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Biomedical subjects

L M Brennan

Publications and source records attributed to L M Brennan.

10 recordsLinked to original sources
PubMed2001

Chronic toxicity of chloroform to Japanese medaka fish.

Japanese medaka (Oryzias latipes) were continually exposed in a flow-through diluter system for 9 months to measured chloroform concentrations of 0.017, 0.151, or 1.463 mg/L. Parameters evaluated were hepatocarcinogenicity, hepatocellular proliferation, hematology, and intrahepatic chloroform concentration. Histopathology was evaluated at 6 and 9 months. Chloroform was not hepatocarcinogenic to the medaka at the concentrations tested. Chronic toxicity was evidenced at these time points by statistically significant ([alpha] = 0.05) levels of gallbladder lesions and bile duct abnormalities in medaka treated with 1.463 mg/L chloroform. We assessed hepatocellular proliferation by exposing test fish to 5-bromo-2'-deoxyuridine in the aquarium water for 72 hr after 4 and 20 days of chloroform exposure; we then quantified area-labeling indices of the livers using computer-assisted image analysis. We observed no treatment-related increases in cellular proliferation. We analyzed cells in circulating blood in medaka after 6 months of chloroform exposure. Hematocrit, leukocrit, cell viability, and cell counts of treated fish were not significantly different from those of control fish. Using gas chromatography (GC), we evaluated intrahepatic concentrations of chloroform in fish after 9 months of exposure. Livers from the 0.151 and 1.463 mg/L chloroform-treated fish had detectable amounts of chloroform, but these levels were always lower than the aquaria concentrations of chloroform. Thus, it appeared that chloroform did not bioaccumulate in the liver. Unidentified presumptive metabolite peaks were found in the GC tracings of these fish livers.

Animals↗
PubMed1998

Environmental complex mixture toxicity assessment.

Trichloroethylene (TCE) was found as a contaminant in the well supplying water to an aquatic testing laboratory. The groundwater was routinely screened by a commercial laboratory for volatile and semivolatile compounds, metals, herbicides, pesticides, and polychlorinated biphenyls using U.S. Environmental Protection Agency methods. Although TCE was the only reportable peak on the gas chromatograph, with average concentrations of 0.200 mg/l, other small peaks were also present, indicating the possibility that the contamination was not limited to TCE alone. A chronic 6-month carcinogenicity assay was conducted on-site in a biomonitoring trailer, using the Japanese medaka fish (Oryzias latipes) in an initiation-promotion protocol, with diethylnitrosamine (DEN) as the initiator and the TCE-contaminated groundwater as a promoter. Study results indicated no evidence of carcinogenic potential of the groundwater without initiation. There was, however, a tumor-promotional effect of the groundwater after DEN initiation. A follow-up laboratory study was conducted using reagent grade TCE added to carbon-filtered groundwater to simulate TCE concentrations comparable to those found in the contaminated groundwater. Study results indicated no promotional effects of TCE. These studies emphasize the necessity for on-site bioassays to assess potential environmental hazards. In this instance, chemical analysis of the groundwater identified TCE as the only reportable contaminant, but other compounds present below reportable limits were noted and may have had a synergistic effect on tumor promotion observed with the groundwater exposure. Laboratory toxicity testing of single compounds can produce toxicity data specific to that compound for that species but cannot take into account the possible toxic effects of mixtures of compounds.

Adenoma, Liver Cell↗
PubMed1984

A sequential study of methapyrilene hydrochloride-induced liver carcinogenesis in male F344 rats.

Methapyrilene hydrochloride [2-[2-(dimethylamino)-ethyl)-2-thenylamino)pyridine monohydrochloride (CAS: 135-23-9)]-induced hepatocarcinogenesis was studied in male F344/NCr rats by sequential histologic, histochemical, and biologic methods. Methapyrilene hydrochloride was administered in the feed to rats at a concentration of 1,000 ppm for periods up to 89 weeks. Groups of rats were killed after 5, 10, 15, 29, 40, or 73 weeks of ingesting the carcinogen. Another group was allowed to live out their life-span. Hepatocellular eosinophilic foci and adenomas were seen after 10 and 15 weeks, respectively. Basophilic foci and adenomas were found after 29 and 40 weeks, respectively. Hepatocellular carcinomas developed in 5 of 10 rats at week 40, in 3 of 5 rats at week 73, and in 19 of 19 rats that lived out their life-span. Carcinomas arose within adenomas or as small in situ carcinomas. The histologic types included trabecular, adenocarcinoma, mixed, and solid poorly differentiated hepatocellular carcinomas. Eleven of the mixed and solid poorly differentiated carcinomas metastasized to the lung. Solid poorly differentiated hepatocellular carcinomas grew upon transplantation to the mammary fat pad of weanling F344 rats. Cholangiocarcinomas were found in 7 of 19 rats only in the life-span group. Mucous cholangiofibrosis was seen in all rats after 15 weeks. With the use of Regaud's mitochondrial stain, an increased cellular density of mitochondria was seen in some hepatocytes of peripheral and central lobular areas and in some hepatocellular carcinoma cells, but not in cells in many of the adenomas and foci. Cellular alpha-fetoprotein was found by immunoperoxidase staining in portions of hepatocellular carcinomas, but not in foci, adenomas, and nonneoplastic areas. The majority of hepatocytes in foci, adenomas, and hepatocellular carcinomas contained gamma-glutamyl transpeptidase. The findings suggest that multiple pathways may be followed in the development of methapyrilene-induced liver cancer that are similar to those found in rats exposed to many other hepatic carcinogens.

Aminopyridines↗
PubMed1983

In vivo and in vitro NO2 exposures enhance phagocytic and tumoricidal activities of rat alveolar macrophages.

Rat alveolar macrophages (AM) were exposed in vivo or in vitro to nitrogen dioxide (NO2) and subsequently tested for phagocytic and tumoricidal activities. AM obtained by lavage from Fischer 344/N rats exposed for 4 h to 40 ppm NO2 were significantly more phagocytic to opsonized sheep red blood cells (SRBC), exhibited an increased cytotoxic response toward syngeneic mammary adenocarcinoma cells, and were more sensitive to activation by agents such as lipopolysaccharide, muramyl dipeptide, and macrophage-activating factor, as compared with the response of AM obtained from unexposed control rats. Repeated 4 h/d NO2 exposures over 7-d or 14-d periods usually resulted in AM activity similar to control levels, with some instances of increased phagocytic activity of the AM but not to the extent of that observed for a single 4 h exposure. There were no significant decreases in the cytotoxic or phagocytic activities of the AM during any of the exposure periods. For the in vitro exposures, AM were lavaged from normal rats and then exposed for various periods to 10, 20, or 40 ppm NO2. A dose-related and time-dependent enhanced cytotoxic response of AM was observed. Maximum AM-mediated cytotoxicity occurred after an in vitro exposure to 10 ppm NO2 for 2 h. The cytotoxic response was directed toward syngeneic mammary adenocarcinoma cells but not against syngeneic embryoblast cells, indicating that the AM retained the ability to distinguish between normal and abnormal cells. No inhibitory effects of NO2 on AM-mediated cytotoxicity were observed. These experiments suggest that the host AM-mediated immune defense of the lung may be modulated by host exposure to inhaled chemicals.

Animals↗
PubMed1981

Urine cytology: early diagnosis of induced carcinoma of the rat urinary bladder.

Transitional cell carcinoma of the urinary bladder was induced in F344 rats by intragastric intubation of the animals with the known bladder carcinogen N-nitroso-N-methyl-N-dodecylamine (NMDA). Urinary cytology was used to follow the development of bladder lesions. As early as 8 weeks after the beginning of NMDA exposure, small, but distinct, differences could be detected between the morphology of exfoliated transitional cells found in the urine if animals treated with NMDA and those of control animals. Atypia was noted in the cells from some of the NMDA treated animals at about 20 weeks, and after 32 weeks definitely malignant transitional cells were identified in the urine of all NMDA treated animals. When the NMDA treated animals were killed, at 55-60 weeks after the beginning of NMDA treatment, transitional cell carcinoma of the urinary bladder was confirmed in all animals. No abnormal cells were noted in urine from any of the control animals. Urine cytology is an excellent technique for early detection of experimental urinary bladder cancer, and may be especially useful in screening industrial workers exposed to suspect bladder carcinogens.

Animals↗
PubMedDate not supplied

An in vivo method for using 5-bromo-2'-deoxyuridine (BrdU) as a marker of chemically-induced hepatocellular proliferation in the Japanese medaka (Oryzias latipes).

Japanese medaka fish (Oryzias latipes) were used to develop an in vivo method to assess hepatocellular proliferation in a nonmammalian model. Proliferative responses were assessed in medaka at 7, 17, 24, and 94 days after a 48-hour exposure to 10 or 100 mg/L diethylnitrosamine (DEN). Subgroups of medaka were exposed to 50 or 75 mg/L of 5-bromo-2'-deoxyuridine (BrdU) in water for 72 hours, sacrificed, and then processed for immunohistochemical staining. Proliferative indices of BrdU-labeled hepatocytes were quantified and compared using both count and area measurements. There was a significant increase (p < 0.05) in hepatocellular proliferation in the 100 mg/L DEN-treated fish as compared to controls and 10 mg/L DEN-treated fish for the first 3 time points. Hepatocarcinogenicity was evaluated 26 weeks post-DEN exposure. There was a significant increase (p < 0.0001) in hepatocellular neoplasms in 100 mg/L DEN-treated fish compared to other fish. Effective BrdU-labeling of S-phase hepatocytes in medaka was achieved by adding BrdU to the aquarium water, and an increase in hepatocellular proliferation using this method was detected 7 days after exposure to a carcinogenic concentration of DEN. Additionally, the new method of area measurement indices of proliferation were as precise as count indices (R2 > or = 0.92).

Adenoma, Liver Cell↗
PubMedDate not supplied

Chronic toxicity of bromodichloromethane to the Japanese medaka (Oryzias latipes).

Japanese medaka (Oryzias latipes) were continually exposed in a flow-through diluter system for 9 months to measured bromodichloromethane (BDCM) concentrations of 0.018, 0.143, or 1.424 mg/L. Parameters evaluated were hepatocarcinogenicity, hepatocellular proliferation, hematology, and intrahepatic BDCM concentration. BDCM was not hepatocarcinogenic to medaka at the concentrations tested. Chronic toxicity was evidenced at 6 and 9 months by statistically significant (alpha = 0.05) levels of gallbladder lesions and bile duct abnormalities in medaka treated with 1.424 mg/L BDCM. Hepatocellular proliferation was assessed after 1, 4, and 20 days of BDCM exposure. Treatment-related increases or decreases in cellular proliferation were not observed at any time point. Hematocrit, leukocrit, cell viability, and cell counts of treated fish after 9 months of BDCM exposure were not significantly different from control fish. Intrahepatic concentrations were evaluated by gas chromatography after 9 months of BDCM exposure. Fish livers from all three BDCM treatments had detectable amounts of BDCM, with median intrahepatic concentrations of 1.02, 2.89, and 21.25 mg BDCM/kg fish liver in the low, middle, and high concentrations, respectively. Medaka chronic toxicity effects of statistically significant gallbladder and bile duct abnormalities occurred at 1.424 mg/L BDCM, well above median drinking water levels.

Animals↗