Carcinogenicity of 1,3-butadiene.
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Animals↗
Biomedical subjects
M S Legator
Publications and source records attributed to M S Legator.
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↗
Evaluation of the genotoxic effects of a folk medicine, Petiveria alliacea (Anamu).
Crude extract from a plant known as Petiveria alliacea (Anamu) is used extensively as folk medicine in developing countries like Colombia, South America. Although the plant is known to contain toxic ingredients potential adverse health effects from its use have not been adequately evaluated. We investigated its genotoxic activities by conducting a sister chromatid exchange (SCE) assay using cells in vitro and in vivo. Lymphocytes from humans were treated at 24 h after initiation of culture for 6 h with alcohol extract from the folk medicine. Concentrations of 0, 10, 100, 250, 275, 500, 750, and 1000 micrograms/ml of the extract were used. Significant dose-dependent increase of SCE (3.7-7.4 SCE per cell) were observed (analysis of variances, p less than 0.01). Delay in cell proliferation but not inhibition of mitosis was also observed. In another experiment, mice were exposed once orally to 1x, 200x, 300x and 400x the human daily consumption dose of Anamu. The induction of sister chromatid exchanges in bone marrow cells were investigated. We observed a significant dose dependent increase of SCE compared with the saline control (2.15-4.53; p less than 0.01) and compared with the solvent control (3.04-4.53; p less than 0.01). Our data suggest, therefore, that the folk medicine contains mutagenic and potentially carcinogenic agents although the medicine is not a potent mutagen. Individuals who consume large amounts of this drug may be at risk for development of health problems. Further studies with cells from exposed individuals and from experimental animals should be conducted to provide a better evaluation of health risk from the use of this drug.
Animals↗
Incidence of sperm with two fluorescent bodies in men with impaired fertility.
OBJECTIVE: To determine the two fluorescent body (2FLB) frequency in males with impaired fertility. DESIGN: Males of couples were evaluated along with their female partners for reproductive function. They were classified as having the potential for fertility (control group) or as infertile (test group). This was based on the evaluation of both members of the couple. Semen parameters were determined and analyzed for differences among diagnostic groups. SETTING: The setting was clinical secondary care in both private and institutional practice. PATIENTS, PARTICIPANTS: The study population was composed of males of couples who were being evaluated for infertility. Classification as to reproductive potential and categories of abnormality was based on measurement of semen parameters and clinical judgment. INTERVENTIONS: Semen specimens were obtained and analyzed from 78 control and 93 test subjects. MAIN OUTCOME MEASURES: Semen parameters including volume, sperm count, sperm motility, percent morphologically abnormal sperm, and percent of quinacrine-stained sperm containing zero, one, or two FLBs were determined. RESULTS: The test group was found to have a 2FLB frequency that was significantly different from that of the control group. The data were then analyzed for significant differences in 2FLB frequencies in subpopulations. When subjects from all diagnostic subgroups that included varicocele were compared with the controls, the 2FLB frequency was significantly elevated (median percent of 2FLB was 1.2 versus 0.7). The 2FLB frequency in the remaining diagnostic groups was not elevated. CONCLUSIONS: This is the first report of an elevated 2FLB frequency associated with a biological abnormality. The cause of the elevated 2FLB frequency is not known. However, other anomalies that have been identified in varicocele patients have been associated with elevated intrascrotal temperatures. There are data available that associates elevated temperature with aneuploidy in mouse oocytes.
Humans↗
Factors contributing to chromosome damage in lymphocytes of cigarette smokers.
Cigarette smoking is generally believed to be responsible for a substantial number of human health problems. However, the causal relationship between smoking, the induction of biological effects and the extent of health problems among smokers have not been fully documented. Using the recently developed lymphocyte micronucleus (MN) assay, we have evaluated the chromosome aberration frequencies in 67 cigarette smokers and 59 matched non-smoking control subjects. We found that the mean MN frequency (per 100 cells) in the smokers was slightly higher than that found in the non-smokers (0.71 +/- 0.23 and 0.58 +/- 0.05 respectively; p less than 0.08). Factors which contribute to the expression of chromosome aberrations were also investigated. A significant age-dependent increase in MN frequencies was observed in both groups (p less than 0.05). Linear regression analysis showed that the age-dependent effects among smokers (r = 0.54; p less than 0.02) was further enhanced by cigarette consumption (r = 0.62; p less than 0.005). Consumption of low potency 'one-a-day' type multivitamins had no effect on MN frequencies in either sex of non-smokers and in the 1 male smoker who took multivitamins but vitamin intake consistently reduced the MN frequencies among female smokers. Using a challenge assay, fidelity of DNA repair was evaluated. Lymphocytes from both smokers and non-smokers were irradiated with single doses of 0 or 100 cGy of X-rays or with double doses of 100 cGy of X-rays each separated by 15 or 60 min (100/15 or 100/60). Chromosome translocation frequencies were consistently higher after irradiation in lymphocytes from smokers than in those from non-smokers. Statistically significant differences were detected when the cells were irradiated with the double doses of 100 cGy X-rays each separated by 60 min (p less than 0.05). These data suggest that lymphocytes from smokers made more mistakes in the repair of DNA damage than cells from non-smokers. Our studies provide new insights into the genotoxic effects of cigarette smoke and new information which may be useful for understanding the mechanisms for induction of health problems from smoking.
Aging↗
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↗
Dangerous and cancer-causing properties of products and chemicals in the oil refining and petrochemical industry--Part II: Carcinogenicity, mutagenicity, and developmental toxicity of 1,3-butadiene.
1,3-butadiene (BD) is present in synthetic rubber and motor fuels (gasoline). BD is shown to cause lymphocytic lymphomas, heart hemangiosarcomas, lung alveolar bronchiolar cancers, forestomach-squamous cell cancers, harderian gland neoplasms, preputial gland adenoma or carcinoma, liver-hepatocellular cancers, mammary gland acinar cell carcinomas, ovary-glanulosa cell carcinoma, brain cancers, pancreas adenoma and carcinoma, testis-Leydig cell tumors, thyroid follicular adenoma and carcinoma, and zymbal gland carcinoma in rodents and to date no exposure level has been established at which this chemical does not cause cancers. In humans BD causes increase in lymphomas, leukemias, and other cancers of hematopoietic systems and organs. BD is also a potent alkylating agent, directly toxic to developing embryos and damages progeny after parental exposure.
Animals↗
Distribution of X-ray-induced chromosome breakpoints in Down syndrome lymphocytes.
Down syndrome (DS) individuals are known to be predisposed to develop leukemia and their lymphocytes are highly sensitive to the induction of chromosome aberrations by X-rays. A study was conducted to identify the chromosome breakpoints and to evaluate whether site specificity for chromosome breakage and rearrangement may exist which may explain the predisposition phenomenon. DS lymphocytes at the G1 phase of the cell cycle were irradiated with 300, 450, and 600 rad of X-rays. Cells were harvested after 3 days in culture and 193 G-banded karyotypes were analyzed to identify the induced chromosome abnormalities. Out of 273 breakpoints identified, 122 were involved in the formation of stable chromosome rearrangements and 151 in the formation of unstable abnormalities. The Poisson analysis of these breakpoints demonstrated that 16 chromosome bands located in chromosomes 1, 3, 7, 12, 17, 19 and X were preferentially involved in breakage and rearrangement (P less than 0.05). These 16 bands are also found to be locations of "cancer breakpoints," oncogenes, or fragile sites. Many abnormal cells were observed to carry stable chromosome rearrangements only. Therefore, these cells are presumed to be compatible with survival and to be "initiated" in the transformation process. We propose that similar stable and site-specific chromosome rearrangements may exist in proliferating cells in DS individuals after exposure to clastogens and that this abnormality predisposes them to develop leukemia.
Cells, Cultured↗
Cytogenetic assays in genotoxic studies: somatic cell effects of benzene and germinal cell effects of dibromochloropropane.
We have reviewed the results of our cytogenetic studies to evaluate the usefulness of these assays in genotoxic studies. In one study, we observed unusual dose-response in lymphocyte chromosome aberration frequencies after exposure of mice to low doses of a chemical mixture (benzene, chloroprene, epichlorohydrin, and xylene). The frequency in the high dose group is lower than those of the medium and low dose groups. This reduction of genotoxicity is correlated with a significant induction of a detoxifying enzyme, glutathione-S-transferase. The data also suggest that extrapolation of effects from high to low doses for risk assessment may be erroneous. Using benzene as a model clastogen, we found that the clastogenic effect persists for a long time after termination of exposure in mice. This phenomenon is probably due to a gradual release of benzene from absorption of the chemical in body fat. In an inhalation study, we observed that chromosome aberrations are induced in mice after exposure to benzene at below the occupational exposure limit of 1 ppm. Since benzene is a ubiquitous environmental contaminant, it may interact with other environmental agents to modify its genotoxic effects. We found that a nongenotoxic drug, praziquantel, and a free radical scavenger, DMSO, can enhance or reduce respectively the clastogenic activities of benzene in mice. Both modifying agents acted by altering the metabolic pathways of benzene. In a study with rats, we showed that carcinogenic doses of benzene can induce chromosome aberrations in lymphocytes of rats long before the expression of cancer. With dibromochloropropane, we observed that this chemical can induce dominant lethality in rats.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
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↗
Biological monitoring--consider the alternatives.
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Carcinogens↗
Male-mediated behavioral abnormalities.
The assessment of behavioral development in the progeny of males exposed to known mutagenic chemicals is a potentially sensitive endpoint for detecting transmissible abnormalities. A genetic component is demonstrated as these behavioral abnormalities can also be passed on to the F2 generation. In this review, experimental studies exploring transmission of behavioral deficits from paternal exposure to drugs, chemicals and radiation are addressed. Additionally included is a brief synopsis of recent work performed in our laboratory investigating such abnormalities in offspring from male rats exposed to ionizing radiations. The implications of these behavioral endpoints to humans is also discussed.
Abnormalities, Drug-Induced↗
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↗
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↗
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↗
Genotoxic effects of fly ash in bacteria, mammalian cells and animals.
The increasing use of fossil fuels has raised concerns about possible deleterious health effects of the final combustion product, fly ash. Seven ash samples from coal sources obtained from Battelle Columbus Laboratories were evaluated in the Salmonella/mammalian microsome mutagenicity assay to determine their mutagenic potential. While dimethyl sulfoxide extracts of five samples showed no mutagenicity, sample 102 caused an increase in the number of revertants per plate over controls in TA100 and TA98 with activation by liver homogenate (2-fold and 2.4-fold, respectively), and without (2-fold and 6-fold). This ash was thus evaluated in whole animal studies. Animals treated by inhalation or oral gavage were assayed for the presence of mutagens in the urine, micronuclei in polychromatic erythrocytes, and chromosomal aberrations in metaphase bone marrow cells. Those animals treated by inhalation were also examined for local damage in the lung. The assay for mutagens in the urine was negative as shown by the Ames assay with TA100 and TA98 and there was no increase in micronuclei or in metaphase aberrations. Histological sections from the animals treated by inhalation did not show the presence of particles, macrophage infiltrations and generalized lung damage. We tested the same fly ash with an in vitro cell transformation assay with the cell line Balb/c 3T3 subclone A31-1-13. Although there was not an increase in Type III foci, there was a dose-dependent increase of Type II foci in the treated cells over the controls. In one assay, there was approximately a 14-fold increase in Type II foci in the highest dose (2 mg/ml) compared to the solvent control. One other ash sample induced cell transformation without being markedly cytotoxic, while a third sample was highly toxic but did not induce transformation.
Animals↗