Subchronic Inhalation Toxicity Studies with Hydrochlorofluorocarbon 123 (HCFC 123)

Rusch, George M.; Trochimowicz, Henry J.; MALLEY, LINDA J.; Kelly, Donovan P.; PECKHAM, JOHN; Hansen, John F.; CHARM, JOEL B.

doi:10.1093/toxsci/23.2.169

Cited by 2 publications

(3 citation statements)

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“…In a 90-day subchronic inhalation study with Sprague-Dawley (CD) rats, the alternative fluorocarbon, HCFC-123, was shown to be a peroxisome proliferator at levels ≥300 ppm based on measurement of hepatic β-oxidation activity (Rusch et al, 1994). The potential chronic toxicity and oncogenicity of HCFC-123 was also evaluated by exposing male and female CD rats to 0, 300, 1000, or 5000 ppm HCFC-123 for 6 h/d, 5 d/week, for 2 years (Malley et al, 1995).…”

Section: E Peroxisome Proliferatorsmentioning

confidence: 99%

“…The alternative fluorochemicals, HCFC-123 (Malley et al, 1995), HCFC-133a (Longstaff et al, 1984), HCFC-141b (Turnbull et al, 1994), and HFC-134a , have been shown to induce LCTs in either gavage or inhalation bioassay studies with rats. HCFC-123 has been shown to be a peroxisome proliferator (Rusch et al, 1994) and may induce LCTs by a mechanism(s) similar to other peroxisome proliferators (Section VII.A.2.e), although mechanistic data for such a linkage have not been published with HCFC-123. HCFC-133a produces testicular atrophy possibly by formation of trifluoroacetaldehyde (Ellis et al, 1995).…”

Section: A Fluorochemicalsmentioning

confidence: 99%

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Rodent Leydig Cell Tumorigenesis: A Review of the Physiology, Pathology, Mechanisms, and Relevance to Humans

Cook

Klinefelter

Hardisty

et al. 1999

Critical Reviews in Toxicology

175

122

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Leydig cells (LCs) are the cells of the testis that have as their primary function the production of testosterone. LCs are a common target of compounds tested in rodent carcinogenicity bioassays. The number of reviews on Leydig cell tumors (LCTs) has increased in recent years because of its common occurrence in rodent bioassays and the importance in assessing the relevance of this tumor type to humans. To date, there have been no comprehensive reviews to identify all the compounds that have been shown to induce LCTs in rodents or has any review systematically evaluated the epidemiology data to determine whether humans were at increased risk for developing LCTs from exposure to these agents. This review attempts to fill these deficiencies in the literature by comparing the cytology and ontogeny of the LC, as well as the endocrine and paracrine regulation of both normal and tumorigenic LCs. In addition, the pathology of LCTs in rodents and humans is compared, compounds that induce LC hyperplasia or tumors are enumerated, and the human relevance of chemical-induced LCTs is discussed. There are plausible mechanisms for the chemical induction of LCTs, as typified by agonists of estrogen, gonadotropin releasing hormone (GnRH), and dopamine receptors, androgen receptor antagonists, and inhibitors of 5alpha-reductase, testosterone biosynthesis, and aromatase. Most of these ultimately involve elevation in serum luteinizing hormone (LH) and/or LC responsiveness to LH as proximate mediators. It is expected that further work will uncover additional mechanisms by which LCTs may arise, especially the role of growth factors in modulating LC tumorigenesis. Regarding human relevance, the pathways for regulation of the hypothalamo-pituitary-testis (HPT) axis of rats and humans are similar, such that compounds that either decrease testosterone or estradiol levels or their recognition will increase LH levels. Hence, compounds that induce LCTs in rats by disruption of the HPT axis pose a risk to human health, except for possibly two classes of compounds (GnRH and dopamine agonists). Because GnRH and prolactin receptors are either not expressed or are expressed at very low levels in the testes in humans, the induction of LCTs in rats by GnRH and dopamine agonists would appear not to be relevant to humans; however, the potential relevance to humans of the remaining five pathways of LCT induction cannot be ruled out. Therefore, the central issue becomes what is the relative sensitivity between rat and human LCs in their response to increased LH levels; specifically, is the proliferative stimulus initiated by increased levels of LH attenuated, similar, or enhanced in human vs. rat LCs? There are several lines of evidence that suggest that human LCs are quantitatively less sensitive than rats in their proliferative response to LH, and hence in their sensitivity to chemically induced LCTs. This evidence includes the following: (1) the human incidence of LCTs is much lower than in rodents even when corrected for detection bias; (2) several ...

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Section: E Peroxisome Proliferatorsmentioning

confidence: 99%

Section: A Fluorochemicalsmentioning

confidence: 99%

Rodent Leydig Cell Tumorigenesis: A Review of the Physiology, Pathology, Mechanisms, and Relevance to Humans

Cook

Klinefelter

Hardisty

et al. 1999

Critical Reviews in Toxicology

175

122

View full text Add to dashboard Cite

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“…This is a common nding with many uorinated alkanes (Ellis et al 1993;Malley et al 1996;Rusch et al 1994). Increases in these parameters generally have not been considered to be adverse, but represent the apparent absorption, metabolism, and subsequent elimination of inorganic uoride.…”

Section: Discussionmentioning

confidence: 99%

Inhalation Toxicity and Genotoxicity of Hydrofluorocarbon (HFC)-236fa and HFC-236ea

et al. 2000

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The acute, subchronic, and developmental and genetic toxicity of hydro uorocarbon (HFC)-236fa and HFC-236ea were evaluated to assist in establishing proper handling guidance. In acute inhalation studies, rats were exposed whole body for 4 hours to various concentrations of each isomer. Based on the lack of mortality, the approximate lethal concentration for HFC-236ea for male rats was > 85,000 ppm. For HFC-236fa, the LC 50 for males and females (combined) was > 457,000 ppm. Narcotic-like effects, e.g., prostration, incoordination, and reduced motor activity, were observed only during exposure to either isomer, but were not evident after termination of exposure. In cardiac sensitization studies, HFC236ea induced cardiac sensitization at¸35,000 ppm, with fatal responses occurring at 50,000 ppm and greater. For HFC-236fa, a cardiac sensitization response was observed at 150,000 ppm and greater but not at 100,000 ppm. A fatal cardiac sensitization response was observed in one dog exposed to 150,000 ppm HFC236fa. In 90-day subchronic inhalation studies, male and female rats were exposed whole body to HFC-236ea at concentrations of 0, 5000, 20,000, or 50,000 ppm for 6 hours/day, 5 days/week. Similarly, male and female rats were exposed whole body to HFC-236fa at concentrations of 0, 5000, 20,000, or 50,000 ppm for 6 hours/day, 5 days/week. During exposure, narcotic-like effect (reduced acoustic startle response) was observed at 50,000 ppm with both isomers, although there appeared to be an adaptive response to this effect as the study progressed. With HFC-236ea, dilatation of the seminiferous tubules, without effects on germ or Sertoli cells, was observed only in rats at 50,000 ppm. No other effects on in-life measures or on clinical or anatomic pathology, including histopathology, were observed for either isomer. In rat developmental toxicity studies, no evidence of embryotoxicity or teratogenicity was observed with either isomer exposed up to 50,000 ppm during gestational days 7 to 16. Also, no developmental toxicity was observed in rabbits exposed to HFC-236fa at concentrations of up to 50,000 ppm during gestational days 7 to 19. Neither of the HFC-236 isomers was mutagenic in the Ames reverse mutation assay or clastogenic in the chromosomal aberration assay with human lymphocytes. No increase in chromosomal aberrations was observed in in vivo micronucleus studies with either isomer.

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Subchronic Inhalation Toxicity Studies with Hydrochlorofluorocarbon 123 (HCFC 123)

Cited by 2 publications

References 0 publications

Rodent Leydig Cell Tumorigenesis: A Review of the Physiology, Pathology, Mechanisms, and Relevance to Humans

Rodent Leydig Cell Tumorigenesis: A Review of the Physiology, Pathology, Mechanisms, and Relevance to Humans

Inhalation Toxicity and Genotoxicity of Hydrofluorocarbon (HFC)-236fa and HFC-236ea

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