p-Chlorophenyl Methyl Sulfide, p-Chlorophenyl Methyl Sulfoxide, and p-Chlorophenyl Methyl Sulfone. II. Subchronic Effects in Rodents and Rhesus Monkeys

1993 ◽  
Vol 12 (4) ◽  
pp. 377-395 ◽  
Author(s):  
Daryl C. Thake ◽  
Dennis C. Mays ◽  
A. Philip Leber ◽  
Jack C. Dacre
Keyword(s):  
Rhesus Monkeys ◽  
Clinical Chemistry ◽  
Clinical Signs ◽  
Recovery Phase ◽  
Exposure Level ◽  
Cell Hyperplasia ◽  
Methyl Sulfide ◽  
Methyl Sulfoxide ◽  
Serum Blood Urea Nitrogen ◽  
Cns Depression

Rats, mice, and rhesus monkeys were subjected in subchronic exposures to the chemicals p-chlorophenyl methyl sulfide, p-chlorophenyl methyl sulfoxide, and p-chlorophenyl sulfone. Ninety-one-day toxicity studies were conducted by administering test chemicals to rodents at dietary concentrations of 750, 1500, and 3000 ppm. Clinical signs observed included transient central nervous system (CNS) depression, anorexia, and depressed weight gains. Minor alterations of hematologic and clinical chemistry parameters were also present. Gross and microscopic tissue findings in mice and rats included enlargement, necrotic and megalocytic changes of the liver. Damage to bronchiolar epithelium was observed in mice only at the highest exposure level. A 14-day gavage study in monkeys used daily dosages ranging from 2.5 to 80 mg/kg with an additional 15 days allotted for a recovery phase in one-half the test animals. Compound-related findings included lethality, CNS depression, and emesis. There were no significant compound-induced alterations in electrocardiographic or ophthalmic parameters. Serum blood urea nitrogen and serum glutamic pyruvic transaminase values were elevated in the highest dosage groups for the three test materials concomitant with increases in liver and kidney weights. Microscopic lesions included proliferative changes in lymph nodes, spleen, and bone marrow; hepatocellular vacuolization, degeneration, and necrosis; thyroid follicular cell hyperplasia; and degenerative lesions in gastric and intestinal epithelium. No-observable-effect levels (NOELs) were not established for any of the three test chemicals in the species tested.

scholarly journals Inhalational Botulism in Rhesus Macaques Exposed to Botulinum Neurotoxin Complex Serotypes A1 and B1

2010 ◽  
Vol 17 (9) ◽  
pp. 1293-1304 ◽  
Author(s):  
Daniel C. Sanford ◽  
Roy E. Barnewall ◽  
Michelle L. Vassar ◽  
Nancy Niemuth ◽  
Karen Metcalfe ◽  
...  
Keyword(s):  
Disease Progression ◽  
Dose Response ◽  
Botulinum Neurotoxin ◽  
Rhesus Macaques ◽  
Clinical Chemistry ◽  
Clinical Signs ◽  
Exposure Level ◽  
Clinical Observations ◽  
Aerosol Exposure ◽  
Serotype B

ABSTRACT A recombinant botulinum vaccine (rBV A/B) is being developed for protection against inhalational intoxication with botulinum neurotoxin (BoNT) complex serotype A, subtype A1 (BoNT/A1), and BoNT serotype B, subtype B1 (BoNT/B1). A critical component for evaluating rBV A/B efficacy will be the use of animal models in which the pathophysiology and dose-response relationships following aerosol exposure to well-characterized BoNT are thoroughly understood and documented. This study was designed to estimate inhaled 50% lethal doses (LD50) and to estimate 50% lethal exposure concentrations relative to time (LCt50) in rhesus macaques exposed to well-characterized BoNT/A1 and BoNT/B1. During the course of this study, clinical observations, body weights, clinical hematology results, clinical chemistry results, circulating neurotoxin levels, and telemetric parameters were documented to aid in the understanding of disease progression. The inhaled LD50 and LCt50 for BoNT/A1 and BoNT/B1 in rhesus macaques were determined using well-characterized challenge material. Clinical observations were consistent with the recognized pattern of botulism disease progression. A dose response was demonstrated with regard to the onset of these clinical signs for both BoNT/A1 and BoNT/B1. Dose-related changes in physiologic parameters measured by telemetry were also observed. In contrast, notable changes in body weight, hematology, and clinical chemistry parameters were not observed. Circulating levels of BoNT/B1 were detected in animals exposed to the highest levels of BoNT/B1; however, BoNT/A1 was not detected in the circulation at any aerosol exposure level. The rhesus macaque aerosol challenge model will be used for future evaluations of rBV A/B efficacy against inhalational BoNT/A1 and BoNT/B1 intoxication.

p-Chlorophenyl Methyl Sulfide, p-Chlorophenyl Methyl Sulfoxide, and p-Chlorophenyl Methyl Sulfone. III. Toxicokinetics and Metabolism in Rats and Rhesus Monkeys

1993 ◽  
Vol 12 (4) ◽  
pp. 397-407 ◽  
Author(s):  
Jack C. Dacre ◽  
A. Philip Leber ◽  
Dennis C. Mays
Keyword(s):  
Rhesus Monkeys ◽  
Day Treatment ◽  
Sleep Time ◽  
Water Soluble ◽  
Blood Levels ◽  
Dependent Manner ◽  
Metabolite Formation ◽  
Methyl Sulfide ◽  
Methyl Sulfoxide ◽  
Test Materials

Pharmacokinetic properties of p-chlorophenyl methyl sulfide, p-chlorophenyl methyl sulfoxide, and p-chlorophenyl methyl sulfone were evaluated in rats and rhesus monkeys following oral administration of 14C radiolabeled test materials. In addition, urinary metabolite formation in treated rats was partially assessed, as was microsomal enzyme induction as determined by hexobarbital sleep time assays. All test materials were found to be rapidly absorbed following gavage dosing with a biphasic diminution of blood radiolabel in the rat. As an apparent result of higher dosage levels, rhesus monkeys exhibited both a delayed attainment of peak blood levels and a lower rate of elimination of blood 14C. A minor portion (5–7%) of urinary radioactivity from treated rats was not extractable with chloroform until incubation with deconjugation enzymes was conducted, releasing up to 50%. The values for rhesus monkeys were 15–62% and 50%, respectively; the former values are apparently elevated (relative to rat) due to saturation of conjugate-formation pathways. Decreases were observed for hexobarbital sleep times following 3-day treatment with 50 mg/kg of each of the test compounds and, consistent with hepatomegaly observed in subchronic studies, suggest induction of hepatic microsomal enzymes. The study supports evidence that these chemicals are cleared primarily via the urine in a dose-dependent manner, and are conjugated to water-soluble metabolites in both rats and rhesus monkeys.

Experimental delayed radiation necrosis of the brain

1979 ◽  
Vol 51 (5) ◽  
pp. 587-596 ◽  
Author(s):  
Albert N. Martins ◽  
Ralph E. Severance ◽  
James M. Henry ◽  
Thomas F. Doyle
Keyword(s):  
Rhesus Monkeys ◽  
Radiation Necrosis ◽  
Clinical Signs ◽  
Control Group ◽  
Content Type ◽  
Brain Irradiation ◽  
Primate Brain ◽  
High Doses ◽  
The Brain ◽  
Male Rhesus

✓ The authors have designed an experiment to detect a hitherto unrecognized interaction between high doses of the glucocorticoid, dexamethasone, and brain irradiation. Eighteen juvenile male rhesus monkeys received 1800 rads to the whole brain in 8.5 minutes. For 1½ days before and 10½ days after the irradiation, nine animals received approximately 2.9 mg/kg/day of dexamethasone intramuscularly in addition to irradiation, while the remaining nine animals served as the control group and received saline. All animals eventually developed a progressive neurological syndrome, and died of delayed radiation necrosis of the brain. The two groups were compared with regard to latency to onset of clinical signs, survival time, and number, distribution, and location of lesions of radionecrosis. Large doses of dexamethasone did not alter the susceptibility of the primate brain to delayed radiation necrosis. Detailed morphological study of the radionecrotic lesions supports the hypothesis that most, if not all, of the lesions develop as the consequence of injury to blood vessels.

scholarly journals Molecular cloning of mouse intestinal trefoil factor and its expression during goblet cell changes

1995 ◽  
Vol 311 (1) ◽  
pp. 293-297 ◽  
Author(s):  
M Tomita ◽  
H Itoh ◽  
N Ishikawa ◽  
A Higa ◽  
H Ide ◽  
...  
Keyword(s):  
Goblet Cell ◽  
Goblet Cells ◽  
Recovery Phase ◽  
Nippostrongylus Brasiliensis ◽  
Trefoil Factor ◽  
Intestinal Trefoil Factor ◽  
Cell Hyperplasia ◽  
Reverse Transcription Pcr ◽  
Rapid Amplification ◽  
Mitf Expression

A cDNA encoding mouse intestinal trefoil factor (mITF) was successfully cloned and sequenced from the small intestine of C57BL/6 mouse by using the combination of reverse transcription-PCR and rapid amplification of cDNA ends methods. The gene was, similar to rat and human ITFs, mainly expressed in the small and large intestine. The mITF expression was up-regulated during the recovery phase after depletion of goblet cells in acetic acid-induced colitis. On the other hand, the expression in the jejunum was not altered, while goblet cell hyperplasia was induced by Nippostrongylus brasiliensis infection. These results suggest that the mITF expression did not simply correlate with the number of goblet cells. The mITF may play an important role in the maintenance and repair of mucosal function of the rectum. Additionally, the mITF in the jejunum may play a role in alteration of the physicochemical nature of goblet cell mucins, thereby affecting the establishment of intestinal helminths.

Oral (Drinking Water) Two-Generation Reproductive Toxicity Study of Bromodichloromethane (BDCM) in Rats

2002 ◽  
Vol 21 (2) ◽  
pp. 115-146 ◽  
Author(s):  
M. S. Christian ◽  
R. G. York ◽  
A. M. Hoberman ◽  
L. C. Fisher ◽  
W. Ray Brown
Keyword(s):  
Drinking Water ◽  
Reproductive Toxicity ◽  
Clinical Signs ◽  
Sperm Parameters ◽  
Feed Consumption ◽  
Exposure Level ◽  
Organ Weights ◽  
Reduced Body ◽  
Body Weights ◽  
Adult Exposure

Bromodichloromethane (BDCM) was tested for reproductive toxicity in a two-generation study in CRL SD rats. Thirty rats/sex/group/generation were continuously provided BDCM in drinking water at 0 (control carrier, reverse osmosis membrane-processed water), 50, 150, and 450 ppm (0,4.1 to 12.6, 11.6 to 40.2, and 29.5 to 109.0 mg/kg/day, respectively). Adult human intake approximates 0.8 μg/kg/day (0.0008 mg/kg/day). P and F1 rats were observed for general toxicity (viability, clinical signs, water and feed consumption, body weights, organ weights [also three weanling F1 and F2 pups/sex/litter], histopathology [10/sex, 0-and 450-ppm exposure groups]) and reproduction (mating, fertility, abortions, premature deliveries, durations of gestation, litter sizes, sex ratios, viabilities, maternal behaviors, reproductive organ weights [also three weanling F1 and F2 pups/sex/litter], sperm parameters, and implantations. F1 rats were evaluated for age at vaginal patency or preputial separation. Ten P and F1 rats/sex from the 0-and 450-ppm exposure groups and rats at 50 and 150 ppm with reduced fertility were evaluated for histopathology (gross lesions, testes, intact epididymis, all F1 dams for number of primordial follicles). Developmental parameters in offspring included implantation and pup numbers, sexes, viabilities, body weights, gross external alterations, and reproductive parameters (F1 adults). Toxicologically important, statistically significant effects at 150 and/or 450 ppm included mortality and clinical signs associated with reduced absolute and relative water consumption, reduced body weights and weight gains, and reduced absolute and relative feed consumption (P and F1 rats). Significantly reduced body weights at 150 and 450 ppm were associated with reduced organ weights and increased organ weight ratios (% body and/or brain weight). Histopathology did not identify abnormalities. Small delays in sexual maturation (preputial separation, vaginal patency) and more F1 rats with prolonged diestrus were also attributable to severely reduced pup body weights. Mating, fertility, sperm parameters, and primordial ovarian follicular counts were unaffected. The no-observable-adverse-effect level (NOAEL) and the reproductive and developmental NOAELs for BDCM were at least 50 ppm (4.1 to 12.6 mg/kg/day), 5125 to 15,750 times the human adult exposure level, if delayed sexual maturational associated with severely reduced body weights is considered reproductive toxicity. If considered general toxicity, reproductive and developmental NOAELs for BDCM are greater than 450 ppm (29.5 to 109.0 mg/kg/day), or 36,875 to 136,250 times the human adult exposure level. Regardless, these data indicate that BDCM should not be identified as a risk to human reproductive performance or development of human conceptuses.

Chimera of Dimethylene Sulfone-, Methyl Sulfide-, and Methyl Sulfoxide-Linked Ribonucleotides and DNA

1996 ◽  
Vol 61 (21) ◽  
pp. 7620-7626 ◽  
Author(s):  
Daniel K. Baeschlin ◽  
Birgitte Hyrup ◽  
Steven A. Benner ◽  
Clemens Richert
Keyword(s):  
Methyl Sulfide ◽  
Methyl Sulfoxide

scholarly journals Quantification of Allyl Methyl Sulfide, Allyl Methyl Sulfoxide, and Allyl Methyl Sulfone in Human Milk and Urine After Ingestion of Cooked and Roasted Garlic

2020 ◽  
Vol 7 ◽  
Author(s):  
Wen Qin ◽  
Katrin Huber ◽  
Moritz Popp ◽  
Patrick Bauer ◽  
Andrea Buettner ◽  
...  
Keyword(s):  
Human Milk ◽  
Methyl Sulfide ◽  
Methyl Sulfoxide

Evidence of Hepatitis A Infection in Immature Rhesus Monkeys

1987 ◽  
Vol 24 (4) ◽  
pp. 340-344 ◽  
Author(s):  
G. R. Lankas ◽  
R. D. Jensen
Keyword(s):  
Rhesus Monkeys ◽  
Hepatitis A ◽  
Mononuclear Cells ◽  
Hepatitis A Virus ◽  
Clinical Signs ◽  
Hepatic Function ◽  
Serum Aminotransferase ◽  
Hepatic Lesions ◽  
Serological Data ◽  
Observation Period

Forty immature (< 2 years old) rhesus monkeys ( Macaca mulatta) with marked increases in aspartate and alanine aminotransferase activities were examined. Serological and histopathological evaluations were done to determine if affected animals were infected with hepatitis A virus. Although no clinical signs of illness were noted in any of the monkeys, an excellent correlation was found between the increased serum aminotransferase values and seropositivity with the acute phase (IgM) HAVAB-M antibody. Histopathological evaluations of livers of selected animals revealed hepatic lesions consistent with those in chimpanzees and marmosets infected with hepatitis A virus: generalized activation of sinusoidal lining cells, focal hepatocellular necrosis with occasional acidophilic bodies, and cuffs of mononuclear cells in the portal areas. Although no animals were seropositive for HAVAB upon receipt from the breeding colony, a total of ten of 18 animals for which serological data were available had seroconverted to HAVAB positivity during the 4-month observation period. These results are consistent with hepatitis A infection in immature rhesus monkeys and indicate the potential significance of serological testing in animals in which hepatic function is being evaluated.

scholarly journals A Comprehensive Toxicological Assessment of Fulvic Acid

2020 ◽  
Vol 2020 ◽  
pp. 1-11
Author(s):  
Chongshan Dai ◽  
Xilong Xiao ◽  
Yonglei Yuan ◽  
Gaurav Sharma ◽  
Shusheng Tang
Keyword(s):  
Oral Administration ◽  
Fulvic Acid ◽  
Clinical Chemistry ◽  
Clinical Signs ◽  
Micronucleus Assay ◽  
The Body ◽  
Feed Consumption ◽  
Control Group ◽  
Toxicological Studies

Fulvic acid (FA), a humic substance, has several nutraceutical properties, including anti-inflammation, antimicrobial, and immune regulation abilities. However, systematic safety assessment remains insufficient. In the present study, a battery of toxicological studies was conducted per internationally accepted standards to investigate the genotoxicity and repeated-dose oral toxicity of FA. Sprague-Dawley (SD) rats or ICR mice were used. Compared to the control group, there were no significant changes (all p > 0.05 ) in all FA treatment groups in the bacterial reverse mutation test, in vitro mammalian chromosome aberration test, in vivo sperm shape abnormality assay, and in vivo mouse micronucleus assay. The acute toxicity test showed that no mortality or toxic effect was observed following oral administration of the maximum dose of 5,000 mg/kg BW/day to mice or rats. A 60-day subchronic study was conducted at 0 (control), 200, 1,000, and 5,000 mg/kg/day. Compared to the control group, there were no significant changes (all p > 0.05 ) in the body weights, feed consumption, clinical signs, hematology, clinical chemistry, organ weights, or histopathology examinations. In conclusion, the no-observed-adverse-effect-level (NOAEL) of FA supplementation from the 60-day study was determined to be 5,000 mg/kg body weight/day, the highest dose tested. Our findings suggest that the oral administration of FA may have higher safety.

scholarly journals Susceptibility and pathological consequences of catla, Catla catla (Hamilton) experimentally infected with Edwardsiella tarda

2016 ◽  
Vol 24 (4) ◽  
pp. 209-217 ◽  
Author(s):  
Thongam Bidya Devi ◽  
T. Jawahar Abraham ◽  
Dibyendu Kamilya
Keyword(s):  
Lethal Dose ◽  
Clinical Signs ◽  
Infected Fish ◽  
Edwardsiella Tarda ◽  
Catla Catla ◽  
Cell Hyperplasia ◽  
Hydropic Degeneration ◽  
Leucocyte Infiltration ◽  
Gill Lamellae ◽  
Kidney Liver

AbstractThe present study tested the susceptibility and pathological changes of catla, Catla catla (Hamilton) infected with Edwardsiella tarda (ET-PG-29). The bacterium was isolated from the kidney of a diseased pangas catfish. To determine the median lethal dose (LD50), C. catla were challenged with this bacterium (108-103CFU ml-1), and the LD50was calculated as 105.5CFU ml-1. Another set of healthy C. catla were injected intraperitoneally with the LD50dose to induce edwardsiellosis. The clinical signs of the infected C. catla were observed and recorded. Tissues such as kidney, liver, intestine, heart, and gill from the infected fish with clinical signs of edwardsiellosis were used for histopathology. The clinical and gross signs were first visible at 1 d post-injection, and the infected fish showed typical signs of hemorrhagic septicemia. The most striking histopathological features were found in the kidney which showed multi-focal necrosis with the formation of granuloma indicating an inflammatory response against the pathogen. The intestine displayed goblet cell hyperplasia, the liver showed hydropic degeneration with hyperemic central veins, and there was inflammation of gill lamellae and cardiac myositis associated with leucocyte infiltration. Collectively, the results confirmed the susceptibility of C. catla to E. tarda infection and that this bacterium is a threat to C. catla in aquaculture practices.

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