Exacerbation Of Chronic Progressive Nephropathy Research Articles

Confounders for kidney carcinogenesis in rodent cancer bioassays.

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.

Tetrahydrofuran-induced tumors in rodents are not relevant to humans: Quantitative weight of evidence analysis of mode of action information does not support classification of tetrahydrofuran as a possible human carcinogen

Inhalation of tetrahydrofuran (THF) causes a marginal increase in the incidence of renal tumors in male rats and an increase in the incidence of liver tumors in female mice. Quantitative weight of evidence (QWoE) was applied to assess experimental support for biologically plausible modes of action (MoA) of tumor formation by THF and their human relevance. QWoE did not obtain support for a MoA to induce kidney tumors in male rats from THF exposure via α2u -globulin nephropathy, exacerbation of chronic progressive nephropathy (CPN), DNA-damage, or recurrent cytotoxicity but obtained moderate to good support for a constitutive androgen receptor (CAR)-mediated MoA for the induction of liver tumors in female mice. Tumors as a consequence of CAR-activation are not considered relevant to humans. Considering the previous conclusion that the increases in kidney tumors in male rats are unlikely related to THF-exposure and the support for a CAR-mediated MoA in mice obtained here, these tumors should not be used as a basis for THF cancer classification.

Mechanisms of Rodent Renal Carcinogenesis Revisited.

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.

Two-year carcinogenicity study in rats with a nonnucleoside reverse transcriptase inhibitor.

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.

A 26-week repeated-dose toxicity study of allisartan isoproxil in Sprague-Dawley rats

Allisartan isoproxil (ALS-3) is a selective, nonpeptide blocker of the angiotensin II type 1 receptor. It is a new antihypertensive drug under development with a novel chemical structure. The aim of this study was to evaluate the potential toxicity of ALS-3 in Sprague-Dawley rats. Animals were orally administered either vehicle or ALS-3 at doses of 20, 80 and 320 mg/kg once-daily for 26 weeks, followed by a 6-week recovery period. Toxicity was assessed by mortality, clinical signs, body weight, food consumption, hematology, coagulation, serum chemistry, gross necropsy, organ weights and microscopic examination. Decreased body-weight gain was noted at 320 mg/kg/day in both sexes as well as at the 80-mg/kg/day dose in females. Food consumption was decreased at all doses in males and at 80- and 320-mg/kg/day doses in females. Decreased erythrocyte parameters (erythrocyte count, hemoglobin and hematocrit) were observed in males receiving 320 mg/kg/day. Elevated urea nitrogen (BUN), increased kidney weight, decreased heart weight and exacerbation of chronic progressive nephropathy (CPN) severity were all observed in males at 80 and 320 mg/kg/day. However, only an exacerbated incidence of CPN was observed in females at 320 mg/kg/day. All changes were reversed after the 6-week recovery period, except BUN and CPN. Based on these results, we concluded that a dose of 20 mg/kg/day was the no observed adverse effect level. The toxicity target organ was the kidney. Males were more affected than females.

Toxicity of methyl tertiary‐butyl ether (MTBE) following exposure of Wistar Rats for 13 weeks or one year via drinking water

Thirteen-week and one-year toxicity studies of methyl tertiary-butyl ether (MTBE) administered in drinking water to Wistar rats were conducted. Male and female rats were exposed to MTBE in drinking water at 0.5, 3, 7.5 and 15 mg ml(-1) for 13 weeks and at 0.5, 3 and 7.5 (males) or 0.5, 3 and 15 mg ml(-1) (females) for 1 year. Body weights were reduced only in males following 13 weeks of exposure. Reduced water consumption and urine output were observed in males and females exposed to MTBE. Kidney cell replication and α(2u)-globulin levels in males were increased at 1 and 4 weeks of MTBE exposure and tubular cell regeneration was increased in male kidneys exposed to MTBE concentrations of 7.5 mg ml(-1) or greater for 13 weeks. Wet weights of male kidneys were increased following 13 weeks, 6 months and 1 year of exposure to MTBE concentrations of 7.5 mg ml(-1) or greater. Kidney wet weights were increased in females at MTBE concentrations of 15 mg ml(-1) for 13 weeks. Tertiary-butyl alcohol blood levels increased linearly with dose in males and females following 1 year of exposure. Chronic progressive nephropathy (CPN), of minimal to mild severity, increased in males, but not females, with 1 year of MTBE exposure. In summary, exposure of Wistar rats to MTBE in the drinking water resulted in minimal exposure-related effects including limited renal changes in male rats suggestive of α(2u)-globulin nephropathy following 13 weeks of exposure and an exacerbation of CPN in males at the end of 1 year of exposure.

The Subacute and Subchronic Oral Toxicity of 1,3-Dichloropropane in the Rat

1,3-Dichloropropane (DCP) was administered by gavage for 14 and 90 days to male and female Sprague-Dawley-derived rats (10/sex/group). In the 14-day study using dose levels of 200, 600, and 1800 mg/kg/day, all high-dose group animals died, and none died in the other two treatment groups. Other signs associated with treatment in high-dose animals included languid behavior, salivation (also seen in middose group animals), dyspnea, and prostration. No differences were found between animals in the low-dose or middose groups compared to the control animals for body weight, food consumption, hematology, and gross postmortem and histopathology data. Total protein and albumin blood levels were increased for low-dose and middose females, and middose females, respectively. The clinical chemistry findings appeared to be treatment-related, since they were accompanied by significantly increased liver weights (absolute and relative; both sexes of middose animals) and kidney weights (absolute and relative; middose males). The dose levels used in the 90-day study, chosen on the results of the 14-day study, were 50, 200, and 800 mg/kg/day. All animals survived to termination. Males in the high-dose group exhibited a significant decrease in body weight, whereas females in this group exhibited urine-stained fur. No treatment-related effects were found in food consumption or hematology data. Alkaline phosphatase, alanine aminotransferase (males only), albumin, and total protein for high-dose group animals were increased. These findings were accompanied by increases in liver weight for low-dose (females only), middose, and high-dose animals and kidney weights for middose and high-dose group animals. Microscopic evaluations revealed centrilobular hepatocellular hypertrophy for the high-dose group animals and an exacerbation of chronic progressive nephropathy for middose (males only) and high-dose animals.

Subacute and Subchronic Oral Toxicity of p-Chlorotoluene in the Rat

p-Chlorotoluene was administered by corn oil gavage for 14 and 90 days to male and female Sprague-Dawley-derived rats at dosages of 200, 600, and 1800 mg/kg per day and 50, 200, and 800 mg/kg per day, respectively. In the 14-day study, 8 of 10 animals of each sex in the high-dose group died due to treatment. Other treatment-related signs for these animals included an adverse effect upon body weight and clinical signs of salivation, tremors, and prostration. In the 200 and 600 mg/kg per day groups there were no apparent treatment-related effects. In the 90-day study, 4 of 10 males and 2 of 10 females in the high-dose group died due to treatment. Other signs for this treatment group included an adverse effect upon body weight and clinical signs of languid behavior, prostration, tremors, sensitivity to touch, epistaxis, and respiratory distress. Increases in alkaline phosphatase and creatinine (males only), and increases in adrenal (absolute and relative, females), kidney (relative, both sexes), and liver (relative, both sexes) weights were also noted. Histopathologic findings of centrilobular hepatocellular hypertrophy, adrenal cortical hyperplasia, and exacerbation of chronic progressive nephropathy confirmed the clinical laboratory and organ weight results as being treatment related for the animals receiving 800 mg/kg per day for 90 days. Animals receiving 50 or 200 mg/kg per day (90 days) did not exhibit treatment-related findings.