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G M Shopp

Publications and source records attributed to G M Shopp.

32 records · Page 2Linked to original sources
PubMed1985

Suppression of the antibody response by a formamidine pesticide: dependence on the route of exposure.

These studies investigated the effects of exposure to chlordimeform (CDM), a formamidine pesticide, on selected in vivo immune parameters in the random bred CD-1 mouse. Further studies were done on the effects of this compound on the in vitro PFC response in C57BL/6 mice. Acute and 14-d exposure to CDM via the i.p. route resulted in a decrease in IgM antibody-forming (plaque-forming) cells (PFC) directed at the sheep red blood cell (sRBC) antigen when measured 4 d after i.p. immunization. This suppression was seen at doses as low as 20 mg/kg . d for 14 d. These same doses of CDM did not result in any alteration of cell-mediated immunity as measured by the delayed hypersensitivity response (DHR) to both keyhole limpet hemocyanin (KLH) and sRBC. Lymphocyte blastogenesis was increased in spleen cells from mice exposed to 40 mg/kg . d CDM in response to media alone, concanavalin A (Con A), and lipopolysaccharide (LPS). The in vitro PFC response by C57BL/6 mice was utilized to determine if CDM could suppress the antibody response due to a direct effect on the immune cells. CDM suppressed the in vitro PFC response only at concentrations that were directly cytolytic. A direct cytolytic effect was considered unlikely following exposure in the whole animal, since the suppression of the antibody response occurred in the absence of any effects on spleen cell number or spleen weight. To determine if route of exposure was a factor in the suppressive effects of CDM, 14-d studies were conducted administering CDM orally at doses up to 120 mg/kg . d. Both the CD-1 and C57BL/6 mouse were used to verify that a strain difference was not a factor. There was no effect on either the d 4 or d 5 antibody response, even though 43% of the mice exposed to 120 mg/kg died from the acute toxicity that can characterize this chemical. From an operational standpoint, these results indicate that the route of exposure of a compound relative to the route of administration of an antigen is an important consideration when determining the effects of that compound on an immune response. From an environmental standpoint, these results indicate that relatively high doses of chlordimeform do not result in consistent immunotoxicity as determined by the assays utilized.

Administration, Oral↗
PubMed1985

Immunotoxicological investigations in the mouse: general approach and methods.

The adverse effects of chemicals on the lymphoreticular system have generated considerable toxicological interest. In this series of papers, the effects of selected environmentally relevant compounds are reported. This first paper describes the methods and general approach used in judging a chemical's potential risk to the immune system. Risk evaluation was approached utilizing acute, 14- and 90-day studies. Both sexes of the CD-1 random-bred mouse were employed. The immune system was evaluated against a background of more standard toxicological parameters, which included fluid consumption, body and organ weights, hematology, serum and liver chemistries, hepatic microsomal enzyme activities and blood coagulation. Bone marrow status was evaluated by assessing DNA synthesis. Humoral immunity was evaluated by determining the number of IgM spleen antibody-forming cells (AFC) to sheep erythrocytes (sRBC), the serum antibody level to sRBC, and spleen lymphocyte response to the B cell mitogen, lipopolysaccharide (LPS). The status of cell-mediated immunity was assessed by quantitating the delayed type hypersensitivity (DTH) response to sRBC, proliferation of the popliteal lymph node, and the spleen cell response to the T lymphocyte mitogen, Concanavalin A (Con A). Macrophage function was evaluated by measurement of the vascular clearance rate and distribution of radiolabeled sRBC in the liver, spleen, lungs, and thymus, and recruitability, adherence, chemotaxis, and phagocytic activity of peritoneal exudate cells (PEC). Historical control data from six 14- and 90-day studies conducted over a one year period are given. The data resulting from these types of studies can provide a basis for the initial evaluation of a chemical's adverse effect on the immune system.

Animals↗
PubMed1985

Toxicology of 1,1,2-trichloroethane in the mouse.

1,1,2-Trichloroethane (TCE) was administered to male and female CD-1 mice to evaluate its effect on standard toxicological parameters. Following determination of the acute LD50 (378 mg/kg in males and 491 mg/kg in females), and a 14-day range-finding study, a 90-day drinking water study was performed in which the doses consumed were 4.4, 46, and 305 mg/kg for males and 3.9, 44, and 384 mg/kg for females. The liver was a target of TCE toxicity in both sexes as demonstrated by dose-dependent alterations in hepatic microsomal enzyme activities and serum enzyme levels. The erythroid element of the female mice was also affected, as indicated by significantly decreased hematocrit and hemoglobin levels.

Animals↗
PubMed1985

Humoral and cell-mediated immune status of mice exposed to 1,1,2-trichloroethane.

The purpose of this study was to assess the immunological effects of 1,1,2-trichloroethane (TCE) on random-bred CD-1 mice following 14 and 90 days of oral exposure. A toxicological evaluation conducted at the same time revealed the target organs to be the liver of both sexes and the erythroid elements of the females. The 14-day immunological range-finding study in males exposed to doses 1/10 and 1/100 the LD50 (38 and 3.8 mg/kg) revealed no alterations in either humoral or cell-mediated immune status. Following 90 days of exposure in the drinking water (4.4., 46, and 305 mg/kg for males and 3.9, 44, and 384 mg/kg for females), a more detailed series of immunological parameters was assessed. Cell-mediated immunity was unaltered in both sexes, while humoral immune status was depressed in both sexes, particularly when determined by hemagglutination titers. Macrophage function was depressed only in the males as indicated by the ability of thioglycolate-recruited peritoneal exudate cells (PEC) to phagocytize sheep erythrocytes (sRBC).

Animals↗
PubMed1985

Toxicology of trans-1,2-dichloroethylene in the mouse.

Trans-1,2-dichloroethylene (DCE) was administered to male and female CD-1 mice in order to evaluate its effects on standard toxicological parameters. Following an acute LD50 determination (2122 mg/kg in males and 2391 mg/kg in females) and a 14-day range-finding study, a 90-day drinking water study was performed using levels of DCE calculated to deliver approximately 1/100, 1/10, and 1/5 the LD50. Various toxicological assessments were made, including body and organ weights, hematology, serum chemistries, and hepatic microsomal activities. Few alterations were observed in either sex following 90 days of exposure. The most noteworthy changes occurred in the males exposed to the highest level of DCE, where there was a significant decrease in glutathione levels, and in the females exposed to all three DCE levels, where there was a significant decrease in aniline hydroxylase activity. These data served as background for the immunotoxicological evaluation presented in the following manuscript.

Animals↗
PubMed1985

Humoral and cell-mediated immune status of mice exposed to trans-1,2-dichloroethylene.

This study assessed possible adverse immunological effects of trans-1,2-dichloroethylene (DCE) on random-bred CD-1 mice following 14 and 90 days of exposure. A 14-day range-finding study was performed on male mice by gavage at doses 1/10 and 1/100 the LD50 (210 and 21 mg/kg). No alterations in either humoral or cell-mediated immunity were observed following this exposure. A 90-day study was conducted in which DCE was administered in the drinking water of male and female mice. The levels of DCE in the drinking water were calculated to deliver levels equivalent to, and higher than, those delivered for 14 days (17, 175, and 387 mg/kg for males and 23, 224, and 452 mg/kg for females). No changes were observed in the cell-mediated immune status of either sex or in the humoral immune status of females. However, a marked suppression in humoral immune status was observed in male mice exposed to all three levels of DCE, as indicated by a decreased ability of spleen cells to produce antibody against sheep erythrocytes (sRBC). Macrophage function was depressed only in females, as indicated by the decreased ability of thioglycollate-recruited peritoneal exudate cells (PEC) to phagocytize sRBC.

Animals↗
PubMed1984

Suppression of the in vitro specific antibody response by 12-O-tetradecanoylphorbol-13-acetate (TPA) in the mouse.

The tumor promoter, 12-O-tetradecanoylphorbol-13-acetate (TPA), has several effects on the immune system. The effect of TPA on the in vitro antibody response to sheep red blood cells (sRBC) was studied. Spleen cells treated in vitro with TPA resulted in a dose-dependent inhibition of the IgM antibody forming cell (AFC) response with an IC50 of 0.74 nM. Nontumor promoting analogs at concentrations up to 1000 nM had no effect on this system. 2-Mercaptoethanol (2ME), which is known to augment macrophage function in this assay, did not reverse the inhibition. Spleen cells were separated into plastic adherent cells (ADC) and nonadherent cells (NAC). When NAC were treated with TPA and cultured with untreated ADC, the inhibition was seen. However, treating the ADC alone did not result in an inhibition. These results show that TPA will suppress the in vitro antibody response in the mouse and that the suppression is due to a selective effect on the plastic nonadherent cell population. The study of these effects of TPA may allow us to gain insight into the mechanism of its tumor promoting activity and to use it as a tool to study the modulation of the immune system.

Animals↗
PubMed1984

Characterization of the delayed hypersensitivity response to a protein antigen in the mouse--I. Kinetics of reactivity and sensitivity to classical immunosuppressants.

Several parameters of the delayed hypersensitivity response (DHR) to a protein antigen, keyhole limpet hemocyanin (KLH), were investigated. Female B6C3F1 mice were sensitized with KLH suspended in either complete Freund's Adjuvant (CFA) or sterile saline. When the mice were sensitized twice, the magnitudes of these responses were equivalent as measured by a radioisotopic procedure reflecting the influx of monocytes. With only a single sensitization, there was a 37% decrease in the response of CFA-treated mice and a dramatic (82%) decrease in the response of saline-treated mice. Utilizing two sensitizing injections in male CD-1 mice, the kinetics of the responses were determined to be equivalent regardless of whether KLH was suspended in CFA or saline in that both responses were persistent for up to 5 weeks between the second sensitization and challenge. Ear thickness in CFA-treated mice was twice that of the saline-treated mice at 1, 3 and 5 weeks. This increased swelling was not due to an increase in the vascular permeability as measured by the extravasation of a radiolabelled protein. There was a marked increase in the total area of fibrin in both sensitized groups when compared to unsensitized mice; but no difference between the groups. The sensitivity of these responses to immunosuppressants was determined in male CD-1 mice exposed subchronically (14 day) to dexamethasone (DEX) and cytoxan (CTX). There was a marked increase in the suppression by DEX in mice sensitized to KLH in saline as compared to mice sensitized to KLH in CFA. In contrast, the sensitivity to suppression by cyclophosphamide was not affected by the presence of CFA.

Animals↗
PubMed1984

Naphthalene toxicity in CD-1 mice: general toxicology and immunotoxicology.

Random bred CD-1 mice were used to evaluate the acute oral toxicity and subchronic toxicity of naphthalene administered in corn oil. The acute oral LD50 of naphthalene was 533 and 710 mg/kg in male and female mice, respectively. Subchronic toxicity was evaluated with 14- and 90-day daily oral gavage studies. Doses utilized in the 14-day study were 27, 53, and 267 mg/kg, with the latter representing one-half of the male LD50. Both males and females demonstrated a 5-10% mortality and depressed body weight at the high dose only. Males had decreased thymus weights, and females had decreased spleen and increased lung weights at the high dose only. Other organ weights were unaffected at any dosage level. Serum enzyme and electrolyte levels were not altered in a dose-related manner. To assess the potential immunotoxicity of naphthalene the following screen was utilized: humoral immune response, response to mitogens, delayed hypersensitivity response, popliteal lymph node response, bone marrow stem cell number, and DNA synthesis. No evidence of immunotoxicity was demonstrated. The 90-day study employed daily oral doses of 5.3, 53, and 133 mg/kg. There was no treatment-related mortality in either sex, nor was body weight affected. Organ weights were not affected in males, and females showed reduced spleen weights only at the high dose. Serum enzyme and electrolyte levels, as well as the immunotoxicity screen, indicated that naphthalene doses up to one-fourth the LD50 for 90 days failed to elicit consistent statistically significant and biologically relevant compound-related effects. A screen of the effects of the 90-day naphthalene treatment on various aspects of the hepatic drug metabolizing system indicated no alterations, with the exception of a specific dose-related inhibition of aryl hydrocarbon hydroxylase activity in both male and female mice.

Animals↗
PubMedDate not supplied

The determination of biurea in the presence of azodicarbonamide by HPLC.

Azodicarbonamide (ADA), a solid blowing agent used in the manufacture of plastics, has been selected for inhalation toxicity testing by the National Toxicology Program. To test for decomposition of ADA during aerosolization, an HPLC method was developed to quantitate the relative amounts of one possible degradation product, biurea, in bulk samples and filter samples collected after aerosolization. The method uses a C18 column with 10-micron particles, UV monitoring at 190 nm for biurea and 425 nm for ADA, and a mobile phase of 100% water. Quantitation is with 14C-labeled biurea and ADA as external standards. The assay was validated by spiking bulk ADA with projected levels of 1, 2, and 3% biurea. Levels of biurea bound in both bulk and filter-collected aerosol samples of ADA were both 0.50%, with relative standard deviations of 13 and 26%, respectively.

Animals↗
PubMedDate not supplied

Preclinical safety evaluation of rhuMAbVEGF, an antiangiogenic humanized monoclonal antibody.

Recombinant humanized antivascular endothelial growth factor (rhuMAbVEGF) is a monoclonal IgG1 antibody that is being developed as an antiangiogenic agent for use in treating a variety of solid tumors. Preclinical safety studies included an immunohistochemical tissue cross-reactivity study, in vitro hemolytic potential and blood compatibility studies, and multiple dose toxicity studies. Toxicity studies were conducted in cynomolgus monkey because rhuMAbVEGF is pharmacologically active in this species and does not bind rat or mouse vascular endothelial growth factor (VEGF). Following twice weekly administration of rhuMAbVEGF for 4 or 13 wk, young adult cynomolgus monkeys exhibited physeal dysplasia characterized by a dose-related increase in hypertrophied chondrocytes, subchondral bony plate formation, and inhibition of vascular invasion of the growth plate. In addition, decreased ovarian and uterine weights and an absence of corpora lutea were observed in females receiving 10 and 50 mg/kg/dose in the 13-wk study. Both the physeal and ovarian changes were reversible with cessation of treatment. No other treatment-related effects were observed following rhuMAbVEGF administration at doses up to 50 mg/kg. These findings indicate that VEGF is required for longitudinal bone growth and corpora lutea formation and that rhuMAbVEGF can reversibly inhibit physiologic neovascularization at these sites.

Animals↗