Urinary System

Alden, Carl L.

doi:10.1016/b978-0-12-330220-5.50020-6

Cited by 34 publications

(22 citation statements)

References 124 publications

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“…The increased incidences of urothelial hyperplasia of the pelvis and mineral deposition in the renal papilla observed in the present study have been reported to be associated with hyaline droplet nephropathy resulting from excessive accumulation of α2u-globulin in the cytoplasm of renal tubular epithelium (Alden and Frith, 1991). In the 13-week preliminary study preceding the current 2-year study, a significant enhancement of the degree of hyaline droplet accumulation in the renal tubular epithelium was noted in the kidneys of male rats administered 10,000 ppm ETBE in their drinking water.…”

Section: Discussionmentioning

confidence: 55%

“…These results suggest that the urothelial hyperplasia of the pelvis and the mineral deposition in the renal papilla observed in male rats administered ETBE in the present study resulted from accumulation of α2u-globulin in the renal tubular epithelium. Induction of α2u-globulin nephropathy in male rats has been reported for many chemicals including d-Limonene and unleaded gasoline (Alden and Frith, 1991). Because there is no evidence that the nephropathy induced by α2u-globulin accumulation occurs in humans, the U.S. EPA proposes that nephropathy in male rats associated with the induction of α2u-globulin accumulation in hyaline droplets is not an appropriate endpoint to determine renal toxic effects potentially occurring in humans (U.S. EPA, 1991).…”

Section: Discussionmentioning

confidence: 99%

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No carcinogenicity of ethyl <i>tertiary</i>-butyl ether by 2-year oral administration in rats

et al. 2012

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Section: Discussionmentioning

confidence: 55%

Section: Discussionmentioning

confidence: 99%

No carcinogenicity of ethyl <i>tertiary</i>-butyl ether by 2-year oral administration in rats

et al. 2012

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“…Classical renal carcinogens can induce renal tubule cancer in rats or mice in high incidence, with minimal duration of exposure, clear dose-response relationships, and with decreased latent period of development (147,207). Tumor frequencies are often over 50% and up to 100%, much higher than the low incidences (2-28% adjusted) recorded for CIGA.…”

Section: Tumor Incidencementioning

confidence: 95%

“…Although single-cell necrosis has been clearly demonstrated in association with cellular hyaline droplet accumulation (6,143), there are no dose-response studies quantitating the relationship between increased hyaline droplets and cell necrosis in histological sections or between cell necrosis and cell regeneration. However, Alden (147) has shown a correlation between the hyaline droplet response, increased mitotic index in proximal convoluted tubules, and elevation ofthe number ofcells excreted hourly in the urine (an index ofexfoliated necrotic tubule cells) using two dose levels of d-limonene given orally for 3 weeks.…”

Section: Initiation-promotion Studiesmentioning

confidence: 99%

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Hazard evaluation of chemicals that cause accumulation of alpha 2u-globulin, hyaline droplet nephropathy, and tubule neoplasia in the kidneys of male rats.

Hard

Rodgers

Baetcke

et al. 1993

Environ Health Perspect

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This review paper examines the relationship between chemicals inducing ewessive accumulation of a2u-globulin (ai21g) (CIGA) in hyline droplets inmale rat kidneys and the subsequent development of nephoit and rnal tubule nopaia in the male rt. This dose-responsive hyaline droplet accumulation distinguishes CIGA carcinogens fromclssical renal carcinogens. CIGA carcinogens also do not appear to react with DNA and are generally negative in short-term tests for genotoxicity. CIGA or their metabolites bind specifically, but reversibly, tomale rat a2,-g The resulting complex appears to be more resistant to hydrolytic degradation in the proximaltubule than native, unbound a2,-g Singlecell necrosis of the tubule epithelium, with associated granular cast formation and papillary mineralization, is followed by sustained regenerative tubule cell prolifertin, foci oftubulehyerl a inthe aovoited pronal bules, and renal tubule tumor Although stnrcturally similar proteins have been detected in other species, including hu_ms, renal lesios characteristic Of a2,-g nephropathy have not been observed. Epidemiologic investigation has not specifically examined the CIGA hypothesis for humans. Based on cancer bioassays, hormone manipulation studies, investigations in an ae,-g-deficient strain of rat, and other laboratory data, an increased proliferative response caused by chemically induced cytotoxicity appears to play a role in the development ofrenal tubule tumors in male rats Thus, it is reasonable to suggest that the renal effects induced in male rats by chemicals causing a2.-g accumulation are unlikely to occur in humans. IntroductionFor most hazardous chemicals, adequate human data are not available, and risk analyses must rely on information from laboratory studies of rats or mice. The inference that the results ofanimal experiments can be applied to humans is a fundamental principle of all toxicologic research. This analysis deals with a specific case, however, where the male rat seems to respond in a manner different from other laboratory species. The possibility of a unique response in the rat among laboratory animals raises questions about the applicability of the rat data to other species, including humans. Our review evaluates the matter of human 'Medical Research Council relevance and describes the types of information needed for hazard assessment of such chemicals.A variety of organic chemicals have produced specific renal lesions in male rats in the form of a protein (hyaline) droplet nephropathy accompanied by accumulation of a2%-globulin (a2.-g) [reviewed in (1,2)]. Among the chemicals tested are paraffins (3,4), decalin (decahydronaphthalene) (5,6), petroleum-based and synthetic fuels (7), military aviation propellants (8), and 2,2,4-trimethylpentane (TMP) (9). As seen in Table 1, which lists a sampling ofchemicals that have been tested, many are of considerable regulatory and commercial interest. For example, isophorone is a chemical intermediate of major industrial importance. Aviation and automotive fuels fit i...

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Toxicology and Nonclinical Safety Assessment in Pharmaceutical Discovery and Development

Reynolds

Abernathy

Baracani

et al. 2021

Burger's Medicinal Chemistry and Drug Discovery

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Nonclinical safety assessment is an essential component of drug discovery and development. Early in the drug discovery/development continuum, there are no regulatory guidelines and sponsors typically harness a range of in silico , in vitro , and short‐term in vivo toxicology screens and pilot studies to develop comparative toxicity profiles for compounds under consideration. Results from these early evaluations can be used to terminate the development of compounds with undesirable toxicity liabilities as well as to prioritize other compounds for further evaluation. As drug candidate molecules approach entry into clinical trials, regulatory expectations regarding nonclinical safety assessment become more explicit. Scientists in the pharmaceutical industry have worked with their regulatory counterparts to establish an organizational structure – the International Conference on Harmonisation (ICH) – to develop internationally accepted guidelines that specify requirements for nonclinical safety assessment activities in a phase‐specific manner. The ICH guidelines cover the need for repeat‐dose toxicology studies of increasing duration in rodents and nonrodents, safety pharmacology studies, genetic toxicity tests, immunotoxicity and immunogenicity evaluations, phototoxicity assessments, developmental and reproductive toxicity studies, and carcinogenicity assessments. In planning, conducting, and reporting these studies, the toxicologist must ensure that a fully integrated assessment of potential safety liabilities associated with the test drug is communicated to the development team so that potential safety concerns can be properly addressed.

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Urinary System

Cited by 34 publications

References 124 publications

No carcinogenicity of ethyl <i>tertiary</i>-butyl ether by 2-year oral administration in rats

No carcinogenicity of ethyl <i>tertiary</i>-butyl ether by 2-year oral administration in rats

Hazard evaluation of chemicals that cause accumulation of alpha 2u-globulin, hyaline droplet nephropathy, and tubule neoplasia in the kidneys of male rats.

Toxicology and Nonclinical Safety Assessment in Pharmaceutical Discovery and Development

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