of CHGj in mice and rats treated with chloidecooe or mirex. Fundim. Appi Toxicol 3,489-493. Hewitt, L. A.. Masson, S, and Plaa. G. L. (1986c). Evidence for the involvement ofmitochondria and lysosomes in chlordeconepotentiation ofCHQ, hepato toxidty. Toxicologist 6,112. Hewitt, W. R., and Plaa, G. I- (1983). Dose-depen dent modification of 1,1-dichloroethylene toxicity by acetone. Toxicol. Lett. 16, 145-152. Hewitt, l. a., Vauquette. C. and Plaa, G. L. (1983b). Correlation al biotransformation-detoxication parameters with 2-hexanone, 2-butanone and acetone-potentiated chloroform hepatotoxidty. Toxi cologist 3,99. Hewitt, W. R., Brown, M., and Plaa, G. L. (1983c). Relationship between the carbon skeleton length of ketonic solvents and potentiation ofchloro- SL 040440 570 GABRIEL L. PLAA form-induced hepatotoxicity in rats. Toxical. Lett. 16, 297-304. Hewitt, W. R., Brown, e. M., and Plaa. G. L (1983d). Acetone-induced potentiation of trihaiomethane toxicity in male tats. Toxicol. Lett. 16,285296. Hewitt, W. R,, Miyajima, H., C6te, M. G., and Plaa, G. L. (1979). Acute alteration of chloroform-induced hepato- and nephrotoxicity by mirex and Kepone. Toxicol. Appl. Pharmacol 48,509-527. Hewitt, W. R,, Miyajima, H.. Cote, M. G.. and Plaa, G. L (1980a). Acute alteration ofchloroform-induced hepato- and nephrotoxicity by n-hexane, methyl n-butyi ketone, and 2,5-hcxandione. Toxicol. Appl. Phar macol. 53,230-248. Hewitt, w. R., Miyajima. H,, Cote, M. G., and Plaa, G. L. (1980b). Modification of haloakane-induced hepatotoxicity by exogenous ketones and metabolic ketosis. Fed. Proc. 39,3118-3123. MacDonald, J. R., Gandolfl A. J, and Sipes, I. G. (1982). Acetone potentiation of 1,1,2-trichloroethane hepatotoxicity. Toxicol. Lm. 13,57-69. Pessayre, D.. Cobert, B,, Descatoire. V., Degott, G, Babany, G,, FUnck-Brentano, C. Delaforge, M., and Larrey. D. (1982). Hepatotoxicity of tri chloroethylene-carbon tetrachloride mixtures in rats. Gastroenterology83,761-772. PILON, D., Brodeur, J., and Plaa, G. L. (1986a). 1,3Butanediol-induced increases in ketone bodies and po tentiation of CCL hepatotoxicity. Toxicology 40, 165-180. Pilon, D., Charronneau. M.. Brodeur, J- and Plaa, G. L. (1986b). Metabolites and ketone body production following methyl n-butyl ketone exposure as possible indices of MnBK potentiation of carbon tetrachloride hepatotoxicity. Toxicol Appl Pharma col. 85,49-59. Plaa, G. L., and Ayotte, P. (1985). Taurolithocholateinduced intrahcpatic cholestasis: potentiation by methyl isobutyl ketone and methyl n-butyl ketone in rats. Toxicol. AppL Pharmacol. 80,228-234. Plaa, G. L.. and Hewitt. W. R. (1982a). Methodologi cal approaches for interaction studies: potentiation of haloalkane-induoed hepatotoxicity. In Workshop on the Combined Effects ofXenobiotics, pp. 67-96. Na tional Research Council. Publication No. 18978. Plaa, G. I_. and Hewitt, W. R. (1982b). Potentiation of liver and kidney injury by ketones and ketogenic substances. In Admixes in Pharmacology and Thera peutics II. VoL 5, Toxicology and Experimental Models (H. Yoshida, Y. Hagihara. and S. Ebashi Eds.), pp. 65-75. Pergsnoii, Oxford. Plaa, G. L.. Hewitt. W. R., du Souich, P,, Caille, G,, and Lock, S. (1982). Isopropanol and acetone po tentiation ofcarbon tetrachloride-induced hepatotox icity: Single versus repetitive pretreatments in rats. J. Toxicol Environ. Health 4,235-250. PRICE, V. F., and Jollow, D. J. (1982). Increased resis tance ofdiabetic ran to acetaminophen-induced hepatotoxicity. J. Pharmacol. Exp. Ther. 220,504-513. Sipes, L G,, Strut, R. Krishna, G., Mating, H. M,, andGillette, J. R. (1973). Enhanced hepatic micro somal activity by prencatment ofrats with acetone or isopropanol. Proc. Soc. Exp. Biol. Med. 142,237-240. Traiger. G. J., and Bruckner, J. V. (1976). The par ticipation of 2-butmtooe in 2-butanol-induccd poten tiation ofcarbon tetrachloride hepatotoxicity. J. Phar macol Exp. Ther. 196,493-500. Traiger, G. J., and Plaa, G. L. (1971). Differences in the poienuabonofcarbon tetrachloride in rats by etha nol and isopropnol pretreatment. Toxicol Appl Pharmacol. 20,105-112. Traiger. G. J- am> Plaa, G. I- (1972), Relationship ofalcohol metabolism to the potentiation ofCC1 hepatotondty induced by aliphatic alcohols. J. Pharma col Exp. Ther. 183,481-488. Traiger. G. J,, aM> Plaa, G. L. (1974). Chlorinated hydrocarbon toxiritr Potentiation by isopropyl alco hol and acetone. Arch. Environ. Health 28,276-278. VfeziNA. M.. AYOTTE, P., and Plaa. G. L. (1985). Po tentiation of necrotic and cholestatic liver injury by 4metbyi-2-pentanooe. Canad. Fed. Biol Sac. Proc 28, 221. Vezwa, M, and Piaa. G. L (1986). Potentiation of necrogenic and cholestatic liver injury by metabolites ofmethyl isobutyl ketone. Toxicologist 6, 111. SL 040441