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J T MacGregor

Publications and source records attributed to J T MacGregor.

At least 19 recordsLinked to original sources
PubMed1991

Micronuclei as an index of cytogenetic damage: past, present, and future.

The workshop was designed to present what is known about the production of micronuclei, what protocols are now accepted or proposed internationally, what new results have been obtained, and what new methods and protocols are likely to be forthcoming. This report is designed to convey the flavour of the workshop and to provide the essence of the new information. After the workshop an effort was made to determine what single protocol would satisfy the requirements set for the micronucleus test by as many regulatory agencies as possible. The result, reported here, includes the requirements of six regulatory authorities in Canada, the European Economic Community, the Organization for Economic Co-operation and Development, Japan, and the United States.

Animals↗
PubMed1990

Micronucleated erythrocytes as an index of cytogenetic damage in humans: demographic and dietary factors associated with micronucleated erythrocytes in splenectomized subjects.

Erythrocytes containing micronuclei serve as an indicator of genotoxic exposure in splenectomized individuals. Micronucleated erythrocytes, derived from cytogenetically damaged RBC precursors, are not selectively removed from peripheral blood in individuals who lack splenic function. The relationship between micronucleated cell frequencies and demographic, environmental, and dietary factors was examined in 44 subjects with previous splenectomy due to trauma. Their micronucleated cell counts fit a log-normal distribution, with geometric means of 3.3 micronucleus-containing cells/1000 reticulocytes and 2.7/1000 normochromatic erythrocytes. A multiple regression analysis showed that drinking five cups of coffee or tea/day (relative to none) was associated with an approximately 2-fold higher frequency of micronucleated cells. Weaker statistical associations were also noted with micronucleus frequency and the consumption of calcium supplements (associated with a higher frequency) and vitamins A, C, or E (lower frequency). An apparent trend of higher micronucleus counts with age was attenuated when other factors were considered in the regression. Cigarette smoking and decaffeinated coffee consumption were among the factors not associated with elevated micronucleated cell frequencies. Because the occurrence of micronuclei in reticulocytes reflects cytotoxic exposures within the past 3-8 days, it may be possible to test directly the relationship of these factors to micronucleus formation through intervention studies.

Chromosome Aberrations↗
PubMed1990

Effect of repeated benzene inhalation exposures on benzene metabolism, binding to hemoglobin, and induction of micronuclei.

Metabolism of benzene is thought to be necessary to produce the toxic effects, including carcinogenicity, associated with benzene exposure. To extrapolate from the results of rodent studies to potential health risks in man, one must know how benzene metabolism is affected by species, dose, dose rate, and repeated versus single exposures. The purpose of our studies was to determine the effect of repeated inhalation exposures on the metabolism of [14C]benzene by rodents. Benzene metabolism was assessed by characterizing and quantitating urinary metabolites, and by quantitating 14C bound to hemoglobin and micronuclei induction. F344/N rats and B6C3F1 mice were exposed, nose-only, to 600 ppm benzene or to air (control) for 6 hr/day, 5 days/week for 3 weeks. On the last day, both benzene-pretreated and control animals were exposed to 600 ppm, 14C-labeled benzene for 6 hr. Individual benzene metabolites in urine collected for 24 hr after the exposure were analyzed. There was a significant decrease in the respiratory rate of mice (but not rats) pretreated with benzene which resulted in lower levels of urinary [14C]benzene metabolites. The analyses indicated that the only effects of benzene pretreatment on the metabolite profile in rat or mouse urine were a slight shift from glucuronidation to sulfation in mice and a shift from sulfation to glucuronidation in rats. Benzene pretreatment also had no effect, in either species, on formation of [14C]benzene-derived hemoglobin adducts. Mice and rats had similar levels of hemoglobin adduct binding, despite the higher metabolism of benzene by mice. This indicates that hemoglobin adduct formation occurs with higher efficiency in rats. After 1 week of exposure to 600 ppm benzene, the frequency of micronucleated, polychromatic erythrocytes (PCEs) in mice was significantly increased. Exposure to the same level of benzene for an additional 2 weeks did not further increase the frequency of micronuclei in PCEs. These results indicate that repeated exposures to benzene, such as might be encountered by humans as a result of occupational or environmental exposures, are not likely to change or increase benzene metabolism.

Administration, Inhalation↗
PubMed1990

The in vivo erythrocyte micronucleus test: measurement at steady state increases assay efficiency and permits integration with toxicity studies.

The mouse erythrocyte micronucleus assay has been traditionally carried out using one or two exposures to the test agent, followed by sampling at two or three postexposure times to obtain a sample near the time of the transient peak of micronucleated polychromatic erythrocytes (PCEs). We have demonstrated that frequencies of micronucleated RNA-positive (PCEs) and RNA-negative erythrocytes in blood and bone marrow come to steady state during "continuous" exposure via diet or drinking water, or during repeated daily exposures to test agents by ip injection, gavage, or inhalation. Under these exposure conditions, frequencies of micronucleated cells in peripheral blood approached steady state within 2-3 days in RNA-positive erythrocytes and in 5-6 weeks in RNA-negative erythrocytes. With exposure durations of 6 days (monocrotaline or Crotalaria seeds in diet), 10 days (triethylenemelamine, mitomycin C, 7,12-dimethylbenzanthracene, or colchicine, ip daily), 90 days (triethylenemelamine or urethan in drinking water or 1,3-butadiene via inhalation), or 2 years (benezene by daily gavage), frequencies of micronucleated cells attained and remained at steady state for prolonged periods. At steady state, frequencies of micronucleated RNA-positive cells in bone marrow samples were similar to those in RNA-positive and RNA-negative cells in peripheral blood (e.g., triethylenemelamine in drinking water at 4 micrograms/ml resulted in frequencies of micronucleated RNA-negative erythrocytes in peripheral blood of 27/1000 after 45 days of exposure and 24/1000 after 90 days, with a frequency of 28/1000 in bone marrow RNA-positive erythrocytes after 90 days). The data suggest that the efficiency of the assay would be markedly improved by using a repeated dose schedule with a single sample taken at steady state, rather than scoring multiple samples at various times after a single dose. This approach allows the frequency of micronucleated cells to be measured in a sample of bone marrow or blood obtained at almost any stage of routine toxicity testing.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1990

Cytogenetic damage induced by folate deficiency in mice is enhanced by caffeine.

Folate deficiency in Swiss mice increased the incidence of micronuclei in peripheral blood erythrocytes, indicating increased chromosomal damage in nucleated erythrocyte precursors. Caffeine enhanced the incidence of micronuclei in blood and bone marrow by up to 5-fold in folate-deficient mice at doses that did not significantly alter the micronucleus frequency in the presence of adequate dietary folate. The lower dose of caffeine used in this study (75 mg/kg) approaches doses received by humans who consume large amounts of caffeinated beverages. Since folate deficiency and caffeine consumption are highly prevalent in the human population, the potential for a similar interaction in man should be evaluated.

Animals↗
PubMed1990

Evaluation of the mutagenicity of the anti-inflammatory drug salicylazosulfapyridine (SASP).

Salicylazosulfapyridine, commonly known as sulfasalazine or SASP, is an anti-inflammatory drug that is widely used in the treatment of diseases such as ulcerative colitis and Crohn's disease. Increases in sister chromatid exchanges (SCE) and micronuclei (MN) frequencies have been reported in lymphocytes of patients maintained on SASP therapy for up to 21 months. We have tested SASP for its ability to induce chromosome aberrations (ABS) and SCE in cultured Chinese hamster ovary (CHO) cells, ABS in mouse bone marrow cells, and MN in erythrocytes from both bone marrow and peripheral blood of mice. In vitro assays for ABS and SCE were negative. In vivo, SASP administered by single gavage at doses up to 1000 mg/kg did not increase ABS in bone marrow cells of male B6C3F1 mice; however, increases in MN were observed in the peripheral blood erythrocytes of male and female B6C3F1 mice administered 675, 1350 or 2700 mg/kg SASP by gavage for 90 days. Weak but significant dose-related increases in MN were also observed in the bone marrow cells of male B6C3F1 mice administered 500, 1000 and 2000 mg/kg SASP for 3 days. These positive findings in mice support the role of SASP in the induction of MN and SCE in humans, and suggest the need for further evaluation of possible adverse human health effects associated with SASP therapy.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1990

Dietary factors affecting spontaneous chromosomal damage in man.

The data summarized above demonstrate that dietary and nutritional factors can influence spontaneous rates of chromosomal damage in laboratory animals, and suggest strongly that certain of these dietary factors may exert a quantitatively significant influence on spontaneous chromosomal damage frequencies in human populations. Among a total of 77 splenectomized human subjects examined in two separate studies, consumption of caffeinated beverages, mild folate deficiency, and consumption of calcium supplements by older women were statistically associated with higher frequencies of micronucleated cells. Subjects who reported taking dietary supplements of vitamins C, E, or A had significantly lower values. Age was strongly associated with micronucleus frequency when other factors were not considered, but was only weakly associated when all factors were included in a multiple regression analysis. Followup studies in laboratory animals established that caffeine is a strong inducer of micronuclei in marginally folate-deficient mice, but not in folate-sufficient mice. Deficiencies of magnesium or zinc, two metals required for DNA synthesis and/or maintenance of chromatin structure, increase the rate of spontaneous chromosomal damage in laboratory animals. These and other data discussed above suggest that dietary deficiencies of nutrients required for nucleotide synthesis, such as folate, vitamin B12, and magnesium, may increase spontaneous chromosomal damage, and may strongly influence the genotoxic response to other dietary factors. It is critically important to systematically investigate the quantitative importance of the above factors in man, using 1) human cross-sectional epidemiology and supporting animal data to identify potentially significant risk factors and to elucidate the mechanisms of interaction among these factors, and 2) controlled intervention studies in man to determine the quantitative significance of these factors in human populations. We feel the use of splenectomized populations, in which chromosomal damage is easily monitored and in which the marker of damage is temporally responsive to removal of risk factors, will play an important role in the intervention phase of such studies.

Animals↗
PubMed1989

Assays of three carcinogen/non-carcinogen chemical pairs for in vivo induction of chromosome aberrations, sister chromatid exchanges and micronuclei.

Three pairs of structurally similar carcinogenic/non-carcinogenic chemicals were tested for in vivo genotoxic activity in B6C3F1 mice. The carcinogenic/non-carcinogenic pairs, respectively, were o-toluidine hydrochloride/o-anthranilic acid, 4-chloro-o-phenylenediamine/4-nitro-o-phenylenediamine, and 3-(chloromethyl)pyridine hydrochloride/2-(chloromethyl)pyridine hydrochloride. Bone marrow cells from mice given intraperitoneal injections of up to the maximum tolerated dose were evaluated for chromosomal aberration, sister chromatid exchange, and micronucleus induction, o-anthranilic acid and o-toluidine hydrochloride did not increase the frequency of chromosomal aberrations or micronuclei. o-Toluidine hydrochloride increased the frequency of sister chromatid exchanges in two successive trials, while o-anthranilic acid had a positive effect on sister chromatid exchanges in two of three trials. Both 2-(chloromethyl) and 3-(chloromethyl)pyridine hydrochloride were negative for all three endpoints. Assays for chromosomal aberrations and micronuclei each distinguished between 4-chloro-o-phenylenediamine and its non-carcinogenic companion, 4-nitro-o-phenylenediamine. In the aberration test, 4-chloro-o-phenylenediamine produced a few cells with very large numbers of aberrations rather than an even distribution of damage among cells.

Animals↗
PubMed1989

Non-clastogenicity in mouse bone marrow of fructose/lysine and other sugar/amino acid browning products with in vitro genotoxicity.

Heated sugar/amino acid reaction mixtures, known to contain products that are clastogenic and/or mutagenic to cells in vitro, were evaluated for clastogenic activity in mouse bone marrow using the erythrocyte micronucleus assay. Heated (i.e. browned) fructose/lysine reaction mixtures were also evaluated in the Salmonella his-reversion assay and the Chinese hamster ovary (CHO) cell chromosomal aberration assay to confirm and extend previous in vitro observations. Significant mutagenicity of fructose/lysine mixtures was observed in Salmonella typhimurium strains TA100, TA2637, TA98 and TA102, with greater activity in mixtures heated at pH 10 than at pH 7. S-9 decreased the activity in strains TA100, TA2637 and TA98, but increased the activity in strain TA102. Both pH 7 and pH 10 reaction mixtures of the fructose/lysine browning reaction were highly clastogenic in CHO cells. Heated mixtures of fructose and lysine, and of glucose or ribose with lysine, histidine, tryptophan or cysteine, did not increase the frequency of micronucleated erythrocytes in mice when administered by the oral route. This indicates the absence of chromosomal aberrations in erythrocyte precursor cells, and indicates that the genotoxic components of the browned mixtures are not absorbed and distributed to bone marrow cells in amounts sufficient to induce micronuclei when given orally. Because sugar/amino acid browning reactions occur commonly in heated foods, it is important to evaluate further the in vivo genotoxicity of browning products in cell populations other than bone marrow.

Animals↗
PubMed1989

The fetal blood erythrocyte micronucleus assay: classification of RNA-positive erythrocytes into two age populations by RNA aggregation state.

The use of a fluorescent stain containing Hoechst 33258 and pyronin Y in the fetal mouse transplacental micronucleus assay allows classification of erythrocytes into three subpopulations on the basis of RNA staining, and permits micronuclei to be scored in all three subpopulations. The youngest erythrocytes stain uniformly positive for RNA (UEs). In older erythrocytes RNA aggregates to give the cells a stippled appearance (SEs) and ultimately disappears, leaving cells which do not stain positively for RNA. Frequencies of micronucleated UEs and SEs were determined at 30 and 48 h following a single dose of methyl methanesulfonate, benzo[a]pyrene, lasiocarpine, monocrotaline or heliotrine. With each agent and dose tested, the frequency of micronuclei increased first in the younger UEs and later in SEs. The use of the Hoechst/pyronin staining procedure, which permits DNA to be distinguished from RNA, minimizes the potential for mis-scoring RNA artefacts as micronuclei and also increases the efficiency of the assay by permitting two age populations of erythrocytes to be scored in each sample.

Animals↗
PubMed1979

The micronucleus test: statistical design and analysis.

Alternative statistical procedures are discussed which may be employed to compare the incidences among treatment groups of micronucleated polychromatic and normochromatic erythrocytes and their ratios. Comparison of incidences of micronucleated polychromatic erythrocytes using a sequential sampling strategy based on the negative binomial distribution is shown to require fewer animals for the same sensitivity of test than a similar procedure based on the binomial distribution. The sequential test is superior, both in power and number of animals required, to an alternative 1-stage test based on the same distribution. The procedure described permits the investigator to optimize the number of animals in each test group and the number of cells counted per animal to detect a predetermined increase in the incidence of micronucleated cells over that observed in the control population within chosen limits of type I and type II error. An alternative sequential approach based on the binomial distribution is presented, which is applicable when the number of cells analyzed per animal is variable.

Animals↗
PubMed1978

Mutagenicity of plant flavonoids: structural requirements for mutagenic activity in Salmonella typhimurium.

40 compounds structurally related to the plant flavonol quercetin were tested for mutagenic activity in Salmonella typhimurium strain TA98. 10 flavonols, quercetin, myricetin, rhamnetin, galangin, kaempferol, tamarixetin, morin, 3'-O-methylquercetin, 7,4'-di-O-methylquercetin and 5,7-di-O-methyl-quercetin, exhibited unequivocal mutagenic activity. 4 compounds, quercetin, myricetin, rhamnetin and 5,7-di-O-methylquercetin, were active without metabolic activation, although metabolic activation markedly enhanced their activity. All 4 have free hydroxyl groups at the 3' and 4' positions of the B ring. The other active compounds required an in vitro rat-liver metabolizing system for significant activity. Structural features which appear essential for mutagenic activity in this strain are a basic flavanoid ring structure with (1) a free hydroxyl group at the 3 position, (2) a double bond at the 2, 3 position, (3) a keto group at the 4 position, and (4) a structure which permits the proton of the 3-hydroxyl group to tautomerise to a 3-keto compound. The data are consistent with the requirement for a B ring structure that permits oxidation to quininoid intermediates. Free hydroxyl groups in the B ring are not essential for activity if a rat-liver metabolic activating system is employed. Data from 12 compounds which differ only at the essential sites described above indicate that the structural requirements for mutagenicity in strain TA100 are the same as those for activity in strain TA98. Based on the above structural requirements, a metabolic pathway for flavonol activation to DNA-reactive species is proposed.

Animals↗
PubMed1978

Pesticide use in agriculture.

During the last three decades, the use of modern organic synthetic pesticides has increased about 40-fold. Total U.S. production, for domestic and expert use, in 1976 was about 1.4 million pounds. Crops receiving the most intensive application of various pesticides were cotton for insecticides, corn for herbicides, and fruits and vegetables for fungicides. Examination of use trends of pesticides indicates that the volume in pounds of herbicides used on crops is increasing, whereas the quantities of insecticides and fungicides remain stable. New chemical classes of compounds such as the synthetic pyrethroid insecticides are being introduced, but are not yet significant in terms of their share of the market. The increased usage of pesticides, together with knowledge of some of their adverse effects, has alerted the public to the need for regulation. To assist in the regulatory decision-making process, emphasis is being placed on benefit-cost analyses. Additional and improved biological inputs and methodologies are needed to provide accurate analyses.

Agriculture↗
PubMed1977

Biological effects of alkali-treated protein and lysinoalanine: an overview.

The renal alterations induced by alkali-treated protein and lysinoalanine are reviewed and their biological implications discussed. Alkali-treated proteins and lysinoalanine, an unusual amino acid formed in proteins during alkali treatment, have been shown to produce a renal alteration characterized by nuclear and cytoplasmic enlargement, with alterations in DNA synthesis, mitotsis and nucleoprotein. These changes are localized in the straight portion of the proximal renal tubule and have been observed in rats but not in several other species. The nephrotoxic effect of synthetic lysinoalanine has been consistently demonstrated, but the ability of alkali-treated protein to induce renal alterations is apparently modified by factors other than lysinoalanine content. Factors which may influence the development of the kidney lesions in animals fed alkali-treatment protein are discussed, including nutritional factors, the chemical form of lysinoalanine in the protein, species differences, and metabolic fate. Other clinical and experimental conditions that result in similar renal alterations are presented for comparison with the lysinoalanine induced lesion, and possible functional consequences are considred.

Alanine↗