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K L White

Publications and source records attributed to K L White.

At least 163 records · Page 9Linked to original sources
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

Measurement of modulation of mouse complement levels in vivo, utilizing a microtiter hemolytic assay.

The complement system, with its protein components, plays a fundamental role in host defense as the major immunological mechanism of innate immunity. Effects of immunotoxic agents on serum complement have not been studied due to the lack of an assay capable of measuring the in vivo effects of compounds in the mouse, the species of choice for immunotoxicological testing. A microtiter hemolytic assay was developed and utilized to measure modulation of serum complement in vivo in B6C3F1 mice. In order to validate this functional assay. Cobra Venom Factor (CVF) was used to produce decomplementation. CVF administered intravenously produced a dose-dependent suppression of complement activity when evaluated 24 hours after a single injection. Administration of 25 or more anticomplementary units (ACU/kg) completely abolished functional hemolytic activity. The duration of the effect was dose dependent with 100 ACU/kg suppressing the response for 48 hours. A decomplemented state could be maintained for up to 6 days, with a second injection. A third injection failed to prolong the decomplementation. Elevated complement levels were obtained following a single injection with Pyran Copolymer. Pyran, a macrophage activator, produce a dose dependent increase in serum complement levels 8 days after administration. The microtiter hemolytic complement assay represents a useful tool capable of evaluating the in vivo effects of agents on serum complement in the mouse.

Animals↗
PubMed1984

In vivo and in vitro effects of sodium azide on mouse complement.

A microtiter hemolytic assay was utilized to determine sodium azide (NaN3) modulation of B6C3F1 and C3H mouse serum complement levels in vivo and in vitro. Functional complement was expressed in CH50 units per milliliter. Experiments were performed to determine the in vitro effect of NaN3 on complement mediated lysis of IgM sensitized rabbit erythrocytes. Concentrations of 5, 10, 20, 30, 40, 60, and 80 mM NaN3 were added to microtiter wells containing Tris buffer, IgM sensitized rabbit erythrocytes, and serum complement from naive female C3H mice. Although NaCl and KCl controls had an inhibitory effect, NaN3 demonstrated a significant dose-dependent inhibition of complement-mediated lysis. In the three in vivo experiments, female B6C3F1 mice were exposed to NaN3 and physiological saline (vehicle control). Complement hemolytic ability was evaluated after a 1-day, single iv injection of 0.2, 2.0, and 20.0 mg/kg NaN3; at Days 1, 2, 3, 4, and 6 of a 6-day time course study after ip administration of 20 mg/kg NaN3; and at the end of an 11-day study involving daily injections of 10, 15, and 20 mg/kg NaN3 given ip. No significant changes in complement-mediated hemolysis were observed in the in vivo experiments. These studies indicate that NaN3 does not affect mouse complement levels in vivo. However, NaN3 suppresses in vitro complement hemolytic ability.

Animals↗
PubMed1984

Effects of subchronic exposure to diethylstilbestrol on humoral immune function in adult female (C3B6)F1 mice.

Adult female (C57BL/6 X C3H)F1 (B6C3F1) mice were treated with diethylstilbestrol for 14 days and assayed for the ability to produce antibody to a T-dependent antigen, a T-independent antigen, and to respond in vitro to stimulation by a polyclonal activator, bacterial lipopolysaccharide (LPS). No suppression of the in vivo antibody responses were observed. DES produced a subtle alteration in the response to the T-dependent antigen, sheep erythrocyte (sRBC), as treated groups maintained higher PFC values than vehicle groups after the peak day of the response. DES induced an enhanced response to the T-independent antigen, DNP-Ficoll. Spleen cells from DES-exposed animals were only marginally altered in their ability to produce antibody in vitro in response to LPS. Parallel experiments indicated a comparable reduction of LPS-induced blastogenesis. Serum immunoglobulin levels were determined following DES exposure, as a measure of baseline immunocompetence. DES only caused a reduction in the immunoglobulin M (IgM) isotype. DES exposure caused a significant enhancement of the activity of the reticuloendothelial (RES) system. Experiments were performed to assess the effects of enhanced RES function on concentrations of 51Cr labeled sRBC, which were optimal for antibody production. When sRBC were administered i.p., there was no effect on either the Ab response (as reported above) or on the number of sRBC localized in the spleen. In contrast, when sRBC were administered i.v., exposure to DES reduced (approximately 50%) both the Ab response and the number of sRBC localized in the spleen. Enhanced phagocytic function and alterations in antigen distribution must be considered in the interpretation of in vivo immune responses.

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↗
PubMed1984

Direct suppression of in vitro antibody production by mouse spleen cells by the carcinogen benzo(a)pyrene but not by the noncarcinogenic congener benzo(e)pyrene.

The role of metabolic activation of benzo(a)pyrene B(a)P in mediating its suppression of humoral immune responsiveness of the female C57BL/6 X C3H F1 (hereafter called B6C3F1) mouse was addressed in these studies. The model was the in vitro antibody response by untreated splenic suspensions, to which was added directly either B(a)P or benzo(e)pyrene B(e)P. B(a)P suppressed the antibody response to DNP-Ficoll and sheep erythrocytes but not the polyclonal antibody response to LPS. This activity neither required nor was affected by addition of a metabolic activation system (i.e., S-9 crude liver homogenate from Aroclor-induced B6C3F1 mice) at 3 times the concentration (based on determination of protein content) which readily activated cyclophosphamide. Preliminary results with radiolabeled B(a)P verified that appreciable amounts of hydroxylated metabolites of B(a)P were obtained after only a 30-min preincubation. Therefore, production of the reactive metabolites of B(a)P which mediate its carcinogenicity are not essential for its immunosuppressive activity. The results, showing a parallel in the immunosuppressive profile of activity of B(a)P and the lack of immunosuppressive activity of B(e)P following in vivo and in vitro exposure, indicate that the in vitro antibody systems offer an ideal model system to characterize the PAHs.

Animals↗
PubMed1984

Suppression of humoral antibody production by exposure to 1,2,3,6,7,8-hexachlorodibenzo-p-dioxin.

The day 4 IgM antibody (AB) response to sheep red blood cells was suppressed in adult female B6C3F1 mice subchronically (14 day) exposed to 1,2,3,6,7,8-hexachlorodibenzo-p-dioxin (1,2,3,6,7,8-HCDD) at concentrations reflecting the levels of this dioxin isomer as a contaminant in technical-grade pentachlorophenol. Hepatic microsomal parameters were also measured in these mice and indicated the characteristic induction of mixed-function oxidase enzyme activities, particularly aryl hydrocarbon hydroxylase. The response to sheep red blood cells was also suppressed when measured in vitro by culturing the antigen with spleen cells from a second group of mice subchronically exposed to 1,2,3,6,7,8-HCDD. Enumeration studies with fluorescent-labeled antisera in these animals indicated a dose-related suppression in the number of T-lymphocytes with no effect on B-lymphocytes. 1,2,3,6,7,8-HCDD directly suppressed several in vitro AB responses when added to cultures of spleen cell suspensions from untreated B6C3F1 mice. The rank order of sensitivity was determined to be: polyclonal AB response to LPS greater than or equal to T-independent AB response to DNP-Ficoll greater than T-dependent AB response to sheep red blood cells. Subsequent studies indicated that the suppression by 1,2,3,6,7,8-HCDD could be produced after only a 30-min preincubation. The suppression of all in vitro AB responses was abolished when the dioxin was preincubated with a metabolic activation system: crude liver homogenate (B6C3F1 mice pretreated with the mixed-function oxidase inducer; Aroclor 1254) plus NADP and isocitrate. The suppression of the T-dependent AB response was still evident when the metabolic activation system was heat-inactivated (as verified by an inability to activate cyclophosphamide) prior to the preincubation.

Animals↗
PubMed1984

Effects of N-nitrosodimethylamine on humoral immunity.

Female B6C3F1 mice were given i.p. injections with 1.5, 3.0 and 5.0 mg/kg N-nitrosodimethylamine (DMN) daily for 14 days and evaluated on day 15. The day 4 immunoglobulin M (peak day) antibody response to sheep red blood cells (sRBC) was inhibited by 20, 53 and 81%, respectively. The day 5 immunoglobulin G (peak day) antibody response to sRBC was only inhibited significantly (60%) at the highest dose. Recovery studies indicated that the IgM antibody response was still significantly inhibited (48%) 30 days after the completion of the exposure to 5 mg/kg of DMN. The peak response (day 3) to 100 micrograms of the B-cell mitogen, lipopolysaccharide, was inhibited by 15, 26 and 32%, respectively, indicating that a portion of the suppression of the antibody response by DMN may be due to an effect on the ability of the lymphocytes to proliferate. Concentrations of DMN up to 100 mM added directly to untreated spleen cell suspensions had no effect on the in vitro antibody responses to lipopolysaccharide and sRBC. Preincubating DMN (100 mM) with either phenobarbital-induced or 3-methylcholanthrene-induced liver proteins (postmitochondrial supernatant from a 9000 X g liver homogenate) was still ineffective. The activation of DMN by either preparation was verified by measuring formaldehyde production, which reflects demethylation. In contrast to the results with DMN added directly to untreated spleen cell suspensions, the most sensitive indicator of suppression by DMN was the in vitro antibody responses to lipopolysaccharide and sRBC by spleen cell suspensions from DMN-treated mice.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1983

The safety and efficacy of combined amitriptyline and tranylcypromine antidepressant treatment. A controlled trial.

Sixty patients meeting DSM-III criteria for major depression were assigned randomly to double-blind treatment for four weeks according to fixed-dosage steps with (1) amitriptyline hydrochloride alone, up to a maximum dosage of 300 mg/day; (2) tranylcypromine alone, up to 40 mg/day; or (3) the combination of amitriptyline hydrochloride, up to 150 mg/day, and tranylcypromine, up to 20 mg/day. The conditions of patients in all three treatment groups improved equally. The combined treatment did not produce a higher frequency of side effects, and no side effects, such as hypertensive or hyperthermic crises, occurred in any patient. Both amitriptyline alone and combined treatment produced substantially more anticholinergic side effects than did tranylcypromine. These results support the safety and efficacy of the combined treatment, although claims for superior efficacy over single-antidepressant treatments in this heterogenous population were not supported.

Adult↗
PubMed1983

Cytolytic and fluorescent detection of H-Y antigen on preimplantation mouse embryos.

Monoclonal antibodies to histocompatibility (H-Y) antigen, of IgM subclass, were used to immunologically determine the sex of mouse embryos prior to transfer to pseudopregnant recipients. Two experiments were performed, one using cytolysis of H-Y positive embryos and the other using binding of a Fluorescein Isothiocyanate-(FITC) labeled second antibody. Eight- to 16-cell embryos used in the cytolytic assay were cultured in Whitten's Medium without bovine serum albumin (WM), to which monoclonal antibody and normal guinea pig serum were added. Embryos were classified as affected or unaffected, based on morphology of the embryo and its blastomeres. A total of 550 embryos were cultured; 294 (53.5%) were scored as unaffected and 263 of these were transferred to recipients. Forty-three (81.1%) of 53 pups born were female. Morulae and early blastocysts were used in the FITC-labeled second antibody assay. Embryos were cultured in WM containing monoclonal antibody, washed and placed in drops of WM containing FITC-labeled anti-IgM. Following another wash embryos were individually evaluated at 200X for fluorescence. Fifty-five percent (169 of 305) of the embryos displayed cell-specific fluorescence. A total of twenty-three pups, 18 males (78.3%) and five females (21.7%), were born following transfer of 156 fluorescing embryos. Four male (17.4%) and nineteen female (82.6%) pups resulted from embryos classified as non-fluorescing.

Journal Article↗