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1.
Toxicol Pathol ; 43(3): 354-65, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25122632

RESUMO

Administration of lersivirine, a nonnucleotide reverse transcriptase inhibitor, daily by oral gavage to Sprague-Dawley rats for up to 2 yr was associated with decreased survival, decreased body weights, and an increase in neoplasms and related proliferative lesions in the liver, thyroid, kidney, and urinary bladder. Thyroid follicular adenoma and carcinoma, the associated thyroid follicular hypertrophy/hyperplasia, hepatocellular adenoma/adenocarcinoma, altered cell foci, and hepatocellular hypertrophy were consistent with lersivirine-related induction of hepatic microsomal enzymes. Renal tubular adenoma and renal tubular hyperplasia were attributed to the lersivirine-related exacerbation of chronic progressive nephropathy (CPN), while urinary bladder hyperplasia and transitional cell carcinoma in the renal pelvis and urinary bladder were attributed to urinary calculi. Renal tubular neoplasms associated with increased incidence and severity of CPN, neoplasms of transitional epithelium attributed to crystalluria, and thyroid follicular and hepatocellular neoplasms related to hepatic enzyme induction have low relevance for human risk assessment.


Assuntos
Carcinógenos/toxicidade , Nitrilas/toxicidade , Pirazóis/toxicidade , Inibidores da Transcriptase Reversa/toxicidade , Animais , Peso Corporal/efeitos dos fármacos , Testes de Carcinogenicidade , Relação Dose-Resposta a Droga , Ingestão de Alimentos/efeitos dos fármacos , Feminino , Estimativa de Kaplan-Meier , Neoplasias Renais/induzido quimicamente , Neoplasias Renais/patologia , Neoplasias Hepáticas/induzido quimicamente , Neoplasias Hepáticas/patologia , Masculino , Nitrilas/farmacocinética , Pirazóis/farmacocinética , Ratos , Ratos Sprague-Dawley , Inibidores da Transcriptase Reversa/farmacocinética , Análise de Sobrevida , Neoplasias da Glândula Tireoide/induzido quimicamente , Neoplasias da Glândula Tireoide/patologia , Urinálise , Neoplasias da Bexiga Urinária/induzido quimicamente , Neoplasias da Bexiga Urinária/patologia
2.
Toxicology ; 293(1-3): 1-15, 2012 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-22266392

RESUMO

To investigate toxicity and neoplastic potential from chronic exposure to perfluorooctanesulfonate (PFOS), a two-year toxicity and cancer bioassay was conducted with potassium PFOS (K⁺ PFOS) in male and female Sprague Dawley rats via dietary exposure at nominal K⁺ PFOS concentrations of 0, 0.5, 2, 5, and 20 µg/g (ppm) diet for up to 104 weeks. Additional groups were fed 20 ppm for the first 52 weeks, after which they were fed control diet through study termination (20 ppm Recovery groups). Scheduled interim sacrifices occurred on Weeks 4, 14, and 53, with terminal sacrifice between Weeks 103 and 106. K⁺ PFOS appeared to be well-tolerated, with some reductions in body weight occurring in treated rats relative to controls over certain study periods. Male rats experienced a statistically significant decreased trend in mortality with significantly increased survival to term at the two highest treatment levels. Decreased serum total cholesterol, especially in males, and increased serum urea nitrogen were consistent clinical chemistry observations that were clearly related to treatment. The principal non-neoplastic effect associated with K⁺ PFOS exposure was in livers of males and females and included hepatocellular hypertrophy, with proliferation of endoplasmic reticulum, vacuolation, and increased eosinophilic granulation of the cytoplasm. Statistically significant increases in hepatocellular adenoma were observed in males (p=0.046) and females (p=0.039) of the 20 ppm treatment group, and all of these tumors were observed in rats surviving to terminal sacrifice. The only hepatocellular carcinoma observed was in a 20 ppm dose group female. There were no treatment-related findings for thyroid tissue in rats fed K⁺ PFOS through study termination; however, male rats in the 20 ppm Recovery group had statistically significantly increased thyroid follicular cell adenoma, which was considered spurious. There was no evidence of kidney or bladder effects. In rats, the dietary dose estimated as the lower 95% confidence limit of the benchmark dose for a 10% increase in hepatic tumors was 8 ppm for both sexes. Recent mechanistic studies suggest a PPARα/CAR/PXR-mediated mode of action for the liver tumors observed in the present two-year study.


Assuntos
Adenoma de Células Hepáticas/induzido quimicamente , Ácidos Alcanossulfônicos/toxicidade , Carcinógenos/toxicidade , Poluentes Ambientais/toxicidade , Fluorocarbonos/toxicidade , Neoplasias Hepáticas/induzido quimicamente , Adenoma de Células Hepáticas/sangue , Adenoma de Células Hepáticas/química , Adenoma de Células Hepáticas/patologia , Ácidos Alcanossulfônicos/administração & dosagem , Ácidos Alcanossulfônicos/análise , Ácidos Alcanossulfônicos/farmacocinética , Animais , Carcinógenos/administração & dosagem , Carcinógenos/análise , Carcinógenos/farmacocinética , Carcinoma Hepatocelular/sangue , Carcinoma Hepatocelular/induzido quimicamente , Carcinoma Hepatocelular/química , Carcinoma Hepatocelular/patologia , Relação Dose-Resposta a Droga , Poluentes Ambientais/administração & dosagem , Poluentes Ambientais/análise , Poluentes Ambientais/farmacocinética , Feminino , Fluorocarbonos/administração & dosagem , Fluorocarbonos/análise , Fluorocarbonos/farmacocinética , Hipertrofia/induzido quimicamente , Fígado/química , Fígado/efeitos dos fármacos , Fígado/patologia , Neoplasias Hepáticas/sangue , Neoplasias Hepáticas/química , Neoplasias Hepáticas/patologia , Masculino , Especificidade de Órgãos , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Caracteres Sexuais , Análise de Sobrevida , Testes de Toxicidade Crônica , Vacúolos/efeitos dos fármacos , Vacúolos/patologia
3.
Toxicology ; 183(1-3): 117-31, 2003 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-12504346

RESUMO

Perfluorooctanesulfonate (PFOS) is a widely disseminated persistent compound found at low (part-per-billion) concentrations in serum and liver samples from humans and fish-eating wildlife. This study investigated the hypotheses that early hepatocellular peroxisomal proliferation and hepatic cellular proliferation are factors in chronic liver response to dietary dosing, that lowering of serum total cholesterol is an early clinical measure of response to treatment, and that liver and serum PFOS concentrations are proportional to dose and cumulative dose after sub-chronic treatment. PFOS was administered in diet as the potassium salt at 0, 0.5, 2.0, 5.0, and 20 parts per million (ppm) to Sprague Dawley rats for 4 or 14 weeks. At 4 weeks, effects included decreased serum glucose and an equivocal (

Assuntos
Ácidos Alcanossulfônicos/toxicidade , Fluorocarbonos/toxicidade , Alanina Transaminase/sangue , Ácidos Alcanossulfônicos/administração & dosagem , Animais , Análise Química do Sangue , Peso Corporal , Colesterol/sangue , Relação Dose-Resposta a Droga , Feminino , Fluorocarbonos/administração & dosagem , Testes Hematológicos , Hepatócitos/enzimologia , Hepatócitos/metabolismo , Hepatócitos/patologia , Fígado/efeitos dos fármacos , Fígado/enzimologia , Fígado/metabolismo , Fígado/patologia , Masculino , Nível de Efeito Adverso não Observado , Tamanho do Órgão , Oxirredutases/biossíntese , Oxirredutases/metabolismo , Antígeno Nuclear de Célula em Proliferação/metabolismo , Ratos , Ratos Sprague-Dawley , Urinálise
4.
Toxicol Sci ; 68(1): 249-64, 2002 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-12075127

RESUMO

This study was conducted to determine the earliest measurable response of primates to low-level perfluorooctanesulfonate (PFOS) exposure and to provide information to reduce uncertainty in human health risk assessment. Groups of male and female monkeys received 0, 0.03, 0.15, or 0.75 mg/kg/day potassium PFOS orally for 182 days. Recovery animals from each group, except the 0.03 mg/kg/day dose group, were monitored for one year after treatment. Significant adverse effects occurred only in the 0.75 mg/kg/day dose group and included compound-related mortality in 2 of 6 male monkeys, decreased body weights, increased liver weights, lowered serum total cholesterol, lowered triiodothyronine concentrations (without evidence of hypothyroidism), and lowered estradiol levels. Decreased serum total cholesterol occurred in the 0.75 mg/kg/day dose group at serum PFOS levels > 100 ppm. Hepatocellular hypertrophy and lipid vacuolation were present at term in the 0.75 mg/kg/day dose group. No peroxisomal (palmitoyl CoA oxidase) or cell proliferation (proliferating cell nuclear antigen immunohistochemistry) was detected. Complete reversal of clinical and hepatic effects and significant decreases in serum and liver PFOS occurred within 211 days posttreatment. Liver-to-serum PFOS ratios were comparable in all dose groups, with a range of 1:1 to 2:1. Serum concentrations associated with no adverse effects (0.15 mg/kg/day) were 82.6 +/- 25.2 ppm for males and 66.8 +/- 10.8 ppm for females. Comparison of serum PFOS concentrations associated with no adverse effect in this study to those reported in human blood samples (0.028 +/- 0.014 ppm) indicated an adequate margin of safety.


Assuntos
Ácidos Alcanossulfônicos/toxicidade , Fluorocarbonos/toxicidade , Macaca fascicularis , Testes de Toxicidade/métodos , Administração Oral , Ácidos Alcanossulfônicos/administração & dosagem , Ácidos Alcanossulfônicos/farmacocinética , Animais , Peso Corporal/efeitos dos fármacos , Divisão Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Feminino , Fluorocarbonos/administração & dosagem , Fluorocarbonos/farmacocinética , Imuno-Histoquímica , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Longevidade/efeitos dos fármacos , Masculino , Tamanho do Órgão/efeitos dos fármacos , Peroxissomos/efeitos dos fármacos , Peroxissomos/enzimologia , Peroxissomos/ultraestrutura , Antígeno Nuclear de Célula em Proliferação/metabolismo , Indução de Remissão
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