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Biomedical subjects

B D Goldstein

Publications and source records attributed to B D Goldstein.

At least 73 records · Page 4Linked to original sources
PubMed1990

Genetic toxicity of the benzene metabolite trans, trans-muconaldehyde in mammalian and bacterial cells.

Previous studies in our laboratory identified trans,trans-muconaldehyde (MUC), a six-carbon diene dialdehyde, as a microsomal metabolite of benzene. This ring-opened metabolite of benzene was also shown to be hematotoxic in mice in a manner similar to benzene. To further explore the role of MUC in relation to benzene toxicity, a number of test systems were utilized to determine its genotoxic potential. In B6C3F1 mice, MUC induced a highly significant increase in sister-chromatid exchange (SCE), the lowest effective dose being 3 mg/kg, but failed to induce any micronuclei (MN). In Chinese hamster ovary (CHO) cells, MUC at concentrations up to 0.8 micrograms/ml was negative in the hypoxanthine-guanine phosphoribosyl transferase (HGPRT) assay. Dose-related increases in the percentage of cells with MN were observed in CHO cells treated with 0.4-0.8 micrograms/ml MUC. MUC did not-cause unscheduled DNA synthesis in rat primary hepatocytes. Treatment of Salmonella typhimurium TA97 with MUC induced a low level of mutations at concentrations ranging from 10 to 70 micrograms/ml with or without S9 activation. MUC was inactive in strains TA1535, TA100, TA1538 and TA98. In CHO cells and rat primary hepatocytes, MUC was cytotoxic at 0.4 and 4.0 micrograms/ml, respectively. Concentrations of 100 micrograms/plate MUC were toxic for bacterial cells. The present findings indicate that MUC is nonmutagenic or minimally mutagenic in bacterial and mammalian in vitro systems. In mammalian cells, MUC is highly cytotoxic and genotoxic.

Aldehydes↗
PubMed1990

Role of the physician in environmental medicine.

This article describes the role of the medical history and of laboratory findings in diagnosing diseases caused by environmental chemicals. An understanding of routes of exposure is crucial in appropriate diagnosis and in preventing further harm. A listing of potential sources of information is also included.

Environmental Health↗
PubMed1990

Free radicals and carcinogenesis.

The role of free radicals and active states of oxygen in human cancer is as yet unresolved. Various lines of evidence provide strong but inferential evidence that free radical reactions can be of crucial importance in certain carcinogenic mechanisms. A central point in considering free radical reactions in carcinogenesis is that human cancer is really a group of highly diverse diseases for which the initial causation and the progression to clinical disease occur through a wide variety of mechanisms. Furthermore, for many human cancers it appears that there are alternate pathways capable of tumor initiation and tumor progression. While for certain of these pathways free radical reactions appear necessary, it is unlikely that there are human cancers for which free radicals, or any other mechanism, are sufficient for the entire process beginning with the genetic alteration leading to a somatic mutation and eventually resulting in clinically overt disease. It is crucial that we view free radical reactions as among a panoply of mechanisms leading to human cancer, and consider research about the role of free radicals in cancer as opportunities to prevent the initiation or progression of human cancer.

Animals↗
PubMed1990

The pharmacology of the spinal monosynaptic reflex following conditioning of a cutaneous and muscle nerve.

Conditioning of the spinal monosynaptic reflex from cutaneous or muscle afferents results in facilitation followed by inhibition. We administered a series of agents which have been shown to alter the monosynaptic reflex by blocking specific inhibitory pathways. We found that administration of mecamylamine and atropine, agents which affect recurrent inhibition had no effect on the facilitation or inhibition of the MSR by conditioning the sural or medial gastrocnemius nerve. Similarly, bicuculline, an agent which blocks pre-synaptic inhibition, had no effect on the conditioning of the MSR. However, strychnine, a glycine antagonist which blocks post-synaptic inhibition, did alter both the facilitation and inhibition of the MSR by conditioning pulses. Strychnine enhanced the facilitation and partially blocked the inhibition of the MSR by both sural and medial gastrocnemius conditioning. These data show that the flexor reflex afferents and the larger diameter afferents alter the MSR solely through glycine-mediated post-synaptic inhibition.

Afferent Pathways↗
PubMed1989

Metabolism of trans, trans-muconaldehyde, a microsomal hematotoxic metabolite of benzene, by purified yeast aldehyde dehydrogenase and a mouse liver soluble fraction.

Aldehyde dehydrogenase (ALDH) from yeast, in the presence of NAD+, oxidizes trans, trans-muconaldehyde (MUC) in a biphasic manner with apparent Km values of 0.48 and 3.2 microM and corresponding Vmax values of 604 and 1227 nmol/min/mg protein. Concentrations above 10 microM trans,trans-muconaldehyde produce an inhibition of enzyme activity. Removal of NAD+, MUC, or use of boiled enzyme results in no oxidation. Using thin-layer chromatography and high-pressure liquid chromatography techniques, a product with polarity intermediate between that of the dialdehyde trans,trans-muconaldehyde and the diacid trans,trans-muconic acid (MA) was detected in the ALDH incubation mixtures. The same product was also detected in a DBA/2J mouse liver soluble fraction supplemented with NAD+ and incubated with MUC. This product was isolated from a scaled-up incubation mixture containing trans,trans-muconaldehyde, purified yeast aldehyde dehydrogenase, and NAD+. Mass spectral analysis of the compound indicates a molecular weight of 126 and an empirical formula C6H6O3 containing four double bonds. This product also tested positive with reagents specific for carboxylic and aldehydic functional groups. In the presence of the mouse liver soluble fraction supplemented with NAD+, this intermediate was metabolized to MA. These findings indicate that MUC is oxidized by yeast aldehyde dehydrogenase to the monocarboxylic acid derivative which is an intermediate in the conversion of MUC to MA. The role of the monocarboxylic acid alpha,beta-unsaturated aldehyde in benzene hematotoxicity remains to be explored.

Aldehyde Dehydrogenase↗
PubMed1989

Electrophysiological evidence for nicotinic and muscarinic modulation of spinal cord reflexes.

Intravenous administration of physostigmine has been found to produce dose- and time-dependent alterations of the lumbar monosynaptic and polysynaptic reflexes in spinal cats. A small dose of physostigmine (0.8 mg/kg) enhanced the monosynaptic reflex for 3 hr, while a larger dose (2.0 mg/kg) produced a pattern of initial depression which peaked at 5 min, followed by an increase which was maintained for 3 hr after injection. Both doses of physostigmine were found to produce a similar pattern of enhancement of the polysynaptic reflex. Atropine and mecamylamine antagonized the increase of the monosynaptic reflex produced by both doses of physostigmine. The initial depression of the monosynaptic reflex produced by the large dose of physostigmine was blocked by mecamylamine, but unaffected by atropine. The enhancement of the polysynaptic reflex, produced by both doses of physostigmine, was antagonized by atropine but not by mecamylamine. In addition, nicotine and oxotremorine were found to mimic the initial effects of physostigmine in the presence of the appropriate antagonist. These data show that both muscarinic and nicotinic receptors are involved differentially in the modulation of spinal reflexes and that physostigmine had an additional late effect which consistently occurred at 20 min after administration.

Animals↗
PubMed1989

Changes in spinal cord reflexes following subchronic exposure to soman and sarin.

The organophosphorus agents soman and sarin were administered subchronically and the spinal monosynaptic (MSR) and dorsal root (DRR) reflexes were assessed in spinal cord-transected cats. Neither soman nor sarin produced behavioral signs of delayed neurotoxicity. However, both soman and sarin significantly reduced the area under the MSR and DRR with only minimal changes in the excitability of the potentials as determined using quipazine, a serotonin agonist. The changes observed in these reflexes resulting from soman or sarin exposure are discussed in relation to alterations in the central terminals of primary afferent neurons.

Action Potentials↗
PubMed1989

The role of free radicals in tumor promotion.

A role has been suggested for free radicals and active states of oxygen in tumor promotion. There are a number of lines of support for this hypothesis, but no definitive evidence. The hypothesis has proven of value in leading to the development of models pertinent to understanding the mechanism of action of tumor promoters.

Animals↗
PubMed1989

Metabolism and toxicity of trans,trans-muconaldehyde, an open-ring microsomal metabolite of benzene.

We have previously hypothesized that ring-opened metabolites may play an important role in benzene toxicity. In this paper we review recent work related to this hypothesis. trans,trans-Muconaldehyde (TTM), a six-carbon diene dialdehyde, was shown by our laboratory to be a microsomal metabolite of benzene. This compound is a ring-opened metabolite of benzene that is hematotoxic in mice. The toxicity of TTM may stem in part from its ability to act as a direct-acting alkylating agent involving interaction with cellular sulfhydryls and/or amino groups. On the other hand, metabolism to the diacid trans,trans-muconic acid (MA), a known urinary metabolite of benzene, may represent detoxification since this results in loss of electrophilicity of the compound. Preliminary results indicate that TTM can be metabolized to MA in vitro and in vivo. The interaction of TTM in vitro with macrophages and neutrophils, key cells in the bone marrow, results in cell membrane changes, including loss of activity in the plasma membrane-bound NADPH-dependent oxidase and decreases in membrane lipid fluidity. Deoxyguanosine also was found to react with TTM, forming several different products. These findings may be due to TTM acting directly as an alkylating agent.

Aldehydes↗
PubMed1989

Use of longitudinal analysis of peripheral blood counts to validate historical reconstructions of benzene exposure.

We studied over 17,000 peripheral blood counts, accumulated during hematologic surveillance from 1940 through 1975, from a cohort of 459 benzene-exposed workers. Linear regressions demonstrated significant decreases in white and red cell counts, as well as hemoglobin, for workers exposed during the 1940s, without persistent trends over the ensuing 25 years. Strongly positive correlations were observed between these blood count fluctuations and fluctuations in retrospective estimates of benzene exposures for these workers in the earlier period of surveillance (mean estimated exposure 1940 to 1948, 75 ppm), but not for later years, (mean estimated exposure 1948 to 1975, 15 to 20 ppm). These data suggest substantial limitations of hematologic examination of populations to detect abnormalities in populations currently exposed to benzene. The analysis also demonstrates a novel approach to the biological validation of exposure estimates based upon limited industrial hygiene and historical record data. The application of biologic monitoring data may be useful for assisting decisions in reconstruction of a previous exposure.

Air Pollutants, Occupational↗
PubMed1989

Chromatographic and spectrophotometric characterization of adducts formed during the reaction of trans,trans-muconaldehyde with 14C-deoxyguanosine 5'-phosphate.

Mice liver microsomes oxidatively open the benzene ring to form trans,trans-muconaldehyde, a hematotoxic unsaturated aldehyde. In the present studies, 4.5 mumole trans,trans-muconaldehyde was reacted with 14C-2'deoxyguanosine 5'-phosphate in phosphate buffer. Products were separated by high performance liquid chromatography (HPLC). Absorbance was monitored using a diode array detector, and aliquots of the HPLC eluant were collected for UV spectrophotometric analysis and scintillation counting. Under these conditions, deoxyguanosine 5'-phosphate eluted at 12.5 min and muconaldehyde at 22.0 min. The HPLC and radioactivity profiles of the muconaldehyde/deoxyguanosine reaction mixture indicated the presence of multiple adducts. Three adducts were detected eluting at 36, 39, and 42 min, which represented approximately 2.5, 2.5, and 1% of the radioactivity, respectively. These adducts had similar UV spectra with absorption maxima between 334 and 347 nm. Another product of the reaction mixture, eluting at 19.0 min and accounting for 10% of the radioactivity, was also observed. This compound had absorption maxima at 348 and 372 nm. These results suggest that trans,trans-muconaldehyde can react with deoxyguanosine monophosphate in vitro under physiological conditions to form stable adducts. Studies are being conducted to determine the structure of these adducts and whether these adducts are formed by the reaction of DNA with muconaldehyde or metabolically activated benzene.

Aldehydes↗
PubMed1989

Studies on the mechanism of benzene toxicity.

Using the 59Fe uptake method of Lee et al. it was shown that erythropoiesis in female mice was inhibited following IP administration of benzene, hydroquinone, p-benzoquinone, and muconaldehyde. Toluene protected against the effects of benzene. Coadministration of phenol plus either hydroquinone or catechol resulted in greatly increased toxicity. The combination of metabolites most effective in reducing iron uptake was hydroquinone plus muconaldehyde. We have also shown that treating animals with benzene leads to the formation of adducts of bone marrow DNA as measured by the 32P-postlabeling technique.

Aldehydes↗
PubMed1988

EPA as a public health agency.

Much of EPA's actions are driven by concerns for public health. The public's perception of the potential adverse consequences to their health of chemical and physical agents in the general environment is a common motivating force in setting EPA's agenda and in making regulatory decisions. Despite its responsibilities in public health, and the major role that public health plays in its decision making, EPA is not part of the Department of Health and Human Services, the federal cabinent-level department with primary responsibility for human health. Rather, EPA is an independent agency with its own Administrator who is the decision maker for over a dozen legislative acts, many of which are based on public health concerns. For very few of these laws is there more than a minimal tie to the activities of classic public health agencies in the Department of Health and Human Services. Unfortunately, this organizational approach has led to a relative lack of individuals trained in the discipline of public health which hinders EPA's ability to approach public health problems. While there are many good reasons to keep EPA a separate entity from the Department of Health and Human Services, it is imperative there be close cooperation between EPA and the appropriate units of the U.S. Public Health Service. Most importantly, the number of people within EPA who are trained in public health disciplines must be increased. As a corollary there must be a concerted effort to educate students in a manner responsive to the need for public health manpower at EPA and at State and local agencies active directly or indirectly in environmental health issues.

Asbestos↗
PubMed1988

Utility of occupational blood pressure screening for the detection of potential hypertension.

A potential limiting factor in the detection and control of hypertension has been the assumption that a routine periodic sphygmomanometric blood pressure recording is characteristic of usual blood pressure throughout the activities of daily living. The relationship between routine periodic clinic blood pressure and ambulatory blood pressure was investigated in employed workers. Ambulatory readings were obtained at regular intervals using an automatic self-inflating and recording sphygmomanometer at home and at work. Mean ambulatory systolic and diastolic pressures were significantly higher than clinic pressures, both at home and at work, and in every position except reclining. Eleven of the 113 employees considered normotensive from clinic screening had an average of 46% of their diastolic ambulatory readings greater than or equal to 90. These persons may be considered functionally hypertensive. The authors suggest the need to focus attention on those persons with high-normal clinic blood pressures discovered in workplace screening.

Adult↗
PubMed1988

Inhalation of ozone produces a decrease in superoxide anion radical production in mouse alveolar macrophages.

The potentiation of fatal bacterial pneumonia in mice by prior inhalation of ozone occurs at levels of this oxidant pollutant that are frequently present in ambient air. A likely mechanism for this effect is an ozone-induced inhibition in the ability of pulmonary alveolar macrophages (PAM) to produce superoxide anion radical (O2-) demonstrated in the present study. A 25% decrease in PAM O2- production, as measured by nitroblue tetrazolium reduction, occurred after exposure of Swiss-Webster mice to 0.11 ppm ozone for 3 h (p less than 0.05). After 1 ppm there was almost complete inhibition of O2- release. In contrast, the rat, which is highly resistant to the potentiation of bacterial infections by ozone, was less sensitive to inhibition of PAM O2- production, as measured by cytochrome c reduction (mouse IC50, 0.41 ppm; rat IC50, 3.0 ppm ozone for 3 h). The observed decrement in mouse PAM O2- production was not associated with any change in phagocytic ability, as measured by both latex bead ingestion and 51Cr-labeled sheep red blood cell ingestion. This decrease in O2- production in the presence of normal phagocytic activity is analogous to certain of the findings in the neutrophils of children with chronic granulomatous disease. A decrease in rat PAM membrane cytochrome b558 levels was observed after ozone exposure of 3 ppm for 3 h, preliminarily suggesting that the mechanism by which ozone interferes with PAM O2- production may be through interaction with this heme-containing electron carrier.

Administration, Inhalation↗