Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A cDNA representing a 5.2-kb defective, endogenous murine leukemia proviral sequence (EPI-EPS) was isolated from a C57BL/6 mouse cDNA epididymal library. Northern blot analysis demonstrated that EPI-EPS was predominantly expressed in the C57BL/6 mouse epididymis and vas deferens with 10-fold lower expression in the seminal vesicle, kidney, and submandibular gland. Analysis of tissues from other inbred strains of mice as well as the wild mouse, Mus musculus musculus, showed a similar pattern of tissue expression. EPI-EPS expression was also highly androgen regulated in both the reproductive and nonreproductive tissues of the C57BL/6 strain. However, a differential response to testosterone replacement was observed between tissues. Expression of EPI-EPS mRNA in the epididymis and vas deferens exhibited only a partial recovery to precastration levels after testosterone replacement; in the kidney and submandibular gland there was a complete recovery of EPI-EPS expression. Finally, EPI-EPS expression was also highly restricted in the female tissues, with expression limited to the oviduct and uterus. EPI-EPS, however, was not estrogen regulated in the female. These results suggest that a proviral sequence, EPI-EPS, is expressed in M. m. musculus and several inbred strains of mice due to its integration near a highly tissue-specific and androgen-regulated genetic locus.
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PMID:Expression of an endogenous murine leukemia virus-related proviral sequence is androgen regulated and primarily restricted to the epididymis/vas deferens and oviduct/uterus. 132 10

In the absence of infectious virus, strains of mice express polyadenylated RNA transcripts homologous to the genome of murine leukemia virus. In addition to transcripts consistent with full-length and spliced env retroviral RNAs, several unique RNA species which lack the env sequence accumulate in a tissue-specific manner. These RNA species are presumed to be transcribed from endogenous retroviral sequences that constitute the bulk of the murine leukemia virus-related sequences in the murine genome. To determine the relationship of these RNA transcripts to infectious murine leukemia virus and the precise structural basis of the heterogeneity observed for the env-lacking transcripts, we isolated and sequenced cDNA recombinants representing the RNAs expressed in strain 129 GIX+ mice. Comparisons of the nucleotide sequences demonstrated that the endogenous retroviral transcripts differed in pol, p15E, and R-peptide regions by single nucleotide changes. In contrast, the gp70-coding regions of two cDNA clones derived from epididymis and liver were completely homologous over a 599-nucleotide overlapping sequence. The structures of env-lacking transcripts were examined in two independent cDNA clones, and each was found to contain a different deletion that was potentially mediated by seven-base pair direct repeats in the intact sequence. The extensive sequence homology between cDNAs allowed construction of a cumulative sequence map of the 3' end of an intact endogenous retroviral transcript. A comparison of this sequence with infectious ecotropic and mink cell focus-forming viruses revealed that the endogenous transcripts are highly homologous with the substituted portions of leukemogenic mink cell focus-forming viruses and therefore further define the boundaries of recombination required to generate these viruses.
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PMID:Normal expression of polymorphic endogenous retroviral RNA containing segments identical to mink cell focus-forming virus. 241 14

Sperm adsorbed with retrovirus particles were recovered from the epididymis of apparently normal male mice. Epididymal semen from all four mouse strains examined was positive for retrovirus (10(5) to 10(8) particles per microgram of protein) indicating that epididymal fluids and sperm may be important vehicles for murine retrovirus spread. Immunoblot analyses revealed that the banding patterns of electrophoretically separated epididymal viral proteins from the four strains of males were more similar to each other than to either xenotropic New Zealand Black virus or ecotropic Rauscher leukemia virus proteins. The results indicate that retrovirus particles, possibly a unique strain, are commonly expressed at relatively high titers in the reproductive tract of male mice and are sperm-associated.
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PMID:Sperm-associated retroviruses in the mouse epididymis. 282 4

Fluorescence probes for the active centre of an enzyme associated with tumour cells have been used to locate leukaemia cells in a model rat system. These fluorescent techniques are inexpensive and rapid to carry out. The leukaemic cells can be located by fluorescence microscopy in frozen sections, wax embedded sections and resin embedded sections. The technique is illustrated with reference to sections of leukaemic rat kidney, epididymis and testis. These studies confirm earlier histological findings employing conventional staining techniques and have the advantage that individual leukaemia cells can be detected in leukaemic animals undergoing drug therapy. The evidence suggests that these techniques will be of value in further studies of the design of drugs directed to leukaemia cells.
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PMID:Location of T-cell leukaemia cells in a model rat system by means of a fluorescent probe. 381 72

129 GIX- mice, unlike animals of the congeneic partner strain GIX+, do not express significant amounts of the retroviral antigens gp70 and p30. Evidence is presented indicating that the GIX phenotype is specified by a distinct regulatory gene acting on multiple transcription units to control the levels of accumulation of specific mRNA species. The steady-state levels of retroviral-homologous mRNA from the tissues of GIX+ and GIX- mice were examined by blot hybridization using as probes DNA fragments from cloned murine leukemia viruses. RNA potentially encoding viral antigens was reduced or absent in GIX- mice, even though no differences in integrated viral genomes were detected between these congeneic strains by DNA blotting. Tissue-specific patterns of accumulation of these RNA species were detected in brain, epididymis, liver, spleen, and thymus, and several distinct RNA species were found to be coordinately regulated with the GIX phenotype. Measurements of RNA synthesis suggest a major role for transcriptional control in the regulation of some retroviral messages.
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PMID:A genetic locus regulates the expression of tissue-specific mRNAs from multiple transcription units. 631 May 47

During the haematogenous dissemination of this acute rat T-cell (Roser) leukaemia, infiltration of both epididymal and testicular interstitial tissue has now been demonstrated, probably as an invariable occurrence. The gonadal duct system itself was not invaded. In contrast to an earlier histopathological study with this leukaemia, meningeal invasion has also been encountered during routine passage. Furthermore, subsequent to remissions induced by carmustine (BCNU), relapse could occur as long as 80 days after the 20 day end point in control animals. This was associated with extensive infiltration of the meninges as well as in the male gonadal interstitium, the proximal epididymis being particularly vulnerable. Two doses of carmustine at intervals of one week could eradicate the disease even during the phase of logarithmic growth of the leukaemic cells, this result depending upon the level of treatment and time of dosing post-inoculation with leukaemic cells. Females carrying the disease were shown to be more readily cured than males, probably related to entry of leukaemia cells into the gonadal interstitium. This T-cell leukaemia appears to be an excellent model for the study and prospective chemotherapy of testicular relapse in acute lymphoblastic leukaemia.
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PMID:Testicular invasion and relapse and meningeal involvement in a rat T-cell leukaemia. 633 87

Combined androgen and oestrogen treatment of male or female Syrian hamsters results via an unknown mechanism in the formation of leiomyosarcomas in the reproductive tract. We have examined the possibility that retroviral gene expression may play a role in tumorigenesis. Evidence of virus-like particles in epididymis and seminal fluid is shown in electron micrographs. We identified expressed retroviral sequences by using RT-PCR to amplify a conserved retroviral reverse transcriptase coding region in RNA isolated from epididymis, testis, clarified seminal fluid and uterus. Phylogenetic analysis allowed us to classify the sequences into two distinct groups: (1) mammalian type-C viruses, having similarity to Moloney murine leukaemia virus, feline leukaemia virus and gibbon ape leukaemia virus amongst others; (2) a mixed ABCD group containing, for example, Chinese hamster and murine intracisternal A-particle virus sequences, mouse mammary tumour virus and human and simian retroviral sequences. The presence of putative full-length retrovirus related to mammalian type-C viruses in the epididymis and uterus was confirmed by Northern blot analysis. However, steroid treatment did not alter retroviral RNA levels in the epididymis or in a uterine tumour relative to untreated uterus. In summary, Syrian hamster reproductive tissues were found to express unique retroviral sequences; however, their role, if any, in hormonal carcinogenesis remains unresolved.
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PMID:Novel retroviral sequences are expressed in the epididymis and uterus of Syrian hamsters. 982 Jan 44

Gallium arsenide is used primarily to make light- emitting diodes, lasers, laser windows, and photodetectors and in the photoelectronic transmission of data through optical fibers. Gallium arsenide was nominated for study because of its widespread use in the microelectronics industry, the potential for worker exposure, and the absence of chronic toxicity data. Male and female F344/N rats and B6C3F1 mice were exposed to gallium arsenide particles (greater than 98% pure; mass median aerodynamic diameter = 0.8 to 1.0 &mgr;m) by inhalation for 16 days, 14 weeks, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, and the frequency of micronuclei was determined in the peripheral blood of mice exposed to gallium arsenide for 14 weeks. 16-DAY STUDY IN RATS: Groups of five male and five female rats were exposed to particulate aerosols of gallium arsenide with a mass median aerodynamic diameter of approximately 1 &mgr;m at concentrations of 0, 1, 10, 37, 75, or 150 mg/m(3) by inhalation, 6 hours per day, 5 days per week, for 16 days. All rats survived to the end of the study. The final mean body weights of all exposed groups of males and females were similar to those of the chamber controls. Compared to chamber controls, the liver and lung weights of males exposed to 1 mg/m(3) or greater and females exposed to 10 mg/m(3) or greater were increased; the thymus weights of all exposed groups of males were decreased. Gallium arsenide particles were visible in the alveolar spaces and, to a lesser extent, within alveolar macrophages of exposed rats. Moderate proteinosis (surfactant mixed with small amounts of fibrin) and minimal histiocytic cellular infiltrate were observed in the alveoli of exposed males and females. Epithelial hyperplasia and squamous metaplasia of the larynx were observed primarily in males exposed to 150 mg/m(3). 16-DAY STUDY IN MICE: Groups of five male and four or five female mice were exposed to particulate aerosols of gallium arsenide with a mass median aerodynamic diameter of approximately 1 &mgr;m at concentrations of 0, 1, 10, 37, 75, or 150 mg/m(3) by inhalation, 6 hours per day, 5 days per week, for 16 days. The final mean body weights were similar among exposed and chamber control groups. Compared to chamber controls, the lung weights of males and females exposed to 10 mg/m(3) or greater were increased. Gallium ar senide particles were visible in alveolar spaces and macrophages in some mice exposed to 150 mg/m(3). Moderate proteinosis, mild epithelial hyperplasia, and histiocytic infiltration of the lung were observed in males and females exposed to 10 mg/m(3) or greater. In the larynx, mild squamous metaplasia was seen in mice exposed to 10 mg/m(3) or greater, and mild chronic inflammation occurred in mice exposed to 75 or 150 mg/m(3). 14-WEEK STUDY IN RATS: Groups of 10 male and 10 female rats were exposed by inhalation to gallium arsenide particulate at concentrations of 0, 0.1, 1, 10, 37, or 75 mg/m(3), 6 hours per day, 5 days per week, for 14 weeks. All rats survived until the end of the study. The final mean body weight and body weight gain of males exposed to 75 mg/m(3) were significantly less than those of the chamber controls. Hematology and clinical chemistry results indicated that exposure to gallium arsenide induced a microcytic responsive anemia with an erythrocytosis and increased zinc protoporphyrin/heme ratios in exposed groups of rats. There were also increases in platelet and neutrophil counts, a transient decrease in leukocyte counts, and increases in the serum activities of alanine aminotransferase and sorbitol dehydrogenase. These changes were of greater magnitude in male rats. The lung weights of all exposed groups of rats were increased, while testis, cauda epididymis, and epididymis weights of males exposed to 37 or 75 mg/m(3) were generally less than those of chamber controls. Total spermatid heads and spermatid counts were significantly decreased in males exposed to 75 mg/m(3), while epididymal spermatozoa motility was significantly reduced in males ees exposed to 10 mg/m(3) or greater. Gallium arsenide particles were visible in alveolar spaces and macrophages in the lungs of exposed rats. Minimal to marked proteinosis and minimal histiocytic cellular infiltration of the alveoli were observed in all exposed groups; minimal squamous metaplasia in the larynx and lymphoid cell hyperplasia of the mediastinal lymph node were observed in some males and females exposed to 37 or 75 mg/m(3). Exposure-related increases in the incidences of plasma cell hyperplasia of the mandibular lymph node, testicular atrophy, epididymal hypospermia, bone marrow hyperplasia (males), and hemosiderosis in the liver were observed in the 37 and 75 mg/m(3) groups. 14-WEEK STUDY IN MICE: Groups of 10 male and 10 female mice were exposed by inhalation to gallium arsenide particulate at concentrations of 0, 0.1, 1, 10, 37, or 75 mg/m(3), 6 hours per day, 5 days per week, for 14 weeks. One female mouse exposed to 75 mg/m(3) died before the end of the study. Final mean body weights and body weight gains of males in the 75 mg/m(3) group were signifi cantly less than the chamber controls. Hematology and clinical chemistry results indicated that exposure to gallium arsenide affected the circulating erythroid mass and induced a microcytic responsive anemia with an erythrocytosis and increased zinc protoporphyrin/heme ratios in male and female mice. There were also increases in platelet and neutrophil counts. Compared to the chamber controls, the lung weights of males exposed to 1 mg/m(3) or greater and females exposed to 10 mg/m(3) or greater were increased. Testis, cauda epididymis, and epididymis weights, total spermatid heads, spermatid counts, and concentration and motility of epididymal spermatozoa were generally decreased. Gallium arsenide particles were visible in alveolar spaces and macrophages in the lungs of mice exposed to 1 mg/m(3) or greater. Mild to marked proteinosis, histiocytic infiltration, and epithelial hyperplasia were observed in the alveoli of males and females exposed to 1 mg/m(3) or greater. Minimal to mild suppurative inflammation and granuloma in the lung and squamous metaplasia in the larynx were present in males and females exposed to 10 mg/m(3) or greater. Min imal hyperplasia was observed in the tracheobronchial lymph node of males exposed to 10 mg/m(3) or greater and females exposed to 37 or 75 mg/m(3). Exposure- related increases in the incidences of testicular atrophy, epididymal hypospermia, hematopoietic cell proliferation of the spleen, and hemosiderosis of the liver and spleen were observed in groups of male and female mice exposed to 10 mg/m(3) or greater. 2-YEAR STUDY IN RATS: Groups of 50 male and 50 female rats were exposed by inhalation to gallium arsenide particulate at concentrations of 0, 0.01, 0.1, or 1.0 mg/m(3), 6 hours per day, 5 days per week, for 105 weeks. Survival and Body Weights: Survival of exposed male and female rats was similar to the chamber controls. Mean body weights of males exposed to 1.0 mg/m(3) were generally less than those of the chamber controls throughout the study; females exposed to 1.0 mg/m(3) had slightly lower mean body weights during the second year. Pathology Findings: Compared to the chamber controls, the incidences of alveolar/bronchiolar neoplasms were significantly increased in females exposed to 1.0 mg/m(3) and exceeded the historical control ranges. Exposure-related nonneoplastic lesions in the lungs of male and female rats included atypical hyperplasia, alveolar epithelial hyperplasia, chronic active inflammation, proteinosis, and alveolar epithelial metaplasia. In the larynx of males exposed to 1.0 mg/m(3), the incidences of hyperplasia, chronic active inflammation, squamous metaplasia, and hyperplasia of the epiglottis were significantly increased. The incidences of benign pheochromocytoma of the adrenal medulla occurred with a positive trend in female rats, and the incidence was significantly increased in the 1.0 mg/m(3) group and exceeded the historical control range. The incidence of mononuclear cell leukemia was significantly increased in females exposed to 1.0 mg/m(3) and exceeded the historical control range. 2-YEAR STUDY IN MICE: Groups of 50 male and 50 female mice were exposed by inhalation to gallium arsenide particulate at concentrations of 0, 0.1, 0.5, or 1.0 mg/m(3), 6 hours per day, 5 days per week, for 105 (males) or 106 (females) weeks. Survival and Body Weights: Survival of male and female mice was similar to the chamber controls. Mean body weights of exposed groups of males were similar to those of the chamber controls throughout the study; mean body weights of exposed groups of females were greater than those of the chamber controls from week 13 until the end of the study. Pathology Findings: Exposure-related nonneoplastic lesions in the lung of all groups of exposed mice included suppurative focal inflammation, chronic focal inflammation, histiocyte cellular infiltration, alveolar epithelial hyperplasia, and proteinosis. Increased incidences of minimal lymphoid hyperplasia of the tracheobronchial lymph node occurred in mice exposed to 1.0 mg/m(3) and in 0.5 mg/m(3)mg/m(3) males. GENETIC TOXICOLOGY: Gallium arsenide was not mutagenic in several strains of Salmonella typhimurium, with or without S9 metabolic activation enzymes, and no increase in the frequency of micronucleated erythrocytes was observed in peripheral blood of male or female mice exposed to gallium arsenide by inhalation for 14 weeks. CONCLUSIONS: Under the conditions of these 2-year inhalation studies, there was no evidence of carcinogenic activity of gallium arsenide in male F344/N rats exposed to 0.01, 0.1, or 1.0 mg/m(3). There was clear evidence of carcinogenic activity in female F344/N rats based on increased incidences of benign and malignant neoplasms in the lung. Increased incidences of benign neoplasms of the adrenal medulla and increased incidences of mononuclear cell leukemia were also considered to be exposure related. There was no evidence of carcinogenic activity in male or female B6C3F1 mice exposed to 0.1, 0.5, or 1.0 mg/m(3). Exposure to gallium arsenide caused a spectrum of nonneoplastic lesions in the lung of rats and mice, the larynx of male rats and hyperplasia of the tracheobronchial lymph node in mice. Synonym: Gallium monoarsenide.
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PMID:NTP Toxicology and Carcinogenesis Studies of Gallium Arsenide (CAS No. 1303-00-0) in F344/N Rats and B6C3F1 Mice (Inhalation Studies). 1256 48

Oxymetholone is a synthetic anabolic steroid used to treat a variety of conditions, including hypogonadism and delayed puberty. It is also used to correct hereditary angioneurotic edema, manage carcinoma of the breast, promote a positive nitrogen balance following injury or surgery, and stimulate erythropoiesis. Considerable amounts of androgens are consumed by athletes in attempts to improve athletic performance. The National Institute of Environmental Health Sciences and the National Cancer Institute nominated oxymetholone for study based on its extensive illicit pharmaceutical use and the limited evidence that it is a potential human carcinogen. Male and female F344/N rats received oxymetholone (greater than 99% pure) in 0.5% methylcellulose by gavage for 16 days, 14 weeks, or 2 years, and male and female B6C3F1 mice received oxymetholone in 0.5% methylcellulose by gavage for 16 days or 14 weeks. Genetic toxicology studies were conducted in Salmonella typhimurium, cultured Chinese hamster ovary cells, and mouse peripheral blood erythrocytes. 16-DAY STUDY IN RATS: Groups of five male and five female F344/N rats were administered 0, 160, 315, 625, 1,250, or 2,500 mg oxymetholone/kg body weight in 0.5% methylcellulose by gavage for 16 days. All male rats survived to the end of the study; one 2,500 mg/kg female died on day 14. The mean body weights of all dosed groups of males were significantly less than those of the vehicle controls, while those of 160 and 315 mg/kg females were significantly greater. 16-DAY STUDY IN MICE: Groups of five male and five female B6C3F1 mice were administered 0, 320, 630, 1,250, 2,500, or 5,000 mg/kg in 0.5% methylcellulose by gavage for 16 days. All mice survived to the end of the study. The final mean body weights of all dosed groups of females were greater than those of the vehicle controls. 14-WEEK STUDY IN RATS: Groups of 10 male and 10 female F344/N rats were administered 0, 80, 160, 315, 625, or 1,250 mg/kg in 0.5% methylcellulose by gavage for 14 weeks. One male rat each in the 625 and 1,250 mg/kg groups died before the end of the study. The mean body weights of males administered 160 mg/kg or greater were significantly less than those of the vehicle controls; in contrast, the mean body weights of all dosed groups of females were significantly greater. A dose-related erythrocytosis, evidenced by increases in erythrocyte counts, total hemoglobin concentrations, and hematocrit values, occurred in dosed groups of rats at week 14. A dose-related hypocholesterolemia occurred at all time points in all dosed groups of rats. Dose- and time-related decreases in 5 -nucleotidase activity occurred in treated rats. There was a transient, treatment-related increase in the activity of alanine aminotransferase in males and females. For male rats administered oxymetholone, cauda epididymis, epididymis, and testis weights and spermatid counts and total spermatid heads per testis were significantly less than those of the vehicle controls, and total spermatid heads per gram testis were significantly greater. Female rats in the 80 mg/kg group spent more time in diestrus and less time in estrus than did the vehicle controls. Kidney weights of males and females and liver and uterus weights of females were increased compared to vehicle controls in rats that received 315 mg/kg or greater; thymus weights of males and females and sartorius muscle and testis weights of males were less. Compared to the vehicle controls, rats that received 160 mg/kg or greater had increased incidences of nonneoplastic lesions of the kidney and mammary gland, and the incidences of hydrometra of the uterus and dysgenesis of the ovary were increased in dosed groups of females. Female rats administered 315 mg/kg or greater had increased incidences of cytoplasmic vacuolization of the adrenal gland and myocardial degeneration of the heart. The severities of these lesions generally increased with increasing dose. 14-WEEK STUDY IN MICE: Groups of 10 male and 10 female B6C3F1 mice were administered 0, 160, 320, 630, 1,250, or 2,500 mg/kged 0, 160, 320, 630, 1,250, or 2,500 mg/kg in 0.5% methylcellulose by gavage for 14 weeks. All mice administered oxymetholone survived until the end of the study. The mean body weights of all dosed groups were similar to those of the vehicle controls. The percentages of motile sperm in 1,250 and 2,500 mg/kg males were significantly less than those of the vehicle controls. The estrous cycle lengths of 630, 1,250, and 2,500 mg/kg females were significantly longer, and females in the 1,250 and 2,500 mg/kg groups spent more time in diestrus and less time in estrus. Kidney and liver weights of males and females were greater and thymus weights of females were less than those of the vehicle controls. All dosed females had hyperplasia of the clitoral gland, metaplasia of the parietal layer epithelium of the Bowman's capsule in the kidney, and cytoplasmic alteration of the submandibular gland; these lesions were not observed in the vehicle control group. The incidences of hypoplasia of the ovary in 320 mg/kg or greater females and of parotid gland atrophy in 1,250 and 2,500 mg/kg females were increased. The results of the 14-week oral gavage studies were generally similar in rats and mice, but rats were much more sensitive to oxymetholone. Because it was not likely that a long-term mouse study would provide significant additional toxicity information, the NTP decided to conduct a 2-year study in rats only. 2-YEAR STUDY IN RATS: Groups of 90 male F344/N rats were administered 0, 3, 30, or 150 mg/kg in 0.5% methylcellulose by gavage, and 90 female F344/N rats were administered 0, 3, 30, or 100 mg/kg in 0.5% methylcellulose by gavage for up to 104 weeks, with 9 or 10 rats per group evaluated at 3, 6, 12, or 18 months. Survival and Body Weights: Survival of all dosed groups was similar to that of the vehicle controls. The mean body weights of the 30 mg/kg male group were generally within 10% of those of the vehicle controls, but those of the 150 mg/kg group were markedly decreased. Mean body weights of 3 and 30 mg/kg females were generally greater than those of the vehicle controls throughout the study. Determinations of Oxymetholone in Plasma: The concentrations of oxymetholone in plasma of male and female rats receiving 3 mg/kg for 6, 12, or 18 months were generally below the limits of quantification; therefore, all plasma concentrations in the 3 mg/kg group are considered to be estimates (Table 8). The plasma concentrations at 30 mg/kg were approximately one order of magnitude greater than those of the estimates for males and females receiving 3 mg/kg. There were no dose-related differences in plasma concentrations in female rats receiving 30 or 100 mg/kg, but plasma concentrations in males were significantly elevated in the 150 mg/kg group. It was concluded that oxymetholone kinetics was saturated at 30 mg/kg in female but not male rats. Pathology Findings: A wide spectrum of neoplasms and nonneoplastic lesions was seen in rats administered oxymetholone for 2 years. The incidences of hepatocellular adenoma and hepatocellular adenoma or carcinoma (combined) were significantly increased in 100 mg/kg females as were the incidences of basophilic and clear cell foci in 150 mg/kg males and 100 mg/kg females compared to vehicle controls. The incidences of alveolar/bronchiolar adenoma and adenoma or carcinoma (combined) were significantly increased in 30 mg/kg females. The incidences of mineralization in the lung of 150 mg/kg males and 30 and 100 mg/kg females were significantly increased. The incidence of keratoacanthoma was increased in 30 mg/kg females, and the combined incidence of squamous cell papilloma, keratoacanthoma, basal cell adenoma, squamous cell carcinoma, or carcinoma of the sweat gland was significantly increased in 100 mg/kg females. The incidences of subcutaneous tissue fibroma and fibroma or fibrosarcoma (combined) were significantly increased in 3 mg/kg males. At 2 years, the incidences of benign pheochromocytoma and benign or malignant pheochromocytoma (combined) of the adrenal gland in 150 mg/kg males and medullary hyperplasia in 100 mg/kg females were significantly increased. The incidences of cytoplasmic vacuolization of adrenal cortical cells were significantly increased in 30 and 150 mg/kg males at 18 months and 2 years and in 100 mg/kg females beginning at 12 months and in 30 mg/kg females at 2 years. The incidences of renal tubule adenoma in 3 and 150 mg/kg males were slightly increased. An extended evaluation of the kidney was conducted, and additional incidences of renal tubule adenoma were observed in step sections in vehicle control and dosed male rats. The combined single- and step-section incidence of renal tubule adenoma was significantly increased in 3 mg/kg males. The incidences of nephropathy were significantly increased in 30 and 150 mg/kg males at 2 years and in 100 mg/kg females beginning at 3 months. The severities of nephropathy were significantly increased in dosed groups of males at 2 years and in 100 mg/kg females at 18 months and 2 years. The incidences of mineralization of the kidney were significantly increased in 150 mg/kg males at all time points. The incidences of ovarian dysgenesis were significantly increased in 100 mg/kg females beginning at 3 months and in 30 mg/kg females beginning at 6 months, and severities increased with increasing dose. The incidences of chronic myocardial degeneration (cardiomyopathy) were significantly increased in 100 mg/kg females at 6 months and 2 years and the severity was increased at 2 years. The incidences of lobular hyperplasia were increased in 150 mg/kg males at 18 months and 2 years and in 30 and 100 mg/kg females at all time points. The incidences of seminiferous tubule degeneration were significantly increased in 30 and 150 mg/kg males at 2 years, and the incidences of mineralization of the testis were increased in 150 mg/kg males at 12 months and in 30 mg/kg males at 18 months and at 2 years. Decreased incidences of neoplasms occurred in male and female rats. The incidence of uterine stromal polyp or stromal sarcoma (combined) was significantly decreased in 100 mg/kg females at 2 years. The incidences of mammary gland fibroadenoma and fibroadenoma or carcinoma (combined) were significantly decreased in all dosed groups of females. The incidences of pituitary gland pars distalis adenoma were significantly decreased in 30 and 100 mg/kg females at 2 years. The incidences of testicular interstitial cell adenoma were significantly decreased in 30 and 150 mg/kg males at 18 months and in all dosed groups at 12 months and 2 years. The incidences of mononuclear cell leukemia were significantly decreased in 30 and 150 mg/kg males and 100 mg/kg females at 2 years. GENETIC TOXICOLOGY: Oxymetholone was not mutagenic in S. typhimurium strain TA97, TA98, TA100, or TA1535, with or without S9 metabolic activation. It did not induce chromosomal aberrations in cultured Chinese hamster ovary cells, with or without S9, and no increase in the frequency of micronucleated normochromatic erythrocytes was noted in peripheral blood samples from male or female mice treated for 14 weeks with oxymetholone. CONCLUSIONS: Under the conditions of this 2-year gavage study, there was equivocal evidence of carcinogenic activity of oxymetholone in male F344/N rats based on increased incidences of subcutaneous tissue fibromas and fibromas or fibrosarcomas (combined) of the skin, variably increased incidences of benign and benign or malignant pheochromocytomas (combined) of the adrenal gland, and increased incidences of renal tubule adenomas. There was clear evidence of carcinogenic activity of oxymetholone in female F344/N rats based on increased incidences of hepatocellular neoplasms. Increased incidences of alveolar/bronchiolar neoplasms and skin neoplasms in female rats were also related to oxymetholone administration. Decreased incidences of alveolar/bronchiolar neoplasms and testicular interstitial cell adenomas in males; uterine stromal polyps or stromal sarcomas (combined), mammary gland neoplasms, and pituitary gland pars distalis adenomas in females; and mononuclear cell leukemia in males and females were related to oxymetholone administration. In addition, gavage administration of oxymetholone to male and female F344/N rats resulted in a spectrum of nonneoplastic effects frequently reported with administration of synthetic anabolic androgens. Synonyms: Adroidin; anadroyd; anasteron; anasteronal; anasterone; androstan-3-one, androstano[2,3-c]1,2,5-oxadiazol-17-ol, 17-methyl-, (5-a,17-b)-; becorel; 4,5-dihydro-2-hydroxymethylene-17-a-methyltestosterone; dynasten; HMD; 17b-hydroxy-2- (hydroxymethyl)-17-methyl-5-a-androstan-3-one; 17-hydroxy-2-(hydroxymethylene)-17-methyl-(5-a,17-b)-; 17-hydroxy- 2-(hydroxymethylene)-17-methyl-5-a-17-b-androst-3-one; 17b-hydroxy-2-(hydroxymethylene)-17-a-methyl-5-a-androstan-3-one; 17b-hydroxy-2-(hydroxymethylene)-17-methyl-5a-androstan-3-one; 17-hydroxy-2-(hydroxymethylene)-17-methyl-5-a-17- b-androstan-3-one; 17b-hydroxy-2-hydroxymethylene-17a-methyl-3-androstanone; 2-hydroxymethylene-17-a-methyl-5- a-androstan-17-b-ol-3-one; 2-hydroxymethylene-17a-methyl dihydrotestosterone; 2-hydroxymethylene-17-a-methyl-17-b- hydroxy-3-androstanone; methabol; 17a-methyl-2-hydroxymethylene-17-hydroxy-5-a-androstan-3-one; oximetholonum; oximetolona; oxitosona-50; oxymethenolone; roboral; zenalosyn Trade names: Adroyd; Anadrol; Anapolon; Anapolon 50; Nastenon; Pardroyd; Pavisoid; Plenastril; Protanabol; Synasteron
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PMID:NTP Toxicology and Carcinogenesis Studies of Oxymetholone (CAS NO. 434-07-1) in F344/N Rats and Toxicology Studies of Oxymetholone in B6C3F1 Mice (Gavage Studies). 1257 78

Butyl benzyl phthalate is a plasticizer added to polymers to give flexibility and softness. It is used extensively in polyvinyl chloride and in cellulose plastics, polyvinyl acetate, polysulfides, and polyurethane. Butyl benzyl phthalate was nominated as part of a class study of phthalates. Previous studies of butyl benzyl phthalate by the NTP (1982a) resulted in chemical-related mortality in male rats beginning at about 14 weeks of exposure and, thus, were inadequate for evaluating carcinogenicity in male rats. The companion studies revealed a marginal increase in leukemia in female rats and no evidence of carcinogenicity in B6C3F1 mice. Consequently, the present evaluations were conducted only in F344/N rats. Male and female F344/N rats were given butyl benzyl phthalate (at least 97% pure) in feed for 10 weeks, 26 weeks, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, L5178Y mouse lymphoma cells, cultured Chinese hamster ovary cells, mouse bone marrow cells, and Drosophila melanogaster. 10-WEEK MODIFIED MATING STUDY IN RATS: Groups of 15 male F344/N rats were given 0, 300, 2,800, or 25,000 ppm butyl benzyl phthalate (equivalent to average daily doses of approximately 20, 200, or 2,200 mg butyl benzyl phthalate/kg body weight) in feed for 10 weeks. All rats survived to the end of the study. The final mean body weight and body weight gain of the 25,000 ppm group were significantly less than those of the controls. Feed consumption by the 25,000 ppm group was less than that by the controls at the end of the study. A few minimal hematology changes occurred in the 25,000 ppm male rats. There was some evidence of a minimal anemia characterized by a decreased erythrocyte count and increases in mean cell hemoglobin and platelet count. The absolute and relative prostate gland weights of the 25,000 ppm males were significantly less than those of the controls. Degeneration of the seminiferous tubule germinal epithelium was observed in all males from the 25,000 ppm group. The absolute right cauda, right epididymis, and right testis weights of the 25,000 ppm males were significantly less than those of the controls. The epididymal spermatozoal concentrations in 2,800 and 25,000 ppm males were significantly less than that in the controls. Although 10 females mated to 25,000 ppm males were initially found to be sperm positive, none of these females were pregnant at necropsy. The fertility indices of males and females in the 25,000 ppm group were significantly lower than those of the controls. The maternal body weights of females mated to 300 and 2,800 ppm males were similar to those of females mated to control males. There were no significant differences in litter data between the controls and the 300 and 2,800 ppm groups. 26-WEEK STUDY IN RATS: Groups of 15 male F344/N rats were given 0, 300, 900, 2,800, 8,300, or 25,000 ppm butyl benzyl phthalate in feed for 26 weeks. Dietary levels of 300, 900, 2,800, and 8,300 ppm delivered average daily doses of approximately 30, 60, 180, and 550 mg butyl benzyl phthalate/kg body weight. The final mean body weight and body weight gain of the 25,000 ppm males were significantly less than those of the controls. Except for the 25,000 ppm males, feed consumption by all exposed groups was similar to that by the controls. An exposure-related macrocytic responsive anemia was present in the 25,000 ppm group at all time points. Additionally, minimal erythrocyte count decreases occurred sporadically in the 2,800 and 8,300 ppm groups at various time points. Reticulocyte counts were increased on days 60 and 90. Increases in mean cell hemoglobin and mean cell hemoglobin concentrations occurred in the 8,300 and 25,000 ppm rats. The absolute right cauda, right epididymis, and right testis weights and the sperm concentration of 25,000 ppm males were significantly less than those of the controls. The incidences of hypospermia and of atrophy of the seminiferous tubule in the testis and of hypospermia in the epididymis in 25,000 ppm males were significantly greater than those in the in the controls. Degenerative changes of the testis and epididymis in the 25,000 ppm males were qualitatively and quantitatively similar to those observed in males in the 10-week modified mating study. 2-YEAR STUDY IN RATS: Groups of 60 male F344/N rats were given 0, 3,000, 6,000, or 12,000 ppm butyl benzyl phthalate (equivalent to average daily doses of approximately 120, 240, or 500 mg butyl benzyl phthalate/kg body weight), and groups of 60 female F344/N rats were given 0, 6,000, 12,000, or 24,000 ppm butyl benzyl phthalate (equivalent to average daily doses of approximately 300, 600, or 1,200 mg/kg) in feed for 2 years. Survival, Body Weights, and Feed Consumption: Survival of all exposed groups of male and female rats was similar to that of the controls. Mean body weights of the 12,000 ppm males and 24,000 ppm females were less than those of the controls throughout most of the study. Feed consumption by the females exposed to 24,000 ppm was less than that by the controls at the beginning of the study, but was similar to that by the controls by week 6. Hematology and Hormone Assays: In general, hematology changes were sporadic and minor. At 6 months, a minimal decrease in erythrocyte count and an increase in mean cell hemoglobin, similar to that which occurred in the 26-week study, occurred in male rats in the 12,000 ppm group. In female rats, a decreased hematocrit value occurred at 15 months in the 24,000 ppm group. There was also a mild decrease in triiodothyronine concentrations in the 24,000 ppm females at 6 and 15 months and at the end of the study. Pathology Findings: of pancreatic acinar cell adenoma and adenoma or carcinoma (combined) in 12,000 ppm males were significantly greater than those in the controls. The incidences of adenoma and of adenoma or carcinoma (combined) in 12,000 ppm males exceeded the ranges of historical controls from NTP 2-year feed studies. One carcinoma was observed in one 12,000 ppm male, and two adenomas were observed in 24,000 ppm females. At 2 years, the incidence of focal hyperplasia of the pancreatic acinar cell in 12,000 ppm males was significantly greater than that in the controls. At 2 years, transitional epithelial papillomas in the urinary bladder were observed in one control female and in two 24,000 ppm females. The incidence of this neoplasm exceeded the range of historical controls from NTP 2-year feed studies. The incidence of transitional epithelial hyperplasia in 24,000 ppm females was significantly greater than that in the controls. The absolute right kidney weight of 12,000 ppm females and the relative right kidney weights of all exposed groups of males and of 24,000 ppm females were significantly greater than those of the controls at the 15-month interim evaluation. The severities of renal tubule pigmentation in 12,000 ppm males and in 24,000 ppm females were greater than those in the controls at 15 months and 2 years. At 2 years, the incidences of kidney mineralization in 6,000 and 24,000 ppm females were significantly less than that in the controls, and the severity was decreased in exposed females. The incidence of preputial gland adenoma or carcinoma (combined) in 12,000 ppm male rats was significantly less than in the controls, and the incidences occurred with a negative trend. GENETIC TOXICOLOGY: Results from in vitro mutagenicity tests with butyl benzyl phthalate were uniformly negative. No mutagenic response was obtained in any of several strains of Salmonella typhimurium treated with up to 11,550 mg/plate butyl benzyl phthalate, with or without S9 metabolic activation enzymes. Negative results were also obtained in in vitro studies of mammalian cell systems with and without S9. No induction of trifluorothymidine resistance in L5178Y mouse lymphoma cells or sister chromatid exchanges and chromosomal aberrations in cultured Chinese hamster ovary cells were observed. These assays also were conducted with and without S9. No significant increase in sex-linked recessive lethal mutations was observed in germ cells of male Drosophila melanogaster after administration of butyl benzyl phthalate either in feed or by injection. In contrast to the negative results obtained in vitro and in Drosophila, butyl benzyl phthalate gave positive responses in two in vivo studies with mice. Results of a mouse bone marrow sister chromatid exchange test were positive at sample times of 23 and 42 hours, but no confirmatory test was conducted. Chromosomal aberrations were induced in bone marrow cells of male mice sampled 17 hours after intraperitoneal injection of 5,000 mg/kg butyl benzyl phthalate. CONCLUSIONS: Under the conditions of this 2-year feed study, there was some evidence of carcinogenic activity of butyl benzyl phthalate in male F344/N rats based on the increased incidences of pancreatic acinar cell adenoma and of acinar cell adenoma or carcinoma (combined). There was equivocal evidence of carcinogenic activity of butyl benzyl phthalate in female 344/N rats based on the marginally increased incidences of pancreatic acinar cell adenoma and of transitional epithelial papilloma of the urinary bladder. Exposure of rats to butyl benzyl phthalate in feed for 2 years resulted in focal hyperplasia in the pancreas in male rats and in transitional epithelial hyperplasia in the urinary bladder of female rats. Synonyms: A13-14777; BBP; 1,2-benzenedicarboxylic acid butyl phenylmethyl ester (9CI); benzyl n-butyl phthalate; n-butyl benzyl phthalate; butyl phenylmethyl 1,2-benzenedicarboxylate; NCI-C54375; phthalic acid benzyl butyl ester (8CI) Trade names: Palatinol BB; Santicizer 160; Sicol 160; Unimoll BB
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PMID:NTP Toxicology and Carcinogenesis Studies of Butyl Benzyl Phthalate (CAS No. 85-68-7) in F344/N Rats (Feed Studies). 1258 18


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