Chemically Induced Renal Tubule Tumors in the Laboratory Rat and Mouse: Review of the NCI/NTP Database and Categorization of Renal Carcinogens Based on Mechanistic Information

Abstract

The incidence of renal tubule carcinogenesis in male and female rats or mice with 69 chemicals from the 513 bioassays conducted to date by the NCI/NTP has been collated, the chemicals categorized, and the relationship between carcinogenesis and renal tubule hyperplasia and exacerbation of the spontaneous, age-related rodent disease chronic progressive nephropathy (CPN) examined. Where information on mechanism or mode of action exists, the chemicals have been categorized based on their ability to directly or indirectly interact with renal DNA, or on their activity via epigenetic pathways involving either direct or indirect cytotoxicity with regenerative hyperplasia, or exacerbation of CPN. Nine chemicals were identified as directly interacting with DNA, with six of these producing renal tubule tumors at high incidence in rats of both sexes, and in some cases also in mice. Ochratoxin A was the most potent compound in this group, producing a high tumor incidence at very low doses, often with metastasis. Three chemicals were discussed in the context of indirect DNA damage mediated by an oxidative free radical mechanism, one of these being from the NTP database. A third category included four chemicals that had the potential to cause DNA damage following conjugation with glutathione and subsequent enzymatic activation to a reactive species, usually a thiol-containing entity. Two chemicals were allocated into the category involving a direct cytotoxic action on the renal tubule followed by sustained compensatory cell proliferation, while nine were included in a group where the cell loss and sustained increase in renal tubule cell turnover were dependent on lysosomal accumulation of the male rat-specific protein, alpha2mu-globulin. In a sixth category, morphologic evidence on two chemicals indicated that the renal tumors were a consequence of exacerbated CPN. For the remaining chemicals, there were no pertinent data enabling assignment to a mechanistic category. Accordingly, these chemicals, acting through an as yet unknown mechanism, were grouped as either being associated with an enhancement of CPN (category 7, 16 chemicals), or not associated with enhanced CPN (category 8, 4 chemicals). A ninth category dealt with 11 chemicals that were regarded as producing increases in renal tubule tumors that did not reach statistical significance. A 10th category discussed 6 chemicals that induced renal tumors in mice but not in rats, plus 8 chemicals that produced a low incidence of renal tubule tumors in mice that did not reach statistical significance. As more mechanistic data are generated, some chemicals will inevitably be placed in different groups, particularly those from categories 7 and 8. A large number of chemicals in the series exacerbated CPN, but those in category 7 especially may be candidates for inclusion in category 6 when further information is gleaned from the relevant NTP studies. Also, new data on specific chemicals will probably expand category 5 as cytotoxicity and cell regeneration are identified as obliga...

Spontaneous Occurrence of a Distinctive Renal Tubule Tumor Phenotype in Rat Carcinogenicity Studies Conducted by the National Toxicology Program

“…Across carcinogenicity studies, there is a preponderance of basophilic tumors in male rats compared to females (Lock and Hard, 2004). In contrast, the frequency of the AV tumor was equal between males and females in this survey.…”

DNA adduct formation by ochratoxin A: Review of the available evidence

“…The involvement of a nephrotoxic S-conjugate in OTA toxicity and carcinogenicity is also not consistent with the potency of other hydroquinones activated by a glutathione-conjugation pathway, which usually require administration of much higher doses to induce nephrotoxicity (English et al 1994;Monks and Lau 1994;Boatman et al 1996) and/or renal tumours. Furthermore, it is well established that nephrotoxic hydroquinone S-conjugates promote tumour formation by inducing sustained regenerative cell proliferation in response to cytotoxicity and tissue necrosis, which is also not consistent with the histopathological changes observed after treatment with OTA (NTP 1989;Boorman et al 1992;English et al 1994;Nakagawa et al 1998;Lock and Hard 2004).…”

“…Histopathological changes induced by OTA in the kidney consist of disorganization of the S3 tubules, single cell death, karyomegaly, polyploidy and frequent mitosis (Boorman et al 1992;Maaroufi et al 1999;Rasonyi et al 1999). These histopathological alterations together with the aggressive nature of the tumours are unique to OTA and suggest that the mechanism of OTA carcinogenicity is not merely based on sustained regenerative cell proliferation as a consequence of cytotoxicity, as frequently observed in response to nongenotoxic renal carcinogens such as chloroform and d-limonene (Lock and Hard 2004). However, results of genotoxicity studies also do not suggest that OTA is mutagenic or a potent genotoxin.…”

Ochratoxin A and Aristolochic Acid Involvement in Nephropathies and Associated Urothelial Tract Tumours

“…CANCERS RISK: OTA VS. AA OTA is one of the most potent renal carcinogens found to date (27,28). Previous studies indicate that renal carcinoma metastases occurred mainly in the lungs and mammary glands of both male and female rats.…”