Perchloroethylene-induced rat kidney tumors: An investigation of the mechanisms involved and their relevance to humans

Green, Trevor; Odum, J.; Nash, John A.; Foster, John R.

doi:10.1016/0041-008x(90)90264-u

Cited by 113 publications

(66 citation statements)

References 17 publications

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“…This line of reasoning leads supporters ofthe hypothesis to conclude that the acute and chronic renal effects induced in male rats by these chemicals will be unlikely to occur in any species not producing c2u-g, or a very closely related protein, in the large quantities typically seen in the male rat (21)(22)(23)(24)(25)(26).…”

Section: Introductionmentioning

confidence: 99%

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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Section: Introductionmentioning

confidence: 99%

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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“…Detoxification and dearance of DCVC takes place by urinary excretion of the N-acetyl derivative (103,135). In a study with PERC (136), it was determined that the excretion of the N-acetyl derivative was dose related (a higher fraction of N-acetyl derivative was excreted at doses where the oxidative pathway was saturated) and was significantly greater in the rat than in the mouse. However, measurements of acid-labile protein adducts associated with DCVC suggest that the activation of DCVC in the kidney may be as much as 12-fold greater in mice than in rats and that the kidney tissue exposure to DCVC-derived reactive species from oral dosing with TCE may be twice as great in the mouse as in the rat (137,138).…”

Section: Metabolism Oftcementioning

confidence: 99%

“…Another research group, however, has reported a maximum velocity (Vmax) of only 0.8 nmol/min/mg cytosol in the human, with an affinity (Ki) of 0.29 mM, compared to Vmax = 7.5 nmol/min/mg cytosol and Km = 1.6 mM in rat kidney cytosol in the same study (141). Data for PERC on the relative activity of liver cytosolic GST and kidney cytosolic cysteine conjugate ,B-lyase suggest that the human activity of both enzymes is roughly 10-fold lower than that in the rat (136). On the other hand, the specific activity of N-acetyltransferase in kidney cytosol appears to be very similar across species: 0.41 nmol/min/mg cytosol in the human, compared to 0.35-0.61 in the rat and 0.94 in the mouse (142).…”

Section: Metabolism Oftcementioning

confidence: 99%

Development of a Physiologically-Based Pharmacokinetic Model of Trichloroethylene and Its Metabolites for Use in Risk Assessment

Covington¹,

Clewell²,

Fisher³

2004

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A physiologically based pharmacokinetic (PBPK) model was developed that provides a comprehensive description of the kinetics of trichloroethylene (TCE) and its metabolites, trichloroethanol (TCOH), trichloroacetic acid (TCA), and dichloroacetic acid (DCA), in the mouse, rat, and human for both oral and inhalation exposure. The model includes descriptions of the three principal target tissues for cancer identified in animal bioassays: liver, lung, and kidney. Cancer dose metrics provided in the model include the area under the concentration curve (AUC) for TCA and DCA in the plasma, the peak concentration and AUC for chloral in the tracheobronchial region of the lung, and the production of a thioacetylating intermediate from dichlorovinylcysteine in the kidney. Additional dose metrics provided for noncancer risk assessment include the peak concentrations and AUCs for TCE and TCOH in the blood, as well as the total metabolism of TCE divided by the body weight. Sensitivity and uncertainty analyses were performed on the model to evaluate its suitability for use in a pharmacokinetic risk assessment for TCE. Model predictions of TCE, TCA, DCA, and TCOH concentrations in rodents and humans are in good agreement with a variety of experimental data, suggesting that the model should provide a useful basis for evaluating crossspecies differences in pharmacokinetics for these chemicals. In the case of the lung and kidney target tissues, however, only limited data are available for establishing cross-species pharmacokinetics. As a result, PBPK model calculations of target tissue dose for lung and kidney should be used with caution.

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“…Twenty-onemonth recovery studies after 3 months of exposure to decaline or JP-8 were not associated with a tumor response, suggesting that a longer exposure period may be required for tumor formation (17,33). Perchloroethylene causes aG nephropathy at high gavage or inhalation concentrations, but a 28-day inhalation exposure study of male rats to 400 ppm, a concentration associated with kidney tumors, did not cause aG nephropathy in these rats (14,34). Recently, the pharmaceutical agent, 1-(aminomethyl)cyclohexaneacetic acid, was shown to induce aG nephropathy but not renal tumors in a 2-year bioassay in rats (35).…”

Section: A2u-globulin Inducing Agentsmentioning

confidence: 99%

“…Although increased cell proliferation appears to be a necessary event for the formation of renal tumors caused by aG-inducing agents, other contributing mechanisms may also be present in some cases. For example, genotoxicity of perchloroethylene through the glutathione conjugation/4-lyase pathway in the rat may contribute to the development of kidney tumors caused by this aG-inducing agent (34).…”

Section: A2u-globulin Inducing Agentsmentioning

confidence: 99%

Cell Proliferation and Renal Carcinogenesis

Short¹

1993

Environmental Health Perspectives

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Enhanced cell proliferation occurs at several stages of renal tumorigenesis. Initiation by genotoxic nephrocarcinogens such as dimethylnitrosamine (DMN) is likely a result of DNA damage coupled with an initial burst of DNA synthesis associated with the cytotoxic effects of the compound. The level of initiation by DMN can be further enhanced by unilateral nephrectomy or hydronephrosis, which induces a brief burst of cell proliferation followed by tumorigenesis in the contralateral kidney. The role of sustained cell proliferation in renal tumor development is less well understood. The most compelling evidence comes from studies with nongenotoxic renal carcinogens such as unleaded gasoline and d-limonene, which induce a2U-globulin (aG) nephropathy and renal epithelial tumors exclusively in male rats. Sustained increases in cell proliferation in these studies depend on the presence of a chemical-aG complex in phagolysosomes of P2 proximal tubule cells, which results in cytotoxicity and compensatory hyperplasia only in male F344 rats, but not female F344 rats or aG deficient male NBR rats. Furthermore, initiation-promotion experiments demonstrated a strong correlation between the dose-response of cell proliferation and the incidence of preneoplastic and neoplastic lesions. Clearly, similar correlative studies with a number of other renal carcinogens and noncarcinogens are warranted before general conclusions can be made. Cell proliferation is excessively elevated in tubules affected by chronic progressive nephropathy, but the significance of the lesion to renal carcinogenesis is unclear. Elucidating mechanisms of renal cell proliferation are necessary for our understanding of cause and effect relationships. An exciting recent finding is altered expression of transforming growth factor-a in hereditary rat renal cell carcinoma. This animal model may be useful for studying detailed histochemical relationships between altered growth factors and cell proliferation in various stages of renal carcinogenesis.

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Perchloroethylene-induced rat kidney tumors: An investigation of the mechanisms involved and their relevance to humans

Cited by 113 publications

References 17 publications

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

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

Development of a Physiologically-Based Pharmacokinetic Model of Trichloroethylene and Its Metabolites for Use in Risk Assessment

Cell Proliferation and Renal Carcinogenesis

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