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1.
Toxicol Pathol ; 50(2): 167-175, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34727809

RESUMO

Spontaneous primary pleural mesotheliomas in Fischer 344 (F344) or other rat strains have rarely been reported. The objectives of this retrospective study were to develop historical incidence data and better characterize the light-microscopic morphology of these naturally occurring neoplasms in a large cohort of rats of several strains. A retrospective review was performed of National Toxicology Program (NTP) studies in rats conducted between 1980 and 2019 and comprising a total of 104,029 rats (51,326 males, 52,703 females), predominantly (90%) of the F344 strain. Of the 94,062 F344 rats surveyed, there were 30 cases of primary pleural mesotheliomas (22 males, 8 females). Of the 2998 Wistar Han rats surveyed, primary pleural mesotheliomas were present in 2 male rats. No primary pleural mesotheliomas were noted in male and female rats of other strains (6669 Sprague Dawley; 300 Osborne-Mendel). All primary pleural mesotheliomas in control and treated F344 and Wistar Han rats were considered spontaneous and unrelated to treatment. Based on light-microscopic evaluation of paraffin-embedded hematoxylin and eosin stained sections, only epithelioid and biphasic histologic subtypes were observed: 18 and 12 in F344 rats, respectively, and one each in Wistar Han rats. No sarcomatoid subtype cases were noted in any strain of rat.


Assuntos
Mesotelioma , Animais , Feminino , Humanos , Masculino , Mesotelioma/patologia , Ratos , Ratos Endogâmicos F344 , Ratos Sprague-Dawley , Ratos Wistar , Estudos Retrospectivos
2.
Toxicol Pathol ; 45(1): 11-51, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27821709

RESUMO

The 2016 annual National Toxicology Program Satellite Symposium, entitled "Pathology Potpourri" was held in San Diego, CA, at the Society of Toxicologic Pathology's (STP) 35th annual meeting. The goal of this symposium was to present and discuss challenging diagnostic pathology and/or nomenclature issues. This article presents summaries of the speakers' talks, along with select images that were used by the audience for voting and discussion. Some lesions and topics covered during the symposium included malignant glioma and histiocytic sarcoma in the rodent brain; a new statistical method designed for histopathology data evaluation; uterine stromal/glandular polyp in a rat; malignant plasma cell tumor in a mouse brain; Schwann cell proliferative lesions in rat hearts; axillary schwannoma in a cat; necrosis and granulomatous inflammation in a rat brain; adenoma/carcinoma in a rat adrenal gland; hepatocyte maturation defect and liver/spleen hematopoietic defects in an embryonic mouse; distinguishing malignant glioma, malignant mixed glioma, and malignant oligodendroglioma in the rat; comparison of mammary gland whole mounts and histopathology from mice; and discussion of the International Harmonization of Nomenclature and Diagnostic Criteria collaborations.


Assuntos
Patologia , Toxicologia , Animais , Congressos como Assunto , Técnicas e Procedimentos Diagnósticos , Humanos , Terminologia como Assunto
3.
Part Fibre Toxicol ; 13: 17, 2016 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-27083413

RESUMO

BACKGROUND: Human exposure to Libby amphibole (LA) asbestos increases risk of lung cancer, mesothelioma, and non-malignant respiratory disease. This study evaluated potency and time-course effects of LA and positive control amosite (AM) asbestos fibers in male F344 rats following nose-only inhalation exposure. METHODS: Rats were exposed to air, LA (0.5, 3.5, or 25.0 mg/m(3) targets), or AM (3.5 mg/m(3) target) for 10 days and assessed for markers of lung inflammation, injury, and cell proliferation. Short-term results guided concentration levels for a stop-exposure study in which rats were exposed to air, LA (1.0, 3.3, or 10.0 mg/m(3)), or AM (3.3 mg/m(3)) 6 h/day, 5 days/week for 13 weeks, and assessed 1 day, 1, 3, and 18 months post-exposure. Fibers were relatively short; for 10 mg/m(3) LA, mean length of all structures was 3.7 µm and 1% were longer than 20 µm. RESULTS: Ten days exposure to 25.0 mg/m(3) LA resulted in significantly increased lung inflammation, fibrosis, bronchiolar epithelial cell proliferation and hyperplasia, and inflammatory cytokine gene expression compared to air. Exposure to 3.5 mg/m(3) LA resulted in modestly higher markers of acute lung injury and inflammation compared to AM. Following 13 weeks exposure, lung fiber burdens correlated with exposure mass concentrations, declining gradually over 18 months. LA (3.3 and 10.0 mg/m(3)) and AM produced significantly higher bronchoalveolar lavage markers of inflammation and lung tissue cytokines, Akt, and MAPK/ERK pathway components compared to air control from 1 day to 3 months post-exposure. Histopathology showed alveolar inflammation and interstitial fibrosis in all fiber-exposed groups up to 18 months post-exposure. Positive dose trends for incidence of alveolar epithelial hyperplasia and bronchiolar/alveolar adenoma or carcinoma were observed among LA groups. CONCLUSIONS: Inhalation of relatively short LA fibers produced inflammatory, fibrogenic, and tumorigenic effects in rats which replicate essential attributes of asbestos-related disease in exposed humans. Fiber burden, inflammation, and activation of growth factor pathways may persist and contribute to lung tumorigenesis long after initial LA exposure. Fiber burden data are being used to develop a dosimetry model for LA fibers, which may provide insights on mode of action for hazard assessment.


Assuntos
Adenocarcinoma Bronquioloalveolar/induzido quimicamente , Adenoma/induzido quimicamente , Amianto Amosita/toxicidade , Amiantos Anfibólicos/toxicidade , Exposição por Inalação , Neoplasias Pulmonares/induzido quimicamente , Pulmão/efeitos dos fármacos , Pneumonia/induzido quimicamente , Fibrose Pulmonar/induzido quimicamente , Adenocarcinoma Bronquioloalveolar/genética , Adenocarcinoma Bronquioloalveolar/metabolismo , Adenocarcinoma Bronquioloalveolar/patologia , Adenoma/metabolismo , Adenoma/patologia , Animais , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Transformação Celular Neoplásica/induzido quimicamente , Citocinas/genética , Citocinas/metabolismo , Relação Dose-Resposta a Droga , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Hiperplasia , Mediadores da Inflamação/metabolismo , Pulmão/metabolismo , Pulmão/patologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Masculino , Pneumonia/genética , Pneumonia/metabolismo , Pneumonia/patologia , Fibrose Pulmonar/genética , Fibrose Pulmonar/metabolismo , Fibrose Pulmonar/patologia , Ratos Endogâmicos F344 , Medição de Risco , Transdução de Sinais/efeitos dos fármacos , Fatores de Tempo
4.
Toxicol Pathol ; 43(8): 1149-57, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26511845

RESUMO

This article describes the results of comparisons of digitally scanned whole slide images (WSIs) and glass microscope slides for diagnosis of tissues under peer review by the National Toxicology Program. Findings in this article were developed as a result of the data collected from 6 pathology working groups (PWGs), 1 pathology peer review, and survey comments from over 25 participating pathologists. For each PWG, 6-14 pathologists examined 10-143 tissues per study from 6- and 9-month perinatal studies and 2-year carcinogenicity studies. Overall it was found that evaluation of WSIs is generally equivalent to using glass slides. Concordance of PWG consensus diagnoses based upon review of WSIs versus glass slides ranged from 74% to 100% (median 86%). The intra- and interobserver diagnostic variation did not appear to influence the conclusions of any study. Based upon user opinions collected from surveys, WSIs may be less optimal than glass slides for evaluation of subtle lesions, large complex lesions, small lesions in a large section of tissue, and foci of altered hepatocytes. These results indicate that, although there may be some limitations, the use of WSIs can effectively accomplish the objectives of a conventional glass slide review and definitely serves as a useful adjunct to the conduct of PWGs.


Assuntos
Processamento de Imagem Assistida por Computador/métodos , Microscopia/métodos , Patologia Clínica/métodos , Animais , Histocitoquímica , Humanos , Camundongos , Patologia/educação , Ratos
5.
Int J Toxicol ; 32(5): 358-67, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23966314

RESUMO

Female F344 rats were exposed to anthraquinone (AQ) by dietary feed at concentrations of 0, 50, 150, 469, 938, 1875, or 3750 ppm for 2 or 13 weeks. End points evaluated included clinical observations, body weights, serum chemistry, blood AQ, gross pathology, organ weights, and select tissue histopathology. Mean body weight and food consumption were 5% to 10% lower than control values in rats of the ≥938 ppm group during study weeks 2 through 13. Occasional decreases in body weight means were also observed in rats of the 150 and 469 ppm groups. Increases in liver, kidney, and spleen weights were observed in rats exposed to AQ diet concentrations ≥150 ppm for 13 weeks. Urinary bladder weights were increased at ≥469 ppm. Liver and spleen weights were also increased following 2 weeks of exposure. Liver weight increases were clearly dependent on AQ concentration. At 2 weeks, decreases in serum aspartate aminotransferase (AST), blood urea nitrogen, and creatinine concentrations were observed in higher AQ exposure groups, and AST was decreased at 13 weeks (≥1875 ppm). Microscopic alterations were observed in the liver (mild centrilobular hypertrophy), spleen (mild hematopoietic cell proliferation and pigmentation), and kidneys (minimal hyaline droplets) of rats exposed to AQ for 13 weeks. Blood AQ concentrations ranged from 0.75 to 14.8 µg/mL in rats of the 150 to 3750 ppm groups, respectively, and were similar in value following either 2 weeks or 13 weeks of exposure. A no observed adverse effect level of 469 ppm AQ (31.3 mg/kg/d) was selected based on the absence of liver histopathology.


Assuntos
Antraquinonas/toxicidade , Poluentes Ambientais/toxicidade , Animais , Antraquinonas/sangue , Antraquinonas/farmacocinética , Peso Corporal/efeitos dos fármacos , Poluentes Ambientais/sangue , Poluentes Ambientais/farmacocinética , Feminino , Rim/efeitos dos fármacos , Rim/patologia , Fígado/efeitos dos fármacos , Fígado/patologia , Nível de Efeito Adverso não Observado , Tamanho do Órgão/efeitos dos fármacos , Ratos , Ratos Endogâmicos F344 , Baço/efeitos dos fármacos , Baço/patologia , Testes de Toxicidade Subcrônica , Bexiga Urinária/efeitos dos fármacos , Bexiga Urinária/patologia
6.
Toxicol Pathol ; 39(1): 240-66, 2011 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21177527

RESUMO

The 2010 annual National Toxicology Program (NTP) Satellite Symposium, entitled "Pathology Potpourri," was held in Chicago, Illinois, in advance of the scientific symposium sponsored jointly by the Society of Toxicologic Pathology (STP) and the International Federation of Societies of Toxicologic Pathologists (IFSTP). The goal of the annual NTP Symposium is to present current diagnostic pathology or nomenclature issues to the toxicologic pathology community. This article presents summaries of the speakers' presentations, including diagnostic or nomenclature issues that were presented, along with select images that were used for voting or discussion. Some topics covered during the symposium included a comparison of rat and mouse hepatocholangiocarcinoma, a comparison of cholangiofibrosis and cholangiocarcinoma in rats, a mixed pancreatic neoplasm with acinar and islet cell components, an unusual preputial gland tumor, renal hyaline glomerulopathy in rats and mice, eosinophilic substance in the nasal septum of mice, INHAND nomenclature for proliferative and nonproliferative lesions of the CNS/PNS, retinal gliosis in a rat, fibroadnexal hamartoma in rats, intramural plaque in a mouse, a treatment-related chloracne-like lesion in mice, and an overview of mouse ovarian tumors.


Assuntos
Neoplasias/patologia , Terminologia como Assunto , Toxicologia , Animais , Axônios/patologia , Carcinoma de Células Acinares/patologia , Carcinoma de Células das Ilhotas Pancreáticas/patologia , Cloracne/patologia , Colangiocarcinoma/patologia , Congressos como Assunto , Ependimoma/patologia , Camundongos , Degeneração Neural/patologia , Neoplasias Pancreáticas/patologia , Ratos
7.
Toxicol Pathol ; 38(1): 9-36, 2010 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-20008954

RESUMO

The National Toxicology Program (NTP) Satellite Symposium is a one-day meeting that is held in conjunction with the annual Society of Toxicologic Pathology (STP) meeting. The topic of the 2009 Symposium was "Tumor Pathology and INHAND (International Harmonization of Nomenclature and Diagnostic Criteria for Lesions in Rats and Mice) Nomenclature." The goal of this article is to provide summaries of each speaker's presentation, including the diagnostic or nomenclature issues that were presented, along with a few select images that were used for voting. The results of the voting process and interesting points of discussion that were raised during the presentation are also provided. A supplemental file with voting choices and voting results for each case presented at the symposium is available at http://tpx.sagepub.com/supplemental.


Assuntos
Neoplasias/patologia , Medula Suprarrenal/patologia , Animais , Proliferação de Células , Colangiocarcinoma/patologia , Imuno-Histoquímica , Neoplasias Hepáticas/patologia , Meningioma/patologia , Camundongos , Ratos , Terminologia como Assunto
8.
Drug Chem Toxicol ; 33(2): 131-7, 2010 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-20307141

RESUMO

Perfluorooctanoate (PFO) is a perfluorinated carboxylate that is widely distributed in the environment. A 2-year chronic study was conducted in rats fed either 30 or 300 ppm of ammonium perfluorooctanoate (APFO). To investigate the possible relationship of APFO exposure to proliferative mammary lesions, a Pathology Working Group (PWG) review of the original slides was performed. The consensus reached by the PWG was that the incidence of mammary-gland neoplasms was not affected by chronic dietary administration of APFO. Therefore, feeding female rats up to 300 ppm of APFO resulted in no increase in proliferative lesions of the mammary tissue.


Assuntos
Adenocarcinoma/induzido quimicamente , Adenoma/induzido quimicamente , Caprilatos/toxicidade , Poluentes Ambientais/toxicidade , Fibroadenoma/induzido quimicamente , Fluorocarbonos/toxicidade , Glândulas Mamárias Animais/efeitos dos fármacos , Neoplasias Mamárias Animais/induzido quimicamente , Neoplasias Primárias Múltiplas/induzido quimicamente , Adenocarcinoma/patologia , Adenoma/patologia , Administração Oral , Ração Animal , Animais , Proliferação de Células/efeitos dos fármacos , Feminino , Fibroadenoma/patologia , Hiperplasia/induzido quimicamente , Hiperplasia/patologia , Glândulas Mamárias Animais/patologia , Neoplasias Mamárias Animais/patologia , Neoplasias Primárias Múltiplas/patologia , Lesões Pré-Cancerosas/induzido quimicamente , Lesões Pré-Cancerosas/patologia , Ratos , Ratos Sprague-Dawley
9.
Birth Defects Res B Dev Reprod Toxicol ; 86(4): 345-54, 2009 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-19585553

RESUMO

Most rodent developmental toxicity studies of dibutylphthalate (DBP) have relied on bolus gavage dosing. This study characterized the developmental toxicity of dietary DBP. Pregnant CD rats were given nominal doses of 0, 100, or 500 mg DBP/kg/day in diet (actual intake 0, 112, and 582 mg/kg/day) from gestational day (GD) 12 through the morning of GD 19. Rats were killed 4 or 24 hr thereafter. DBP dietary exposure resulted in significant dose-dependent reductions in testicular mRNA concentration of scavenger receptor class B, member 1; steroidogenic acute regulatory protein; cytochrome P450, family 11, subfamily a, polypeptide 1; and cytochrome P450 family 17, subfamily a, polypeptide 1. These effects were most pronounced 4 hr after the end of exposure. Testicular testosterone was reduced 24 hr post-exposure in both DBP dose groups and 4 hr after termination of the 500-mg DBP/kg/day exposure. Maternal exposure to 500 mg DBP/kg/day induced a significant reduction in male offspring's anogenital distance indicating in utero disruption of androgen function. Leydig cell aggregates, increased cord diameters, and multinucleated gonocytes were present in DBP-treated rats. Monobutyl phthalate, the developmentally toxic metabolite of DBP, and its glucuronide conjugate were found in maternal and fetal plasma, amniotic fluid, and maternal urine. Our results, when compared to previously conducted gavage studies, indicate that approximately equal doses of oral DBP exposure of pregnant rats, from diet or gavage, result in similar responses in male offspring.


Assuntos
Antagonistas de Androgênios/toxicidade , Dibutilftalato/toxicidade , Ácidos Ftálicos/análise , Administração Oral , Líquido Amniótico/química , Antagonistas de Androgênios/administração & dosagem , Antagonistas de Androgênios/farmacocinética , Animais , Biotransformação , Peso Corporal/efeitos dos fármacos , Dibutilftalato/administração & dosagem , Dibutilftalato/farmacocinética , Relação Dose-Resposta a Droga , Feminino , Cromatografia Gasosa-Espectrometria de Massas , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Genitália Masculina/efeitos dos fármacos , Genitália Masculina/embriologia , Genitália Masculina/patologia , Idade Gestacional , Glucuronídeos/análise , Glucuronídeos/sangue , Glucuronídeos/farmacocinética , Glucuronídeos/urina , Masculino , Ácidos Ftálicos/sangue , Ácidos Ftálicos/urina , Gravidez , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Receptores Depuradores Classe B/efeitos dos fármacos , Esteroides/biossíntese , Testículo/efeitos dos fármacos , Testículo/embriologia , Testículo/metabolismo , Testículo/patologia , Testosterona/biossíntese
10.
Inhal Toxicol ; 20(3): 205-16, 2008 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-18300043

RESUMO

The goal of this study was to characterize the respiratory tract toxicity of acrolein, including nasal and pulmonary effects, in adult male F344 rats. Animals underwent whole-body exposure to 0, 0.02, 0.06, 0.2, 0.6, or 1.8 ppm acrolein for 6 hr/day, five days/week for up to 65 exposure days (13 exposure weeks). Respiratory tract histopathology was evaluated after 4, 14, 30, and 65 exposure days, as well as 60 days after the end of the 13 week exposure. Acrolein exposure was associated with reduced body weight gain. Rats exposed to > or = 0.06 ppm acrolein had depressed terminal body weights when compared with air-exposed controls. Histologic evaluation of the nasal cavity showed olfactory epithelial inflammation and olfactory neuronal loss (ONL) following exposure to 1.8 ppm acrolein. Moderately severe ONL in the dorsal meatus and ethmoid turbinates occurred within four days while septal involvement developed with ongoing exposure. A rostral-caudal gradient in lesion severity was noted, with the anterior portion of the nasal cavity being more severely affected. Acrolein exposure was associated with inflammation, hyperplasia, and squamous metaplasia of the respiratory epithelium. The lateral wall was amongst the most sensitive locations for these responses and increased respiratory epithelial cell proliferation occurred at this site following 4 to 30 days of exposure to > or = 0.6 ppm acrolein. The NOAEL for nasal pathology seen in this study was 0.2 ppm acrolein.


Assuntos
Acroleína/toxicidade , Poluentes Atmosféricos/toxicidade , Mucosa Nasal/efeitos dos fármacos , Sistema Respiratório/efeitos dos fármacos , Animais , Peso Corporal/efeitos dos fármacos , Relação Dose-Resposta a Droga , Exposição por Inalação , Masculino , Metaplasia/induzido quimicamente , Metaplasia/patologia , Mucosa Nasal/patologia , Neurônios Aferentes/efeitos dos fármacos , Neurônios Aferentes/patologia , Condutos Olfatórios/efeitos dos fármacos , Condutos Olfatórios/patologia , Ratos , Ratos Endogâmicos F344 , Sistema Respiratório/patologia , Rinite/induzido quimicamente , Rinite/patologia , Conchas Nasais/efeitos dos fármacos , Conchas Nasais/patologia
11.
Inhal Toxicol ; 20(3): 227-43, 2008 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-18300045

RESUMO

Acrolein is a highly soluble and reactive aldehyde and is a potent upper-respiratory-tract irritant. Acrolein-induced nasal lesions in rodents include olfactory epithelial atrophy and inflammation, epithelial hyperplasia, and squamous metaplasia of the respiratory epithelium. Nasal uptake of inhaled acrolein in rats is moderate to high, and depends on inspiratory flow rate, exposure duration, and concentration. In this study, anatomically accurate three-dimensional computational fluid dynamics (CFD) models were used to simulate steady-state inspiratory airflow and to quantitatively predict acrolein tissue dose in rat and human nasal passages. A multilayered epithelial structure was included in the CFD models to incorporate clearance of inhaled acrolein by diffusion, blood flow, and first-order and saturable metabolic pathways. Kinetic parameters for these pathways were initially estimated by fitting a pharmacokinetic model with a similar epithelial structure to time-averaged acrolein nasal extraction data and were then further adjusted using the CFD model. Predicted air:tissue flux from the rat nasal CFD model compared well with the distribution of acrolein-induced nasal lesions from a subchronic acrolein inhalation study. These correlations were used to estimate a tissue dose-based no-observed-adverse-effect level (NOAEL) for inhaled acrolein. A human nasal CFD model was used to extrapolate effects in laboratory animals to human exposure conditions on the basis of localized tissue dose and tissue responses. Assuming that equivalent tissue dose will induce similar effects across species, a NOAEL human equivalent concentration for inhaled acrolein was estimated to be 8 ppb.


Assuntos
Acroleína/farmacocinética , Poluentes Atmosféricos/farmacocinética , Modelos Biológicos , Cavidade Nasal/metabolismo , Mucosa Nasal/metabolismo , Acroleína/toxicidade , Poluentes Atmosféricos/toxicidade , Animais , Simulação por Computador , Relação Dose-Resposta a Droga , Humanos , Exposição por Inalação , Cavidade Nasal/efeitos dos fármacos , Cavidade Nasal/patologia , Mucosa Nasal/efeitos dos fármacos , Mucosa Nasal/patologia , Ratos
12.
Inhal Toxicol ; 20(3): 245-56, 2008 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-18300046

RESUMO

Acetaldehyde inhalation induces neoplastic and nonneoplastic responses in the rodent nasal cavity. This experiment further characterizes the dose-response relationship for nasal pathology, nasal epithelial cell proliferation, and DNA-protein cross-link formation in F-344 rats exposed subchronically to acetaldehyde. Animals underwent whole-body exposure to 0, 50, 150, 500, or 1500 ppm acetaldehyde for 6 h/day, 5 days/wk for up to 65 exposure days. Respiratory tract histopathology was evaluated after 4, 9, 14, 30, and 65 exposure days. Acetaldehyde exposure was not associated with reduced body weight gain or other evidence of systemic toxicity. Histologic evaluation of the nasal cavity showed an increased incidence of olfactory neuronal loss (ONL) following acute to subchronic exposure to > or = 150 ppm acetaldehyde and increased olfactory epithelial cell proliferation following exposure to 1500 ppm acetaldehyde. The severity of the ONL demonstrated dose- and temporal-dependent behaviors, with minimal effects noted at 150-500 ppm acetaldehyde and moderately severe lesions seen in the highest exposure group, with increased lesion severity and extent as the exposure duration increased. Acetaldehyde exposure was also associated with inflammation, hyperplasia, and squamous metaplasia of the respiratory epithelium. These responses were seen in animals exposed to > or = 500 ppm acetaldehyde. Acetaldehyde exposure was not associated with increased DNA-protein cross-link formation in the respiratory or olfactory epithelium. A model of acetaldehyde pharmacokinetics in the nose was used to derive an inhalation reference concentration (RfC) of 0.4 ppm, based on the no-observed-adverse-effect level (NOAEL) of 50 ppm for the nasal pathology seen in this study.


Assuntos
Acetaldeído/toxicidade , Poluentes Atmosféricos/toxicidade , Cavidade Nasal/efeitos dos fármacos , Neurônios Aferentes/efeitos dos fármacos , Condutos Olfatórios/efeitos dos fármacos , Animais , Benchmarking , Proliferação de Células/efeitos dos fármacos , Reagentes de Ligações Cruzadas/toxicidade , DNA/química , DNA/efeitos dos fármacos , Relação Dose-Resposta a Droga , Exposição por Inalação , Masculino , Metaplasia/induzido quimicamente , Metaplasia/patologia , Cavidade Nasal/metabolismo , Cavidade Nasal/patologia , Neurônios Aferentes/patologia , Nível de Efeito Adverso não Observado , Mucosa Olfatória/efeitos dos fármacos , Mucosa Olfatória/patologia , Condutos Olfatórios/patologia , Ligação Proteica/efeitos dos fármacos , Proteínas/química , Proteínas/efeitos dos fármacos , Ratos , Ratos Endogâmicos F344 , Rinite/induzido quimicamente , Rinite/patologia
13.
Environ Toxicol Pharmacol ; 36(3): 1227-34, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-24200600

RESUMO

Male F344 rats were exposed to potassium bromate (KBrO3) in drinking water at concentrations of 0, 5, 20, 100, 200, or 400 mg/L for 2 or 13 weeks. Endpoints evaluated included clinical observations, body weights, serum chemistry, gross pathology, organ weights, and select tissue histopathology (kidney, lung, liver, thyroid, and tunica vaginalis). Weekly body weight and water consumption means were similar between KBrO3 and control groups throughout the study. Increases in kidney weights were observed in rats of the 400 mg/L group following 2- or 13-weeks exposure. Hyaline droplets were observed in renal tubules of rats of the 200 and 400 mg/L groups following 2 weeks exposure and in rats of the 400 mg/L group at 13 weeks. There were no KBrO3-related microscopic findings in the lung, liver, thyroid, and tunica vaginalis at the 2- and 13-week time points. A no observed effect level of 100 mg/L KBrO3 (8.1 mg/kg/day) was selected based on the absence of microscopic alterations in the kidney.


Assuntos
Bromatos/toxicidade , Animais , Análise Química do Sangue , Peso Corporal/efeitos dos fármacos , Ingestão de Líquidos/efeitos dos fármacos , Determinação de Ponto Final , Rim/patologia , Nefropatias/induzido quimicamente , Nefropatias/patologia , Fígado/patologia , Masculino , Nível de Efeito Adverso não Observado , Tamanho do Órgão/efeitos dos fármacos , Ratos , Ratos Endogâmicos F344 , Glândula Tireoide/patologia
14.
Toxicol Sci ; 118(2): 716-31, 2010 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-20884683

RESUMO

Formaldehyde (FA), an endogenous cellular aldehyde, is a rat nasal carcinogen. In this study, concentration and exposure duration transitions in FA mode of action (MOA) were examined with pharmacokinetic (PK) modeling for tissue formaldehyde acetal (FAcetal) and glutathione (GSH) and with histopathology and gene expression in nasal epithelium from rats exposed to 0, 0.7, 2, 6, 10, or 15 ppm FA 6 h/day for 1, 4, or 13 weeks. Patterns of gene expression varied with concentration and duration. At 2 ppm, sensitive response genes (SRGs)-associated with cellular stress, thiol transport/reduction, inflammation, and cell proliferation-were upregulated at all exposure durations. At 6 ppm and greater, gene expression changes showed enrichment of pathways involved in cell cycle, DNA repair, and apoptosis. ERBB, EGFR, WNT, TGF-ß, Hedgehog, and Notch signaling were also enriched. Benchmark doses for significantly enriched pathways were lowest at 13 weeks. Transcriptional and histological changes at 6 ppm and greater corresponded to dose ranges in which the PK model predicted significant reductions in free GSH and increases in FAcetal. Genomic changes at 0.7-2 ppm likely represent changes in extracellular FAcetal and GSH. DNA replication stress, enhanced proliferation, squamous metaplasia, and stem cell niche activation appear to be associated with FA carcinogenesis. Dose dependencies in MOA, high background FAcetal, and nonlinear FAcetal/GSH tissue kinetics indicate that FA concentrations below 1 or 2 ppm would not increase risk of cancer in the nose or any other tissue or affect FA homeostasis within epithelial cells.


Assuntos
Carcinógenos/farmacocinética , Carcinógenos/toxicidade , Formaldeído/farmacocinética , Formaldeído/toxicidade , Mucosa Nasal/efeitos dos fármacos , Animais , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Formaldeído/análogos & derivados , Perfilação da Expressão Gênica , Genômica , Glutationa/metabolismo , Exposição por Inalação , Modelos Biológicos , Mucosa Nasal/patologia , Ratos , Medição de Risco , Regulação para Cima/efeitos dos fármacos
15.
Toxicol Sci ; 105(2): 368-83, 2008 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-18499655

RESUMO

Repeated and acute exposure studies assessed time and concentration-dependencies of nasal responses to formaldehyde. Exposures were to 0, 0.7, 2, and 6 ppm for 6 h/day, 5 days/week for up to 3 weeks. Neither cell proliferation nor histopathology was observed at 0.7 ppm. At 6 ppm, cell proliferation increased at the end of the first week (day 5), but not at the end of week 3 (day 15). Squamous metaplasia occurred at day 5; epithelial hyperplasia occurred at both day 5 and day 15. In microarray studies, no genes were altered at 0.7 ppm. At 2 ppm, 15 genes were changed on day 5; only half of them were changed at 6 ppm. No genes were changed significantly at 2 ppm at day 15. The pattern of gene changes at 2 and 6 ppm, with transient squamous metaplasia at day 5, indicated tissue adaptation and reduced tissue sensitivity by day 15. The acute study included an additional concentration (15 ppm) and an instillation group (40 microl, 400 mM per nostril). Three times more genes were affected by instillation than inhalation. U-shaped dose responses were noted in the acute study for many genes that were also altered at 2 ppm on day 5. On the basis of cellular component gene ontology benchmark dose analysis, the most sensitive changes were for genes were associated with extracellular components and plasma membrane. With formaldehyde, there are temporal and concentration-dependent transitions in epithelial responses and genomic signatures between 0.7 and 6 ppm. Low concentrations primarily affect extracellular matrix or external plasma membrane portions of the epithelium.


Assuntos
Formaldeído/toxicidade , Perfilação da Expressão Gênica , Regulação da Expressão Gênica/efeitos dos fármacos , Exposição por Inalação , Mucosa Nasal/efeitos dos fármacos , Testes de Toxicidade , Transcrição Gênica/efeitos dos fármacos , Animais , Membrana Celular/efeitos dos fármacos , Membrana Celular/genética , Proliferação de Células/efeitos dos fármacos , Análise por Conglomerados , Relação Dose-Resposta a Droga , Matriz Extracelular/efeitos dos fármacos , Matriz Extracelular/genética , Formaldeído/administração & dosagem , Perfilação da Expressão Gênica/métodos , Hiperplasia , Masculino , Metaplasia , Mucosa Nasal/patologia , Análise de Sequência com Séries de Oligonucleotídeos , Ratos , Ratos Endogâmicos F344 , Fatores de Tempo
16.
Toxicol Pathol ; 30(5): 580-91, 2002.
Artigo em Inglês | MEDLINE | ID: mdl-12371667

RESUMO

Over the last 8 years, a 5-fold increase in the incidence of mice with spontaneous hepatoblastomas and a moderate increase in the incidence of chemically induced hepatoblastomas in B6C3F1 mice occurred in 2-year NTP studies compared to the previous 7 years. There was a positive association between an increased incidence of mice with hepatoblastoma and an increased incidence of mice with hepatocellular tumors in the treated mice. The rate of pulmonary metastases for hepatoblastoma was similar to that of pulmonary metastasis for hepatocellular carcinomas. Although a variety of chemicals caused an increased incidence of mice with hepatoblastoma, there was no apparent association between a specific chemical structure or a biological class of compounds and their capacity to induce hepatoblastomas. Hepatoblastomas frequently arose within hepatocellular carcinomas or adenomas and were induced by the same compounds that induced hepatocellular neoplasms. Therefore, it seems reasonable to combine the incidence of mice with hepatoblastomas and the incidence of mice with hepatocellular carcinomas in hazard identification studies.


Assuntos
Hepatoblastoma/secundário , Neoplasias Hepáticas/patologia , Doenças dos Roedores/patologia , Adenoma de Células Hepáticas/induzido quimicamente , Adenoma de Células Hepáticas/epidemiologia , Adenoma de Células Hepáticas/patologia , Animais , Carcinoma Hepatocelular/induzido quimicamente , Carcinoma Hepatocelular/epidemiologia , Carcinoma Hepatocelular/patologia , Hepatoblastoma/induzido quimicamente , Hepatoblastoma/epidemiologia , Neoplasias Hepáticas/induzido quimicamente , Neoplasias Hepáticas/epidemiologia , Camundongos , Camundongos Endogâmicos , National Institutes of Health (U.S.) , Neoplasias Primárias Múltiplas , Doenças dos Roedores/induzido quimicamente , Doenças dos Roedores/epidemiologia , Estados Unidos/epidemiologia
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