Ti Efft fTi Efft fToxic Effects ofToxic Effects ofHydrocarbons and AlcoholsHydrocarbons and AlcoholsHydrocarbons and AlcoholsHydrocarbons and AlcoholsAliphatic Hydrocarbons:Non-Halogenated (Hexane)Halogenated:Chlorinated Hydrocarbons (Trichloroethylene) Brominated Hydrocarbons(Halothane)Brominated Hydrocarbons(Halothane)Fluorinated Hydrocarbons (Methoxyflurane)Cyclic Hydrocarbons(Cyclohexane)Cyclic Hydrocarbons(Cyclohexane)Aromatic Hydrocarbons:Monocyclic(Benzene)Monocyclic(Benzene)Polycyclic (Benzo(a)pyrine)Alcohols (Ethanol)•High production volume chemical• Colorless liquid with a sweet, chloroform‐like odor• 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, ( , p,electrical and electronic equipment, transport equipment, and miscellaneous manufacturing industries)•Exposure: Mainly by inhalation in the workplace but also in gener al population•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.html•TCE is rapidly absorbedTCE is rapidly absorbed from the stomach, intestines, and lung• After absorption, TCE is p,distributed throughout the body and concentrates in fatty tissues, such as the liver brain and body fatliver, brain, and body fat• TCE is metabolized primarily through oxidation by cytochromeoxidation by cytochrome P-450 and conjugation with GSH•TCE metabolism in mice•TCE metabolism in mice, rats, and humans is qualitatively similar, producing the same primary metabolites.Cancer Classification (EPA): TCE isreasonably anticipated to be a humancarcinogen (? 2010 reTCE is reasonably anticipated to be a human carcinogen (? 2010 re-assessment in the works) 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.Human 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 firstprostate 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 http://ehp.niehs.nih.gov/roc/toc10.htmltestis, and possibly leukemia.Mechanisms of Carcinogenesis by TCELiver Cancer (M and F B6C3F1 mice, but not Fisher 344 rats):•Major contribution by P450 metabolism of TCE (CH, TCA, DCA)jy (,,)• 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 TCEKidney Cancer (M Fisher 344 rats only):•Major contribution by GSH conjugation metabolism of TCE:jyjg(DCVC, S-(1,2-dichlorovinyl)-L-cysteine)• Initiating effects:DCVC is metabolically activated in proximal renal tubules (-lyase) to 1,2-dicholovinylthiol that is unstable and gives raise to alkylating species that damage DNAalkylating species that damage DNA• Promotional effects:cytotoxicity and compensatory regeneration;yy pygoxidative stress, ATP depletion, Ca2+-perturbations, etc.;Alpha-2u-globilin nephropathy.a2u-Globulin Nephropathy• 2uis the major component of the urinary protein load in male rats and is unique to male rats although homologous male rats and is unique to male rats, although homologous proteins exist in other species, including humans;• Renal proximal tubules reabsorbprotein from the ppglomerular filtrate, and toxicants or pathological conditionsthat interfere with this process cause an excessive accumulation of a2uin lysosomes of renal proximal tubular 2ucells;• Similar phenomenon has not been observed in female rats or in other species;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 (protein) droplet nephropathy in male rats.Mechanism for the induction of nephropathy and renal tumors by chemicals that induce 2unephropathy• Protein droplets containing 2uincrease in number and size in renal proximal convoluted tubular cells of male rats exposed to certain halogenated hydrocarbonsis a low molecular weight proteinhydrocarbons. 2uis 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 2u, resulting in the lysosomal degradation of the complex. • The excessive accumulation of reabsorbed proteins in secondary lysosomes of the renal proximal convoluted tubules (S2 segment) is then thought to lldftidlllicause 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 Henleof 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.Mechanisms of Carcinogenesis by TCELung Cancer (only by inhalation exposure in mice, but not in rats):•Major contribution by P450 metabolism of TCE in Clara cells:jy(CH accumulation due to low activity of alcohol dehydrogenase that rapidly converts CH to TCOH in liver and lack of
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