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1.
J Toxicol Environ Health ; 47(3): 233-47, 1996 Feb 23.
Artigo em Inglês | MEDLINE | ID: mdl-8604148

RESUMO

Trichloroacetonitrile (TCAN) is a by-product of the chlorine disinfection of water containing natural organic material. When administered by gavage to pregnant Long-Evans rats in a medium-chain triglyceride vehicle, tricaprylin oil (Tricap), at a volume of 10 ml/kg, TCAN induced fetal cardiovascular anomalies at doses as low as 1 mg/kg/d (Smith et al., 1988). A slight but possibly biologically significant increase over the water control group in adverse pregnancy outcomes (resorptions, reduced fetal weight, and anomalies) was observed in the Tricap control group. This led us to reexamine the development effects of TCAN in a second vehicle, corn oil (CO). Five groups of approximately 20 pregnant female rats received TCAN in CO at 15, 35, 55, and 75 mg/kg/d, and in Tricap at 15 mg/kg/d (10 ml/kg dosing volume). Corn oil, Tricap, and water served as vehicle controls. Animals were treated by oral intubation on gestation d 6-18 (vaginal plug = d 0). Five out of 20 dams (75 mg/kg) died during treatment. Adjusted maternal weight gain was lower in females receiving 35 mg/kg TCAN or greater. The mean percent of nonlive implants per litter was elevated at 55 and 75 mg/kg TCAN (CO). The TCAN dose-response curve for fetal (but not maternal) effects was shifted to the right when CO was compared to Tricap. Fetal weight was reduced at 15 mg/kg TCAN (Tricap) and at > or = 55 mg/kg TCAN (CO). When TCAN was administered in CO, the mean frequency of soft-tissue malformations decreased with significantly fewer septal and great vessel cardiovascular defects observed. We hypothesize that the volatile haloacetonitrile, TCAN, may interact with the Tricap vehicle in such a way that effects on the developing cardiovascular system are potentiated. The lowest observed adverse effect level for TCAN (CO) was determined to be 35 kg/kg.


Assuntos
Acetonitrilas/toxicidade , Óleo de Milho , Desenvolvimento Embrionário e Fetal/efeitos dos fármacos , Acetonitrilas/administração & dosagem , Administração Oral , Animais , Caprilatos , Sistema Cardiovascular/efeitos dos fármacos , Sistema Cardiovascular/embriologia , Relação Dose-Resposta a Droga , Excipientes , Feminino , Reabsorção do Feto/induzido quimicamente , Rim/efeitos dos fármacos , Tamanho da Ninhada de Vivíparos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Tamanho do Órgão/efeitos dos fármacos , Gravidez , Distribuição Aleatória , Ratos , Baço/efeitos dos fármacos , Triglicerídeos , Água
2.
J Toxicol Environ Health ; 39(3): 383-93, 1993 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-8350384

RESUMO

1,1,1-Trichloro-2-propanone (1,1,1-TCP) has been identified as a chlorination by-product in finished drinking water supplies. Since little was known of its oral toxicity, exposure studies were conducted with male and female Sprague-Dawley rats (10 males and 10 females/group) exposed by corn oil gavage at 0, 16, 48, 161, or 483 mg/kg for 10 d or 0, 30, 90, or 270 mg/kg for 90 d. Evaluations included mortality, clinical signs, body weight, food consumption, ophthalmology, hematology, clinical chemistry, urinalysis, organ weights, gross pathology, and histopathology. In the 10-d study, severe toxicity was observed at the highest dose level, since most treated animals (8/10 males and 7/10 females) died. Toxicity was also noted at 161 and 48 mg/kg. At 161 mg/kg, 2 males died and an increase in liver weights in both sexes was observed. Acanthosis and hyperkeratosis of the forestomach was present in males and females at 48 mg/kg and above. In the 90-d study, toxicity was significant at 270 mg/kg, with acanthosis and hyperkeratosis of the forestomach evident in most animals and ataxia in about one-half of them. Retinal degeneration, increased serum potassium, and increased blood urea nitrogen were present in females and increased blood calcium in males at that same dose level. Acanthosis and hyperkeratosis were observed in both sexes, and retinal degeneration was prominent in 2 females at 90 mg/kg. It was concluded that 16 mg/kg was the NOAEL (no observed adverse effect level) for the 10-d study while 30 mg/kg was the NOAEL for the 90-d exposure of Sprague-Dawley rats to 1,1,1,-trichloro-2-propanone.


Assuntos
Acetona/análogos & derivados , Mutagênicos/toxicidade , Estômago/efeitos dos fármacos , Acetona/administração & dosagem , Acetona/toxicidade , Administração Oral , Animais , Peso Corporal/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ingestão de Alimentos/efeitos dos fármacos , Feminino , Masculino , Mutagênicos/administração & dosagem , Tamanho do Órgão/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Estômago/patologia
3.
Environ Res ; 61(2): 200-11, 1993 May.
Artigo em Inglês | MEDLINE | ID: mdl-8495662

RESUMO

Several reports have suggested that soluble nickel salts may affect development. In this study female Long-Evans rats drank nickel chloride solutions (0, 10, 50, or 250 ppm Ni) for 11 weeks prior to mating and then during two successive gestation (G1, G2) and lactation (L1, L2) periods. Pups were observed until weaning; breeder males were unexposed. Dams drinking 250 ppm consumed less liquid and more food per kilogram body weight than did controls (liquid: prebreeding, G1, and G2; food: prebreeding, G2 and L2). Maternal weight gain was reduced during G1 in the high- and middle-dose groups; indices of reproductive performance were comparable across groups. Pup birth weight was unaltered by treatment and weight gain was reduced only in male pups exposed to 50 ppm Ni during L1. The frequency of perinatal death is the most significant toxicologic finding of the study. The proportion of dead pups per litter was significantly elevated at the high dose in L1 and at 10 and 250 ppm in L2 (50 ppm, P = 0.076), with a dose-related response in both experimental segments. The number of dead pups per litter was significantly increased at each dose in L2. Prolactin levels in pups were unchanged by treatment and were reduced in dams at the high dose. We conclude that 10 ppm Ni represents the lowest observed adverse effect level (LOAEL) in this study.


Assuntos
Níquel/toxicidade , Animais , Animais Recém-Nascidos , Peso Corporal , Comportamento de Ingestão de Líquido/efeitos dos fármacos , Comportamento Alimentar/efeitos dos fármacos , Feminino , Masculino , Gravidez , Efeitos Tardios da Exposição Pré-Natal , Ratos
4.
Drug Chem Toxicol ; 16(4): 341-50, 1993.
Artigo em Inglês | MEDLINE | ID: mdl-8281888

RESUMO

1,3-Dichloropropanone (1,3-DCP) has been identified as a by-product of the chlorination of water and thus a potential contaminant in drinking water. Since little was known of its oral toxicity, subchronic exposure studies were conducted with male and female Sprague-Dawley rats exposed to 1,3-DCP in drinking water at 0, 5, 65, or 125 ppm for 90 days. Evaluations included mortality, clinical signs, body weight, food consumption, hematology, clinical chemistry, organ weights, gross pathology, and histopathology. No significant organ toxicity was detected although an aversion to drinking 1,3-DCP treated water was observed at 65 and 125 ppm. The only consistent change was a decrease in BUN at 125 ppm in both sexes. Based on a decrease in BUN levels and decreased water consumption, 5 ppm (0.5 mg/kg/day) was considered the NOAEL.


Assuntos
Acetona/análogos & derivados , Acetona/toxicidade , Animais , Peso Corporal/efeitos dos fármacos , Relação Dose-Resposta a Droga , Feminino , Leucócitos/efeitos dos fármacos , Masculino , Tamanho do Órgão/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley
5.
Teratology ; 46(3): 217-23, 1992 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-1523579

RESUMO

Dichloroacetic acid (DCA) is a principal by-product of the chlorine disinfection of water containing humic and fulvic acids, and is also a drug of interest in the therapeutic management of metabolic disorders. The developmental effects of DCA were evaluated in the pregnant Long-Evans rat. In two separate studies, animals were dosed by oral intubation on gestation days 6-15 (plug = 0) with 0, 900, 1,400, 1,900 or 2,400 mg/kg/day and 0, 14, 140, or 400 mg/kg/day. The vehicle control was distilled water. Maternal observations included clinical signs, weight change, and gross evaluation of organ weights and uterine contents at necropsy (day 20). Corpora lutea were counted and uteri stained for implantation sites. Live fetuses were examined for external, skeletal, and soft tissue malformations. Seven dams died during treatment (1,400 mg 1/19, 1,900 mg 2/19, 2,400 mg 4/21), and maternal weight gain was reduced at all except the lowest treatment levels. Liver, spleen, and kidney weights increased in a dose-related manner. The mean percentage of resorbed implants per litter was significantly elevated at greater than or equal to 900 mg/kg/day. Live fetuses showed dose-dependent reductions in weight and length at doses above 140 mg/kg. Statistically significant frequencies of soft tissue malformations ranged from 2.6% (140 mg/kg) to 73% (2,400 mg/kg). These were principally in the cardiovascular system and predominantly comprised defects between the ascending aorta and the right ventricle. Skeletal malformations were not observed in significant numbers in any dose group.(ABSTRACT TRUNCATED AT 250 WORDS)


Assuntos
Anormalidades Induzidas por Medicamentos , Ácido Dicloroacético/toxicidade , Cardiopatias Congênitas/induzido quimicamente , Animais , Peso Corporal/efeitos dos fármacos , Relação Dose-Resposta a Droga , Feminino , Rim/efeitos dos fármacos , Fígado/efeitos dos fármacos , Gravidez , Ratos , Ratos Endogâmicos , Baço/efeitos dos fármacos
6.
Teratology ; 46(3): 225-35, 1992 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-1523580

RESUMO

Dichloroacetic acid (DCA) is a by-product of the chlorine disinfection of water and may occur in treated water at levels exceeding 100 micrograms/L. Previous studies revealed teratogenic effects, particularly heart malformations, at high doses (900-2,400 mg/kg given on days 6-15 of pregnancy). In a series of three studies, groups of 7-10 Long-Evans rats were dosed with 1,900 mg/kg of DCA on days 6-8, 9-11, or 12-15; with 2,400 mg/kg on days 10, 11, 12, or 13; and with 3,500 mg/kg on days 9, 10, 11, 12, or 13, in an attempt to determine the most sensitive period and further characterize the heart defect. In a fourth study, six dams were treated with 1,900 mg/kg of DCA days 6-15 of pregnancy, and 56 fetuses were harvested for light microscopy of the heart. Eight control fetuses from four litters were also examined. No heart malformations were seen in the groups treated with 1,900 mg/kg DCA days 6-8 but were present in the group treated on days 9-11 and 12-15, with the higher incidence occurring on days 12-15. Single doses of 2,400 mg/kg DCA given on days 10, 11, 12, or 13 resulted in a much lower incidence of cardiac malformations, which occurred only on days 10 and 12. The high dose of DCA (3,500 mg/kg) did not increase the incidence of heart defects but showed that dosing on day 9 as well as on days 10 and 12 would produce the defect. The defects seen were characterized as high interventricular septal defects (H-IVSD). Light microscopy showed that the defect was caudal to the semilunar valves, with the anterior right wall of the aorta communicating with the right ventricle. Another aspect of the defect is at the level of the semilunar valves, with the right cusp or sinus of Valsalva in communication with the right ventricle. The defects are discussed more fully and methods for further study suggested.


Assuntos
Ácido Dicloroacético/toxicidade , Cardiopatias Congênitas/induzido quimicamente , Comunicação Interventricular/induzido quimicamente , Animais , Aorta/anormalidades , Feminino , Idade Gestacional , Comunicação Interventricular/patologia , Gravidez , Ratos , Ratos Endogâmicos
7.
Fundam Appl Toxicol ; 19(2): 159-68, 1992 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-1516771

RESUMO

The chlorinated acetaldehydes, chloral hydrate (CH) and 2-chloroacetaldehyde (CAA), have been identified as chlorination by-products in finished drinking water supplies. Although both chemicals are genotoxic, their potential for carcinogenicity had not been adequately explored. The studies reported here are chronic bioassays conducted with male B6C3F1 mice exposed to levels of 1 g/liter CH and 0.1 g/liter CAA via the drinking water for 104 weeks. Distilled water (H2O) served as the untreated control and dichloroacetic acid (DCA; 0.5 g/liter), another chlorine disinfection by-product, was included. The mean daily ingested doses were approximately 166 mg/kg/day for CH, 17 mg/kg/day for CAA, and 93 mg/kg/day for DCA. Evaluations included mortality, body weight, organ weights, gross pathology, and histopathology. The primary target organ was the liver as the organ weights and pathological changes in the other organs (spleen, kidneys, and testes) were comparable between the treated groups and the H2O control group. Liver weights were increased for all three test chemicals at the terminal euthanasia with the greatest increase seen in the CH and DCA groups. Hepatocellular necrosis was induced by all three test chemicals, and it was also most prevalent and severe in the CH and DCA groups. A significant increase in the prevalence of liver tumors was seen for all three chemicals. The strongest response was with DCA, in which 63% of the 104-week survivors had hepatocellular carcinomas (carcinomas) and 42% possessed hepatocellular adenomas (adenomas) and the combined prevalence for carcinomas plus adenoma was 75%. The corresponding prevalence rate for carcinomas, adenomas, and combined tumors were 46, 29, and 71%; 31, 8, and 38%; and 10, 5, and 15% for CH, CAA, and H2O, respectively. In addition to the tumors we evaluated the prevalence of a possible preneoplastic lesion, the hepatocellular hyperplastic nodule (nodules), a lesion which occurred in all three treated groups but not in the H2O group.


Assuntos
Acetaldeído/análogos & derivados , Carcinógenos/toxicidade , Hidrato de Cloral/toxicidade , Ácido Dicloroacético/toxicidade , Neoplasias Hepáticas Experimentais/induzido quimicamente , Acetaldeído/toxicidade , Animais , Peso Corporal/efeitos dos fármacos , Comportamento de Ingestão de Líquido/efeitos dos fármacos , Feminino , Rim/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Tamanho do Órgão/efeitos dos fármacos , Baço/patologia , Testículo/patologia
8.
Carcinogenesis ; 13(8): 1325-30, 1992 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-1354081

RESUMO

In this study we demonstrate that chloroform, a widely used industrial solvent, a medicinal chemical and a common drinking water contaminant, reduces the number of detectable preneoplastic enzyme-altered foci [gamma-glutamyltranspeptidase-positive (GGT+) and placental form glutathione S-transferase-positive (GST-P+)] in the liver of male Fischer 344 rats. The animals were given a partial hepatectomy and 18 h later received a single oral dose of either 0.5 mmol/kg diethylnitrosamine (DENA) or saline. Two weeks later, groups of 12 animals were started on drinking water containing phenobarbital with varying concentrations (200-1800 mg/l) of chloroform fro 12 weeks. Treated and control animals were killed and the number and the volume of GGT+ and GST-P+ expressing hepatic foci were tabulated. The numbers of foci per unit volume (and per unit area), the percent focal volume and the focal liver were reduced by chloroform in a dose-dependent manner. The mean focal volume was not influenced by chloroform. A plausible explanation for these results could be that chloroform exerts its focal inhibitory effect either by selectively killing the putative initiated cells, by retarding the inherent growth rate of enzyme-altered cells or by reducing the effectiveness of the promoter, phenobarbital. The available evidence suggests that the first hypothesis is the most likely explanation for these observations. These results are consistent with earlier studies showing that chloroform inhibits tumorigenesis in rodents.


Assuntos
Clorofórmio/farmacologia , Dietilnitrosamina/farmacologia , Glutationa Transferase/metabolismo , Fígado/efeitos dos fármacos , Fígado/enzimologia , Fenobarbital/farmacologia , gama-Glutamiltransferase/metabolismo , Análise de Variância , Animais , Peso Corporal , Citocromo P-450 CYP1A1 , Citocromo P-450 CYP2B1 , Sistema Enzimático do Citocromo P-450/metabolismo , Relação Dose-Resposta a Droga , Ingestão de Líquidos , Humanos , Masculino , Microssomos Hepáticos/enzimologia , Tamanho do Órgão , Oxirredutases/metabolismo , Ratos , Ratos Endogâmicos F344
9.
Drug Chem Toxicol ; 15(3): 217-32, 1992.
Artigo em Inglês | MEDLINE | ID: mdl-1425361

RESUMO

Male and female Sprague-Dawley rats were administered drinking water containing 300, 600, 1200, or 2400 mg/L chloral hydrate for 90 days. A control group received distilled water only. No animals died during the study and no differences were observed in body weight gain or food and water consumption, except for males at the highest-dose level. Minor treatment-related effects were observed for organ weights and hematological parameters and these did not appear to be of toxicological significance. Some indications of toxicity were evident in the 2400 mg/L male group (equivalent to 168 mg/kg-day) including a significant decrease in food and water consumption and in weight gain. In addition, histopathological examination of these animals revealed an apparent increase in the incidence of focal hepatocellular necrosis. Increases in AST, ALT, and LDH, which occurred at several dose levels in males, but particularly at 200 mg/L, are consistent with the hepatocellular necrosis of minimal to mild severity diagnosed by microscopic examination. These liver changes, except for sporadic enzyme changes, were not seen in the female rats which actually consumed higher doses of chloral hydrate (e.g., 288 mg/kg-day at 2400 mg/L). On the basis of the mild liver toxicity (histopathological and clinical) observed in males at the highest doses (168 mg/kg-day), the no observed adverse effect level (NOAEL) for oral exposure of rats to chloral hydrate for 90 days is considered to be 96 mg/kg-day (600 mg/L).


Assuntos
Hidrato de Cloral/toxicidade , Alanina Transaminase/sangue , Animais , Aspartato Aminotransferases/sangue , Comportamento Animal/efeitos dos fármacos , Nitrogênio da Ureia Sanguínea , Peso Corporal/efeitos dos fármacos , Cálcio/sangue , Creatinina/sangue , Relação Dose-Resposta a Droga , Ingestão de Líquidos/efeitos dos fármacos , Ingestão de Alimentos/efeitos dos fármacos , Índices de Eritrócitos/efeitos dos fármacos , Feminino , L-Lactato Desidrogenase/sangue , Fígado/efeitos dos fármacos , Fígado/patologia , Masculino , Necrose , Tamanho do Órgão/efeitos dos fármacos , Fosfatos/sangue , Ratos , Ratos Sprague-Dawley
10.
Toxicology ; 67(2): 171-85, 1991 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-2031251

RESUMO

Male and female Sprague-Dawley rats were administered the sodium salt of monochloroacetic acid (SMCA) by oral gavage for a period of 90 consecutive days. Dosage levels of 15, 30, 60 or 120 mg/kg per day were employed. SMCA clearly induced toxicity in both females and males, with the greatest severity in the male animals. Both the liver and kidneys were identified as target organs. At 120 mg/kg per day, 30% of females and 80% of the males died, most within the first 2 days of treatment. Hemorrhagic and congested lungs (possibly a postmortem change) were seen in the early deaths (1-3 days) whereas liver lesions were observed in later deaths. In addition, there was nephrotoxicity as evidenced by elevated creatinine, blood calcium (BCAL), and blood urea nitrogen (BUN) levels. Hepatotoxicity was indicated by increases in the serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Both organs showed increased organ-to-body weight ratios. Microscopic examination revealed a significant (P less than or equal to 0.001) increase in chronic renal nephropathy and increased splenic pigmentation at 60 mg/kg per day in the males. Based on the observation of toxicity at all treatment levels in males, a lowest observed adverse effect level (LOAEL) of 15 mg/kg per day is proposed for a 90-day exposure to SMCA by oral gavage to the Sprague--Dawley rat.


Assuntos
Acetatos/toxicidade , Rim/efeitos dos fármacos , Fígado/efeitos dos fármacos , Alanina Transaminase/sangue , Animais , Aspartato Aminotransferases/sangue , Nitrogênio da Ureia Sanguínea , Peso Corporal/efeitos dos fármacos , Cálcio/sangue , Creatinina/sangue , Ingestão de Líquidos/efeitos dos fármacos , Ingestão de Alimentos/efeitos dos fármacos , Feminino , Coração/efeitos dos fármacos , Pulmão/efeitos dos fármacos , Masculino , Tamanho do Órgão/efeitos dos fármacos , Ratos , Ratos Endogâmicos , Caracteres Sexuais , Baço/efeitos dos fármacos
11.
Cancer Lett ; 56(3): 215-24, 1991 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-2021925

RESUMO

A selective list of polycyclic aromatic hydrocarbons (PAH) with varied carcinogenic and mutagenic potencies, which are identified as common contaminants at industrial sites and which often contaminate the neighboring ground water, are investigated for their ability to induce nuclear anomalies (NA) in the mouse gastrointestinal (G.I.) tract. These studies examined the hypothesis that a relationship between NA induction and carcinogenic potency of these PAH exists. Among the PAH tested, 7,12-dimethylbenzanthrene (DMBA) was most effective inducer of NA in all G.I. tract tissues examined, with the relative potency in duodenum of DMBA much much greater than benzo[a]pyrene (B[a]P) much greater than benzo[b]fluoranthene (B[b]F). The induction of NA by benzo[a]anthracene (B[a]A), pyrene (PY) and benzo[e]pyrene (B[e]P) was not different from that elicited by vehicle controls. MNU, a known potent inducer of NA in the mouse G.I. tract, yielded a high level of NA in duodenum and proximal colon but was less effective than DMBA in the forestomach. The data suggest that induction of NA by DMBA and B[a]P PAH are in approximate accordance with their relative carcinogenic potency in the gastrointestinal tract. When binary mixtures of some PAH were administered the yield of NA was less than that expected by simple additivity and closer to that expected by averaging the activities of the two PAH comprising the mixture. Thus, this short-term in vivo assay may be useful as a predictor of the genotoxic or carcinogenic strength of individual PAH and/or mixtures of these compounds.


Assuntos
Núcleo Celular/ultraestrutura , Sistema Digestório/patologia , Compostos Policíclicos/toxicidade , Administração Oral , Animais , Núcleo Celular/efeitos dos fármacos , Colo/patologia , Sistema Digestório/efeitos dos fármacos , Sistema Digestório/ultraestrutura , Duodeno/patologia , Feminino , Masculino , Camundongos , Camundongos Endogâmicos , Compostos Policíclicos/administração & dosagem , Estômago/patologia , Relação Estrutura-Atividade
12.
Anticancer Res ; 11(2): 665-70, 1991.
Artigo em Inglês | MEDLINE | ID: mdl-2064320

RESUMO

Chloroform (CHCl3) is an established rodent carcinogen and a prevalent contaminant of chlorine-disinfected drinking water. Thus in the United States CHCl3, along with other trihalomethanes, is regulated not to exceed 100 ppb in potable water. Recently, several studies have shown that CHCl3 also has anti-cancer properties as it inhibits tumor growth in mouse liver and in the gastrointestinal tract of the rat. In this paper we show that CHCl3 also inhibits the propensity for three gastrointestinal tract carcinogens, benzo(a)pyrene (BAP), 1,2-dimethylhydrazine (DMH) and methylnitrosourea (MNU), to induce nuclear anomalies in the proximal colon of the B6C3F1 mouse. For example, in mice pre-adapted to 1800 ppm CHCl3 for 30 days prior to the carcinogen administration the level of nuclear anomalies induced in the proximal colon by BAP was reduced by four-fold (0.9 +/- 0.7 v. 3.6 +/- 1.0 anomalies/10 crypts; p less than 0.001) and two-fold for MNU (2.4 +/- 1.0 v. 4.6 +/- 1.6; p less than 0.001) and DMH (0.9 +/- 0.9 v. 1.7 +/- 0.8; p = 0.03). In the duodenum CHCl3 was effective at inhibiting unclear anomalies only for MNU (45.3 +/- 4.6 v. 30.4 +/- 3.5; p = 0.02). The inhibitory effect of CHCl3 does not extend to nuclear anomalies of the forestomach. The anti-cancer properties of CHCl3 are discussed in light of its cancer causing potential and possible application to human risk assessment.


Assuntos
Antineoplásicos , Carcinógenos/toxicidade , Núcleo Celular/ultraestrutura , Clorofórmio/uso terapêutico , Colo/patologia , Intestino Delgado/patologia , Estômago/patologia , 1,2-Dimetilidrazina , Animais , Benzo(a)pireno/toxicidade , Peso Corporal/efeitos dos fármacos , Núcleo Celular/efeitos dos fármacos , Colo/efeitos dos fármacos , Dimetilidrazinas/uso terapêutico , Intestino Delgado/efeitos dos fármacos , Masculino , Metilnitrosoureia/toxicidade , Camundongos , Camundongos Endogâmicos , Músculo Liso/efeitos dos fármacos , Músculo Liso/patologia , Tamanho do Órgão/efeitos dos fármacos , Estômago/efeitos dos fármacos
13.
Fundam Appl Toxicol ; 16(2): 337-47, 1991 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-2055364

RESUMO

Groups of male B6C3F1 mice (N = 50) were provided drinking water containing 2 g/liter sodium chloride (control) and 0.05, 0.5, and 5 g/liter dichloroacetic acid (DCA). Treatment of 30 animals in each group was carried out to 60 or 75 weeks. In a separate experiment, mice exposed to 3.5 g/liter DCA and the corresponding acetic acid control group were killed at 60 weeks. Groups of 5 mice were killed at 4, 15, 30, and 45 weeks. Time-weighted mean daily doses of 7.6, 77, 410, and 486 mg/kg/day were calculated for 0.05, 0.5, 3.5, and 5 g/liter DCA treatments. Animals exposed to 3.5 and 5 g/liter DCA had final body weights that were 87 and 83%, respectively, of the control value. Relative liver weights of 136, 230, and 351% of the control value were measured for 0.5, 3.5, and 5 g/liter, respectively. At 60 weeks mice receiving 5.0 g/liter DCA had a 90% prevalence of liver neoplasia with a mean multiplicity of 4.50 tumors/animal. Exposure to 3.5 g/liter DCA for 60 weeks resulted in a 100% tumor prevalence with an average of 4.0 tumors/animal. The prevalence of liver neoplasia and tumor multiplicity at 60 and 75 weeks in the 0.05 g/liter DCA (24.1%; 0.31 tumors/animal) and in the 0.5 g/liter group (11.1%; 0.11 tumors/animal) did not differ significantly from the control value (7.1% and 0.07 tumors/animal). No liver tumors were found in the group treated with acetic acid. Hyperplastic nodules were seen in the 3.5 (58%; 0.92/animal) and 5 g/liter DCA groups (83%; 1.27/animal). There was a significant positive dose-related trend in the age-adjusted prevalence of liver tumors. These data confirm the hepatocarcinogenicity of DCA administered in the drinking water to male B6C3F1 mice for 60 weeks. The results together with those in an earlier report from this laboratory suggest, for the conditions under which these assays were conducted, a threshold concentration of at least 0.5 g/liter followed by a steep rise to a maximum tumor incidence at 2 g/liter DCA.


Assuntos
Carcinógenos , Ácido Dicloroacético/toxicidade , Poluentes Químicos da Água/toxicidade , Animais , Peso Corporal/efeitos dos fármacos , Relação Dose-Resposta a Droga , Neoplasias Hepáticas Experimentais/induzido quimicamente , Masculino , Camundongos , Camundongos Endogâmicos , Tamanho do Órgão/efeitos dos fármacos
14.
Environ Mol Mutagen ; 17(1): 32-9, 1991.
Artigo em Inglês | MEDLINE | ID: mdl-1991457

RESUMO

Two chlorinated hydroxylated furanones, 3-chloro-4-(dichloromethyl)-5-hydroxy-2[5H]-furanone (MX) and 3,4-(dichloro)-5-hydroxy-2[5H]-furanone (MA), are bacterial mutagens and they are also byproducts of chlorine disinfection, and frequent contaminants of drinking water. In this work MX is shown to induce nuclear anomalies in the gastrointestinal tract of the B6C3F1 mouse. The other chlorohydroxy-furanone, MA, gives suggestive evidence of activity. In this bioassay MX was approximately equivalent in potency to epichlorohydrin (ECH) but was much less potent than methylnitrosourea (MNU). The latter two chemicals are confirmed rodent gastrointestinal tract carcinogens. The duodenum was the most sensitive tissue responding with both increased numbers of nuclear anomalies per mouse and increased incidence of animals presenting the nuclear aberrations 24 hr after a single oral dose of 0.37 mmol/kg-1 of MX. MA also induced a significant increase in duodenal nuclear anomalies, but only at the highest dose (0.46 mmol/kg-1). The proximal colon and forestomach responded to MX but not MA. This is the first study demonstrating that chlorohydroxyfuranones are capable of inducing nuclear toxicity in vivo. However, it is clear, for MX at least, that its potency in the gastrointestinal tract nuclear anomalies assay is not commensurate with its extreme bacterial mutagenicity. Since the gastrointestinal tract tissues are directly exposed to orally administered genotoxins, one possible explanation for the weak response observed in this study could be that mammalian cells can effectively detoxify chlorohydroxyfuranones.


Assuntos
Núcleo Celular/efeitos dos fármacos , Cloro , Colo/patologia , Desinfetantes , Duodeno/patologia , Furanos/toxicidade , Estômago/patologia , Animais , Núcleo Celular/ultraestrutura , Colo/efeitos dos fármacos , Duodeno/efeitos dos fármacos , Humanos , Masculino , Camundongos , Camundongos Endogâmicos , Testes para Micronúcleos , Músculo Liso/efeitos dos fármacos , Músculo Liso/patologia , Testes de Mutagenicidade , Estômago/efeitos dos fármacos
15.
J Androl ; 12(1): 54-61, 1991.
Artigo em Inglês | MEDLINE | ID: mdl-2010350

RESUMO

We investigated the relationship between fertility and sperm motin endpoints in rats treated subchronically with the male reproductive toxicant, epichlorohydrin (ECH). Male rats were given ECH orally for 23 days at dosages of 0, 6.25, 12.5, or 25 mg/kg/day. They were mated twice (at 19 and 22 days) to estimate fertility by (1) detection of fertilized ova (presence of sperm head and tail or two pronuclei) 18 hours after mating and by (2) counting implants on day 14 of gestation. Both indices showed dose-related reductions (P less than 0.001). Motion parameters of cauda epididymal sperm were assessed using the CellSoft computer-assisted sperm motion analysis (CASA) system after the rats were asphyxiated on day 25. Curvilinear velocity, straight-line velocity, linearity, and amplitude of lateral head displacement were reduced in a dose-related manner. The fertility indices, percent fertilized ova, and percent implantation on day 14 of gestation were correlated significantly (r = 0.68; P = 0.0001). The following motion parameters were also correlated significantly with fertility (P less than 0.0003; r1 = percent fertilized ova and r2 = percent implantation): linearity (r1 = 0.42; r2 = 0.40), amplitude of lateral head displacement (r1 = 0.54; r2 = 0.48), curvilinear velocity (r1 = 0.53; r2 = 0.50), straight-line velocity (r1 = 0.55; r2 = 0.50), and percent motile sperm (r1 = 0.42; r2 = 0.32). These results suggest a relationship between toxicant-induced reductions in sperm motion and fertility.


Assuntos
Epicloroidrina/toxicidade , Fertilidade/efeitos dos fármacos , Motilidade dos Espermatozoides/efeitos dos fármacos , Animais , Peso Corporal , Epididimo/efeitos dos fármacos , Feminino , Masculino , Tamanho do Órgão , Ratos , Análise de Regressão , Testículo/efeitos dos fármacos
16.
Reprod Toxicol ; 5(6): 487-95, 1991.
Artigo em Inglês | MEDLINE | ID: mdl-1810576

RESUMO

Random and nonrandom factors associated with sample preparation and the automated analysis (CellSoft) of rat cauda epididymal sperm motion were studied. Random factors included inherent system variation at both the individual cell level and at the multiple cell level. Repeated analyses of identical tracks across grey level revealed a statistical interaction between grey settings and curvilinear velocity. However, in multiple track analyses, grey level was seen to be a factor only at higher settings. Nonrandom factors included time after sample preparation, dilution medium, and sample preparation procedures. Using a nicked preparation of the entire cauda epididymis from Long-Evans rats, the effects of time were studied on sperm suspended in 1) phosphate-buffered saline + 10 mg BSA/mL, 2) TEST yolk buffer, and 3) Medium 199. In PBS/BSA, the percent motile sperm estimate decreased (50% to 30%) over an hour, while the curvilinear velocity increased (127 to 142 microns/sec). Both sperm motion parameters were maintained in the TEST yolk buffer and in the Medium 199, although at lower values for the latter. Evaluation of the relative contribution of several factors, nested within sample, to the overall variance of three separate motion endpoints revealed that there was a large variation from field to field, negligible variation between overall CellSoft analyses of 200 cells or more, low variation at the preparation aliquot level, and moderate variation at the animal level. In planning experiments to test for effects on sperm motion endpoints, consideration of the relative contribution of the individual study factors to the overall variance of the parameter estimates will result in more sensitive experimental designs.


Assuntos
Epididimo/citologia , Motilidade dos Espermatozoides/fisiologia , Espermatozoides/fisiologia , Animais , Computadores , Técnicas In Vitro , Masculino , Ratos , Espermatozoides/ultraestrutura
17.
Teratology ; 40(5): 445-51, 1989 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-2623633

RESUMO

Trichloroacetic acid (TCA) is a by-product of the chlorine disinfection of water containing natural organic material. It is detectable in finished drinking water at levels comparable to the trihalomethanes (30-160 micrograms/L). TCA is also formed in vivo after ingestion of hypochlorite and has been identified as a major metabolite of chlorinated hydrocarbons such as trichloroethylene. The developmental effects of TCA were evaluated in the pregnant Long-Evans rat. Animals were dosed by oral intubation on gestation days 6-15 (plug = 0) with 0, 330, 800, 1,200, or 1,800 mg/kg/day. The vehicle control was distilled water. Maternal observations included clinical signs, weight change, and gross evaluation of organ weights and uterine contents at necropsy (day 20). Live fetuses were examined for external, skeletal, and soft tissue malformation. There were no maternal deaths associated with toxicity prior to sacrifice. Weight gain during treatment was reduced at 800, 1,200, and 1,800 mg/kg. Spleen and kidney weights were increased in a dose-related manner. The mean percent of resorbed implants per litter was 34, 62, and 90 at 800, 1,200, and 1,800 mg/kg, respectively. Live fetuses showed dose-dependent reductions in weight and length. The mean frequency of soft tissue malformations ranged from 9% at the low dose to 97% at the high dose. These were principally in the cardiovascular system (interventricular septal defect, levocardia). Skeletal malformations were found only at 1,200 and 1,800 mg/kg and were mainly in the orbit. Based on these observations TCA was considered to be developmentally toxic in the pregnant rat at doses of 330 mg/kg and above.


Assuntos
Anormalidades Induzidas por Medicamentos/etiologia , Ácido Tricloroacético/toxicidade , Análise de Variância , Animais , Estatura/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Relação Dose-Resposta a Droga , Desenvolvimento Embrionário e Fetal/efeitos dos fármacos , Feminino , Ratos
18.
J Androl ; 10(5): 401-15, 1989.
Artigo em Inglês | MEDLINE | ID: mdl-2592269

RESUMO

The automated analysis of sperm motion endpoints is potentially useful in identifying male reproductive toxicants and ultimately in predicting fertility in humans. The present study was designed to evaluate the automated analysis of rat sperm motility characteristics following subchronic administration of epichlorohydrin. This type of validation is a prerequisite for inclusion of sperm motion measurements in the process of reproductive risk assessment. In the present studies videotapes were made of cauda epididymal spermatozoa from Long-Evans rats, both untreated and treated with epichlorohydrin. From analysis of videotapes of control epididymal spermatozoa, the relationship of various sperm motion endpoints and settings of the CellSoft computer-assisted sperm motion analysis system (Cryo Resources, Ltd., New York, NY) is described. Optimal settings of the system for analysis of rat spermatozoa are detailed. Employing data from both control and epichlorohydrin-treated animals, a statistical methodology is described that evaluates: (1) the distributions of CellSoft generated sperm motion endpoints, (2) the correlations between these endpoints, and (3) techniques for detection of dose-related effects.


Assuntos
Cloridrinas/farmacologia , Interpretação Estatística de Dados , Processamento Eletrônico de Dados/instrumentação , Epicloroidrina/farmacologia , Motilidade dos Espermatozoides/efeitos dos fármacos , Animais , Relação Dose-Resposta a Droga , Estudos de Avaliação como Assunto , Masculino , Distribuição Aleatória , Ratos , Software , Gravação de Videoteipe
19.
Fundam Appl Toxicol ; 13(1): 40-5, 1989 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-2767360

RESUMO

The effect of chloroform (CHCl3), administered at 0, 900, and 1800 mg/liter in the drinking water, on the carcinogenic potency of 1,2-dimethylhydrazine (DMH) was investigated. Groups of 40 male Fisher 344 rats were given one of the three drinking water solutions for 39 weeks following the subcutaneous injection of 200 mg/kg DMH, a known gastrointestinal (GI) tract carcinogen in this animal strain. When tumors from the GI tract were pooled there was a highly significant (p less than 0.001) decrease in total number of tumors per group with increasing concentration of drinking water CHCl3. In the control group (0 mg/liter CHCl3), 14/39 (36%) of the animals developed tumors of the GI tract, including the duodenum, jejunum, stomach, cecum, and colon. In contrast, the incidence of tumors in the two groups of rats given CHCl3 in the drinking water was significantly lower (p less than 0.001; 900 mg/liter CHCl3, 12.8%; 1800 mg/liter CHCl3, 12.5%). A similar relationship was obtained when colon tumors were analyzed independently (p = 0.01). The incidence of total colon tumors obtained in the control group of this study (10/39, 26%) agrees well with the previous study by B.S. Reddy, K. Watanabe, and J.H. Weisburger (1977, Cancer Res. 37, 4156-4159) conducted in the same rat strain (7/30, 23%). These results demonstrate that CHCl3 in the drinking water inhibits carcinogenesis in the rat GI tract.


Assuntos
Clorofórmio/farmacologia , Dimetilidrazinas/toxicidade , Neoplasias Gastrointestinais/prevenção & controle , Metilidrazinas/toxicidade , 1,2-Dimetilidrazina , Adenoma/induzido quimicamente , Animais , Peso Corporal/efeitos dos fármacos , Dimetilidrazinas/antagonistas & inibidores , Neoplasias Gastrointestinais/induzido quimicamente , Neoplasias Gastrointestinais/patologia , Neoplasias Renais/induzido quimicamente , Masculino , Ratos , Ratos Endogâmicos F344 , Fatores de Tempo
20.
Fundam Appl Toxicol ; 12(4): 765-72, 1989 May.
Artigo em Inglês | MEDLINE | ID: mdl-2744278

RESUMO

Dichloroacetonitrile (DCAN), a by-product of drinking water disinfection formed by reaction of chlorine with background organic materials, was evaluated for its developmental effects in pregnant Long-Evans rats. Animals were dosed by oral intubation on Gestation Days 6-18 (plug = 0) with 0, 5, 15, 25, or 45 mg/kg/day. Tricaprylin was used as a vehicle. The highest dose tested (45 mg/kg) was lethal in 9% of the dams and caused resorption of the entire litter in 60% of the survivors. Embryolethality averaged 6% per litter at the low dose and 80% at the high dose and was statistically significant at 25 and 45 mg/kg/day. The incidence of soft tissue malformations was dose related and was statistically significant at doses toxic to the dam (45 mg/kg). These anomalies were principally in the cardiovascular (interventricular septal defect, levocardia, and abnormalities of the major vessels) and urogenital (hydronephrosis, rudimentary bladder and kidney, fused ureters, pelvic hernia, cryptorchidism) systems. The frequency of skeletal malformations (fused and cervical ribs) was also dose related and significantly increased at 45 mg/kg. The no-observed-adverse-effect dose for toxicity in pregnant Long-Evans rats was established by statistical analysis to be 15 mg/kg/day.


Assuntos
Acetatos/toxicidade , Ácido Dicloroacético/toxicidade , Prenhez/efeitos dos fármacos , Reprodução/efeitos dos fármacos , Abastecimento de Água , Animais , Feminino , Feto/efeitos dos fármacos , Gravidez , Ratos
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