Potassium bromate (KBrO3) is an oxidizing agent that has been used as a food additive, mainly in the bread-making process. Although adverse effects are not evident in animals fed bread-based diets made from flour treated with KBrO3, the agent is carcinogenic in rats and nephrotoxic in both man and experimental animals when given orally. It has been demonstrated that KBrO3 induces renal cell tumors, mesotheliomas of the peritoneum, and follicular cell tumors of the thyroid. In addition, experiments aimed at elucidating the mode of carcinogenic action have revealed that KBrO3 is a complete carcinogen, possessing both initiating and promoting activities for rat renal tumorigenesis. However, the potential seems to be weak in mice and hamsters. In contrast to its weak mutagenic activity in microbial assays, KBrO3 showed relatively strong potential inducing chromosome aberrations both in vitro and in vivo. Glutathione and cysteine degrade KBrO3 in vitro; in turn, the KBrO3 has inhibitory effects on inducing lipid peroxidation in the rat kidney. Active oxygen radicals generated from KBrO3 were implicated in its toxic and carcinogenic effects, especially because KBrO3 produced 8-hydroxydeoxyguanosine in the rat kidney. A wide range of data from applications of various analytical methods are now available for risk assessment purposes.

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Toxicity and Carcinogenicity of Potassium Bromate-A New Renal Carcinogen

The comparative pathobiology of α2u-globulin nephropathy

Lysosomal degradation of α2u-globulin and α2u-globulin-xenobiotic conjugates

alpha 2u-N is a syndrome that has been characterized in male rats exposed to a number of environmental chemicals and pharmacological agents. The chemicals or their metabolites bind to alpha 2u, which is believed to lead to a less digestible chemical-protein complex. Because of the decreased hydrolysis of the chemical-protein complex in the lysosome, alpha 2u accumulates in the form of protein droplets. In extensive nephropathy, the accumulation of alpha 2u in the lysosome results in polyangular crystalloid droplets that lead to lysosomal overload and eventually cell death. This cell death stimulates restorative cell replication which promotes renal carcinogenesis in male rats. As such, it is imperative that extrapolation of risk to humans of chemicals causing this syndrome be performed. Because the nongenotoxic mechanism for carcinogenesis in the male rat involves a unique protein, such extrapolations can only be done incorporating species differences in the critical factors that result in alpha 2u-N in rats. Presently, these data suggest a markedly reduced risk for humans compared to male rats.

Biochemical Mechanisms and Pathobiology of α2u-Globulin Nephropathy

In a 2-year carcinogenesis bioassay, d-limonene (dL) induced kidney tumors in male F344 rats, but not in female F344 rats or either sex of mice, d-Limonene-1,2-oxide, a metabolite of dL, has been shown to bind reversibly the male rat-specific urinary protein, alpha2u-globulin (alpha 2u-G), lysosomal degradation than alpha 2u-G alone. This reduced degradation of alpha 2u-G-chemical complex leads to an accumulation of this protein in the proximal convoluted tubules of the male rat kidney and to the morphological changes characteristic for alpha 2u-globulin nephropathy. The only male rat strain known to be resistant to this renal disease is the alpha 2u-G deficient NCI-Black-Reiter (NBR) rat. The objectives of this study were to determine whether or not dL causes sustained increases in cell proliferation and has promoting activity for renal adenomas in male rats and if the male rat-specific urinary protein, alpha 2u-G, is required. In a 32-week initiation-promotion assay, male F344 and NBR rats were treated with either 0 or 500 ppm N-ethyl-N-hydroxyethylnitrosamine (EHEN) in the drinking water for 2 weeks. Experimental groups of 31 to 38 rats then received 0 or 150 mg d-limonene/kg/day in corn oil for 30 weeks by p.o. gavage 5 days/week. Cell proliferation in the proximal tubules was assessed via 5-bromo-2'-deoxyuridine-filled osmotic mini-pumps and immunohistochemistry after 7 weeks (2 weeks EHEN + 5 weeks dL) and at the end of the study (2 weeks EHEN + 30 weeks dL). Preneoplastic and neoplastic lesions were quantified in perfusion-fixed kidneys. A 5-fold increase in the labeling index of P2-cells was found after 5 weeks and 30 weeks of promotion in all dL-treated F344 rats, whereas no difference between treatment groups was detected in NBR rats. No increase in tumors or preneoplastic lesions was detected in dL-treated NBR rats, whereas a 10-fold increase in renal adenomas and atypical hyperplasias was found in the EHEN-dL-treated F344 rats compared with F344 rats treated with EHEN-corn oil. d-Limonene treatment alone caused a significant increase in the number of atypical tubules and atypical hyperplasias in F344 rats when compared with the F344 vehicle control. On the other hand, a significantly lower incidence of liver tumors was found in EHEN-dL-treated F344 rats compared with F344 rats treated with EHEN-corn oil, suggesting a chemopreventative effect of dL on EHEN-induced liver carcinogenesis in F344 rats.(ABSTRACT TRUNCATED AT 400 WORDS)

https://cancerres.aacrjournals.org/content/canres/51/13/3512.full.pdf

The Presence of α2u-Globulin Is Necessary for d-Limonene Promotion of Male Rat Kidney Tumors

Characterization of spontaneous and decalin-induced hyaline droplets in kidneys of adult male rats

Morphogenesis of decalin-induced renal alterations in the male rat.

Decalin-induced nephrotoxicity: light and electron microscopic examination of the effects of oral dosing on the development of kidney lesions in the rat.

L.C. Stone

Papers

Characterization of spontaneous and decalin-induced hyaline droplets in kidneys of adult male rats

Morphogenesis of decalin-induced renal alterations in the male rat.

Decalin-induced nephrotoxicity: light and electron microscopic examination of the effects of oral dosing on the development of kidney lesions in the rat.

Development of a short-term model of decalin inhalation nephrotoxicity in the male rat.