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Biomedical subjects

V M Ramanujam

Publications and source records attributed to V M Ramanujam.

At least 19 recordsLinked to original sources
PubMed1999

Polyatomics in zinc isotope ratio analysis of plasma samples by inductively coupled plasma-mass spectrometry and applicability of nonextracted samples for zinc kinetics.

Inductively coupled plasma-mass spectrometry (ICP-MS) is a powerful tool for both quantitative multielement analyses of inorganic elements and measurement of isotope ratios (IRs). The main disadvantage of this technique is the existence of polyatomic isobaric interferences at some key masses. Zinc has been investigated for such potential interferences in serum or plasma. The Zn isotopes, 66Zn and 68Zn, have no apparent interferences, but 32S1602 and 32S2 are isobaric with 64Zn. The possible effects of S and other major components of blood plasma-Na, K, Cl, P, Ca-on Zn IRs were investigated using a series of mineral solutions which simulated human plasma with respect to these elements. The mixture of all mineral elements interfered only with 64Zn (6.66 ng/mL) and 70Zn (8.51 ng/mL). Interferences to 66Zn, 67Zn, and 68Zn were minimal containing 0.90, 0.94, and 0.39 ng/mL, respectively. The copresence of Na or S shifted 35Cl16O2 (atomic mass 67 coming from Cl solution) to 35Cl2 which reduced the contribution to 67Zn. The hypothesis that Zn IRs obtained from plasma at various intervals after the intravenous administration of enriched 67Zn to humans would reflect those obtained after extraction of Zn was therefore tested. To compare the two pretreatment methods, "extraction" versus "nonextraction," specimens were collected from 10 human subjects at intervals of 5 min to 24 h postinjection, and in 4 subjects from 5 min to 9 d postinjection. Two separate aliquots of plasma from each time-point were dried and digested with hydrogen peroxide, and the residue dissolved in nitric acid. One specimen was subjected to zinc extraction using ammonium diethyldithiocarbamate chelate followed by back extraction into nitric acid. The matching aliquot received no further pretreatment. The normalized IRs obtained from 67Zn/66Zn and 67Zn/68Zn in both the "extracted" and "nonextracted" samples agreed well (r2 = 0.976 and r2 = 0.985, respectively) compared to those from other ratios (r2 = 0.838 for 67Zn/64Zn and r2 = 0.747 for 67Zn/70Zn). Considering the minimum possibility of isobaric interferences in plasma samples, 67Zn/68Zn obtained from "nonextracted" samples is sufficient for routine Zn kinetic analysis by ICP-MS.

Argon↗
PubMed1998

Population monitoring: experience with residents exposed to uranium mining/milling waste.

More emphasis should be placed upon using biomarkers to address potential health risk among populations exposed to high concentrations of environmental toxicants. Among these studies, those which integrate exposure measurements with analyses of validated biomarkers may provide more reliable information for risk assessment and disease prevention. We have used a multidisciplinary approach to elucidate potential health hazards in a population living around uranium mining/milling facilities. The study included 24 target and 24 control residents who were matched for age and gender and selected based on time of residence in the study areas and proximity to mining/milling sites. Environmental samples were analyzed for uranium-238 (238U) concentrations and lead isotope ratios using inductively coupled plasma-mass spectrometry (ICP-MS) procedures, and blood samples were collected for cytogenetic analysis. We found that the 238U concentrations in soil samples were significantly higher than those in the control areas. In addition, the concentrations in the surface soil were significantly higher than in the subsurface soil (p<0.05) from target areas indicating environmental contamination by the mining/milling activities. Lead isotope data from soil samples taken near a railroad transfer location was significantly different from those of other sites, indicating contamination by non-native ore transported from sources outside of the region to local milling facilities for processing. Therefore, local residents have been exposed to low levels of radioactive contamination from the mining/milling activities on a daily basis for many years. From our cytogenetic analysis, the target population had more chromosome aberrations than the controls, although the differences were not significant (p<0.05). However, using our challenge assay, cells from the target population had a significantly abnormal DNA repair response, compared to cells from the same control population. In conclusion, the observed environmental contamination by uranium is consistent with the observed genotoxic effects in the target residents. Therefore, the residents have increased health risk and some of the health problems will most likely be related to exposure to the radioactive contaminants. Since the chromosome aberration frequency revealed increased, but not significant differences between the exposed and the control populations, we conclude that the health risk among the exposed residents is similar to those among nuclear workers.

Anencephaly↗
PubMed1995

Altered time course of urinary daidzein and genistein excretion during chronic soya diet in healthy male subjects.

Soybean consumption is associated with reduced rates of prostate and other cancers, possibly due in part to the presence of isoflavones. The metabolism and disposition of these soya-derived phytoestrogens after chronic soya exposure were studied on a metabolic unit in six healthy males (21-35 yrs of age) who consumed an unrestricted hospital diet and a 12-oz portion of soymilk with each meal for one month. The daily isoflavone intake was about 100 mg of daidzein (mostly as diadzin) and about 100 of mg of genistein (mostly as genistin). At two-week intervals, excretion of isoflavones in urine was studied, during which time the subjects consumed a constant basal diet for three to four days, ingested the full daily 36-oz portion of soymilk within 30 minutes each day for one to two days, and collected urine continuously. The urinary recovery of ingested diadzin plus daidzein (46.9 +/- 15.2%, mean +/- SD) and genistin plus genistein (14.6 +/- 9.2%) did not change with prolonged soya ingestion. The absorption half-lives (t1/2) for daidzein and genistein and the appearance t1/2 for equol (1 subject) were initially 1.5 +/- 0.4, 1.9 +/- 0.6, and 2.2 hours, respectively, and 2.5 +/- 1.1 (p = 0.06 compared with baseline) 1.4 +/- 0.9 (p = 0.03) compared with baseline), and 4.2 hours, respectively, during one month of soymilk ingestion. The excretion t1/2 for daidzein, genistein, and equol were initially 2.9 +/- 0.5, 3.8 +/- 0.7, and 5.2 hours, respectively, and 3.9 +/- 1.2 (p - 0.03), 5.5 +/- 1.6 (p = 0.02), and 9.7 hours, respectively, during one month of soymilk ingestion. These results indicate that chronic soya exposure did not induce significant changes in the metabolic pathways of isoflavones but altered the time courses of daidzein and genistein excretion. Thus chronic exposure to soya might prolong the tissue exposure to the presumed biologically active free and unconjugated forms of these isoflavones and thereby enhance their oncoprotective effects.

Absorption↗
PubMed1992

The mutagenic effects of low level sub-acute inhalation exposure to benzene in CD-1 mice.

Benzene is a widely used chemical and common environmental contaminant. It is carcinogenic in man and animals and is genotoxic in mice, rats, and occupationally exposed humans at doses above one part per million. In order to evaluate the genotoxic effects of prolonged exposures to very low concentrations of benzene, we exposed CD-1 mice to benzene by inhalation for 22 h per day, seven days per week for six weeks at 40, 100 and 1000 parts per billion (ppb). Additional groups were exposed to purified air or were housed in standard plastic cages. The effects of in vivo exposure to benzene were evaluated by using an autoradiographic assay to determine the frequency of mutants which represent mutations at the hypoxanthine-guanine phosphoribosyl transferase (hprt) locus in spleen lymphocytes. At the end of the six weeks exposure period lymphocytes were recovered from the spleens of the mice and cryopreserved prior to assay. Mutant cells were selected on the basis of their ability to incorporate tritiated thymidine in the presence of 6-thioguanine. The weighted mean variant (mutant) frequencies (Vf) of female mice (three per group) were 7.2 x 10(-6) at 0 ppb; 29.2 x 10(-6) at 40 ppb; 62.5 x 10(-6) at 100 ppb and 25.0 x 10(-6) at 1000 ppb. The Vf of unexposed mice housed in standard cages was 13.2 x 10(-6). In male mice the same pattern of response was observed, but the increases in Vf in response to benzene were not as great. In both sexes of mice, the increases at 40 and 100 ppb were significantly greater than at 0 ppb (P less than 0.05). The increase in Vf with exposure to 100 ppb and the decline at 1000 ppb parallel the results observed for chromosome damage in spleen lymphocytes from the same animals (Au et al., Mutation Res., 260 (1991) 219-224). These results indicate that sub-chronic exposure to benzene at levels below the current Occupational Safety and Health Administration Permitted Exposure Limit may induce gene mutations in lymphocytes in mice.

Administration, Inhalation↗
PubMed1991

Chromosome aberrations in lymphocytes of mice after sub-acute low-level inhalation exposure to benzene.

Male and female CD-1 mice were exposed to near ambient air concentrations of benzene by inhalation for 22 h per day, 7 days per week for 6 weeks. The concentrations were 0, 40, 100 and 1000 ppb. Significant increases in chromosome aberrations in spleen lymphocytes were observed in exposed compared with control mice except in the high-dose group (p less than 0.05 for female mice in 2 experiments and for male mice in 1 experiment; p less than 0.15 for male mice in the second experiment). A lack of increase in aberrations among mice of the high-dose group may be due to an induction of detoxifying enzymes as observed by us in a previous study (Au et al., 1988b). We also found that the female mice were more sensitive to the clastogenic activity of benzene than male mice under our experimental conditions. Our study serves to emphasize the need to conduct subchronic, low-dose in vivo genotoxicity studies using exposure conditions similar to those of humans, for evaluation of potential hazards. Our data suggest that the current occupational exposure concentrations for benzene (less than 1000 ppb) may still be hazardous to humans.

Administration, Inhalation↗
PubMed1991

Ba2+ release from soda glass modifies single maxi K+ channel activity in patch clamp experiments.

Glasses used to fabricate patch pipettes may release components which affect ion channels (Cota, G., and C.M. Armstrong. 1988. Biophys. J. 53:107-109; Furman, R.E., and J.C. Tanaka. 1988. Biophys. J. 53:287-292; Rojas, L., and C. Zuazaga. 1988. Neurosci. Lett. 88:39-44). The gating properties of maxi K+ channels from Necturus gallbladder epithelium depend on whether borosilicate glass (BG) or blue tip hematocrit glass (SG) is used to construct the patch pipettes. The data are consistent with solubilization from SG of a component which exerts voltage-dependent, cytosolic-side specific block, closely resembling "slow block" by Ba2+ ions. Ringer's solution preincubated with SG, but not with BG, blocked inside-out maxi K+ channels when used as bathing solution. Mass spectrometry revealed that Ba2+ is released by the glass from fast and slow-release compartments (SG contains 3% wt/wt BaO), and is the only ion found in the solution at concentrations consistent with the observed channel block. Additionally, SG released O2-, Na+, Ca2+, and Mg2+, all to micromolar concentrations. These elements do not interfere with maxi K+ channels but they could in principle alter the properties of other ion channels. Thus, screening for channel-modifying substances released by the glass may be necessary for the adequate interpretation of patch-clamp results.

Animals↗
PubMed1990

Prediction of toxicological interactions in a binary mixture by using pattern recognition techniques: proposed approach with a developed model.

A model has been suggested to predict the nature of toxicological interaction in binary mixtures. The approach uses the NLM-HSDB computerized data bases, the ATSDR toxicologic profiles, and other literature for categorizing the nature (synergistic, antagonistic or no interaction) and degree of interaction. Multivariate modeling (pattern recognition techniques) is the statistical approach utilized to separate groups of compounds into those that interact synergistically or antagonistically with a given toxic compound. Preliminary results indicate 1) that there are sufficient data in the literature on interactions to permit such modeling and 2) that in the case of carbon tetrachloride those compounds that interact synergistically with it are more similar to each other than those that interact antagonistically with respect to a number of structural and toxicologic parameters. This suggested approach of utilizing pattern recognition tools will be quite useful for regulatory agencies in predicting toxicological interactions occurring in complex chemical mixtures in the environment.

Carcinogenicity Tests↗
PubMed1989

Genetic effects of benzene and radiation in ICR and X/Gf mice.

X/Gf mice (a tumor-resistant strain) were compared with ICR mice (moderately tumor-sensitive) for their sensitivity to chromosomal damage caused by benzene, cyclophosphamide (CP), benzo(a)pyrene (BP) and radiation. There was no difference between strains in the level of micronucleus formation caused by BP, CP or radiation. Although X/Gf mice metabolized somewhat less of the dose of benzene per weight than ICR mice, and had somewhat higher levels of genetic damage, it is not known whether X/Gf mice would be measurably more resistant to benzene carcinogenicity. Short-term genotoxicity tests are used as indicators of initiation, therefore, equal sensitivity to a set of standard clastogens suggests that tumor resistance in X/Gf mice is a function of later stages of carcinogenesis.

Animals↗
PubMed1989

A combined testing protocol for assessing genotoxicity in individual animals: application to environmental toxicology.

A multiple end-point approach to assessing genetic toxicity (the combined testing protocol, CTP) was evaluated in male and female CD-1 mice exposed subacutely (3 and 6 weeks) to low levels of a custom-blended gas mixture (epichlorohydrin, benzene, chloroprene and xylene, at 50, 100, 100, and 100 ppb, respectively, as the low dose, with concentration levels 10-fold and 100-fold higher as the intermediate and high doses, or 0.1, 1 and 10 ppm of benzene). Urine mutagenicity was tested in the Salmonella/microsome assay, chromosome aberrations were examined in bone marrow and spleen lymphocytes, micronuclei were measured in bone marrow and peripheral erythrocytes, and cytochrome P450 and glutathione S-transferases were measured in the liver. Structural aberrations in alveolar macrophages and spermatocytes, and thioguanine resistance in spleen lymphocytes were examined for their suitability for incorporation into the overall protocol. Spleen lymphocytes were the most sensitive indicator cells, and showed a dose-related increase (P less than 0.01) in structural chromosome aberrations and in cytotoxicity after 6 weeks of exposure. Analysis of micronucleus formation and metaphase aberrations in the bone marrow, and micronuclei in peripheral erythrocytes showed an overall statistically non-significant but positive trend at the high dose. No mutagenicity was detected in pooled urine samples. Liver microsomal cytochrome P450 was not increased, but cytosolic glutathione S-transferases were significantly increased in a dose-related manner. Since the probability of detecting a genotoxic effect increases with the number of endpoints and tissues examined, this approach should be applicable to many situations without having to perform separate experiments for each tissue examined.(ABSTRACT TRUNCATED AT 250 WORDS)

Air Pollutants, Occupational↗
PubMed1989

Micronucleus formation by benzene, cyclophosphamide, benzo(a)pyrene, and benzidine in male, female, pregnant female, and fetal mice.

Male, female, pregnant female, and fetal ICR mice were compared for their acute sensitivity to four single doses of model carcinogens, as measured by micronucleus formation in polychromatic erythrocytes 24 h after treatment in adult bone marrow and fetal liver at days 17-19 of gestation. Cyclophosphamide caused a dose-responsive increase in micronuclei in all groups, without a consistent difference based on gender or pregnancy. At doses of 50 and 75 mg/kg given orally to the pregnant female, the fetuses were three to six times as sensitive as was the mother. Benzo(a)pyrene showed a similarly increased sensitivity of the fetus relative to the other groups, although it is a much weaker clastogen. Benzidine did not cause an increase in micronuclei in any group, although it was thought that the fetal liver might have been sensitive enough to detect it, relative to adult bone marrow. Benzene caused much less response in females than in males and almost no response in pregnant females and their fetuses, even though pregnant females metabolized at least half as much of the total dose as did the males (as measured by the presence of urinary metabolites of benzene). No single metabolite of benzene in the urine was consistently correlated with micronucleus formation in the bone marrow. Several factors must be interacting in different ways for different chemicals to influence their clastogenicity.

Administration, Oral↗
PubMed1989

Enhancement of benzene clastogenicity by praziquantel in mice.

Praziquantel (PQ) is a commonly used drug to treat patients with schistosomiasis. Previous studies using cells in vitro have shown that PQ can enhance the mutagenic activities of known mutagens. We have conducted a cytogenetic - urine metabolite study to determine the in vivo clastogenic and co-clastogenic potential of PQ with a ubiquitous environmental contaminant, benzene (BZ). 16 groups of adult male ICR mice (5 animals per group) were used. They were negative control, solvent controls (cremophore E1 3%, olive oil and combined), positive control (BZ 440 mg/kg b.w.) and 11 exposed groups. To test for clastogenicity of PQ, mice were treated orally with 100, 400, 800 and 1200 mg/kg b.w. PQ and sacrificed 30 h later for determination of micronuclei (MN) frequency in bone-marrow polychromatic erythrocytes (PCE). None of these PQ does induced an increase of MN frequency. On the other hand, BZ induced, as expected, a high frequency of MN (46.4 +/- 6.34/1000 PCE). The enhancement effect of PQ was tested in 7 groups of mice using 3 different protocols. Mice were treated with 440 mg/kg b.w. BZ and 1 h later with 0, 100, 200, 400, 800 and 1200 mg/kg b.w. PZ. In another group, 800 mg/kg PQ was administered at 3 h after BZ exposure. In the last group, PQ (800 mg/kg) was administered at 1 h prior to BZ exposure. Results from the first combined exposure group showed a significant PQ dose-dependent increase in the frequency of MN in PCE (p less than 0.05). The increase with the two high doses of praziquantel is significantly higher (p less than 0.05) than the MN frequencies in the benzene control and the expected value based on the additive effects of the two agents. Studies with other combined treatment groups showed that the induction of MN was highest when PQ was administered at 1 h before BZ exposure. Moreover, the presence of BZ metabolites (muconic acid, phenol, catechol and hydroquinone) in urine was studied in 6 of the combined treatment groups. This metabolite study revealed that PQ enhanced the metabolism of BZ towards the pathway to form muconaldehyde which is converted to muconic acid in urine. In conclusion, our study showed that PQ is not a clastogen but can enhance the clastogenic activity of BZ in vivo by shifting the metabolic pathways of BZ towards formation of muconaldehyde which may be responsible for the enhancement effect.

Animals↗
PubMed1988

Persistence of micronuclei in peripheral blood normochromatic erythrocytes of subchronically benzene-treated male mice.

The kinetics of micronucleus (MN) induction and decline in blood normochromatic erythrocytes (NCE) of mice subchronically exposed to benzene was investigated during and after exposure. Swiss (ICR) male mice (10/group) were given 0.0, 36.6, 73.2, and 146.4 mg/kg body weight benzene by gavage daily for 14 days, except for days 5 and 10. The frequency of MN increased significantly (P less than .001) during benzene treatment as a function of both concentration and time. Eleven days after exposure the levels of MN were higher than those observed at the end of exposure. After an initial rapid decline in the frequency of MN from 11 to 18 days postexposure, the decline became linear with time through 60 days postexposure. Using linear regression analysis, the MN level in each treatment group was predicted to reach control levels by approximately 85 days post-treatment. Dose-dependent suppression and recovery of erythropoiesis, estimated by polychromatic erythrocyte frequency, were observed in the 1st and 2nd weeks of exposure, respectively. Red blood cell (RBC) production was markedly increased in the first 3 weeks after benzene treatment. At later times the rate of production of the RBC returned to normal and may account for the linear decline observed in MN frequency. This research indicates that the frequency of MN is dose and duration dependent, while the decline in MN frequency after the end of benzene exposure can be related to changes in the kinetics of erythropoiesis.

Analysis of Variance↗
PubMed1988

Genotoxic effects of a sub-acute low-level inhalation exposure to a mixture of carcinogenic chemicals.

A study was conducted using a combined testing protocol (CTP), to determine whether short-term biological end-points, singly or in combination, are sufficiently sensitive to identify damage induced by exposure to ambient levels of industrial chemicals. A small-scale inhalation set-up which is both economical and easy to assemble was designed. Mice were exposed to 4 concentrations of a custom-blend mixture of benzene, chloroprene, epichlorohydrin and xylene in a ratio of 2:2:1:2, respectively. The concentrations for benzene, chloroprene and xylene were 0, 0.1, 1.0 and 10 ppm each. Concentrations for epichlorohydrin were half those for the other components. Groups of 22 males and 22 female mice were exposed to each concentration of the mixture for 3 and 6 weeks. Selected biological end-points including urine mutagenesis, bone marrow cell aberrations and micronuclei, spleen lymphocyte aberrations and liver enzyme induction were monitored. The spleen lymphocyte aberrations and liver enzyme induction were the most sensitive end-points. The lymphocytes showed a significant induction of chromosome aberrations from exposure for 3 weeks to all 3 concentrations of the mixtures. After 6 weeks of exposure, significant induction of aberrations was observed after exposure to low and medium concentrations but not to the high concentration. This lack of response at the high concentration after 6 weeks exposure, appeared to correlate with a significant induction of glutathione S-transferase in the liver. Since this enzyme is known to detoxify 3 of the 4 chemicals in our mixture, it may indicate a detoxification mechanism after enzyme induction. The present study indicates that the CTP is sufficiently sensitive to identify toxicological effects after exposure to ambient levels of a gas mixture.

Administration, Inhalation↗
PubMed1987

Induction of chromosome aberrations in lymphocytes of mice after subchronic exposure to benzene.

The induction of chromosome aberrations in lymphocytes of mice after subchronic exposure to benzene was investigated. 4 groups of 5 Swiss (ICR) male mice were given orally a solution of benzene every day for 14 days except days 5 and 10. The daily doses were 0, 36.6, 73.2 and 146.4 mg/kg. Mice were sacrificed on day 15, lymphocytes were obtained by perfusion of the spleen and the cells were cultured in RPMI 1640 medium. After 48 h of culture, cells were harvested for cytogenetic analysis. A significant dose-dependent increase in the frequency of cells with chromatid aberrations were found (p less than 0.001). A significant increase in polyploid cells were also observed (p less than or equal to 0.05). This study represents the first report on the induction of chromosome aberrations and polyploid cells in lymphocytes of mice after subchronic exposure to benzene. Such dual activity of benzene suggests that benzene may be responsible for more human health problems than currently estimated.

Animals↗
PubMed1985

Benzene myeloclastogenicity: a function of its metabolism.

Using the micronucleus test we have found no significant difference between germ-free and conventional (non-germ-free) male CD-1 mice gavaged twice with 440 or 880 mg benzene/kg. Hence, the higher myeloclastogenicity observed previously with the p.o. (4-6 times) than with the i.p. route of benzene administration was ruled out as being due to the involvement of gut flora in benzene biotransformation. Pretreatment of males with 3-methylcholanthrene or beta-naphthoflavone, inducers of P-448 monooxygenase, but not phenobarbital, an inducer of P-450, significantly enhanced the myeloclastogenic effect of a single oral dose of benzene (440 mg/kg). Single oral doses of phenol, catechol, or hydroquinone (250, 150, and 200 mg/kg, respectively) failed to reproduce the potent myeloclastogenic effect of benzene. In fact, only hydroquinone was mildly clastogenic. The relation between benzene's myeloclastogenicity and metabolism is discussed.

Animals↗
PubMed1985

trans,trans-Muconic acid, an open-chain urinary metabolite of benzene in mice. Quantification by high-pressure liquid chromatography.

A sensitive h.p.l.c. method is described which separated urinary metabolites from benzene-treated male CD-1 mice. Phenol, trans,trans-muconic acid and quinol in the 48 h urine accounted, respectively, for 12.8-22.8, 1.8-4.7 and 1.5-3.7% of the orally administered single dose of benzene (880, 440 and 220 mg/kg body wt.). Catechol occurred in trace amounts. Ascorbic acid was used to adjust urine pH and increase the extraction efficiency of metabolites, especially muconic acid. It allowed an accurate estimation of quinol by preventing its auto-oxidation. trans,trans-Muconic acid was identified and was unique to benzene as none was detected in urine of mice dosed orally with phenol, catechol or quinol (250, 150 and 200 mg/kg, respectively). The potential existence of a toxic benzene metabolite in the form of an aldehyde precursor of muconic acid in vivo is discussed.

Animals↗