Alpha<sub>2U</sub>‐Globulin Nephropathy and Chronic Progressive Nephropathy as Modes of Action for Renal Tubule Tumor Induction in Rats, and Their Possible Interaction

Lock, Edward A.; Hard, Gordon C.

doi:10.1002/9780470622728.ch18

Cited by 3 publications

(2 citation statements)

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“…(1997), and astrocytomas reported by Dodd et al (2010). This approach is conservative in that it likely overstates risk, especially since some of the positive cancer findings reported in the animal bioassays with MTBE are not reliable (i.e., LCTs, leukemias/lymphomas, and astrocytomas) (Dodd et al., 2010; Goodman, Gaylor, Beyer, Rhomberg, & Beck, 2008; Hoel, 2009; Experimental Pathology Laboratories, Inc., 2011; US EPA, 2012), while others are likely not relevant to humans (i.e., kidney tumors in male rats and liver cancer in female mice) (Bird et al., 1997; European Centre for Ecotoxicity and Toxicology of Chemicals, 2003; Lock & Hard, 2010; Hard, 2010; Hard, Betz, & Seely, 2012). In addition, epidemiologic studies have not shown a relationship between cancer and MTBE exposure in humans (US EPA, 1993).…”

Section: Mos Analysismentioning

confidence: 99%

A Comparative Cancer Risk Evaluation of MTBE and Other Compounds (Including Naturally Occurring Compounds) in Drinking Water in New Hampshire

2020

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Methyl tert-butyl ether (MTBE) was added to gasoline in New Hampshire (NH) between 1995 and 2006 to comply with the oxygenate requirements of the 1990 Amendments to the Clean Air Act. Leaking tanks and spills released MTBE into groundwater, and as a result, MTBE has been detected in drinking water in NH. We conducted a comparative cancer risk assessment and a margin-of-safety (MOS) analysis for several constituents, including MTBE, detected in NH drinking water. Using standard risk assessment methods, we calculated cancer risks from exposure to 12 detected volatile organic compounds (VOCs), including MTBE, and to four naturally occurring compounds (i.e., arsenic, radium-226, radium-228, and radon-222) detected in NH public water supplies. We evaluated exposures to a hypothetical resident ingesting the water, dermally contacting the water while showering, and inhaling compounds volatilizing from water in the home. We then compared risk estimates for MTBE to those of the other 15 compounds. From our analysis, we concluded that the high-end cancer risk from exposure to MTBE in drinking water is lower than the risks from all the other VOCs evaluated and several thousand times lower than the risks from exposure to naturally occurring constituents, including arsenic, radium, and radon. We also conducted an MOS analysis in which we compared toxicological points of departure to the NH maximum contaminant level (MCL) of 13 µg/L. All of the MOSs were greater than or equal to 160,000, indicating a large margin of safety and demonstrating the health-protectiveness of the NH MCL for MTBE.

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Section: Mos Analysismentioning

confidence: 99%

A Comparative Cancer Risk Evaluation of MTBE and Other Compounds (Including Naturally Occurring Compounds) in Drinking Water in New Hampshire

2020

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“…Chemicals that induce a2u-g nephropathy also cause exacerbation of CPN (Hard et al 1993). Hence, a marginal increase in RTT observed near the end of a carcinogenicity bioassay with a hyaline droplet-inducing chemical of low potency could be the result of a combination of the two types of nephropathy-a2u-g nephropathy in concert with exacerbated CPN (Lock and Hard 2010).…”

Section: Chemical Exacerbation Of Chronic Progressive Nephropathy (Cpn)mentioning

confidence: 99%

Mechanisms of Rodent Renal Carcinogenesis Revisited

Hard¹

2018

Toxicol Pathol

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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.

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Histopathologic changes in the kidneys of male F344 rats from a 2-year inhalation carcinogenicity study of tetrahydrofuran: A pathology working group review and re-evaluation

Bruner¹,

Greaves

Hard³

et al. 2010

Regulatory Toxicology and Pharmacology

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Alpha_2U‐Globulin Nephropathy and Chronic Progressive Nephropathy as Modes of Action for Renal Tubule Tumor Induction in Rats, and Their Possible Interaction

Cited by 3 publications

References 74 publications

A Comparative Cancer Risk Evaluation of MTBE and Other Compounds (Including Naturally Occurring Compounds) in Drinking Water in New Hampshire

A Comparative Cancer Risk Evaluation of MTBE and Other Compounds (Including Naturally Occurring Compounds) in Drinking Water in New Hampshire

Mechanisms of Rodent Renal Carcinogenesis Revisited

Histopathologic changes in the kidneys of male F344 rats from a 2-year inhalation carcinogenicity study of tetrahydrofuran: A pathology working group review and re-evaluation

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Alpha2U‐Globulin Nephropathy and Chronic Progressive Nephropathy as Modes of Action for Renal Tubule Tumor Induction in Rats, and Their Possible Interaction

Cited by 3 publications

References 74 publications

A Comparative Cancer Risk Evaluation of MTBE and Other Compounds (Including Naturally Occurring Compounds) in Drinking Water in New Hampshire

A Comparative Cancer Risk Evaluation of MTBE and Other Compounds (Including Naturally Occurring Compounds) in Drinking Water in New Hampshire

Mechanisms of Rodent Renal Carcinogenesis Revisited

Histopathologic changes in the kidneys of male F344 rats from a 2-year inhalation carcinogenicity study of tetrahydrofuran: A pathology working group review and re-evaluation

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Alpha_2U‐Globulin Nephropathy and Chronic Progressive Nephropathy as Modes of Action for Renal Tubule Tumor Induction in Rats, and Their Possible Interaction