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

ABSTRACTThe incidence of renal tubule carcinogenesis in male and female rats or mice with69 chemicals from the 513 bioassays conducted to date by the NCI/NTP has been collated, thechemicals categorized, and the relationship between carcinogenesis and renal tubule hyperplasiaand exacerbation of the spontaneous, age-related rodent disease chronic progressive nephropathy(CPN) examined. Where information on mechanism or mode of action exists, the chemicals havebeen categorized based on their ability to directly or indirectly interact with renal DNA, or on theiractivity via epigenetic pathways involving either direct or indirect cytotoxicity with regenerativehyperplasia, or exacerbation of CPN. Nine chemicals were identified as directly interacting withDNA, 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 werediscussed in the context of indirectDNAdamage mediated by an oxidative free radical mechanism,one of these being from the NTP database. A third category included four chemicals that had thepotential to causeDNAdamage following conjugation with glutathione and subsequent enzymaticactivation to a reactive species, usually a thiol-containing entity. Two chemicals were allocatedinto the category involving a direct cytotoxic action on the renal tubule followed by sustainedcompensatory cell proliferation, while nine were included in a group where the cell loss andsustained increase in renal tubule cell turnover were dependent on lysosomal accumulation ofthe male rat-specific protein, α2µ-globulin. In a sixth category, morphologic evidence on twochemicals indicated that the renal tumors were a consequence of exacerbated CPN. For theremaining chemicals, there were no pertinent data enabling assignment to a mechanistic category.Accordingly, these chemicals, acting through an as yet unknown mechanism, were grouped aseither being associated with an enhancement of CPN (category 7, 16 chemicals), or not associatedwith enhanced CPN (category 8, 4 chemicals). A ninth category dealt with 11 chemicals that wereregarded 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 8chemicals that produced a lowincidence of renal tubule tumors in mice that did not reach statisticalsignificance. As more mechanistic data are generated, some chemicals will inevitably be placedin different groups, particularly those from categories 7 and 8. A large number of chemicals inthe series exacerbated CPN, but those in category 7 especially may be candidates for inclusionin category 6 when further information is gleaned from the relevant NTP studies. Also, newdata on specific chemicals will probably expand category 5 as cytotoxicity and cell regenerationare identified as obligatory steps in renal carcinogenesis in more cases. Additional confirmatoryoutcomes arising from this revieware that metastases from renal tubule tumors, while encounteredwith chemicals causing DNA damage, are rare with those acting through an epigenetic pathway,with the exception being fumonisin B1; that male rats and mice are generally more susceptiblethan female rats and mice to chemical induction of renal tubule tumors; and that a backgroundof atypical tubule hyperplasia is a useful indicator reflecting a chemically associated renal tubuletumor response. With respect to renal tubule tumors and human risk assessment, chemicals incategories 1 and 2, and possibly 3,would currently be judged by linear default methods; chemicalsin category 4 (and probably some in category 3) as exhibiting a threshold of activity warrantingthe benchmark approach; and those in categories 5 and 6 as representing mechanisms that haveno relevance for extrapolation to humans.