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Biomedical subjects

W T Stott

Publications and source records attributed to W T Stott.

At least 37 records · Page 2Linked to original sources
PubMed1990

Chronic toxicity and oncogenicity of picloram in Fischer 344 rats.

The chronic toxicity and oncogenicity of the herbicide picloram was studied in male and female Fischer 344 rats administered 0, 20, 60, or 200 mg/kg.d technical-grade picloram via their feed for 2 yr. A comprehensive set of in-life and clinical pathology parameters was measured and an extensive list of tissues was examined grossly and by light microscopy from control and treatment groups of animals. The primary treatment-related effect observed in the study was hepatocellular swelling and altered tinctorial properties in the central regions of the liver lobules of both sexes of rats ingesting 60 or 200 mg/kg.d picloram. Males were more affected than females. Increases in liver weights accompanied these changes in both sexes of rats ingesting the high dose level of picloram. All other histopathologic lesions observed were typical of those that normally occur in aged Fischer 344 rats. There were no treatment-related increases in the incidence of any particular tumor type or in total tumors. No treatment-related effects were observed in rats ingesting 20 mg/kg.d of the test material.

Animals↗
PubMed1989

The chronic toxicity and oncogenicity of inhaled technical-grade 1,3-dichloropropene in rats and mice.

Male and female Fischer 344 rats and B6C3F1 mice were exposed by inhalation to target concentrations of 0, 5, 20, or 60 ppm (0, 22.7, 90.8, or 272 mg/m3) technical-grade 1,3-dichloropropene (DCPT) 6 hr/day, 5 days/week, for up to 2 years. Ancillary groups of rats and mice were exposed for 6- and 12-month periods. Significant treatment-related nonneoplastic changes following exposure for 2 years were morphological alterations in the nasal tissues of rats exposed to 60 ppm and mice exposed to 20 or 60 ppm DCPT. In addition, mice exposed to 20 or 60 ppm had hyperplasia of the transitional epithelium lining the urinary bladder. Survival of male and female rats and mice exposed to DCPT was similar to that of the corresponding controls. No statistically increased tumor incidence was observed in treated rats. The only neoplastic response observed in mice was an increased incidence of benign lung tumors (bronchioloalveolar adenomas) in male mice exposed to 60 ppm DCPT (22/50 versus 9/50 in controls).

Administration, Inhalation↗
PubMed1988

Subchronic toxicity of inhaled technical grade 1,3-dichloropropene in rats and mice.

In order to provide a comprehensive subchronic inhalation toxicity study of the soil fumigant, technical grade 1,3-dichloropropene (DCPT), male and female Fischer 344 rats and B6C3F1 mice were exposed to 0, 10, 30, 90, or 150 ppm DCPT vapors 6 hr/day, 5 days/week for 13 weeks. The primary target tissues of inhaled DCPT were identified as the nasal mucosa of both sexes of rats and mice, and the urinary bladder of female mice. In addition, depressed growth rates of all animals exposed to 90 or 150 ppm DCPT (up to 20% in rats and 12% in mice) resulted in a variety of alterations in hematologic and clinical chemistry parameters, and changes in organ weights relative to controls. Nasal mucosal effects consisted of a dose-related slight degenerative effect of nasal olfactory epithelium or a mild hyperplasia of the respiratory epithelium or both in all animals exposed to 90 or 150 ppm and 2 of 10 male rats exposed to 30 ppm DCPT. Some focal areas of respiratory metaplasia were also noted in high exposure group mice. Urinary bladder effects consisted of a diffuse, moderate hyperplasia of the transitional epithelium in female mice exposed to 90 or 150 ppm DCPT. No treatment-related effects were observed in rats or mice exposed to 10 ppm DCPT vapors.

Administration, Inhalation↗
PubMed1988

Chemically induced proliferation of peroxisomes: implications for risk assessment.

An increasing number of beneficial and economically important drugs, industrial chemicals, and agrichemicals are being found to cause a dose-related hepatomegaly in rodent species which is associated with the proliferation of the subcellular organelle, the peroxisome. The prolonged proliferation of hepatocellular peroxisomes and the enhanced production of the normal peroxisomal metabolic byproduct, hydrogen peroxide, in these animals during chronic bioassays has been hypothesized to account for the tumorigenicity of several of these compounds, most of which lack any measurable genotoxicity in in vitro and in vivo assays. This paper briefly reviews the basic morphology and enzymology of the peroxisome and its relationship to specific pathologic changes in animals. The potential impact of the mechanism of action of peroxisome proliferators upon the design of toxicity studies and, in conjunction with interspecies sensitivity data, upon risk assessment is discussed.

Animals↗
PubMed1986

Inhalation pharmacokinetics of technical grade 1,3-dichloropropene in rats.

Kinetic data on the uptake of vapors of technical grade 1,3-dichloropropene (DCP) and resultant cis- and trans-DCP blood concentrations were obtained in rats exposed to 30, 90, 300, or 900 ppm DCP for 3 hr. The uptake of DCP did not increase proportionately with increasing exposure concentration due to an exposure level-related decrease in the respiratory ventilatory frequency of rats exposed to greater than or equal to 90 ppm DCP and the saturation of metabolism of DCP by rats exposed to greater than or equal to 300 ppm DCP. Absorption of inhaled DCP occurred primarily in the lower respiratory tract, although a small amount of the chemical was absorbed via the nasal mucosa, a known target tissue of inhaled DCP in rats. Following absorption, both isomers of DCP were, at less than or equal to 300 ppm exposure levels, rapidly eliminated from the bloodstream (3-6 min half-life). In addition, data obtained in rats exposed to 300 ppm DCP revealed that this rapid elimination phase was followed by a slower elimination phase having a 33-43 min half-life. Rats exposed to 900 ppm vapors also eliminated DCP in a biphasic manner; however, in this case the blood half-life of DCP during the initial phase of excretion was 14 to 27 min. Exposure to 90 ppm DCP also produced a significant decrease in renal (31%) and hepatic (41%), but not pulmonary, nonprotein sulfhydryl content. Overall, these data demonstrated that a combination of saturable metabolism and chemically induced changes in respiration control DCP uptake and body burden in rats.

Allyl Compounds↗
PubMed1985

Hydrolysis of several glycol ether acetates and acrylate esters by nasal mucosal carboxylesterase in vitro.

The in vitro activity of carboxylesterase recovered from the nasal mucosal tissue of B6C3F1/CrlBR mice toward several agents known to cause olfactory epithelial lesions when inhaled by rodents was determined. Apparent Vmax and Km values were obtained for mouse nasal carboxylesterase using ethylene glycol monomethyl ether acetate (EGMEAc), ethylene glycol monoethyl ether acetate (EGEEAc), propylene glycol monomethyl ether acetate (PGMEAc), methyl acrylate (ME), ethyl acrylate (EA), and butyl acrylate (BA) as substrates. The short straight-chained glycol ethers, EGMEAc and EGEEAc, appeared to be relatively good substrates for nasal carboxylesterase under enzyme saturating and subsaturating conditions as indicated by their high Vmax and Vmax/Km values. The short-chained acrylate esters MA and EA were also hydrolyzed to a greater extent than BA at enzyme-saturating levels; however, the reverse was true at subsaturating levels as indicated by the relatively high Vmax/Km ratio obtained for BA. MA and BA were observed to cause a loss of carboxylesterase activity at enzyme saturation levels while EA caused a loss of enzyme activity at only one-half Km concentration. Using EGMEAc as a substrate, no sex differences in nasal carboxylesterase activity were observed in mice or rabbits. The specific activity of nasal carboxylesterase was found to be equivalent to that of the liver and greater than that of the kidney, lung, or blood. Mice and dogs were found to have similar nasal carboxylesterase activities which were slightly higher than that found in rats and about six-fold higher than that found in rabbits.(ABSTRACT TRUNCATED AT 250 WORDS)

Acrylates↗
PubMed1984

The comparative absorption and excretion of chemical vapors by the upper, lower, and intact respiratory tract of rats.

Upper respiratory tract (URT) absorption of several compounds with differing water solubilities and potentials to cause lesions of the nasal mucosa were studied in rats. Absorption of propylene glycol monomethyl ether (PGME), PGME acetate (PGMEAc), ethyl acrylate (EA), epichlorohydrin (EPI), styrene (STY), nitroethane (NE), ethylene dibromide (EDB), and methylene chloride (MeCl2) vapors by the isolated URT was compared to that by the isolated lower respiratory tract (LRT) and the intact animal. Nearly all PGME and PGMEAc and 30-70% of EA, EPI, STY, NE, and EDB were absorbed when passed through the URT. In general, similar levels were absorbed by both the isolated LRT and intact animal. It was estimated that intact animals received more than 90% of their total dose of PGME and PGMEAc, and 50% of EA, NE, EPI, and EDB via the URT. Further, the dosage per unit of surface area in the URT may be 5000-6000 times that of the LRT. However, the extent of URT absorption was not related to the ability to cause lesions of the nasal mucosa. Absorption of compounds by the URT was not a simple function of water solubility or of blood or water/air partitioning coefficients suggesting that a more complex mechanism for controlling absorption may exist. In one case, it was demonstrated that URT enzymatic activity could influence the absorption of certain compounds by the URT.

Absorption↗
PubMed1983

Blood-flow distribution in the mouse.

Blood-flow distribution was determined in pentobarbital-anesthetized male B6C3F1 mice, using intracardially administered 141Ce-radiolabelled microspheres (10 micro Ci). The proportion of cardiac output and blood flow per g tissue was determined in 18 organs and tissues, including the nasal cavity, lobes of the liver, individual kidneys and sections of the intestinal tract. To provide comparative data, blood-flow distribution was also determined in pentobarbital-anaesthetized male Fischer 344 rats. In general, there was close agreement between the distribution of blood flow between these two rodent species. The bladder and large intestine of mice appear to receive more, while the testes receive less, of the cardiac output than in rats. Rat liver and kidney, however, appear to receive approximately twice the amount of blood on a weight basis as in the mouse.

Animals↗
PubMed1981

Roles of 2-haloethylene oxides and 2-haloacetaldehydes derived from vinyl bromide and vinyl chloride in irreversible binding to protein and DNA.

The metabolism of [1,2-14C]vinyl bromide (VBR) to products irreversibly bound to DNA and protein was examined in rat liver microsomes, reconstituted cytochrome P-450 systems, and isolated hepatocytes. A role for cytochrome P-450 was confirmed using inhibition and reconstitution experiments. The major form of cytochrome P-450 involved in VBR metabolism does not appear to be either of the major isozymes induced by phenobarbital or beta-naphthoflavone, as determined by induction, reconstitution, and antibody inhibition studies. 2-Bromoethylene oxide and 2-bromoacetaldehyde, suspected metabolites of VBR, were synthesized and found to be substrates for rat liver epoxide hydrolase and equine liver alcohol dehydrogenase, respectively. These enzymes were used to probe the roles of the two possible metabolites in the irreversible binding of products of VBR to protein and DNA. Alcohol dehydrogenase was more effective than epoxide hydrolase in inhibiting the binding of VBR metabolites to protein in microsomal incubations. Epoxide hydrolase was effective in inhibiting the binding of VBR or vinyl chloride metabolites to calf thymus DNA added to such systems, but alcohol dehydrogenase was not. Similar results were obtained for binding of VBR metabolites to DNA in a reconstituted enzyme system. Reduced glutathione blocked nonenzymatic binding of 2-bromo[1,2-14C]acetaldehyde to protein but not DNA. Binding of vinyl chloride and VBR metabolites to protein was blocked by reduced glutathione, but binding to DNA was not. These results are consistent with the view that 2-haloethylene oxides are the major alkylating agents bound to DNA, and 2-haloacetaldehydes are the major alkylating agents bound to protein in these experimental systems. Studies with labeled 2-bromoacetaldehyde indicate that the slow kinetics of DNA binding by this compound is responsible in part for this phenomenon. Studies with isolated rat hepatocytes suggest that a significant portion of the total and reactive metabolites are able to leave these cells. In these systems, binding of metabolites of vinyl chloride to DNA outside the hepatocytes could be partially blocked by epoxide hydrolase or by alcohol dehydrogenase, implying that, as target farther away from sources of reactive species are considered, the stabilities of these species become more important for reaction with nucleophilic sites.

Adenosine↗
PubMed1975

Influence of carbohydrate and nitrogen source on patulin production by Penicillium patulum.

A strain of Penicillium patulum, isolated from cheddar cheese, produced patulin when grown on liquid media containing lactose and milk nitrogen sources. Patulin production was affected by the temperature of incubation, the type and amount of carbohydrate, and the type of nitrogen source present. Patulin levels generally were depressed by incubation at 5 C and low carbohydrate levels. Patulin was produced at low levels in the absence of sugars at 5 C when the mold was grown on milk nitrogen sources. No patulin was detected in cultures grown on 25% casein slurries or cheddar cheese, even though growth of the mold was extensive.

Animals↗
PubMed1975

Microbiological assay of patulin, using Bacillus megaterium.

Bacillus megaterium NRRL 1368 was found to be sensitive to patulin and a suitable test organism for an accurate, quantitative bioassay of the toxin. The optimum conditions for the test were determined. The response of the organism to patulin was found to be linear between 2 and 80 mug. When compared to thin layer chromatographic and spectrophotometric assay methods, the bioassay was found to be comparable in accuracy, but less sensitive. The test was found to be sensitive to 1.7 mug patulin. The assay is rapid (12-15 hr), simple, and inexpensive and can be used to verify the toxicity of samples, as well as to quantitatively measure patulin in samples of liquid media, apple juice, and corn.

Bacillus megaterium↗