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Biomedical subjects

R R Tice

Publications and source records attributed to R R Tice.

At least 73 records · Page 4Linked to original sources
PubMed1987

Comparative cytogenetic analysis of bone marrow damage induced in male B6C3F1 mice by multiple exposures to gaseous 1,3-butadiene.

Groups of male B6C3F1 mice (N = 12) were exposed to ambient air or to gaseous 1,3-butadiene (BD) at 6.25, 62.5, and 625 ppm for 10 exposure days (6 hr + T90/day). Exposure to BD induced in bone marrow: 1) a significant increase in the frequency of chromosomal aberrations (CA); 2) a significant elevation in the frequency of sister chromatid exchanges (SCE); 3) a significant lengthening of the average generation time (AGT); 4) a significant depression in the mitotic index (MI); and, as measured in the peripheral blood, 5) a significant increase in the proportion of circulating polychromatic erythrocytes (%PCE), and 6) a significant increase in the level of micronucleated PCE (MN-PCE) and micronucleated normochromatic erythrocytes (MN-NCE). The most sensitive indicator of genotoxic damage was the frequency of SCE (significant at 6.25 ppm), followed by MN-PCE levels (significant at 62.5 ppm), and then by CA and MN-NCE frequencies (significant at 625 ppm). The most sensitive measure of cytotoxic damage was AGT (significant at 62.5 ppm), followed by %PCE (significant at 625 ppm), and then by MI (significant by trend test only). Because each cytogenetic endpoint was evaluated in every animal, a correlation analysis was conducted to evaluate the degree of concordance among the various indicators of genotoxic and cytotoxic damage. The extent of concordance ranged from a very good correlation between the induction of MN-PCE and the induction of SCE (correlation coefficient r = 0.9562) to the lack of a significant correlation between the depression in the MI and any other endpoint (r less than 0.37).

Animals↗
PubMed1987

The effect of agent treatment time on the induction of sister-chromatid exchanges in mouse bone marrow cells in vivo.

The effect of time of agent administration, via intraperitoneal injection, on the yield of SCEs in bone marrow cells of male B6C3F1 mice was determined for cyclophosphamide (CP), 7,12-dimethylbenz[a]anthracene (DMBA) and mitomycin C (MMC). Animals were treated with several doses of each carcinogen/mutagen at 3 different treatment times: -1, +1 and +8 h in relation to the onset of BrdUrd administration. The results of these studies indicate that the optimal treatment time for inducing a maximal SCE response is agent-specific. For CP, the slope of the SCE response was greatest at the +8 h treatment time while the maximal response for DMBA occurred at the -1 h treatment time. For MMC, the slope of the SCE response was independent of treatment time and of the method of bromodeoxyuridine administration (intravenous infusion vs. tablet implantation) but dependent on the laboratory conducting the study (Brookhaven National Laboratory vs. Oak Ridge Associated Universities). Based on the results of these studies, the +1 h acute treatment time is considered optimal for the in vivo cytogenetic evaluation of suspect chemicals for genotoxic activity when bone marrow is used as the target cell population.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1987

Results of in vitro and in vivo genetic toxicity tests on methyl isocyanate.

Methyl isocyanate (MIC) was tested for genetic toxicity in a variety of in vitro and in vivo assays. Negative results were obtained in the Salmonella/mammalian microsome assay using five bacterial strains in a preincubation protocol. The Drosophila sex-linked recessive lethal test also gave negative results in studies that involved three routes of administration: inhalation, feeding, and injection. Positive results were obtained for three endpoints in cultured mammalian cells. Reproducible, dose-related increases in trifluorothymidine-resistant clones were induced in L5178Y mouse lymphoma cells, and the frequencies of both SCE and chromosomal aberrations increased in Chinese hamster ovary cells. These effects were independent of exogenous metabolism. In mice exposed to methyl isocyanate by inhalation, cytogenetic analyses were carried out on bone marrow, blood, and lung cells. A single, 2-hr exposure to concentrations of 0, 3, 10, and 30 ppm MIC produced no evidence of chromosomal effects in the bone marrow, although significant cell cycle delay was observed. In four experiments involving exposures on 4 consecutive days to 0, 1, 3, or 6 ppm, delays in bone marrow cell cycle were again observed. Increases in SCE and chromosomal aberrations were observed in bone marrow cells, and a dose-related increase in SCE occurred in lung cells but not in peripheral blood lymphocytes. A significant increase in micronucleated polychromatic erythrocytes in the peripheral blood was observed in male mice in one experiment. From these results, it appears that methyl isocyanate has the capacity to affect chromosome structure but not to induce gene mutations.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1985

Aneuploidy and health risk assessment: current status and future directions.

The U.S. Environmental Protection Agency (EPA) recently sponsored a workshop to discuss the contribution of aneuploidy to human disease and disability, the development of tests for detecting chemicals that induce aneuploidy and the relevance of these tests to human risk, and the current understanding of mechanisms by which aneuploidy arises. This summary is based on the presentations given at the workshop. It is hoped that this summary will stimulate thinking in this vitally important area of risk assessment and contribute to the establishment of priorities for basic research, development of new test methods, and validation of existing test approaches. Such research is needed to enhance the scientific basis of risk assessment for aneuploidy-producing chemicals.

Aneuploidy↗
PubMed1984

Statistical design, analysis, and inference issues in studies using sister chromatid exchange.

While underlying biological mechanisms responsible for sister chromatid exchange (SCE) formation are not fully understood, scientists worldwide are increasingly using SCEs in the evaluation of excess risk from exposure to chemical and biological agents. SCEs are being used as endpoint measures of cell damage in many types of experimental and nonexperimental investigations. The former includes both simple and complex randomized experiments using both animals exposed in vivo and cells exposed in vitro as experimental units. The latter includes the important, yet potentially misleading, human case-control studies in which a group of humans who are or have been exposed to some agent are compared with a selected nonexposed group on SCE frequency. As more is learned about those factors which result in SCE variations, the assay techniques and study protocols can be adjusted to enhance study sensitivity and to minimize potential bias. Although research concerning sample sizes and statistical analysis methods has been conducted, more is needed. Search for other sources of intersubject variations in SCEs should continue so that such sources can be controlled in future studies, particularly the human exposure types. A number of experimental designs are presented and contrasted with their nonexperimental counterparts. Statistical methods are summarized and sample size options are given for the human and animal exposure studies and for the studies in which cells are exposed in vitro.

Analysis of Variance↗
PubMed1982

Induction of sister chromatic exchanges and inhibition of cellular proliferation in vitro. I. Caffeine.

Cytogenetic assay systems based on the detection of sister chromatid exchanges (SCE) are widely advocated as a sensitive screening method for assessing genotoxic potential. While many agents have been examined for their ability to induce SCE's, complete dose-response information has often been lacking. We have reexamined the ability of one such compound-caffeine-to induce SCEs and also to inhibit cellular proliferation in human peripheral lymphocytes in vitro. An acute exposure to caffeine prior to the DNA synthetic period did not affect either SCE frequency or the rate of cellular proliferation. Chronic exposure to caffeine throughout the culture period lead to both a dose-dependent increase in SCEs (SCEd or doubling dose = 2.4 mM; SCE10 or the dose capable of inducing 10 SCE = 1.4 mM) and a dose-dependent inhibition of cellular proliferation (IC50 or the 50% inhibition concentration = 2.6 mM). The relative proportion of first generation metaphase cels, an assessment of proliferative inhibition, increased linearly with increasing caffeine concentrations. However, SCE frequency increased nonlinearly over the same range of caffeine concentrations. Examination of the ratio of nonsymmetrical to symmetrical SCEs in third generation metaphase cells indicated that caffeine induced SCEs in equal frequency in each of three successive generations. The dependency of SCE induction and cellular proliferative inhibition on caffeine's presence during the DNa synthetic period suggests that caffeine may act as an antimetabolite in normal human cells. The significance of these results in regard to both caffeine's genotoxic potential and to the reliability of the SCE assay system are discussed.

Caffeine↗
PubMed1981

Diethylstilbestrol-diphosphate induces chromosomal aberrations but not sister chromatid exchanges in murine bone marrow cells in vivo.

Diethylstilbestrol diphosphate (DES-dp) clastogenesis was examined in the bone marrow of C57Bl/6 male and female mice. Significant and sex-related dose effects were observed for the induction of chromatid-type chromosomal aberrations and for the inhibition of cellular proliferation. Females were more sensitive to the effects of DES-dp than males when assessed for either induced chromosomal aberrations or proliferative inhibition. Contrary to other published results, we did not observe either an increase in sister chromatid exchanges or an increased incidence of aneuploidy. Ovariectomy reduced the ability of DES-dp to inhibit cellular proliferation and decreased the high degree of variability between animals at high doses of DES-dp. The results of our studies show that DES is a clastogenic agent in vivo which may relate to its carcinogenicity.

Aneuploidy↗
PubMed1980

Cytogenetic effects of inhaled benzene in murine bone marrow: induction of sister chromatid exchanges, chromosomal aberrations, and cellular proliferation inhibition in DBA/2 mice.

Exposure of adult male and female DBA/2 mice to 3100 ppm benzene for 4 hr significantly increased the frequency of sister chromatid exchanges in bone marrow cells of both sexes, inhibited marrow cellular proliferation (but only in male mice), and did not significantly increase the frequency of chromosomal aberrations in either sex. Phenobarbital pretreatment synergistically interacted with benzene exposure to further increase sister chromatid exchanges in female mice, induce greater inhibition of cellular proliferation in male mice, and induce a significant level of chromatid-type chromosomal aberrations in both sexes. During the second day after exposure to benzene there was increased inhibition of cellular proliferation in male mice and both new DNA damage and persistance of old DNA damage in female mice. The differences in both the type and magnitude of the response of bone marrow cellular populations, as determined by different cytogenetic end points in male and female DBA/2 mice exposed to benzene or to phenobarbital and benzene, suggest not only that a metabolite of benzene is responsible for the observed effects, but that different metabolites may be involved in different end points.

Animals↗
PubMed1979

Cytokinetic analysis of the impaired proliferative response of peripheral lymphocytes from aged humans to phytohemagglutinin.

The effect of donor age on the rate of cell entry into the proliferating pool and subsequent cell cycle duration for peripheral lymphocytes stimulated by phytohemagglutinin (PHA) were examined by using the bromodeoxyuridine incorporation-differential staining technique. Distribution curves for the appearance of metaphase cells in successive generations as a function of culture time were obtained and analyzed both graphically and by a computer simulation model. Peripheral lymphocytes from aged individuals (approximately 75 yr) were stimulated by PHA at approximately one-half of the rate of peripheral lymphocytes from young individuals (approximately 21 yr). Subsequent cell-cycle durations were estimated to range from 10.0 to 25.0 h for aged individual lymphocyte cultures and 10.6-15.6 h for young individual lymphocyte cultures. The possible significance of these findings to aging in general is discussed.

Adult↗
PubMed1979

The effect of aging on sister chromatid exchange.

The advent of the bromodeoxyuridine(BrdU)-differential staining techniques has greatly facilitated the detection of sister chromatid exchanges (SCE). These SCE have been demonstrated to be an accurate reflection of DNA damage both in vitro in cultured cells and in vivo in mouse and rate bone marrow and spleen cells. In this review, we examine the effect of cellular aging on both baseline and mutagen-induced SCE levels. In all systems examined, aging did not appear to significantly affect the baseline levels of SCE. However, in human fibroblast cultures we have found a significant decrease in the levels of mutagen-induced SCE as a function of both in vitro passage level (in vitro aging) and the age of the cell culture donor (in vivo aging). In addition we have found a similar decrease in mutagen-induced SCE levels in both mouse and rat bone marrow cells and mouse spleen cells where examinations were performed entirely in vivo. Diminished mutagen-induced SCE levels were obtained with a wide variety of agents including mitomycin-C, cyclophosphamide, adriamycin, ethyl methanesulfonate and N-acetyl-2-acetoxyamino-fluorene. These decreased SCE levels were accompanied by increased frequencies of chromosomal aberrations in the older cell populations. If SCE represents a form of DNA repair as has been suggested by several investigators, our finding would indicate impaired DNA repair occurring in old cells.

Aging↗
PubMed1979

Cellular replication and aging.

Controversy exists concerning the effect of aging on replicating cell systems. This review summarizes a number of studies which indicate that both in vivo and in vitro, cell replication is significantly altered during aging. In vitro, studies of both human lymphocytes and fibroblasts indicated that a number of replication kinetic parameters are influenced by the age of the cell donor. In vivo, the application of the bromodeoxyuridine-(BrdU)-differential chromatid staining techniques to the analysis of cellular replication kinetics has permitted us to demonstrate that cellular replication is also significantly diminished with aging in mouse and rat cell populations. Therefore, both in vivo and in vitro in human as well as rodent cell populations, the rates of cellular replication are significantly decreased with cellular aging.

Aging↗
PubMed1978

Cytogenetic effects of inhaled ozone.

We have repeated as closely as possible the experiments of Zelac et al., who observed significantly elevated levels of chromosome aberrations in short-term cultures of peripheral lymphocytes from Chinese hamsters that had inhaled ozone. Unlike Zelac et al., we observed no increase in chromosome-type aberration levels, though a small increase in chromatid-aberration levels similar to that reported for exposed human subjects by Merz et al. was seen. No increase in the levels of any chromosomal aberration type was seen in parallel direct bone-marrow preparations. Sister-chromatid exchange (SCE) levels and cell-replication rates, which were determined in the Chinese hamster peripheral lymphocyte cultures and also in bone-marrow samples from similarly treated mice, failed to show any ozone-induced changes.

Animals↗