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R D Irons

Publications and source records attributed to R D Irons.

At least 73 records · Page 4Linked to original sources
PubMed1982

Hydroquinone and catechol reduce the frequency of progenitor B lymphocytes in mouse spleen and bone marrow.

Hydroquinone and catechol are two metabolites of benzene that are potential inducers of hematotoxicity. We investigated the in vivo toxicity of these metabolites toward the development of polyclonal, plaque-forming cells (PC-PFC) from progenitor B lymphocytes. Dextran sulfate (DxS), lipopolysaccharide (LPS), or the two mitogens combined (DxS + LPS) were used to induce proliferation and maturation of these progenitors to PC-PFC. Groups of 4 C57BL/6 mice were exposed to 2 daily doses, either intravenously or intraperitoneally, of hydroquinone (100 mg/kg) or catechol (75 mg/kg) for 3 consecutive days. Spleen and marrow cells were harvested for culture 1 day later. The results demonstrated that both metabolites were cytotoxic to spleen cells. Hydroquinone (100 mg/kg) also reduced marrow cellularity, whereas catechol (75 mg/kg) did not significantly affect marrow cellularity. Each compound reduced the frequency of PC-PFC developed from the spleens and marrows of treated mice, but only catechol selectively inhibited the maturation of LPS-activated marrow progenitors into end-stage PC-PFC. These experiments demonstrate the immunotoxic potential of hydroquinone and catechol in vivo through the reduction of progenitor B lymphocytes and suggest that inhibition of precursor cell maturation may play a significant role in the hematotoxicity observed after chronic exposure to benzene.

Animals↗
PubMed1982

A critical review of the literature on nitrobenzene toxicity.

This literature review encompassing information available through 1980 and limited coverage in 1981, emphasizes results useful in assessing the potential toxic effects of nitrobenzene to man. Nitrobenzene exposure in man or experimental animals is most often associated with methemoglobinemia. Histopathologic changes also are observed in the hemato-lymphoreticular system, central nervous system, and liver. In addition, lesions have been reported in adrenals and testes. No information was found on carcinogenic or teratogenic potential, fertility, or reproductive effects of nitrobenzene. Results from Ames Salmonella assay are negative but test procedures are questionable; metabolites give positive results. Metabolism of nitrobenzene involves either oxidation or reduction yielding p-aminophenol and p-nitrophenol, and other reduced intermediates. From the foregoing, several aspects of nitrobenzene toxicity have been identified which warrant further study. Recommendations are made for chronic and subchronic exposure of test animals via inhalation to assess various toxicological endpoints. In addition, the relationship of nitrobenzene metabolism to its toxicity needs to be established. Genotoxic effects of nitrobenzene also need study.

Abnormalities, Drug-Induced↗
PubMed1982

Effect of benzene metabolites on phytohemagglutinin-stimulated lymphopoiesis in rat bone marrow.

Chronic exposure of animals to benzene results in lymphocytopenia and bone marrow depression. A highly sensitive microculture system was developed to amplify and characterize marrow mitogen response which depended on the isolation of cells by Percoll continuous density gradient centrifugation and strict adherence to optimal culture conditions. Maximal mitogen responses to phytohemagglutinin (PHA) and concanavalin A (con A), as assessed by (3H)-thymidine uptake, occurred at later times in rat bone marrow cultures (days 5-7 of culture) compared with spleen and thymus (days 2-3). Compared with spleen and thymus, the PHA: con A stimulation ratio was inverted for marrow, yet the responsive cells were morphologically identical to those of peripheral lymphoid organs. Populations enriched in lymphoid precursors were inhibited from responding to PHA stimulation at noncytotoxic concentration (less than microM) of the benzene metabolites, p-benzoquinone or 1, 2, 4-benzenetriol. Pretreatment with less than microM concentrations of metabolite resulted in a modulation of lectin-induced responses such the blastogenesis was induced at higher concentrations of lectin relative to untreated cells. These changes indicate that known metabolites of benzene induce a concentration dependent modulation of differentiation and proliferation in lectin-stimulated cells from rat bone marrow in vitro.

Animals↗
PubMed1981

Relationship between benzene toxicity and the disposition of 14C-labelled benzene metabolites in the rat.

The distribution of radioactivity associated with three 14C-labelled benzene metabolites was studied using whole body autoradiography (WBAR). Male Fischer-344 rats were given an intravenous dose of 0.6 mg/kg (60 microCi phenol, 1.2 mg/kg (100 microCi) catechol, or 1.3 mg/kg (100 microCi) hydroquinone. The rats were killed after 2 h and autoradiograms were prepared from whole body sagittal sections. The relative organ uptake of radioactivity associated with each compound was assessed by comparing tissue/blood optical density (O.D.) ratios from X-ray films. Bone marrow, thymus and the white pulp of the spleen concentrated radioactivity associated with hydroquinone or catechol. Radioactivity associated with phenol concentrated in the red pulp of the spleen, but not in the other lymphoid tissues. Radioactivity associated with all three metabolites was found in the lungs, kidneys and small intestines, whereas greater accumulation of radioactivity was observed in subcutaneous tissues, sebaceous glands and the white matter of the brain and spinal cord in rats given hydroquinone or catechol than in animals given phenol. Rats pretreated with a single dose of Aroclor 1254 (250 mg/kg, i.p.), a regimen which was found to protect against benzene-induced lymphocytopenia, were given hydroquinone (100 microCi; 1.3 mg/kg) or catechol (100 microCi; 1.4 mg/kg). For hydroquinone the tissue/blood O.D. ratios for bone marrow and thymus were approx. 60% lower in Aroclor-pretreated than in untreated rats. A 25% reduction in the tissue/blood O.D. ratios for these organs was observed in pretreated rats given catechol. These findings indicate that the uptake and concentration of radioactivity associated with hydroquinone and catechol by bone marrow and lymphoid organs (1) can occur independently of the metabolism of benzene in these tissues and (2) is reduced under conditions in which the animal is less susceptible to benzene toxicity.

Animals↗
PubMed1981

Modulation of benzene-induced lymphocytopenia in the rat by 2,4,5,2',4',5'-hexachlorobiphenyl and 3,4,3',4'-tetrachlorobiphenyl.

Repeated administration of benzene (440 mg/kg/day, s.c.) to 6-week-old male Fischer-344 rats resulted in a progressive decline in the number of circulating lymphocytes. Pretreatment of these animals with 2,4,5,2',4',5'-hexachlorobiphenyl (HCB) or 3,4,3',4'-tetrachlorobiphenyl (TCB) protected against benzene toxicity for as long as 7 days, but not after 10 days of repeated dosing. Representative phase I (mixed-function oxidase) and phase II (conjugating) enzyme activities were measured to determine whether the altered susceptibility to benzene toxicity in TCB- and HCB-pretreated rats could be correlated with changes in the profile of hepatic oxidative and detoxification pathways. Measurement of 7-ethoxycoumarin O-deethylase and benzphetamine N-demethylase activities indicated that the loss of protection by HCB or TCB against benzene toxicity after 7 days was not associated with changes in the activities of hepatic mixed-function oxidases inducible by 3-methylcholanthrene or phenobarbital. The time course for the stimulation by TCB and return to control values, of UDP-glucuronosyl transferase activity, a potential route for the elimination of benzene metabolites, mirrored the time course for the protection against toxicity. Epoxide hydratase activity was induced 2- to 3-fold by HCB. Although stimulation of this pathway could result in a decreased concentration of phenol, this activity did not decline with the loss of protection. Hepatic 10 000 X g supernatant fractions, prepared from livers of rats given TCB, were incubated with a non-saturating concentration of [14C] benzene (equivalent to 19 nmol/mg wet wt. tissue). Under these conditions the metabolism of benzene was depressed (40% of control) 2 days after pretreatment; after 14 days, the metabolism of benzene returned to control values. This pattern correlated temporarily with the protection against lymphocytopenia. The data indicate that the protection against benzene toxicity in rats pretreated with HCB or TCB is not necessarily related to the capacity of these compounds to induce phase I activities. In rats pretreated with TCB, the data suggest that decreasing the concentration of primary benzene metabolites, either by inhibiting the hepatic metabolism of benzene or increasing hepatic conjugation activity is an important factor modulating toxicity.

Animals↗
PubMed1981

Benzene-induced myelotoxicity: application of flow cytofluorometry for the evaluation of early proliferative change in bone marrow.

A detailed description of flow cytofluorometric DNA cell cycle analysis is presented. A number of studies by the author and other investigators are reviewed in which a method is developed for the analysis of cell cycle phase in bone marrow of experimental animals. Bone marrow cell cycle analysis is a sensitive indicator of changes in bone marrow proliferative activity occurring early in chemically-induced myelotoxicity. Cell cycle analysis, used together with other hematologic methods, has revealed benzene-induced toxicity in proliferating bone marrow cells to be cycle specific, appearing to affect a population in late S phase which then accumulate in G2/M.

Animals↗
PubMed1980

Effects of the principal hydroxy-metabolites of benzene on microtubule polymerization.

The principal hydroxy-metabolites of benzene - phenol, catechol and hydroquinone - possess characteristics and produce toxicity similar to those reported for certain inhibitors of microtubule polymerization. In this study we examined the effects of phenol, catechol and hydroquinone on purified microtubule polymerization and the decay of tubulin-colchicine binding activity. Hydroquinone, but not catechol or phenol, inhibited microtubule polymerization and accelerated the decay of tubulin-colchicine binding activity. The latter effect was shown to be dependent on the concentration of GTP. Hydroquinone did not directly complex with GTP or ATP but bound to the high molecular weight fraction of tubulin. concentration ratios of hydroquinone to tubulin resulting in altered activity were low, suggesting a specific interaction, presumably at the tubulin-GTP binding site. The acceleration of tubulin-colchicine binding activity decay was completely prevented under anaerobic conditions, indicative of an oxidative mechanism. These studies suggest that hydroquinone, which auto-oxidizes, may interfere with microtubule function, nucleotide binding or both and that this mechanism may be involved in eliciting the wide range of cytoskeletal-related abnormalities observed in cells exposed to benzene in vivo or its metabolites in vitro.

Animals↗
PubMed1980

A rabbit bone marrow model system for evaluation of cytotoxicity: characterization of normal bone marrow cell cycle parameters by flow cytometry.

Characterization of a rabbit model system for the study of cell cycle effects of myelotoxic agents in normal bone marrow is described. Cell cycle phase distributions are obtained by computer analysis of flow cytometric single cell DNA histograms. Comparison of marrow aspirates with marrow samples from sacrificed animals indicates that dilution of aspirates with peripheral blood is not significant. Aspiration of marrow from one bone does not affect the cell cycle distribution of unsampled bones. Hence, sequential aspirates of different bones in a single animal may be used as representative samples for further study of effects of myelotoxins on marrow proliferation and differentiation.

Animals↗
PubMed1980

Effect of short term benzene administration on circulating lymphocyte subpopulations in the rabbit: evidence of a selective B-lymphocyte sensitivity.

Repeated subcutaneous administration of benzene to rabbits (0.25 or 0.5 ml/kg/day) produced a progressive lymphocytopenia with a 80% reduction in total circulating lymphocytes after 10 days of treatment. This decrease in circulating lymphocytes was due primarily to a reduction in B- cells with 17-30% remaining after 10 days of treatment, depending on the dose. Immunoglobin surface receptor - negative cells, presumably T lymphocytes, were relatively unaffected until late in the experiment at the high dose. It is concluded that benzene has a relatively selective cytotoxic effect on circulating B-lymphocytes in the rabbit.

Animals↗
PubMed1980

Aseptic aspiration of rabbit bone marrow and enrichment for cycling cells.

Female adult New Zealand white rabbits were anesthetized using a combination of xylazine and ketamine administered intramuscularly. Bone marrow was aspirated aseptically from the humerus of femur using an 18-gauge Rosenthal pediatric needle. Marrow was obtained from six animals per hour using this technique. Recovery was rapid and no infection or loss of limb function was observed over the course of more than 100 aspirations. Approximately 2 x 10(8) mononuclear cells were obtained from 0.5 ml of aspirated marrow. Marrow samples were fractioned using isopynic single step density gradients. A 10-fold enrichment of blast cells was achieved using a density of 1.077 g/ml.

Animals↗