RESUMO
The chlorinated acetic acids, in particular dichloroacetic acid (DCA), are found as chlorine disinfection by-products in finished drinking water supplies. DCA has previously been demonstrated to be a mouse liver carcinogen. Chronic studies are described in which male Fischer (F344) rats were exposed to DCA in their drinking water. In the first study, 28 day old rats were exposed to a regimen of 0.05, 0.5 and 5.0 g/l DCA. When animals in the high dose group began to exhibit peripheral hind leg neuropathy, the dose was lowered in stages to 1 g/l. These animals were sacrificed at 60 weeks due to the severe, irreversible neuropathy and were not included in this analysis. The remaining groups of animals were treated for 100 weeks. In the second study, rats were initially exposed to 2.5 g/l DCA which was lowered to 1 g/l after 18 weeks. The mean daily concentration (MDC) of 1.6 g/l was calculated over the 103 week exposure period. Time-weighted mean daily doses (MDD) based on measured water consumption were 3.6, 40.2 and 139 mg/kg bw/day for the 0.05, 0.5 and 1.6 g/l DCA respectively. Based upon the pathologic examination, DCA induced observable signs of toxicity in the nervous system, liver and myocardium. However, treatment related neoplastic lesions were observed only in the liver. A statistically significant increase of carcinogenicity (hepatocellular carcinoma) was noted at 1.6 g/l DCA. Exposure to 0.5 g/l DCA increased-hepatocellular neoplasia, (carcinoma and adenoma) at 100 weeks. These data demonstrate that DCA is an hepatocarcinogen to the male F344 rat. Calculation of the MDD at which 50% of the animals exhibited liver neoplasia indicated that the F344 male rat (approximately 10 mg/kg bw/day) is ten times more sensitive than the B6C3F1 male mouse (approximately 100 mg/kg bw/day). A "no observed effects level' (NOEL) of 0.05 g/l (3.6 mg/kg/day) was the same as for the mouse (3-8 mg/kg/day).
Assuntos
Ácido Dicloroacético/toxicidade , Administração Oral , Animais , Peso Corporal/efeitos dos fármacos , Testes de Carcinogenicidade , Ácido Dicloroacético/administração & dosagem , Ácido Dicloroacético/análise , Fígado/efeitos dos fármacos , Fígado/patologia , Neoplasias Hepáticas/induzido quimicamente , Masculino , Índice Mitótico/efeitos dos fármacos , Tamanho do Órgão/efeitos dos fármacos , Palmitoil Coenzima A/biossíntese , Palmitoil Coenzima A/efeitos dos fármacos , Ratos , Ratos Endogâmicos F344 , Abastecimento de ÁguaRESUMO
The effect of daily i.p. injections of 0, 1, 10 and 80 mg/kg phenobarbital for 1 week on the activity of the hepatic drug-metabolizing enzyme system was measured in the rat by a model substrate assay employing lindane (gamma-HCH) and by a battery of in vitro enzyme assays. Comparison of the dose-response curves of the in vivo and in vitro assays indicated that urinary metabolites of lindane provided a good index of phenobarbital-induced change in both phase I and phase II reactions.
Assuntos
Fígado/efeitos dos fármacos , Preparações Farmacêuticas/metabolismo , Fenobarbital/farmacologia , Animais , Clorofenóis/metabolismo , Relação Dose-Resposta a Droga , Feminino , Glucuronosiltransferase/análise , Glutationa Transferase/análise , Hexaclorocicloexano/metabolismo , Técnicas In Vitro , Fígado/enzimologia , Ratos , Ratos Endogâmicos F344RESUMO
The effect of 7 daily i.p. injections of 0, 2, 20, or 200 microliters/kg carbon tetrachloride on the activity of the hepatic drug-metabolizing enzyme system was measured in the rat by a model substrate assay, employing lindane (gamma-hexachlorocyclohexane), and by a battery of in vitro enzyme assays. The data in this study indicated that repeated administration of CCl4 for 7 days significantly increased phase I and phase II reactions in vivo and in vitro. Though there were differences between the responses of the in vivo and in vitro assays, this is the first report of increased hepatic drug-metabolizing enzyme activity from repeated treatment with CCl4.
Assuntos
Tetracloreto de Carbono/toxicidade , Fígado/efeitos dos fármacos , Animais , Radioisótopos de Carbono , Cromatografia Gasosa , Feminino , Glucose-6-Fosfatase/metabolismo , Hexaclorocicloexano/metabolismo , Hexobarbital/metabolismo , Injeções Intraperitoneais , L-Iditol 2-Desidrogenase/metabolismo , Fígado/enzimologia , Ratos , Ratos Endogâmicos F344RESUMO
The effect of a single i.p. injection of 0, 20, 200, and 1000 microliter/kg carbon tetrachloride on the activity of the hepatic drug-metabolizing enzyme system was measured in the rat by a model substrate assay employing lindane (gamma-hexachlorocyclohexane) and by a battery of in vitro enzyme assays. The data in this study indicated that carbon tetrachloride had a biphasic influence on the phase I reactions with the lowest dose inducing a significant increase in enzyme activity while the highest dose produced significant inhibition. Significant CCl4-induced reductions in glucuronyltransferase and sulfotransferase activities were also observed while the effect on glutathione-S-transferase was ambiguous. The in vivo and in vitro assays showed good agreement.
Assuntos
Tetracloreto de Carbono/toxicidade , Fígado/efeitos dos fármacos , Álcoois/metabolismo , Animais , Tetracloreto de Carbono/administração & dosagem , Clorofenóis/metabolismo , Relação Dose-Resposta a Droga , Indução Enzimática/efeitos dos fármacos , Etilmorfina/metabolismo , Feminino , Glucuronosiltransferase/antagonistas & inibidores , Hexaclorocicloexano/metabolismo , Técnicas In Vitro , Fígado/enzimologia , Fígado/metabolismo , Ratos , Ratos Endogâmicos F344 , Sulfurtransferases/antagonistas & inibidoresRESUMO
The cytotoxicity of four tumorigenic minerals: erionite(w), erionite(c), UICC crocidolite, UICC chrysotile and nontumorigenic mordenite was compared in Chinese hamster lung V79 cells. The results indicate that the tumorigenic minerals were toxic by showing more than 50% toxicity for at least one dose between 10 and 100 micrograms/ml. Mordenite was nontoxic. Higher potency of erionite, however, was not evident in this system when the dose considered was expressed in mass units. On the other hand, when the degree of cytotoxicity was considered per number of mineral fibers, it was clear that fewer erionite fibers of all three dimensions (A greater than or equal to 3; L greater than or equal to 8.0 micrometers, W less than or equal to 0.25 micrometer; and L less than 5.0 micrometers, W less than or equal to 0.1 micrometer) than those of UICC crocidolite and UICC chrysotile were needed to produce similar toxicity. This suggests that the dose in number of fibers may be a better parameter than the total mass dose as a correlate of tumorigenic potential.
Assuntos
Silicatos de Alumínio/toxicidade , Amianto/toxicidade , Carcinógenos , Animais , Asbesto Crocidolita , Asbestos Serpentinas , Células Cultivadas , Cricetinae , Neoplasias Pulmonares/induzido quimicamente , ZeolitasRESUMO
The chlorinated acetic acids monochloroacetic acid (MCA) and trichloroacetic acid (TCA) are found as chlorine disinfection by-products in finished drinking-water supplies. TCA has been demonstrated to be a mouse liver carcinogen. A chronic study in which male Fischer 344/N rats were exposed for 104 wk to TCA and MCA in the drinking water is described. Animals, 28 d old, were exposed to 0.05, 0.5, or 2 g/L MCA, or 0.05, 0.5, or 5 g/L TCA. The 2.0 g/L MCA was lowered in stages to 1 g/L when the animals began to exhibit signs of toxicity. A time-weighted mean daily MCA concentration (MDC) of 1.1 g/L was calculated over the 104-wk exposure period. Time-weighted mean daily doses (MDD) based upon measured water consumption were 3.5, 26.1, and 59.9 mg/kg/d for 0.05, 0.5, and 1.1 g/L MCA, respectively; TCA MDD were 3.6, 32.5, and 363.8 mg/kg/d. Nonneoplastic hepatic changes were for the most part spontaneous and age related. No evidence of hepatic neoplasia was found at any of the MCA or TCA doses. The incidence of neoplastic lesions at other sites was not enhanced over that in the control group. Drinking water concentrations of > or = 0.5 g/L MCA produced a moderate to severe toxicity as reflected by a depressed water consumption and growth rate. A no-observed-effects level (NOEL) for carcinogenicity of 0.5 g/L (26.1 mg/kg/d) MCA was calculated. TCA at drinking water levels as high as 5 g/L produced only minimal toxicity and growth inhibition and provided a NOEL of 364 mg/kg/d. Our results demonstrate that under the conditions of this bioassay, MCA and TCA were not tumorigenic in the male F344/N rat.
Assuntos
Acetatos/toxicidade , Neoplasias Hepáticas Experimentais/induzido quimicamente , Ácido Tricloroacético/toxicidade , Acetatos/administração & dosagem , Administração Oral , Animais , Peso Corporal/efeitos dos fármacos , Neoplasias Hepáticas Experimentais/patologia , Masculino , Nível de Efeito Adverso não Observado , Tamanho do Órgão/efeitos dos fármacos , Ratos , Ratos Endogâmicos F344 , Ácido Tricloroacético/administração & dosagem , Abastecimento de ÁguaRESUMO
K.J. Rothman has explored in some detail the issue of assessing the potential presence of synergism (or antagonism) in data generated from either a cohort or a case-control study. Arguing that the "natural" scale for quantifying the joint effects of two or more factors acting in combination is the probability scale, he has proposed a procedure based on a ratio-type index for evaluating two-factor interaction in the presence of non-zero background effects. In this paper, the authors review the rationale underlying Rothman's approach for a cohort study. They then present what they maintain is a simpler and more appropriate test procedure (utilizing a linear contrast of the observed risks) for the additive approximation to his basic probabilistic model of "no interaction." A likelihood ratio test based on his original model is also proposed, as well as a closed form approximation to it. Finally, the assessment of interaction in cohort studies involving exposure factors measured at more than two levels is addressed.
Assuntos
Epidemiologia , Modelos Teóricos , Probabilidade , HumanosRESUMO
The cytogenetic effects of erionite treatment of V79 cells were compared with those of UICC crocidolite and UICC chrysotile treatment. A significant reduction in diploid cells with an accompanying increase in aneuploid and polyploid cells was observed with all three treatments. In the erionite-treated cultures, an increase in aneuploidy was observed at all dose levels ranging from 10 to 100 micrograms/ml, whereas in the crocidolite- and chrysotile-treated cultures, significant increases in aneuploidy were observed at all dose levels except the low dose, 10 micrograms/ml. Chromatid aberrations were observed in cultures treated with crocidolite and chrysotile and were especially pronounced at dose 100 micrograms/ml of chrysotile. The clastogenic effect of erionite was weaker but statistically significant at dose 100 micrograms/ml. An extrapolation of these cytogenetic changes over dose in number of fibers suggests that erionite was more reactive than the other two minerals in producing aneuploidy. The number of fibers required to produce a similar degree of cytogenetic effects was several orders of magnitude higher for chrysotile and crocidolite than erionite. These results correlate with the higher tumorigenic potency of erionite. In general, fewer cells treated with erionite entered anaphase than those treated with the other two minerals. As a result, abnormal anaphases representing chromosomal mis-segregation were observed only in the chrysotile- and crocidolite-treated cultures. To our knowledge, this is the first report on cytogenetic effects of erionite.
Assuntos
Silicatos de Alumínio/toxicidade , Anáfase/efeitos dos fármacos , Amianto/toxicidade , Metáfase/efeitos dos fármacos , Animais , Asbesto Crocidolita , Asbestos Serpentinas , Células Cultivadas , Aberrações Cromossômicas , Cricetinae , Tamanho da Partícula , Ploidias/efeitos dos fármacos , ZeolitasRESUMO
Mathematical modeling of the kinetics of nickel absorption, distribution, and elimination was performed in healthy human volunteers who ingested NiSO4 drinking water (Experiment 1) or added to food (Experiment 2). Nickel was analyzed by electrothermal atomic absorption spectrophotometry in serum, urine, and feces collected during 2 days before and 4 days after a specified NiSO4 dose (12 micrograms of nickel/kg, n = 4; 18 micrograms of nickel/kg, n = 4; or 50 micrograms of nickel/kg, n = 1). In Experiment 1, each of the subjects fasted 12 hr before and 3 hr after drinking one of the specified NiSO4 doses dissolved in water; in Experiment 2, the respective subjects fasted 12 hr before consuming a standard American breakfast that contained the identical dose of NiSO4 added to scrambled eggs. Kinetic analyses, using a compartmental model, provided excellent goodness-of-fit for paired data sets from all subjects. Absorbed nickel averaged 27 +/- 17% (mean +/- SD) of the dose ingested in water vs 0.7 +/- 0.4% of the same dose ingested in food (a 40-fold difference); rate constants for nickel absorption, transfer, and elimination were not significantly influenced by the oral vehicle. The elimination half-time for absorbed nickel averaged 28 +/- 9 hr. Renal clearance of nickel averaged 8.3 +/- 2.0 ml/min/1.73 m2 in Experiment 1 and 5.8 +/- 4.3 ml/min/1.73 m2 in Experiment 2. This study confirms that dietary constituents profoundly reduce the bioavailability of Ni2+ for alimentary absorption; approximately one-quarter of nickel ingested in drinking water after an over-night fast is absorbed from the human intestine and excreted in urine, compared with only 1% of nickel ingested in food. The compartmental model and kinetic parameters provided by this study will reduce the uncertainty of toxicologic risk assessments of human exposures to nickel in drinking water and food.