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Title: Carcinogenicity of by-products of disinfection in mouse and rat liver

Abstract

By-products of disinfection were tested for initiating and/or promoting activity in rat liver by using the rat liver foci bioassay. The assay uses an increased incidence of ..gamma..-glutamyltranspeptidase-positive foci (GGT foci) as an indicator of carcinogenicity. The by-products of disinfection, including chloramine, halogenated humic acids, halogenated ethanes, halogenated acetonitriles, halogenated methanes, halogenated ethylene, and N-Cl piperidine, did not initiate GGT foci, which would indicate that they are not capable of initiating carcinogenesis. Chloroform and halogenated benzenes were tested in this assay for their ability to promote the occurrence of GGT foci and tumors initiated by diethylnitrosamine (DENA). Chloroform either had no effect or inhibited the occurrence of GGT foci when administered subsequent to a single dose of DENA. However, when the chloroform was administered in drinking water concurrently with weekly doses of DENA, it enhanced the formation of liver tumors. Of 20 halogenated benzenes tested, only 1,2,4,5-tetrachlorobenzene and hexachlorobenzene promoted the occurrence of DENA-initiated GGT foci. Thus in rat liver, the tested by-products of drinking water disinfection did not demonstrate tumor-initiating activity, although a few appeared to possess tumor-promoting activity. Chloroform was also tested for tumor-promoting activity in 15-days-old Swiss mice initiated with ethylnitrosourea (ENU). ENU at 5 and 20more » ..mu..g/g caused a dose-dependent increase in liver tumors. In male mice, chloroform inhibited both spontaneous and ENU-induced liver tumors. When administered in the drinking water, chloroform inhibited, whereas phenobarbital promoted, hepatocarcinogenesis in mice.« less

Authors:
;
Publication Date:
Research Org.:
Environmental Protection Agency, Cincinnati, OH
OSTI Identifier:
5554975
Resource Type:
Journal Article
Resource Relation:
Journal Name: Environ. Health Perspect.; (United States); Journal Volume: 69
Country of Publication:
United States
Language:
English
Subject:
63 RADIATION, THERMAL, AND OTHER ENVIRON. POLLUTANT EFFECTS ON LIVING ORGS. AND BIOL. MAT.; CARCINOGENESIS; DOSE-RESPONSE RELATIONSHIPS; CHLORINATED AROMATIC HYDROCARBONS; BIOLOGICAL EFFECTS; CHLOROFORM; DRINKING WATER; WATER TREATMENT; ACETONITRILE; BY-PRODUCTS; CHLORAMINES; DISINFECTANTS; HALOGENATED ALIPHATIC HYDROCARBONS; HUMIC ACIDS; LIVER; MICE; NITROSAMINES; NITROSOUREAS; PEPTIDE HYDROLASES; RATS; TUMOR PROMOTERS; AMINES; ANIMALS; AROMATICS; BODY; CHLORINATED ALIPHATIC HYDROCARBONS; DIGESTIVE SYSTEM; ENZYMES; GERMICIDES; GLANDS; HALOGENATED AROMATIC HYDROCARBONS; HYDROGEN COMPOUNDS; HYDROLASES; MAMMALS; NITRILES; NITROSO COMPOUNDS; ORGANIC ACIDS; ORGANIC CHLORINE COMPOUNDS; ORGANIC COMPOUNDS; ORGANIC HALOGEN COMPOUNDS; ORGANIC NITROGEN COMPOUNDS; ORGANS; OXYGEN COMPOUNDS; PATHOGENESIS; PROMOTERS; RODENTS; VERTEBRATES; WATER; 560300* - Chemicals Metabolism & Toxicology

Citation Formats

Herren-Freund, S.L., and Pereira, M.A.. Carcinogenicity of by-products of disinfection in mouse and rat liver. United States: N. p., 1986. Web. doi:10.1289/ehp.866959.
Herren-Freund, S.L., & Pereira, M.A.. Carcinogenicity of by-products of disinfection in mouse and rat liver. United States. doi:10.1289/ehp.866959.
Herren-Freund, S.L., and Pereira, M.A.. Sat . "Carcinogenicity of by-products of disinfection in mouse and rat liver". United States. doi:10.1289/ehp.866959.
@article{osti_5554975,
title = {Carcinogenicity of by-products of disinfection in mouse and rat liver},
author = {Herren-Freund, S.L. and Pereira, M.A.},
abstractNote = {By-products of disinfection were tested for initiating and/or promoting activity in rat liver by using the rat liver foci bioassay. The assay uses an increased incidence of ..gamma..-glutamyltranspeptidase-positive foci (GGT foci) as an indicator of carcinogenicity. The by-products of disinfection, including chloramine, halogenated humic acids, halogenated ethanes, halogenated acetonitriles, halogenated methanes, halogenated ethylene, and N-Cl piperidine, did not initiate GGT foci, which would indicate that they are not capable of initiating carcinogenesis. Chloroform and halogenated benzenes were tested in this assay for their ability to promote the occurrence of GGT foci and tumors initiated by diethylnitrosamine (DENA). Chloroform either had no effect or inhibited the occurrence of GGT foci when administered subsequent to a single dose of DENA. However, when the chloroform was administered in drinking water concurrently with weekly doses of DENA, it enhanced the formation of liver tumors. Of 20 halogenated benzenes tested, only 1,2,4,5-tetrachlorobenzene and hexachlorobenzene promoted the occurrence of DENA-initiated GGT foci. Thus in rat liver, the tested by-products of drinking water disinfection did not demonstrate tumor-initiating activity, although a few appeared to possess tumor-promoting activity. Chloroform was also tested for tumor-promoting activity in 15-days-old Swiss mice initiated with ethylnitrosourea (ENU). ENU at 5 and 20 ..mu..g/g caused a dose-dependent increase in liver tumors. In male mice, chloroform inhibited both spontaneous and ENU-induced liver tumors. When administered in the drinking water, chloroform inhibited, whereas phenobarbital promoted, hepatocarcinogenesis in mice.},
doi = {10.1289/ehp.866959},
journal = {Environ. Health Perspect.; (United States)},
number = ,
volume = 69,
place = {United States},
year = {Sat Nov 01 00:00:00 EST 1986},
month = {Sat Nov 01 00:00:00 EST 1986}
}
  • Groups of 30 male Sprague-Dawley rats were given 4-nitrosomorpholine-3,3,5,5-d/sub 4/ in their drinking water at concentrations of 0.35 and 0.07 x 10/sup -3/ M for 30 weeks. Two similar groups of rats were simultaneously given unlabeled 4-nitrosomorpholine (NM) at the same molar concentrations; all animals were observed throughout their lives. Those receiving the ..cap alpha..-deuterium-labeled compound had significantly fewer liver tumors than did the corresponding animals receiving the unlabeled compound. The difference in potency appeared to be at least fivefold, a magnitude consistent with a primary kinetic isotope effect on the carcinogenic action of NM. Thus breakage of a bondmore » linking a hydrogen (deuterium) atom with a carbon adjacent to the nitrosamino function may be involved in a rate-limiting step of carcinogenesis by NM.« less
  • Monomethylarsonic acid (MMA{sup V}), dimethylarsinic acid (DMA{sup V}) and trimethylarsine oxide (TMAO{sup V}) are well-documented inorganic arsenic (iAs) methylated metabolites. In our previous studies, DMA{sup V} and TMAO{sup V} were shown to exert carcinogenicity in the rat bladder and liver, respectively. Furthermore, MMA{sup V}, DMA{sup V} and TMAO{sup V} exhibited promoting activity on rat hepatocarcinogenesis. To clarify mechanisms of arsenical carcinogenicity and compare biological responses in the liver and bladder, male F344 rats were sequentially treated for 5, 10, 15, 20 days with MMA{sup V}, DMA{sup V} and TMAO{sup V} in their drinking water at a dose of 0.02%. Significantmore » increase of P450 total content and generation of hydroxyl radicals in the liver were observed from 10 and 15 days of treatment with arsenicals, respectively, with the highest levels induced by TMAO{sup V}. Similarly, elevation of 8-hydroxy-2'-deoxyguanosine (8-OHdG) formation was found in the DNA with significant increase by TMAO{sup V} treatment in the liver at days 15 and 20, and DMA{sup V} in the bladder after 20 days treatment. In addition, cell proliferation and apoptosis indices were significantly increased by TMAO{sup V} in the liver and by DMA{sup V} in the bladder of rats. These events were accompanied by differential up-regulation of phase I and II metabolizing enzymes, cyclins D1 and E, PCNA, caspase 3 and FasL. The results indicate that early elevation of 8-OHdG and cell proliferation via generation of oxidative stress by TMAO{sup V} and DMA{sup V} contributes to their carcinogenicity in the rat liver and bladder.« less
  • The uptake of [ring A-4-{sup 3}H] colchicine and [ring C-methoxy-{sup 3}H]colchicine has been compared in mice from 1 to 24 hr after administration. Less radioactivity was found in brain after administration of ring-labeled colchicine than after administration of the methoxy-labeled colchicine. Three hr after administration of ring-labeled colchicine, 5% of the label was in liver and about 0.01% of the label was present in brain. Forty percent of the brain radioactivity was bound to tubulin as determined by vinblastine precipitation. After 3 hr, an average of 8% of the radioactivity from methoxy-labeled colchicine was found in the liver and 0.16%more » in brain. However, less than 5% of the activity in brain was precipitated by vinblastine, and the colchicine equivalent was comparable to that found after administration of the ring-labeled colchicine. The amount of colchicine entering mouse brain after subcutaneous injection is comparable to the minimum behaviorally effective dose when administered to the caudate. The metabolism of [ring C-methoxy-{sup 3}H] and [ring A-{sup 3}H]colchicine was also studied in rats. the general pattern was similar to mice; less radioactivity was found in brain after administration of the ring-labeled alkoloid than after administration of methoxy-labeled colchicine. Again, 40-50% of ring-labeled colchicine was precipitated by vinblastine. A much smaller percentage of the methoxy-labeled drug was precipitated by vinblastine than of the ring A-labeled colchicine. These experiments, together with behavioral experiments [7], support the hypotheses that structural alteration in synapses by recently synthesized proteins which are transported down the axons and dendrites may be an essential process for long-term memory formation.« less