Chronic Toxicity/Oncogenicity Study of Styrene in CD Rats by Inhalation Exposure for 104 Weeks

Cruzan, George; Cushman, Janette R.; Andrews, Larry S.; Granville, Geoffrey C.; Johnson, Keith A.; Hardy, Colin; Coombs, Derek W.; Mullins, Pamela A.; Brown, W. Ray

doi:10.1006/toxs.1998.2533

Cited by 26 publications

(20 citation statements)

References 27 publications

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“…Styrene Styrene is carcinogenic for the mouse lung, but not for the rat lung. Upon inhalation lung adenomas were observed starting at 20 ppm, carcinomas at 160 ppm (Cruzan et al 2001), while styrene was not tumorigenic for rats up to 1000 ppm (Cruzan et al 1998). Styrene also proved carcinogenic for mice upon exposure via gavage (Ponomarkov and Tomatis 1978;U.…”

Section: Cyp Catalytic Activities (Table 3)mentioning

confidence: 99%

Xenobiotica-metabolizing enzymes in the lung of experimental animals, man and in human lung models

2019

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The xenobiotic metabolism in the lung, an organ of first entry of xenobiotics into the organism, is crucial for inhaled compounds entering this organ intentionally (e.g. drugs) and unintentionally (e.g. work place and environmental compounds). Additionally, local metabolism by enzymes preferentially or exclusively occurring in the lung is important for favorable or toxic effects of xenobiotics entering the organism also by routes other than by inhalation. The data collected in this review show that generally activities of cytochromes P450 are low in the lung of all investigated species and in vitro models. Other oxidoreductases may turn out to be more important, but are largely not investigated. Phase II enzymes are generally much higher with the exception of UGT glucuronosyltransferases which are generally very low. Insofar as data are available the xenobiotic metabolism in the lung of monkeys comes closed to that in the human lung; however, very few data are available for this comparison. Second best rate the mouse and rat lung, followed by the rabbit. Of the human in vitro model primary cells in culture, such as alveolar macrophages and alveolar type II cells as well as the A549 cell line appear quite acceptable. However, (1) this generalization represents a temporary oversimplification born from the lack of more comparable data; (2) the relative suitability of individual species/models is different for different enzymes; (3) when more data become available, the conclusions derived from these comparisons quite possibly may change.

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Section: Cyp Catalytic Activities (Table 3)mentioning

confidence: 99%

Xenobiotica-metabolizing enzymes in the lung of experimental animals, man and in human lung models

2019

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“…Evidence that local metabolism of styrene is responsible for the lung toxicity of styrene is given by the fact that circulating levels of SO do not correlate with lung tumor incidence. Blood levels of SO were much higher in rats at non-tumorigenic concentrations than in mice at levels associated with an increased incidence of lung tumors (Cruzan et al 1998, 2001). In addition, metabolism and cytotoxicity occur in the mouse lung after oral exposure to styrene (Green et al 2001b), indicating that systemically absorbed concentrations of styrene are preferentially metabolized in the mouse lung.…”

Section: Mode-of-action Datamentioning

confidence: 94%

“…There were no increased tumor incidence rates reported in seven chronic rat studies of styrene that used various rat strains and exposure routes, including inhalation exposure in Sprague-Dawley (SD) rats (Cruzan et al 1998; Conti et al 1988; Jersey et al 1978), oral gavage in SD, F344, and BD IV rats (Conti et al 1988; NCI 1979; Ponomarkov and Tomatis 1978), and drinking water in SD rats (Beliles et al 1985). The NTP profile for styrene states: “The evidence from studies in rats is insufficient for reaching a conclusion concerning the carcinogenicity of styrene” (NTP 2011).…”

Section: Species-specific Effects In Experimental Animalsmentioning

confidence: 99%

“…Inhalation exposures to styrene induce lung toxicity and subsequent tumors in mice and nasal toxicity without tumor development in mice and rats (Cruzan et al 1997, 1998, 2001). Lung toxicity has been reported as decreased cytoplasmic staining and increased replication of Clara cells of the mouse bronchiolar epithelium, cell crowding in the terminal bronchioles, decreased eosinophilia of the mouse bronchiolar epithelium, and hyperplasia of Clara cells in the terminal bronchioles (Cruzan et al 1997, 2001; Green et al 2001b; Roycroft et al 1992).…”

Section: Mode-of-action Datamentioning

confidence: 99%

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The Weight of Evidence Does Not Support the Listing of Styrene as “Reasonably Anticipated to be a Human Carcinogen” in NTP's Twelfth Report on Carcinogens

Rhomberg

Goodman

Prueitt

2013

Human and Ecological Risk Assessment: An International Journal

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Styrene was listed as “reasonably anticipated to be a human carcinogen” in the twelfth edition of the National Toxicology Program's Report on Carcinogens based on what we contend are erroneous findings of limited evidence of carcinogenicity in humans, sufficient evidence of carcinogenicity in experimental animals, and supporting mechanistic data. The epidemiology studies show no consistent increased incidence of, or mortality from, any type of cancer. In animal studies, increased incidence rates of mostly benign tumors have been observed only in certain strains of one species (mice) and at one tissue site (lung). The lack of concordance of tumor incidence and tumor type among animals (even within the same species) and humans indicates that there has been no particular cancer consistently observed among all available studies. The only plausible mechanism for styrene-induced carcinogenesis—a non-genotoxic mode of action that is specific to the mouse lung—is not relevant to humans. As a whole, the evidence does not support the characterization of styrene as “reasonably anticipated to be a human carcinogen,” and styrene should not be listed in the Report on Carcinogens.

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“…These include trichloroethylene (Green, 2000), naphthalene, ethylbenzene, alpha-methylstyrene, cumene, divinylbenzene, benzofuran (Cruzan et al , 2009), coumarin (Felter et al , 2006), and styrene (Cruzan et al , 1998, 2001). The metabolic activation and cell proliferative effects by several of these chemicals were recently systematically investigated and found to support a common mode of action (MOA) that is not relevant to the human lung (Cruzan et al , 2009, 2012).…”

mentioning

confidence: 99%

Relationship of Metabolism and Cell Proliferation to the Mode of Action of Fluensulfone-Induced Mouse Lung Tumors: Analysis of Their Human Relevance Using the IPCS Framework

Strupp¹,

Banas

Cohen

et al. 2012

Toxicological Sciences

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Species-specific lung tumors in the mouse are induced by a number of chemicals. The underlying cause appears to be a high metabolic activity of mouse lung, due to relatively high abundance of Clara cells in mice compared with humans and the mouse-specific cytochrome P450 isoform 2f2 in the Clara cells. The chemicals are activated to reactive intermediates, leading to local cytotoxicity or mitogenicity resulting in increased cell proliferation and tumors. Rats have lower metabolic activity than mice (already below the threshold needed to cause lung tumors upon lifetime exposure) and activity in humans is lower than in rats. The carcinogenic risk for human lung is low for this mode of action (MOA). Fluensulfone has shown an increased incidence of lung adenomas in mice, but not in rats, at high doses. Fluensulfone is not genotoxic. MOA studies were conducted investigating key events of the postulated MOA. Fluensulfone is extensively metabolized by mouse lung microsomes, whereas no metabolic activity is seen with human lung microsomes. Cyp 2f2 is a major contributor in fluensulfone’s metabolism and Cyp 2e1 is not involved. Furthermore, administration of fluensulfone to mice led to an early increase in Clara cell proliferation. The International Programme on Chemical Safety (IPCS) MOA and human relevance framework was used to evaluate the collective data on fluensulfone. We concluded that fluensulfone leads to species-specific mouse lung tumors and that these tumors are likely not relevant to human hazard or risk.

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Chronic Toxicity/Oncogenicity Study of Styrene in CD Rats by Inhalation Exposure for 104 Weeks

Cited by 26 publications

References 27 publications

Xenobiotica-metabolizing enzymes in the lung of experimental animals, man and in human lung models

Xenobiotica-metabolizing enzymes in the lung of experimental animals, man and in human lung models

The Weight of Evidence Does Not Support the Listing of Styrene as “Reasonably Anticipated to be a Human Carcinogen” in NTP's Twelfth Report on Carcinogens

Relationship of Metabolism and Cell Proliferation to the Mode of Action of Fluensulfone-Induced Mouse Lung Tumors: Analysis of Their Human Relevance Using the IPCS Framework

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