1Aliphatic Hydrocarbons:Non-Halogenated (Hexane, )Halogenated:Chlorinated Hydrocarbons (Trichloroethylene, ) Brominated Hydrocarbons (Halothane, )Fluorinated Hydrocarbons (Methoxyflurane, )Cyclic Hydrocarbons (Cyclohexane, )Aromatic Hydrocarbons:Monocyclic (Benzene, )Polycyclic (Benzo(a)pyrine, )Alcohols (Ethanol, )• Colorless liquid with a sweet, chloroform-like odor• High production volume chemical• Common contaminant in more than ½ of Superfund Sites (EPA National Priority List hazardous waste sites)• Used as an industrial solvent (furniture and fixtures, fabricated metal products, electrical and electronic equipment, transport equipment, and miscellaneous manufacturing industries)• Exposure: Mainly by inhalation in the workplace, but also in general population via food, water, and air (approximately 10% of the population has detectable levels of TCE in their blood)http://ehp.niehs.nih.gov/roc/toc10.html2• TCE is rapidly absorbed from the stomach, intestines, and lung• After absorption, TCE is distributed throughout the body and concentrates in fatty tissues, such as the liver, brain, and body fat• TCE is metabolized primarily through oxidation by cytochrome P-450 and conjugation with GSH• TCE metabolism in mice, rats, and humans is qualitatively similar, producing the same primary metabolites.Cancer Classification (EPA): TCA is reasonably anticipated to be a human carcinogen based on limited evidence of carcinogenicity from studies in humans, sufficient evidence of carcinogenicity from studies in experimental animals, which indicates there is an increased incidence of malignant and/or a combination of malignant and benign tumors at multiple tissue sites in multiple species of experimental animals, and information suggesting TCE acts through mechanisms that indicate it would likely cause cancer in humans.http://ehp.niehs.nih.gov/roc/toc10.htmlHuman studies found that occupational exposure to TCE was associated with excess incidences of liver cancer, kidney cancer, non-Hodgkin’s lymphoma, prostate cancer, and multiple myeloma, with the strongest evidence for the first three cancers. Elevated risks of death from Hodgkin’s disease, multiple myeloma, cervical cancer, and liver cancer also were observed.In experimental animals tumors occurred at several of the sites as in humans. In mice, TCE induces benign and malignant tumors of the liver, lung, and blood (lymphoma). In rats, TCE induces kidney cancer, interstitial-cell tumors of the testis, and possibly leukemia.3Mechanisms of Carcinogenesis by TCALiver Cancers(M and F B6C3F1 mice, but not Fisher 344 rats):• Major contribution by P450 metabolism of TCE (CH, TCA, DCA)• Initiating effects:ambiguous data on direct genotoxicity of TCE or metabolites• Promotional effect on spontaneously initiated cells in B6C3F1 mice via:peroxisome proliferation and oxidative stress;cytotoxicity and compensatory regeneration;reduction of apoptosis;perturbation of other cell signaling pathways.Mechanisms of Carcinogenesis by TCAKidney Cancers (M Fisher 344 rats only):• Major contribution by GSH conjugation metabolism of TCE:(DCVC, S-(1,2-dichlorovinyl)-L-cysteine)• Initiating effects:DCVC is metabolically activated in proximal renal tubules (β-lyase) to 1,2-dicholovinylthiol that is unstable and gives raise to alkylating species that damage DNA• Promotional effects:cytotoxicity and compensatory regeneration;oxidative stress, ATP depletion, Ca2+-perturbations, etc.;Alpha-2u-globilin nephropathy.4• α2uis the major component of the urinary protein load in male rats and is unique to male rats, although homologous proteins exist in other species, including humans;• Renal proximal tubules reabsorb protein from the glomerular filtrate, and toxicants or pathological conditionsthat interfere with this process cause an excessive accumulation of a2uin lysosomes of renal proximal tubular cells;• Similar phenomenon has not been observed in female rats or in other species;• A number of chemicals, many of them halogenated organic solvents, have been shown to cause the so-called hyaline (protein) droplet nephropathy in male rats. a2u-Globulin Nephropathy• Protein droplets containing α2uincrease in number and size in renal proximal convoluted tubular cells of male rats exposed to certain halogenated hydrocarbons. α2uis a low molecular weight protein that is synthesized only in the liver of mature male rats under androgenic control. Hydrocarbons or their metabolites that induce the response bind irreversibly to α2u, resulting in the lysosomaldegradation of the complex. • The excessive accumulation of reabsorbed proteins in secondary lysosomes of the renal proximal convoluted tubules (S2 segment) is then thought to cause lysosomal dysfunction and cellular necrosis. • Intratubular granular casts of necrotic cellular debris then accumulate at the junction of the pars recta of the proximal tubules (S3 segment) and the thin loop of Henle. • Regenerative cellular proliferation is then induced in response to the loss of cells from the S2 segment of the proximal tubules. • The increased cellular proliferation is then thought to cause development of renal-cell tumors due to increases in DNA damage in replicating cells. Mechanism for the induction of nephropathy and renal tumors by chemicals that induce α2unephropathy5Mechanisms of Carcinogenesis by TCALung Cancers(only by inhalation exposure in mice, but not in rats):• Major contribution by P450 metabolism of TCE in Clara cells:(CH accumulation due to low activity of alcohol dehydrogenase that rapidly converts CH to TCOH in liver and lack of glucoronosyltransferase that produces TCOH glucuronide)• Initiating effects:CH is most genotoxic of all other TCE metabolites• Promotional effect:cytotoxicity and compensatory regeneration;reduction of apoptosis;perturbation of other cell signaling pathways.Human Risk Assessment of Carcinogenesis by TCALiver cancer:Metabolism similar to rodents (+)Peroxisome proliferation is questionable in humans (-)Kidney cancer:GSH conjugation metabolism in rats is greater than in humans (-)Alpha-2u-globulin accumulation is strictly a male rat event (-)Lung cancer:Humans have much fewer Clara cells than mice (-)P450 content of human Clara cells is much less than in mice (-)6• Colorless liquid with a sweet, ether-like odor.• Slightly soluble in water and