Short-term assays to predict carcinogenicity. Assays for genetic changes in mammalian cells.
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Animals↗
Biomedical subjects
H Vainio
Publications and source records attributed to H Vainio.
Short-term assays to predict carcinogenicity. Assays for germ-cell mutations in mammals.
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Animals↗
Carcinogenicity of selected vinyl compounds, some aldehydes, haloethyl nitrosoureas and furocoumarins: an overview.
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Aldehydes↗
Occupational exposure to anticancer drug--potential and real hazards.
Many anticancer agents have been shown to be mutagenic, teratogenic and carcinogenic in experimental systems and second malignancies are known to be associated with several specific therapeutic treatments. Anticancer agents thus represent a class of occupational carcinogens, the handling of which should involve no unnecessary exposure. The available methodologies to detect possible exposures from ambient air and from biological samples are discussed, and the published data on results are reviewed. Analytical methods are available for the detection of most frequently used anticancer drugs from all groups, i.e., alkylating agents, mitotic inhibitors, antimetabolites and antibiotics. The ambient samples taken from sites of admixture of cytostatics have often shown detectable, but low concentrations of anticancer agents. Urine samples from patients under chemotherapy as well as from personnel handling the drugs occupationally in hospitals have been analyzed both chemically and for excreted mutagenicity. Both cisplatin and cyclophosphamide have been detected in the urine of patients; furthermore, cyclophosphamide was observed in the urine of nurses who formulate and deliver this drug. Urinary mutagenicity assays have given both positive and negative results in various groups of nursing and pharmacy personnel. Cytogenetic methods have, likewise, been applied for monitoring purposes. Most of the available data concerns chromosome aberrations (CA) or sister-chromatid exchanges (SCE) induced in peripheral blood lymphocytes of patients under chemotherapy. A few studies on groups occupationally exposed to anticancer drugs have given positive results, but also negative reports have appeared for these same cytogenetic parameters. No studies are as yet available on the possible carcinogenic effects of occupational handling of anticancer drugs. Two recent case-referent studies among hospital personnel have pointed to slightly increased risks of disorders in pregnancy outcome; one of the studies has shown an excess of spontaneous abortions and other malformations in children of females with a history of work with anticancer agents.
Abnormalities, Drug-Induced↗
Enhanced peroxisomal beta-oxidation of fatty acids and glutathione metabolism in rats exposed to phenoxyacetic acids.
Peroxisomal beta-oxidation of fatty acids and the activities of glutathione-metabolizing enzymes in rat liver were measured after administration of 2,4-dichlorophenoxyacetic acid (2,4-D), 4-chloro-2-methylphenoxyacetic acid (MCPA), clofibrate [ethyl], 2-(p-chlorophenoxy)-2-methylpropionate], glyphosate (N-phosphonomethyl glycine, a herbicide not structurally related to phenoxy acids) or saline for 14 days. beta-Oxidation increased by 6-fold in the group given clofibrate, 3-fold in the 2,4-D-treated group, and 2-fold in the MCPA-treated group over the level in the controls (saline-treated). Glyphosate did not increase beta-oxidation. No significant change in reduced glutathione content from that in controls was found in any of the treated groups. Glutathione reductase activity increased by about 40% after administration of either 2,4-D or MCPA, and glutathione peroxidase activity increased by 30% in animals given MCPA. A slight decrease in glutathione S-transferase activity was found in the group treated with clofibrate. The marked increases in peroxisomal beta-oxidation of fatty acids were accompanied by only minor changes in the activities of enzymes involved in glutathione-dependent inactivation of organic hydroperoxides and other oxygen-centred reactive agents.
2,4-Dichlorophenoxyacetic Acid↗
Data on the carcinogenicity of chemicals in the IARC Monographs programme.
Data were extracted from IARC Monographs volumes 1-38 on chemicals and exposures for which some data on carcinogenicity in humans, or sufficient evidence of carcinogenicity in experimental animals existed. In all, 288 chemicals, industrial processes and complex mixtures fulfilled these criteria. For 30 chemicals or mixtures of chemicals, and nine industrial processes, there was sufficient evidence of carcinogenicity in humans; and for 63 chemicals and mixtures of chemicals and for five industrial processes, there was evidence that these exposures were probably carcinogenic to humans. For 61 chemicals or groups of chemicals and six industrial processes or occupations, no evaluation of carcinogenicity to humans could be made. For 115 chemicals there is sufficient evidence of carcinogenicity to experimental animals, but no epidemiological data are available. Publications not earlier referred to on the carcinogenicity of these chemicals and exposures were found for approximately 70. A call is made for further information on these exposures with a view to updating the IARC Monographs.
Animals↗
Biochemical and morphological effects of long-term inhalation exposure of rats to ethylbenzene.
Male Wistar rats were exposed (six hours/day, five days/week) to 0, 50, 300 or 600 p.p.m. of ethylbenzene vapour in the air, and killed after 2, 5, 9 or 16 weeks of exposure. After 600 p.p.m., liver-microsomal protein but not cytochrome P-450 concn. was slightly increased; NADPH-cytochrome c reductase was increased maximally by 30% (1.3-fold), 7-ethoxycoumarin O-deethylase (1.8-fold) and UDPG-transferase (2.3-fold). The increase in liver-cytosolic D-glucuronolactone dehydrogenase paralleled the glucuronidation activity (less than or equal to 2-fold). In the kidneys, only 7-ethoxycoumarin O-deethylase (less than or equal to 3.5-fold) and UDPG-transferase (less than or equal to 1.8-fold) showed dose-related increases. Ethylbenzene exposure did not deplete hepatic glutathione (GSH); kidney GSH was slightly increased (less than or equal to 1.3-fold) according to dose. Urine excretion of thioethers was increased with dose, and at 600 p.p.m. was eight times control levels. At 600 p.p.m. there was no increase in serum alanine aminotransferase activity, and liver cells showed slight proliferation of smooth endoplasmic reticulum, slight degranulation and splitting of rough endoplasmic reticulum and enlarged mitochondria, but no necrosis.
Air Pollutants, Occupational↗
Current trends in the biological monitoring of exposure to carcinogens.
The biological monitoring of exposure to carcinogens and mutagens has gained a lot of research interest recently. Biological monitoring data, in conjunction with environmental monitoring data, will provide information for the needed exposure assessment for directing preventive actions. For the reviewed carcinogens aromatic amines, benzene, ethylene oxide, aflatoxins, N-nitroso compounds, polynuclear aromatic hydrocarbons, and alkylating anticancer drugs, there are methods which are already routine in practice, whereas some promising methods are still used only for research purposes.
Aflatoxins↗
Mutagenicity of selected organic solvents.
For certain organic solvents, such as benzene, vinyl chloride, styrene, technical grade trichloroethylene, and acrylonitrile, the available studies provide convincing evidence to demonstrate activity in short-term genetic assays. For a few solvents, such as phenol, vinyl toluene, ethanol, and tetrachloroethylene, the evidence is limited to a certain test system and/or test organism. For most of the solvents reviewed, studies are either lacking or they are so inadequate that no final evaluation on the mutagenic activity of the solvents can be made.
Animals↗
Metabolism and disposition of simultaneously inhaled m-xylene and ethylbenzene in the rat.
Rats were exposed for 5 days (6 hr/day) to one of four concentrations of a mixture of m-xylene (XYL) and ethylbenzene (EB) in the air (0 + 0, 75 + 25, 300 + 100, or 600 + 200 ppm). XYL and EB were found in the fat after the 5th day of exposure in the same molar ratio (3:1) as in the inspired air. The urine of the rats in each group was collected in two daily portions. The excretion of urinary thioethers increased linearly up to 12-fold. The urinary excretion of the major metabolites of XYL (methylhippuric acid, dimethylphenols, and methylbenzyl alcohol) and EB (hippuric, mandelic, phenylglyoxylic, and phenaceturic acids, and l-phenylethanol) were measured. XYL metabolites were excreted faster than EB metabolites in a manner pronounced with repetitive exposure and increasing dose. If the urinary elimination was expected to show the same molar ratio as in the inspired air (3:1), then total XYL metabolites were recovered in amounts lower than those of EB (about 2:1). The metabolite pattern of XYL showed no difference between mixed and pure equimolar exposures, whereas the pattern of EB metabolites was variable. The major problem met in quantitation of total output of EB was the estimation of metabolites (hippuric and phenaceturic acids) also formed endogenously. The apparent metabolic capacity for urinary solvent disposition vs the atmospheric concentration showed nonlinear correlation after a single mixed exposure. From the 2nd day onward, the metabolite excretion rates abruptly increased more than expected with the 600 + 200 ppm dose. This dose also increased microsomal drug-metabolizing activity in the liver. In conclusion, the mutual effects characteristic for mixed exposure to XYL + EB were, in a conspicuous manner, enhanced with the dose.
Animals↗
Sister chromatid exchanges and chromosome aberrations in rubber workers.
Sister chromatid exchanges and chromosomal aberrations were studied in peripheral blood lymphocytes of 55 rubber workers (from two different plants) and 35 controls mainly employed in office jobs. In both plants an increased frequency of SCEs (P less than 0.05 for plant A and P less than 0.01 for plant B) was detected in nonsmoking rubber workers as compared with nonsmoking referents. When the SCEs of worker groups belonging to the different job categories were compared with referents, the only groups showing statistically significant increases in SCEs were the smoking workers from the weighing and mixing departments of factory A and the nonsmoking weighers of factory B. A slight increase in the SCE frequencies was seen especially among smoking workers employed in the chemical mixing departments. The frequency of structural chromosome aberrations was not significantly increased in the occupational groups studied, the only exception being the small group of nonsmoking weighers in plant B. Among both the exposed workers and the controls, smokers had a higher mean SCE frequency than nonsmoking referents. This difference was significant between the exposed smokers and nonsmokers of plant A (P less than 0.01) and between smoking and nonsmoking controls for plant B (P less than 0.001). In addition, the chromosome aberration frequency of smoking controls of plant A was significantly higher (P less than 0.01 when gaps excluded and P less than 0.05 when gaps included) than that of nonsmoking referents. Also, smokers among controls for plant B had an increased frequency of aberrations in their cultured blood lymphocytes when compared with nonsmokers. This difference was significant (P less than 0.05) when gaps were excluded.
Chromosome Aberrations↗
Erythrocyte-dependent metabolic activation of styrene and induction of sister chromatid exchange in cultured human lymphocytes.
Human erythrocytes can oxidize styrene to styrene-7,8-oxide in the absence of the co-factors required for metabolic reactions catalysed by the microsomal cytochrome P-450 system. This probably explains the increased incidence of sister chromatid exchanges (SCEs) that was detected in whole blood lymphocyte cultures from 11 male donors after treatment in vitro (48 h) with styrene (2 mM). Styrene-7,8-oxide (0.15 mM) also induced SCEs in these cultures. Styrene (0.5-4.0 mM) increased the incidence of SCEs only slightly in cultures of isolated lymphocytes (2 X 10(4) erythrocytes/ml), but had a clear dose-dependent effect in whole blood cultures (2-4 X 10(8) erythrocytes/ml). When erythrocytes were added to purified cultures, SCE incidence increased after treatment with styrene (2 mM). Cyclophosphamide elevated the incidence of SCEs almost equally efficiently in whole blood and in isolated lymphocytes. It is suggested that styrene induces SCEs after transformation to styrene-7,8-oxide by oxyhemoglobin in erythrocytes, whereas cyclophosphamide is activated by the lymphocytes themselves.
Biotransformation↗
Embryotoxic effects of eight organic peroxides and hydrogen peroxide on three-day chicken embryos.
Nine peroxides were tested for embryotoxicity in 3-day chicken embryos using the air-chamber method. The potencies were expressed by the ED50 for the total embryotoxic effect of the chemicals, including deaths and malformations, up to Day 14 of the incubation. The range of the ED50's was from 0.13 to 2.7 mumoles per egg and the order of the potencies was as follows: cyclohexanoneperoxide greater than cumolhydroperoxide greater than ethylmethylketoneperoxide greater than dibenzoylperoxide greater than acetylacetoneperoxide greater than perbenzoic acid-tert-butylester greater than dicumylperoxide greater than dilauroylperoxide greater than hydrogen peroxide. All nine peroxides caused malformations at a moderate frequency. The maximum percentage of malformed embryos of the treated varied from the 16% of perbenzoic acid-tert-butylester to the 56% of dicumylperoxide. The high percentage caused by the latter could, however, result from slow diffusion of high lethal doses from the air chamber to the embryo.
Abnormalities, Drug-Induced↗
Detection of exposure to mutagenic compounds in low-tar and medium-tar cigarette smokers.
A volunteer study was carried out on groups smoking low-tar (5.4 mg/cig.) and medium-tar (16.3 mg/cig.) cigarettes and on non-smokers. The number of cigarettes smoked was recorded daily throughout a 51-day study period, and the effects of smoking were measured in the beginning and after 3-week terms of smoking medium-tar or low-tar cigarettes. The parameters measured were blood carboxyhemoglobin concentration, thioethers excreted into the urine, mutagenic activity in the urine, and the frequency of sister-chromatid exchanges in blood lymphocytes. For all four parameters, the differences between the smokers and the non-smokers were significant. However, within the study design no differences could be detected between low-tar or medium-tar cigarette smoking in the biological-monitoring tests used.
Adult↗
Effect of blood on styrene oxidation in perfused rat liver.
The oxidation of styrene to styrene oxide was studied in the isolated perfused rat liver in the presence and absence of blood at styrene concentrations of 2.5 and 50 mM. Erythrocytes contained in whole blood increased the levels of styrene glycol about 5 times after a short perfusion time with both concentrations. This increase was observed up to 1 h with 2.5 mM styrene. At both styrene concentrations styrene oxide was not detectable, either in the presence or absence of blood indicating that the liver was able completely to detoxify the styrene oxide produced by the mixed-function oxidases (MFO) and the oxyhemoglobin in the erythrocytes.
Animals↗
Activation of styrene to styrene oxide in hepatocytes and subcellular fractions of rat liver.
The oxidation of styrene to styrene oxide and the hydration of this metabolite to styrene glycol was investigated in hepatocytes, 9000 x g supernatant (S9) and the microsomal fraction from rat liver. Similar amounts of free styrene oxide were found in microsomes, hepatocytes and S9. However, on the basis of the formation of styrene glycol and the depletion of glutathione (GSH), it appeared that hepatocytes were the most active system in the metabolism of styrene, followed by S9 and microsomes.
Animals↗
Identification of chemicals carcinogenic to man.
Although both the epidemiologic and experimental studies have led to the identification of chemical carcinogens, the limitations in epidemiologic approaches and the need for primary prevention of cancer require a greater reliance on experimental studies. Long-term carcinogenicity studies in experimental animals have been instrumental in identifying chemicals with carcinogenic activity, and, in some cases, the experimental evidence has preceded the epidemiologic evidence (for 4-aminobiphenyl, aflatoxin B1, diethylstilbestrol, melphalan, mustard gas, and vinyl chloride). A better understanding of the multistage process of carcinogenesis and the findings from various short-term tests available more recently may provide a more solid basis for extrapolating experimental findings to man.
Animals↗
Target organs for carcinogenicity of chemicals and industrial exposures in humans: a review of results in the IARC monographs on the evaluation of the carcinogenic risk of chemicals to humans.
Epidemiological observations indicate that cancers affecting different organs and systems in humans have different causes. At the descriptive level, cancer incidence and mortality rates exhibit patterns of geographic and temporal variation which are distinct and separate for each cancer site and even, at a given site, for different histological types (for instance, increasing squamous cell carcinoma of the lung and decreasing stomach cancer in most developed countries in recent decades). The existence of these distinct patterns in itself indicates that different causes are at the origin of cancers at different sites. Hence, it is of scientific and practical importance not only to identify agents that are carcinogenic to humans but also to specify as definitely as possible the target organ(s) of their action. This is done in the present review of results in the International Agency for Research on Cancer Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans.
Bibliographies as Topic↗