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4 Liver Toxicity and Cancer
Pages 137-181

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From page 137...
... A review of current knowledge on the proposed modes of action for trichloroethylene-induced liver cancer (peroxisome proliferator-activated receptor agonism, genotoxicity and mutagenicity) and their relevance to humans is provided.
From page 138...
... B6CF1 mice (male) chloral hydrate, 1 g/L; DCA, 0.5 g/L 104 wk Drinking water B6C3F1 mice (male)
From page 139...
... 1990 glycogen evenly distributed throughout the liver; less glycogen accumulation with TCA treatment, which was more prominent in periportal regions. Dose-dependent liver glycogen accumulation associated with decreased Kato-Weinstein glycogen synthase activity.
From page 140...
... ABBREVIATIONS: ALT, alanine aminotransferase; AST, aspartate aminotransferase; DCA, dichloroacetic acid; DCVC, S-1,2-dichlorovinyl-l-cysteine; i.p., intraperitoneal; i.v., intravenous; LC50, concentration lethal to 50% of test animals; N/A, not applicable; ppm, parts per million; TC, taurocholate; TCA, trichloroacetic acid; TCE, trichloroethylene. and O'Flaherty 1985; Soni et al.
From page 141...
... Increases in total and some individual serum bile acids (TC was most Wang and Stacey sensitive)
From page 142...
... The metabolites trichloroacetic acid and chloral hydrate also have the potential to induce autoimmunity in the same autoimmune-prone mice (Blossom et al.
From page 143...
... 143 ecnerefeR .latenoohP 4891 Pantucharoensri 4002.late .lateayagaN 3991 .latellocsirD 2991 .latebahgeN 7991 seidutSnamuHnisetilobate yticixototapeHfoserutaeF amehtyre(emordnysnosnhoJ-snevetS dna,ylagemotapeh,ecidnuaj,) emrofitlum stnevlosrehtO.yhtapolahpecnecitapeh .devlovniebthgim ECTsediseb niksdezilareneg,emordnysnosnhoJ-snevetS ecidnuajonhtiwsititapehdna,snoitpure .)
From page 144...
... The metabolites tested included trichloroacetic acid, dichloroacetic acid, chloral hydrate, trichloroethanol, oxalic acid, and S-1,2-dichlorovinyl-l-glutathione. Despite this lack of cytotoxicity, trichloroethylene and its metabolites produced mitochondrial dysfunction.
From page 145...
... , which further establishes an association between abnormal liver glycogen status and the carcinogenic effect of trichloroethylene and its metabolites. Other halogenated solvents such as bromochloroacetate and dibromoacetate induce glycogen accumulation in the liver to a similar degree as dichloroacetic acid (Kato-Weinstein et al.
From page 146...
... This new information suggests dissociation between glycogen accumulation and the carcinogenic effects of dichloroacetic acid. Clearly, more studies are needed to clarify the relationship between altered glycogen storage and liver cancer in response to trichloroethylene.
From page 147...
... . To determine whether this increase in serum bile acids after low exposure to trichloroethylene is indicative of early liver dysfunction, the mechanism(s)
From page 148...
... It is worth noting that the transport of cadmium chloride and 3-O-methyl-d-glucose does not change. Furthermore, occupational exposure to a mixture of organic solvents including toluene, xylene, acetone, n-butylacetate, n-butanol, and ethylacetate also results in elevation of mean serum bile acid concentrations in the absence of changes in biochemical markers of liver injury (Franco et al.
From page 149...
... . Trichloroacetic Acid Trichloroacetic acid is a peroxisome proliferator and a species-specific carcinogen.
From page 150...
... 10 staRdnaeci ecnerefeR -nerreH ,dnuerF 7891.late .latelluB 0991 olegnAeD 1991.late ariereP 6991 leinaD 3991.late olegnAeD 7991.late MhtiwseidutSreta amonicraCralullecotapeH ) yticilpitlum(n/romuT 0 5.0 0 81.0 71.0 72.0 51.0-70.0 13.0 55.0 2.2 79.0 0 0 0 52.0 20.0 0 0 82.0 0 0 0 540.0 0 0 0 0 ecnedicnI 22/0 22/7 53/0 11/2 42/4 11/3 %01-7.6 %22 %83 %78 %55 04/0 04/0 91/0 02/5 09/2 35/0 72/5 81/5 32/0 42/0 02/0 22/1 0 0 0 0 WgniknirDnidicAcitecaorolhcirTfostceffEcinegonicracotapeH eludoNcitsalprepyHdenibmoC amonedAralullecotapeHdna )
From page 151...
... Dichloroacetic Acid Dichloroacetic acid, which is metabolized much more rapidly than trichloroacetic acid, is an effective inducer of hepatic tumors in mice and rats (see Table 4-4)
From page 152...
... 12 staRdnaeci ecnerefeR dnuerF-nerreH 7891.late .latelluB 0991 olegnAeD 9991.late .lateleinaD 2991 6991ariereP MhtiwseidutSreta WgniknirDnidicAcitecaorolhciDfostceffEcinegonicracotapeH amonicraCralullecotapeH ) yticilpitlum(n/romuT 7.1 RN 52.0 0 7.1 2.2 1.0 36.0 0 0 0 1.0 20.0 0 40.0 73.0 ecnedicnI 62/12 RN 42/5 11/0 21/8 03/52 02/2 42/51 04/0 04/0 02/0 02/1 09/2 05/0 82/1 91/5 eludoNcitsalprepyHdenibmoC amonedAralullecotapeHdna )
From page 153...
... 13 olegnAeD 9991.late olegnAeD 6991.late 82.0 RN 86.0 92.1 74.2 9.2 0 0 0 40.0 0 0 1.0 enodtoN 05/5 RN 42/5 23/61 41/6 8/4 7/0 7/0 7/0 72/1 32/0 62/0 92/2 enodtoN 52.0 5.0 23.0 8.0 58.0 46.0 0 0 0 69.0 40.0 0 13.0 enodtoN 05/41 33/11 42/11 23/32 41/31 8/8 7/0 7/0 7/0 72/62 32/1 62/0 92/9 enodtoN 001 001 001 001 001 001 06 06 06 06 401 401 401 401 0 50.0 5.0 1 2 5.3 0 50.0 5.0 4.2 0 50.0 5.0 4.2 )
From page 154...
... . Chloral hydrate administered to male B6C3F1 mice for 2 years in drinking water at an average dose of 166 mg/kg/day resulted in a 71% incidence of hepatic tumors (combined adenomas and carcinomas)
From page 155...
... 1 ecnerefeR inahgnishjiR 6891.late .lateleinaD 2991 egroeG 0002.late a2002PTN b2002PTN b2002PTN ;b2002PTN .lateyekaeL a3002 ralullecotapeH n/romuT ) yticilpitlum( 11.0 11.0 83.0 01.0 64.0 47.0 27.0 30.1 27.0 0 0 0 0 -- -- - amonicraC ecnedicnI 91/2 9/1 8/3 02/2 42/11 %8.45 %3.45 %0.95 %4.48 0 0 0 0 84/4 84/01 74/01 a 84/7 84/61 a84/52 a74/32 a84/22 84/2 84/5 84/4 84/8 eci MnietardyHlarolhCfostceffEcinegonicracotapeH eludoNcitsalprepyHdenibmoC amonedAralullecotapeHdna n/romuT )
From page 156...
... Collective Assessment of Animal Data Trichloroacetic acid and chloral hydrate appear to be capable of inducing liver tumors only in mice, but dichloroacetic acid also induces liver tumors in rats. The blood concentration of trichloroacetic acid required to induce liver cancer in mice approaches the millimolar range; trichloroacetic acid is a peroxisome proliferator in the same dose range that induces liver cancer.
From page 157...
... Thus, trichloroacetic acid, dichloroacetic acid, and carbon tetrachloride were hypothesized to have individually different modes of action as promoters. In general, interactions between carbon tetrachloride and trichloroacetic acid were seen to be additive and likely acting via different mechanisms whereas interactions between carbon tetrachloride and dichloroacetic acid were generally less than additive with a consistent dose-dependent decrease in the growth rate of tumors promoted by carbon tetrachloride.
From page 158...
... Thus, the species difference in the potency of trichloroethylene and its metabolites to induce liver tumors must be put in context with this historical data. Human Studies Because it was not possible for the committee to provide a comprehensive evaluation of the epidemiologic evidence on trichloroethylene and different cancers, it borrowed a previously compiled summary of the epidemiologic evidence on liver cancer from the Institute of Medicine (IOM 2003)
From page 159...
... Biologically monitored Swedish workers 4a 1.41 (0.38-3) 1994 Cohort Studies -- Mortality Chang et al.
From page 160...
... Aircraft maintenance workers in Utah 1998 Primary liver cancer for all TCE exposed 4 1.7 (0.2-16.2) Liver and biliary cancer by cumulative TCE exposure Males No exposure 3 0.5 (0.1-2.4)
From page 161...
... c Internal cohort analyses for peak and cumulative exposure to trichloroethylene classifications used Cox proportional-hazards models. ABBREVIATIONS: NA, not available; CI, confidence interval: TCE, trichloroethylene; U-TCA, urinary trichloroacetic acid.
From page 162...
... , whereas genotoxicity is a broader term that includes mutational end points, cytogenetic analysis, and primary DNA damage. Most mutagenicity assays for trichloroacetic acid, dichloroacetic acid,
From page 163...
... . The weight of evidence on the mutagenicity of chloral hydrate, dichloroacetic acid, and trichloroacetic acid indicates that a chemically induced mutation is unlikely to be a key event in the induction of tumors (Moore and Harrington-Brock 2000)
From page 164...
... Chloral hydrate is considered either a very weak or a nonperoxisome proliferator. Thus, at least in terms of trichloroethylene, trichloroacetic acid, and dichloroacetic acid, the PPAR agonism (i.e., peroxisome proliferation)
From page 165...
... . A minimal set of data elements to support a convincing demonstration that rodent liver tumors have arisen as a result of a PPAR mode of action would consist of PPAR agonism combined with light- or electronmicroscopic evidence for peroxisome proliferation.
From page 166...
... Whether trichloroethylene and its metabolites meet this minimal data set is discussed below. Trichloroethylene The PPAR mode of action relative to trichloroethylene is summarized in Table 4-7; many of these effects might be attributable to trichloroethylene metabolites -- in particular, trichloroacetic acid and dichloroacetic acid.
From page 167...
... The accepted explanation for this species difference in sensitivity is a difference in metabolism. Trichloroethylene is metabolized by cytochrome P-450s and other noncytochrome P-450 oxidative enzymes to trichloroacetic acid and dichloroacetic acid.
From page 168...
... and cause peroxisome proliferation, the liver hypertrophy is not PPAR dependent. Also, the clonal expansion of preneoplastic foci by dichloroacetic acid is quite different with different phenotypic and genetic markers than by trichloroacetic acid and trichloroethylene.
From page 169...
... Oxidative stress Has not been studied. ABBREVIATIONS: DCA, dichloroacetic acid; GST, glutathione S-transferase; IGF-II, insulinlike growth factor II; TCA, trichloroacetic acid.
From page 170...
... 2004 ABBREVIATIONS: DCA, dichloroacetic acid; GST, glutathione S-transferase; IGF-II, insulinlike growth factor II; TCA, trichloroacetic acid; TGF-, transforming growth factor type . Weight of Evidence Table 4-11 summarizes the committee's evaluation of the weight of evidence for a PPAR mode of action in rodents for trichloroethylene and its metabolites.
From page 171...
... Dose-Response Relationships The dose-response relationships for the key events in the PPAR mode of action are shown in the Table 4-12. Note the results from the comparison of wild-type with PPAR null mice that show the role of this receptor in the toxicity of trichloroethylene or its metabolites (discussed earlier in this chapter)
From page 172...
... . ABBREVIATIONS: DCA, dichloroacetic acid; TCA, trichloroacetic acid; TCE, trichloroethylene.
From page 173...
... 13 ecnerefeR dnayenola namxa M W 9991 dnayenola namxa M W 9991 nergla W b0002.late .lateoaT 9991 .lateoaT 9991 .lateoaT 9991 .lateoaT b0002 .lateoaT b0002 deunitnoc niartS/seicepS detcefsnartsllec1-soC dnanamuhhtiw RAPPesuom detcefsnartsllec1-soC dnanamuhhtiw RAPPesuom sllec5.8LH htiwdetcefsnart RAPPesuom ecim ecim ecim ecim ecim F3C6B 1 F3C6B 1 F3C6B 1 F3C6B 1 F3C6B 1 redneG A/N A/N A/N elameF elameF elameF elameF elameF spihsnoitaleResnopseR-esoDnoitcA-fo-edo noitaruD rh42 rh42 rh42 syad33 kw64 kw64 syad5 syad5 elciheV OS OS MD MD nwonknU lionroC reta reta W W lionroC reta W etuoR ortivnI ortivnI ortivnI 5,egavaglarO kw/syad gniknirD retaw gniknirD retaw egavaglarO egavaglarO a M RAPP noitartnecnoC/esoD Mm5; Mm5, 4ta Mm0.1,ACT Mm0.1,ACD ACD( Mm4,ACT ) tceffeon, Mm 21-4 ELBAT tceffE stnevElasuaC noitavitcARAPP seneGyrotalugeRhtworGfonoitalugeR gk/gm000,1,ECT L/lomm02,ACD L/lomm02,ACT gk/gm000,1,ECT gk/gm005,ACT cym-c,nuj-c ni(cym-c,nuj-c )
From page 174...
... 14 ecnerefeR .lateoaT b0002 rethguaL 4002.late rethguaL 4002.late ginualK 1991.late ginualK 1991.late ginualK 1991.late ginualK 1991.late dnarebuatS 7991lluB dnarebuatS 7991lluB niartS/seicepS ecim F3C6B 1 dnaepyt-dliw921VS ecimllunRAPP dnaepyt-dliw921VS ecimllunRAPP ecim ecim F3C6B 1 F3C6B 1 tar443F tar443F ecim ecim F3C6B 1 F3C6B 1 redneG elameF ela ela ela M M M elameF ela ela ela ela M M M M noitaruD syad5 syad3 kw3 syad41,7 syad41,7,3 syad41,7,3 syad41,7,3 syad41 syad82,41 elciheV reta lyhte W M esolullec )
From page 175...
... 1 .lateinoS 8991 .laterebuatS 8991 nergla W a0002.late .lateeG 1002 rethguaL 4002.late rethguaL 4002.late rethguaL 4002.late deunitnoc staryelwaD-eugarpS morfsetycotapeH ecim F3C6B 1 yramirpnamuH ecim serutluc F3C6B 1 dnaepyt-dliw921VS ecimllunRAPP dnaepyt-dliw921VS ecimllunRAPP dnaepyt-dliw921VS ecimllunRAPP ela ela ela M M M dna elameF elameF ela ela ela M M M )
From page 176...
... 16 ecnerefeR rethguaL 4002.late rethguaL 4002.late rethguaL 4002.late nergla W a0002.late .lateariereP 4002 .lateyekaeL a3002 olegnAeD 7991.late .late mudO 8891 niartS/seicepS dnaepyt-dliw921VS ecimllunRAPP dnaepyt-dliw921VS ecimllunRAPP dnaepyt-dliw921VS ecimllunRAPP revilesuom ecimrtcN/ F3C6B 1 dnaetanegomoh oN.erutlucyramirp htiwneesstceffe namuhrotar HEL serutluc/sllec ecim ecim F3C6B 1 F3C6B 1 star443F star443F FC6B 1 redneG ela ela ela ela M M M M dna elameF elameF ela ela ela M M M dna elameF noitaruD kw1 kw3 kw3 rh42 kw44dna8 kw401 kw401-51 syad82 elciheV reta reta reta aide reta reta reta W W W M W W W riA etuoR gniknirD retaw gniknirD retaw gniknirD retaw ortivnI gniknirD retaw 5(egavaG ) keew/syad gniknirD retaw noitalahnI a deunitnoC noitartnecnoC/esoD ton( M0.2,0.1,ACT )
From page 177...
... 1 .late mudO 8891 nergla W 4002.late amijakaN 0002.late amijakaN 0002.late trahrevE 8991.late yhtrowsdloG ppoPdna 7891 ecim FC6B 1 tarsnavEgnoL setycotapehyramirp nineeston(921/vS citecaorolhconom,AC ) llunRAPP nineeston(921/vS nirollunRAPP )
From page 178...
... Investigators have been able to dissociate the glycogen deposition effect from the peroxisome proliferation produced by trichloroethylene and its metabolites because dichloroacetic acid, which produces significant liver enlargement and no peroxisome proliferation, induces a marked accumulation of liver glycogen. In contrast, exposure to trichloroacetic acid produces only modest glycogen accumulation while stimulating considerable peroxisome proliferation.
From page 179...
... The three major metabolites of trichloroethylene -- trichloroacetic acid, dichloroacetic acid, and chloral hydrate -- can contribute to liver cancer in mice. None of the three is directly mutagenic or genotoxic as the principal mode of action.
From page 180...
... Because the metabolites of chloral hydrate are trichloroacetic acid and dichloroacetic acid, the contribution to liver tumor induction of the specific modes of action of each of these metabolites is also likely; however, an overall lack of potency for chloral hydrate in the carcinogenic response is notable. Induction of peroxisome proliferation in human liver is not a prominent feature; therefore, this key event related to trichloroacetic acid liver carcinogenesis is not likely to occur in humans.
From page 181...
... Studies similar to those car ried out with halothane could be instrumental in elucidating whether autoimmunity is a causal factor in the hepatotoxicity of trichloroethylene. · Studies are needed to determine the metabolic pathway and yield for forming dichloroacetic acid from trichloroethylene either via trichloroacetic acid or via other pathway(s)


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