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1.
J Toxicol Environ Health B Crit Rev ; 25(4): 135-161, 2022 05 19.
Artigo em Inglês | MEDLINE | ID: mdl-35291916

RESUMO

Methyl-tert-butyl ether (MTBE) is a fuel oxygenate used in non-United States geographies. Multiple health reviews conclude that MTBE is not a human-relevant carcinogen, and this review provides updated mode of action (MOA), exposure, dosimetry and risk perspectives supporting those conclusions. MTBE is non-genotoxic and has large margins of exposure between blood concentrations at the overall rat 400 ppm inhalation NOAEL and blood concentrations in typical workplace or general population exposures. Non-cancer and threshold cancer hazard quotients range from a high of 0.046 for fuel-pump gasoline station attendants and are 100-1,000-fold lower for general population exposures. Cancer risks conservatively assuming genotoxicity for these same scenarios are all less than 1 × 10-6. The onset of MTBE nonlinear toxicokinetics (TK) in rats at inhalation exposures less than 3,000 ppm, a dose that is also not practically achievable in fuel-use scenarios, indicates that high-dose specific male rat kidney and testes (3,000 and 8,000 ppm) and female mouse liver tumors (8000 ppm) are not quantitatively relevant to humans. Mode of action analyses also indicate MTBE male rat kidney tumors, and lesser so female mouse liver tumors, are not qualitatively relevant to humans. Thus, an integrated analysis of the toxicology, exposure/dosimetry, TK, and MOA data indicates that MTBE presents minimal human cancer and non-cancer risks.


Assuntos
Poluentes Atmosféricos , Neoplasias Hepáticas , Éteres Metílicos , Poluentes Atmosféricos/toxicidade , Animais , Bioensaio , Carcinógenos/toxicidade , Feminino , Gasolina , Humanos , Masculino , Éteres Metílicos/farmacocinética , Éteres Metílicos/toxicidade , Camundongos , Ratos , Roedores , Toxicocinética
2.
J Toxicol Pathol ; 35(1): 1-6, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-35221490

RESUMO

In the long-term safety testing of chemicals for carcinogenicity the toxicologist needs to be aware of a number of scenarios where renal tubule tumors, or their precursors, arise that are not due to a carcinogenic action of the test article. Situations producing false positive results in the kidney include exacerbation of chronic progressive nephropathy (CPN) in rats, confusion of atypical tubule hyperplasia (the obligate precursor of renal tubule tumor) with foci of benign CPN-related renal tubule cell proliferation, inclusion of spontaneous tumor entities, such as the amphophilic-vacuolar tumor, in the test article tumor count, the possibility of a link between spontaneous forms of tubule dilatation and renal tubule tumor formation in mice, and the supposed predictivity of chemically-induced karyomegaly for renal carcinogenicity in both rats and mice. Examples of these misleading situations are described and discussed.

3.
Toxicol Pathol ; 47(5): 645-648, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31117926

RESUMO

In histopathology, the presence of a tissue change that does not represent the tissue's normal appearance can often lead to an incorrect diagnosis and interpretation. These changes are collectively known as "artifacts" resulting from postmortem autolysis, improper fixation, problems with tissue handling or slide preparation procedures. Most tissue artifacts are obvious, yet some artifacts may be subtle, occur in relatively well-fixed tissue, and demand careful observation to avoid confusion with real biological lesions. The kidney often contains artifacts that may be observed throughout all regions of the renal parenchyma. Cortical tubule artifacts present the greatest challenge when discerning an artifact versus an induced lesion following exposure to a xenobiotic. However, confounding artifacts observed at the tip of the renal papilla may also be problematic for the pathologist. An uncommon artifact involving tinctorial alteration and rarefaction affecting the papillary tip of the rat kidney is described here and differentiated from treatment induced lesions of renal papillary necrosis.


Assuntos
Artefatos , Medula Renal/patologia , Animais , Medula Renal/efeitos dos fármacos , Necrose , Ratos , Xenobióticos/toxicidade
4.
Regul Toxicol Pharmacol ; 102: 65-73, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30590081

RESUMO

Tert-butyl alcohol (TBA) targets the rat kidney following repeated exposures, including renal tubule tumors. The mode of action (MOA) of these tumors, concluded by a pathology working group, involves both alpha2u-globulin nephropathy (α2u-gN) and exacerbated chronic progressive nephropathy (CPN), but has been disputed and an undefined MOA proposed. This study further reviews the histology slides of male and female rat kidneys from the NTP drinking water 13-week toxicity and 2-year carcinogenicity studies, including the 15-month interim sacrifice group. The papillary epithelial lining alteration formerly referred to as "transitional cell hyperplasia" develops as part of advanced CPN and does not represent a separate toxicity. No changes were observed in the kidney pelvis urothelium. The only alterations in subchronic male rats involved α2u-gN and CPN, without test article-related alterations in females. Focused examination of areas of parenchyma unaffected by CPN in TBA-treated male and female rats of the chronic studies revealed no renal tubule abnormalities other than from the effects of α2u-gN and CPN. Unrelated to toxicity were spontaneous amphophilic or vacuolar tubule proliferative lesions. All observed TBA-associated non-neoplastic and neoplastic histopathological changes in the kidney can be explained by α2u-gN or enhanced CPN, neither of which are relevant to humans.


Assuntos
alfa-Globulinas/metabolismo , Nefropatias/induzido quimicamente , Rim/efeitos dos fármacos , terc-Butil Álcool/toxicidade , Animais , Testes de Carcinogenicidade , Feminino , Hiperplasia/induzido quimicamente , Hiperplasia/patologia , Rim/metabolismo , Rim/patologia , Nefropatias/metabolismo , Nefropatias/patologia , Masculino , Ratos Endogâmicos F344 , Medição de Risco , Testes de Toxicidade Subcrônica
5.
Crit Rev Toxicol ; 48(7): 575-595, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-30277423

RESUMO

Scientific databases were searched for terms applicable to karyomegaly in renal tubules of laboratory animals used in preclinical safety evaluation studies, and in humans. Renal tubule karyomegaly was more frequently reported in the rat in response to chemical exposure compared to other laboratory animal species. Renal tubule karyomegaly also occurred in the mouse in response to chemical insult, but much less commonly than in the rat. This nuclear lesion was recorded infrequently for hamster, dog, guinea pig, rabbit, pig, and non-human primate. Most instances of renal karyomegaly reported in humans represented cases of the genetic syndrome, karyomegalic interstitial nephritis, known to be caused by a mutation in the FAN1 gene. Human reports of karyomegaly in the kidney associated with chemical exposure are rare, and linked mainly to chemotherapeutic or antiviral therapies. The rat appears to be highly predisposed to developing karyomegaly as a renal response on exposure to diverse chemical agents, but karyomegaly in the rat is not consistently associated with renal tubule tumor development. Because of this inconsistency, renal tubule karyomegaly is an inaccurate predictor of renal tubule neoplasia, and there is no evidence that karyomegalic cells are involved in tumor development as a form of preneoplasia. A chemically induced karyomegalic response in the rat does not necessarily predict a similar alteration in human kidneys. Because modest nuclear enlargement of kidney tubule cells can occur as physiological or functional responses, it is recommended that the threshold for diagnosing renal tubule karyomegaly in animal studies should be accepted as at least four times normal nuclear size or larger.Abbreviations: BEN: Balkan Endemic Nephropathy; DMN: dimethylnitrosamine; GLP: Good Laboratory Practice; KIN: karyomegalic interstitial nephritis; LAL: lysinoalanine; MeCCNU: 1-(2-chloroethyl)-3-(trans-4-methylcyclohexyl)-1-nitrosourea; NTP: National Toxicology Program; OSOM: outer stripe of outer medulla; OTA: ochratoxin A; RTT: renal tubule tumor.


Assuntos
Nefropatia dos Bálcãs/patologia , Núcleo Celular/patologia , Túbulos Renais/patologia , Animais , Nefropatia dos Bálcãs/epidemiologia , Estudos de Avaliação como Assunto , Humanos , Mamíferos , Medição de Risco
6.
Toxicol Pathol ; 46(8): 956-969, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30270795

RESUMO

The important renal tumors that can be induced by exposure of rats to chemical carcinogens are renal tubule tumors (RTTs) derived from tubule epithelium; renal pelvic carcinoma derived from the urothelial lining of the pelvis; renal mesenchymal tumors (RMTs) derived from the interstitial connective tissue; and nephroblastoma derived from the metanephric primordia. However, almost all of our knowledge concerning mechanisms of renal carcinogenesis in the rodent pertains to the adenomas and carcinomas originating from renal tubule epithelium. Currently, nine mechanistic pathways can be identified in either the rat or mouse following chemical exposure. These include direct DNA reactivity, indirect DNA reactivity through free radical formation, multiphase bioactivation involving glutathione conjugation, mitotic disruption, sustained cell proliferation from direct cytotoxicity, sustained cell proliferation by disruption of a physiologic process (alpha 2u-globulin nephropathy), exaggerated pharmacologic response, species-dominant metabolic pathway, and chemical exacerbation of chronic progressive nephropathy. Spontaneous occurrence of RTTs in the rat will be included since one example is a confounder for interpreting kidney tumor results in chemical carcinogenicity studies in rats.


Assuntos
Carcinogênese/induzido quimicamente , Carcinógenos/toxicidade , Neoplasias Renais/induzido quimicamente , Animais , Camundongos , Ratos
7.
Toxicol Pathol ; 46(3): 266-272, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29504493

RESUMO

Chronic progressive nephropathy (CPN) occurs commonly in rats, more frequently and severely in males than females. High-grade CPN is characterized by increased layers of the renal papilla lining, designated as urothelial hyperplasia in the International Harmonization of Nomenclature and Diagnostic Criteria classification. However, urothelium lining the pelvis is not equivalent to the epithelium lining the papilla. To evaluate whether the epithelium lining the renal papilla is actually urothelial in nature and whether CPN-associated multicellularity represents proliferation, kidney tissues from aged rats with CPN, from rats with multicellularity of the renal papilla epithelium of either low-grade or marked severity, and from young rats with normal kidneys were analyzed and compared. Immunohistochemical staining for uroplakins (urothelial specific proteins) was negative in the papilla epithelium in all rats with multicellularity or not, indicating these cells are not urothelial. Mitotic figures were rarely observed in this epithelium, even with multicellularity. Immunohistochemical staining for Ki-67 was negative. Papilla lining cells and true urothelium differed by scanning electron microscopy. Based on these findings, we recommend that the epithelium lining the papilla not be classified as urothelial, and the CPN-associated lesion be designated as vesicular alteration of renal papilla instead of hyperplasia and distinguished in diagnostic systems from kidney pelvis urothelial hyperplasia.


Assuntos
Epitélio/anatomia & histologia , Medula Renal/citologia , Insuficiência Renal Crônica/patologia , Animais , Masculino , Ratos , Ratos Endogâmicos F344 , Ratos Sprague-Dawley , Urotélio/citologia
8.
Regul Toxicol Pharmacol ; 92: 152-164, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29199065

RESUMO

A 90-day in-country feeding trial in Wistar rats was conducted at Tianjin Laboratory in China to assess toxicity of diets containing DAS-44406-6 soybean meal. There were no treatment-related changes observed when compared with the non-GM isoline control groups but histopathologically, 2 of 10 high-dose females were reported to show kidney lesions. However, these findings contrasted with the absence of any treatment-related kidney lesions in 3 separate 90-day toxicity studies previously conducted in Sprague Dawley rats. Strain difference is not expected in the kidney response, and based on the low incidence and contrary evidence from previous studies, it is likely that these lesions were of spontaneous origin, or artefactual. To determine that the lesions observed were not treatment-related in Wistar rats, a specific follow-up confirmatory study was conducted under Good Laboratory Practices (GLP) in the Wistar strain of rats following an identical study design to the Tianjin study. To increase the power of detecting effects, twice the number of animals per group (20/sex/group) were used, and no treatment-related kidney histopathological changes were observed. Based on these results and entire weight of evidence evaluation, it is concluded that the histopathological changes previously noted in the 2 female Wistar rats of Tianjin study were not treatment-related and that DAS-44406-6 soybeans are as safe as conventional non-GM soybeans.


Assuntos
Ácido 4-Acetamido-4'-isotiocianatostilbeno-2,2'-dissulfônico/análogos & derivados , Ração Animal/efeitos adversos , Glycine max/efeitos adversos , Ácido 4-Acetamido-4'-isotiocianatostilbeno-2,2'-dissulfônico/efeitos adversos , Animais , Peso Corporal/efeitos dos fármacos , China , Dieta/efeitos adversos , Feminino , Alimentos Geneticamente Modificados/efeitos adversos , Rim/efeitos dos fármacos , Plantas Geneticamente Modificadas/efeitos adversos , Ratos , Ratos Sprague-Dawley , Ratos Wistar
10.
Toxicol Pathol ; 44(6): 848-55, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27169591

RESUMO

In order to harmonize diagnostic terminology, confirm diagnostic criteria, and describe aspects of tumor biology characteristic of different tumor types, a total of 165 cases of mesenchyme-related tumors and nephroblastomas of the rat kidney were reexamined from the National Toxicology Program (NTP) Archives. This survey demonstrated that renal mesenchymal tumor (RMT) was the most common spontaneous nonepithelial tumor in the rat kidney, also occurring more frequently in the NTP studies than nephroblastoma. Renal sarcoma was a distinct but very rare tumor entity, representing a malignant, monomorphous population of densely crowded, fibroblast-like cells, in which, unlike RMT, preexisting tubules did not persist. Nephroblastoma was characterized by early death of affected animals, suggesting an embryonal origin for this tumor type. Male and female rats were equally disposed to developing RMT, but most of the cases of nephroblastoma occurred in female rats and liposarcoma occurred mostly in male rats. This survey confirmed discrete histopathological and biological differences between the mesenchyme-related renal tumor types and between RMT and nephroblastoma. Statistical analysis also demonstrated a lack of any relationship of these renal tumor types to test article administration in the NTP data bank.


Assuntos
Neoplasias Renais/patologia , Ratos , Animais , Feminino , Neoplasias Renais/classificação , Masculino , Mesoderma/patologia , Inquéritos e Questionários
11.
Toxicol Pathol ; 44(5): 633-5, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-26883151

RESUMO

We report renal tubular adenomas and a carcinoma in 26-week Tg.rasH2 mouse carcinogenicity studies, which have not been reported to date either at our facility or in other published data. However, during the year 2014, renal tubular tumors were present in 4 studies conducted at our facility. Because of their morphological similarity to the amphophilic-vacuolar (AV) phenotypic variant of renal tubule tumors noted in Sprague-Dawley and Fischer 344 rats, which are thought to be familial, as well as the genetic homogeneity of Tg.rasH2 mice, we tracked the parents of these mice with tumors in each study. The origin of these tumors could not be traced back to any of the parents or even an animal barrier, and these tumors were not attributed to the vehicle or test article. Although the exact mechanism of tumorigenesis was not known, based on the available information, the development of renal tumors in these mice was considered random and spontaneous.


Assuntos
Adenoma/veterinária , Carcinoma/veterinária , Neoplasias Renais/veterinária , Animais , Camundongos , Camundongos Transgênicos
12.
Toxicol Pathol ; 42(5): 936-8, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24652082

RESUMO

The spontaneous incidence of foci of oncocytic proliferation (oncocytic hyperplasia and oncocytoma) was assessed in a histopathological reevaluation of the kidneys of 2,391 male and female Fischer 344 (F344) groups of control rats from long-term carcinogenicity studies (involving 24 chemicals) that had been conducted by the National Toxicology Program. The overall incidence of oncocytic proliferation was 0.3%, with a male preponderance over females at 0.5% (6/1,236) versus 0.09% (1/1,155), respectively. In males, there appeared to be an association of oncocytic proliferation with advanced spontaneous chronic progressive nephropathy. Oncocytoma or oncocytic hyperplasia appear to be rare lesions in F344 rats, and observations from these carcinogenicity studies suggest that they are slow growing and tend to occur late in a rodent's life span.


Assuntos
Proliferação de Células , Neoplasias Renais/patologia , Rim/patologia , Animais , Testes de Carcinogenicidade , Carcinógenos/toxicidade , Feminino , Hiperplasia/patologia , Incidência , Neoplasias Renais/etiologia , Masculino , Ratos , Ratos Endogâmicos F344
13.
Toxicol Pathol ; 41(8): 1068-77, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23531794

RESUMO

Oral gavage studies with ß-myrcene in male F344 rats showed a complex renal pathology comprising both alpha2u-globulin (α2u-g) nephropathy, an unusual nephrosis involving the outer stripe of outer medulla (OSOM), and an increased incidence of renal tubule tumors by 2 years. In the 90-day and 2-year studies, respectively, α2u-g nephropathy and linear papillary mineralization were observed in males at the two lower doses but were absent from the high dose. Nephrosis was characterized by dilation of the S3 tubules, nuclear enlargement (including karyomegaly), and luminal pyknotic cells, all in the outermost OSOM. Nephrosis was minimal at the higher doses in the 90-day study, but progressed to a severe grade in males dosed with 1,000 mg/kg for 2 years. Renal tubule tumors developed in treated groups with incidences up to 30% in the 250 and 500 mg/kg male dose groups. Tumors at the lower doses in males may have been associated with α2u-g nephropathy, while those at higher doses in both sexes may have been due to the nephrosis. Because ß-myrcene induced a complex spectrum of renal pathology, the α2u-g nephropathy mechanism cannot be the sole mechanism of carcinogenesis in these rats.


Assuntos
alfa-Globulinas/metabolismo , Nefropatias/induzido quimicamente , Rim/efeitos dos fármacos , Rim/patologia , Monoterpenos/toxicidade , Monoterpenos Acíclicos , Administração Oral , alfa-Globulinas/química , Animais , Feminino , Hialina/química , Hialina/metabolismo , Rim/química , Rim/metabolismo , Nefropatias/metabolismo , Nefropatias/patologia , Masculino , Monoterpenos/administração & dosagem , Ratos , Ratos Endogâmicos F344
14.
Toxicol Pathol ; 40(3): 473-81, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22298794

RESUMO

From the archives of the National Toxicology Program, National Institutes of Health, kidney sections from twenty-four carcinogenicity studies (representing twenty-three chemicals) in male and female F344 rats were histopathologically re-evaluated to grade the severity of chronic progressive nephropathy (CPN) on an expanded scale of 0-8, and to record the presence of renal tubule tumors (RTT) and their precursor, atypical tubule hyperplasia (ATH). The data were statistically analyzed using SAS software for logistic regression analysis. This histopathological survey of 2,436 F344 rats showed clear evidence of a qualitative and statistically significant association between advanced stages of CPN severity and the development of low-grade RTT and ATH. Advanced CPN severity therefore represents a risk factor for the development of RTT and appears to be an underlying basis for spontaneous occurrence of RTT in the F344 rat. The difference in incidence and severity of CPN between the sexes also explains the 9:1 male-to-female sex difference in the spontaneous occurrence of ATH and RTT observed here. The regulatory significance of this finding is that chemicals exacerbating CPN as their only renal effect are likely to show a numerical increase in RTT with dose, which does not represent a direct tumorigenic effect of the chemical.


Assuntos
Carcinógenos/toxicidade , Nefropatias/induzido quimicamente , Neoplasias Renais/induzido quimicamente , Acetonitrilas/toxicidade , Adenoma/induzido quimicamente , Adenoma/patologia , Animais , Compostos de Cálcio/toxicidade , Testes de Carcinogenicidade , Carcinoma/induzido quimicamente , Carcinoma/patologia , Doença Crônica , Modelos Animais de Doenças , Feminino , Histocitoquímica , Hiperplasia , Nefropatias/patologia , Neoplasias Renais/patologia , Túbulos Renais/efeitos dos fármacos , Túbulos Renais/patologia , Modelos Logísticos , Masculino , Oximetolona/toxicidade , Ratos , Ratos Endogâmicos F344 , Medição de Risco , Silicatos/toxicidade
15.
Toxicol Pathol ; 40(4 Suppl): 14S-86S, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22637735

RESUMO

The INHAND Project (International Harmonization of Nomenclature and Diagnostic Criteria for Lesions in Rats and Mice) is a joint initiative of the Societies of Toxicologic Pathology from Europe (ESTP), Great Britain (BSTP), Japan (JSTP), and North America (STP) to develop an internationally accepted nomenclature for proliferative and nonproliferative lesions in laboratory animals. The purpose of this publication is to provide a standardized nomenclature for classifying lesions observed in the urinary tract of rats and mice. The standardized nomenclature of urinary tract lesions presented in this document is also available electronically on the Internet (http://www.goreni.org/). Sources of material included histopathology databases from government, academia, and industrial laboratories throughout the world. Content includes spontaneous developmental and aging lesions as well as those induced by exposure to test materials. A widely accepted and utilized international harmonization of nomenclature for urinary tract lesions in laboratory animals will decrease confusion among regulatory and scientific research organizations in different countries and provide a common language to increase and enrich international exchanges of information among toxicologists and pathologists.


Assuntos
Sistema Urinário/patologia , Doenças Urológicas/patologia , Neoplasias Urológicas/patologia , Animais , Feminino , Masculino , Camundongos , Ratos , Terminologia como Assunto , Testes de Toxicidade , Sistema Urinário/anatomia & histologia , Doenças Urológicas/classificação , Neoplasias Urológicas/classificação
16.
Toxicol Pathol ; 39(2): 381-9, 2011 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-21422264

RESUMO

The occurrence and severity of spontaneous chronic progressive nephropathy (CPN) in control male F344 rats as well as the frequency of treatment-related CPN exacerbation were histopathologically reevaluated. A series of 43 National Toxicology Program (NTP) 90-day toxicity studies comparing the influence of NIH-07 or NTP-2000 diets was examined. Relationships between the histopathologic findings at 90 days and renal tubule proliferative lesions recorded in subsequent 2-year bioassays for 24 chemicals were statistically analyzed. CPN lesions were observed in 100% of the control male rats regardless of diet, but CPN was more severe in control rats fed NIH-07. Approximately one-third of the 90-day studies demonstrated a treatment-related exacerbation of CPN severity, which was independent of diet. For chemicals that proceeded to 2-year bioassays, all studies with a statistically significant increase in renal tubule tumors (RTT) at 2 years had treatment-related exacerbation of CPN in the 90-day and 2-year studies. These findings indicate that CPN occurs ubiquitously in young male F344 rats and that treatment-related exacerbation of CPN in 90-day studies is a relatively common occurrence, having the potential to be predictive of an increased incidence of RTT in subsequent 2-year bioassays.


Assuntos
Dieta/efeitos adversos , Falência Renal Crônica/induzido quimicamente , Neoplasias Renais/induzido quimicamente , Túbulos Renais/efeitos dos fármacos , Túbulos Renais/patologia , Acroleína/toxicidade , Ração Animal , Animais , Benzofenonas/toxicidade , Bioensaio , Dieta/normas , Índio/toxicidade , Falência Renal Crônica/complicações , Falência Renal Crônica/patologia , Neoplasias Renais/complicações , Neoplasias Renais/patologia , Masculino , Modelos Animais , Fosfinas/toxicidade , Ratos , Ratos Endogâmicos F344 , Testes de Toxicidade , Uretana/toxicidade
17.
Regul Toxicol Pharmacol ; 59(3): 430-6, 2011 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21296119

RESUMO

An independent Pathology Working Group (PWG) re-evaluated the kidney changes in National Toxicology Program (NTP) toxicology/carcinogenicity studies of tert-butyl alcohol (TBA) in F344/N rats to determine possible mode(s) of action underlying renal tubule tumors in male rats at 2-years. In the 13-week study, the PWG confirmed that the normal pattern of round hyaline droplets in proximal convoluted tubules was replaced by angular droplet accumulation, and identified precursors of granular casts in the outer medulla, changes typical of alpha(2u)-globulin (α(2u)-g) nephropathy. In the 2-year study, the PWG confirmed the NTP observation of increased renal tubule tumors in treated male groups. Linear papillary mineralization, another hallmark of the α(2u)-g pathway was present only in treated male rats. Chronic progressive nephropathy (CPN) was exacerbated in high-dose males and females, with a relationship between advanced grades of CPN and renal tumor occurrence. Hyperplasia of the papilla lining was a component of CPN in both sexes, but there was no pelvic urothelial hyperplasia. High-dose females showed no TBA-related nephrotoxicity. The PWG concluded that both α(2u)-g nephropathy and exacerbated CPN modes of action were operative in TBA renal tumorigenicity in male rats, neither of which has relevance for human cancer risk.


Assuntos
Ingestão de Líquidos , Rim/efeitos dos fármacos , Rim/patologia , Água , terc-Butil Álcool/toxicidade , Animais , Testes de Carcinogenicidade/métodos , Avaliação Pré-Clínica de Medicamentos/métodos , Feminino , Neoplasias Renais/induzido quimicamente , Neoplasias Renais/patologia , Masculino , Ratos , Ratos Endogâmicos F344 , Testes de Toxicidade/métodos , Água/administração & dosagem , terc-Butil Álcool/administração & dosagem
18.
Regul Toxicol Pharmacol ; 58(1): 100-5, 2010 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-20447435

RESUMO

Risk evaluation and hazard classification for tetrahydrofuran (THF) is based partly on the incidences of renal tumors in male F344/N rats reported in a 2-year carcinogenicity study by the National Toxicology Program (NTP). A Pathology Working Group (PWG) was commissioned to conduct an independent review of the kidney slides from this bioassay (along with two subchronic studies) to assess renal changes in light of recent scientific work on pathogenesis of pre-neoplastic and neoplastic lesions in rat kidney. PWG pathologists confirmed the NTP assessment that adenomas were non-statistically increased in animals exposed to the highest level of THF. However, when pre-neoplastic and neoplastic lesions were combined, there was no difference between control and THF-exposed groups. Also, the majority of these proliferative lesions were in rats with severe chronic progressive nephropathy (CPN). Accordingly, the PWG concluded that renal lesions in the control and THF-exposed groups resulted primarily from regenerative processes associated with advanced CPN. Based on an alpha(2u)-globulin/hyaline droplet response observed in a 4-week study with THF, the PWG could not exclude the possibility of both advanced CPN and low-grade alpha2u-g nephropathy contributing to the renal proliferative lesions developing chronically in high-dose males. Neither condition has a pathologic counterpart in humans.


Assuntos
Poluentes Atmosféricos/toxicidade , Furanos/toxicidade , Exposição por Inalação , Rim/efeitos dos fármacos , Solventes/toxicidade , Animais , Testes de Carcinogenicidade , Rim/metabolismo , Rim/patologia , Masculino , Ratos , Ratos Endogâmicos F344 , Medição de Risco
19.
Crit Rev Toxicol ; 39(4): 332-46, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-19514917

RESUMO

Chronic progressive nephropathy (CPN) is a single renal disease of unknown etiology, occurring in high incidence in laboratory rats, that can confound subchronic and carcinogenicity bioassay interpretation. It has effects on longevity and, in its early stages, it has a histological similarity to tubular degeneration from other causes. In its advanced stages it is associated with marginally increased renal tubule tumor incidences. Several natural or physiological factors influence its incidence and severity, most prominently protein and caloric intake and male sex hormones. By contrast, there is no entity in humans that presents with the combination or pattern of histological features found in rat CPN. Humans are affected by several different nephropathies of known etiology but generally these are found much less frequently than CPN is found in the rat. There are major differences in pathology between CPN and human nephropathies. Histological characteristics in CPN include prominently dilated tubules filled with proteinaceous casts with consequent kidney enlargement, which contrasts with the shrunken kidneys found in end-stage human nephropathy. Unlike human nephropathy, CPN is devoid of vascular changes, it has no immunological or autoimmune basis, and inflammation is not a prominent feature. Various chemicals exacerbate CPN; no equivalent chemical interactions are seen with human nephropathies. Because some chemicals exacerbate CPN, and advanced CPN is a small risk factor for renal tubule tumor development, an increase in renal tumors can be wrongly attributed to a direct chemical effect on the kidney. On the basis of differences in biology and pathology, this analysis concludes that there is no clear human counterpart of CPN. We recommend that chemically induced exacerbation of CPN not be acknowledged as an indicator of human toxic hazard. Increases in the incidence of CPN-related renal tumor is not considered relevant to humans.


Assuntos
Carcinógenos/farmacologia , Nefropatias/induzido quimicamente , Falência Renal Crônica/patologia , Medição de Risco , Animais , Humanos , Rim/patologia , Nefropatias/patologia , Falência Renal Crônica/etiologia , Ratos , Especificidade da Espécie
20.
Toxicol Pathol ; 37(6): 714-32, 2009 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-19700658

RESUMO

The two-year cancer bioassay in rodents remains the primary testing strategy for in-life screening of compounds that might pose a potential cancer hazard. Yet experimental evidence shows that cancer is often secondary to a biological precursor effect, the mode of action is sometimes not relevant to humans, and key events leading to cancer in rodents from nongenotoxic agents usually occur well before tumorigenesis and at the same or lower doses than those producing tumors. The International Life Sciences Institute (ILSI) Health and Environmental Sciences Institute (HESI) hypothesized that the signals of importance for human cancer hazard identification can be detected in shorter-term studies. Using the National Toxicology Program (NTP) database, a retrospective analysis was conducted on sixteen chemicals with liver, lung, or kidney tumors in two-year rodent cancer bioassays, and for which short-term data were also available. For nongenotoxic compounds, results showed that cellular changes indicative of a tumorigenic endpoint can be identified for many, but not all, of the chemicals producing tumors in two-year studies after thirteen weeks utilizing conventional endpoints. Additional endpoints are needed to identify some signals not detected with routine evaluation. This effort defined critical questions that should be explored to improve the predictivity of human carcinogenic risk.


Assuntos
Testes de Carcinogenicidade/métodos , Carcinógenos/toxicidade , Bases de Dados Factuais , Neoplasias Experimentais/induzido quimicamente , Animais , Feminino , Humanos , Fenômenos do Sistema Imunitário/efeitos dos fármacos , Masculino , Camundongos , Neoplasias Experimentais/imunologia , Neoplasias Experimentais/patologia , Neoplasias Experimentais/prevenção & controle , Ratos , Ratos Endogâmicos F344 , Medição de Risco/métodos
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