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At least 19 recordsLinked to original sources
PubMed1979

Measurement of DNA-excision repair in suspensions of freshly isolated rat hepatocytes after exposure to some carcinogenic compounds: its possible use in carcinogenicity screening.

When suspensions of freshly isolated rat hepatocytes were exposed to a number of carcinogenic compounds, it was possible to measure an increased UDS by a rapid procedure via liquid-scintillation counting. For a number of carcinogenic compounds and some of their non-carcinogenic structural analogues a good correlation between the carcinogenic property and the ability to induce UDS was demonstrable. Out of 12 carcinogenic compounds, belonging to several different chemical classes, 10 gave rise to an increased UDS, whereas only 2 compounds, the polycyclic aromatic hydrocarbons benzo[alpha]pyrene and benz[alpha]anthracene, did not. All 4 noncarcinogenic compounds tested were negative. Possibly this method can be of value as a routine screening test, in combination with other short-term test systems, thus improving the predictive value of screening in vitro with respect to carcinogenicity.

Animals↗
PubMedDate not supplied

Testing of chemicals for carcinogenic activities and some problems related to the assessment of carcinogenic risks to men.

It is recognized that many human cancers are influenced by environmental factors. Therefore, testing of chemicals for carcinogenic activities represents an important part of comprehensive toxicological examinations. Procedures to be employed in bioassays for carcinogenicity will be discussed. Short-term tests should be utilized as screening methods to select suspected chemicals which should or must be further tested in long-term animal experiments. Animal tests can predict carcinogenicity in man. Any substance which is shown conclusively to cause tumors in animals should be considered carcinogenic and therefore a potential hazard for man, but tests on experimental animals cannot provide irrefutable proof of the safety or carcinogenicity of a substance for the human species. Therefore, some of the problems related to the assessment of carcinogenic risks by chemicals will be discussed.

Animals↗
PubMed1977

Selection of an in vitro carcinogenicity test for derivatives of the carcinogen hexamethylphosphoramide.

The demonstration that hexamethylphosphoramide (HMPA) possesses potent carcinogenic properties has raised doubts about the safety of exposure to other phosphoric amides. In order to define a suitable short-term test with which to evaluate such analogues, the response of the Salmonella typhimurium mutation assay of Ames and cell transformation assay of Styles to HMPA and 3 selected analogues has been studied. These analogues were the related leukaemogen phosphoramide, the putative non-carcinogen, phosphoric trianilide and N.N'N''-trimethylphosphorothioic triamide, a compound of unknown and hitherto unpredictable properties. While both tests found the trianilide negative, the Ames test failed to detect phosphoramide as positive and gave an erratic and predominantly negative response to HMPA. In contrast, the transformation assay found both phosphoramide and HMPA positive. This test response profile indicates that the transformation assay is the preferred test with which to evaluate analogues of HMPA for potential carcinogenicity. Some structural requirements for potential carcinogenicity within this class of compounds are tentatively deduced.

Anilides↗
PubMed1975

Carcinogen-induced DNA repair in nucleotide-permeable Escherichia coli cells. Induction of DNA repair by the carcinogens methyl and ethyl nitrosourea and methyl methanesulfonate.

Ether-permeabilized (nucleotide-permeable) cells of Escherichia coli show excision repair of their DNA after having been exposed to the carcinogens N-methyl-N-nitrosourea (MeNOUr), N-ethyl-N-nitrosourea (EtNOUr) and methyl methanesulfonate (MeSO2OMe) which are known to bind covalently to DNA. Defect mutations in genes uvrA, uvrB, uvrC, recA, recB, recC and rep did not inhibit this excision repair. Enzymic activities involved in this repair were identified by measuring size reduction of DNA, DNA degradation to acid-soluble nucleotides and repair polymerization. 1. In permeabilized cells methyl and ethyl nitrosourea induced endonucleolytic cleavage of endogenous DNA, as determined by size reduction of denatured DNA in neutral and alkaline sucrose gradients. An enzymic activity from E. coli K-12 cell extracts was purified (greater than 2000-fold) and was found to cleave preferentially methyl-nitrosourea-treated DNA and to convert the methylated supercoiled DNA duplex (RFI) of phage phiX 174 into the nicked circular form. 2. Degradation of alkylated cellular DNA to acid solubility was diminished in a mutant lacking the 5' leads to 3' exonucleolytic activity of DNA polymerase I but was not affected in a mutant which lacked the DNA polymerizing but retained the 5' leads 3' exonucleolytic activity of DNA polymerase I. 3. An easily measurable effect is carcinogen-induced repair polymerization, making it suitable for detection of covalent binding of carcinogens and potentially carcinogenic compounds.

Carcinogens↗
PubMed1979

Carcinogenic effect of N-nitroso(2-hydroxypropyl)(2-oxopropyl)amine, a postulated proximate pancreatic carcinogen in Syrian hamsters.

N-Nitroso(2-hydroxypropyl)(2-oxopropyl)amine (HPOP) proved to be a potent carcinogen in Syrian golden hamsters. The compound is an in vivo metabolite of N-nitrosobis(2-hydroxypropyl)amine, N-nitrosobis(2-oxopropyl)amine (BOP), and N-nitroso-2,6-dimethylmorpholine and a postulated proximate pancreatic carcinogen in hamsters. As with BOP, HPOP induced a higher incidence of pancreatic ductular adenocarcinomas than did N-nitrosobis(2-hydroxypropyl)amine and N-nitroso-2,6-dimethylmorpholine, and these neoplasms showed a great tendency for invasion and metastasis. Also, HPOP induced tumors of the forestomach, liver, gallbladder, kidneys, and vagina (as did BOP). However, HPOP [unlike BOP, but like N-nitrosobis(2-hydroxypropyl)amine and N-nitroso-2,6-dimethylmorpholine] led to tumor development in the nasal cavity, larynx, trachea, intestine, Harderian gland, lips, and flank organ. The possible mechanisms of HPOP carcinogenicity are discussed.

Animals↗
PubMed1979

The early effects of chemical carcinogens on adult rat hepatocytes in primary culture: I. Quantitative changes in intracellular enzyme activities following a single dose of carcinogen.

The effects of exposure of adult rat hepatocytes to chemical carcinogens have been studied using a short-term maintenance culture system. Scanning microdensitometry was used to quantitate the observed changes in enzyme activity. The dose-response curves showed a biphasic response for all 4 enzymes studied (glucose-6-phosphate dehydrogenase, succinate dehydrogenase, NADPH oxidase and gamma-glutamyl transpeptidase) there being decreased enzyme activities at the higher dose levels used, possibly indicating cytotoxicity. The enhancement of enzyme activity at low dose levels was due to generalised increases occurring in every cell, rather than to selection of a cell species particularly high in enzyme activity. A culture period of 24 h was necessary for the complete adaptation of the cells to the culture environment as evidenced by the response of intracellular glucose-6-phosphate dehydrogenase activity to carcinogen treatment. These findings are discussed in relation to previously reported in vivo studies.

Animals↗
PubMed1976

Carcinogen-induced DNA repair in primary rat liver cell cultures; a possible screen for chemical carcinogens.

Primary rat liver cell cultures were exposed to a direct acting carcinogen, methyl methanesulfonate, and procarcinogens requiring metabolic activation, aflatoxin B1 and B2. DNA damage by these agents was evidenced by the induction of DNA repair, measured as unscheduled DNA synthesis. The sensitivity of these cultures to the potent porcarcinogen aflatoxin B1 indicates that this system may be adapted for screening suspected chemical procarcinogens, and for investigating the relationship between metabolic activation of procarcinogens, DNA damage, DNA repair, and carcinogenicity.

Aflatoxins↗
PubMed1979

Relationship between cytotoxicity and induction of sister-chromatid exchanges in mouse foetal cells exposed to several doses of carcinogenic and non-carcinogenic chemicals.

The increase in sister-chromatid exchanges induced by 5 chemicals, with different DNA damaging and carcinogenic activities, was studied in short-term foetal-mouse cultures. A significant increase in SCE was induced by N-methyl-N'-nitro-N-nitrosoguanidine, N-diazoacetylglycine-amide, azaserine and methotrexate. k-Strophantin, on the contrary, was totally inactive. On a molar basis, MNNG was the most active chemical followed by MTX, AZS and DGA, in that order. At equitoxic concentrations (D37), the order of SCE-inducing abilities was MNNG, DGA, AZS and MTX. Compared with previous data, at equitoxic concentrations, the most DNA-damaging agents were also the most effective in inducing SCE. The SCE increase seems to correlate not with unspecific cytotoxicity but more with DNA damage or other damage at the genome level. MTX, a non-mutagen, which induced SCE only at toxic levels, could be considered a false positive because this positivity may reflect an enhancement of incorporation of 5-BrdUrd into DNA. The positive results obtained with AZS suggest a sufficient sensitivity of the method for detecting relatively weak carcinogens.

Animals↗
PubMed1978

Carcinogen-induced DNA repair in nucleotide-permeable Escherichia coli cells. Analysis of DNA repair induced by carcinogenic K-region epoxides and 1,2,3,4-diepoxybutane.

Ether-permeabilized (nucleotide-permeable) Escherichia coli cells exhibited DNA excision repair when exposed to the following carcinogenic K-region epoxides: 7-methyl- and 7,12-dimethyl-benz[a]anthracene-5,6-oxide, chrysene-5,6-oxide and benzo[a]pyrene-4,5-oxide. This DNA excision repair was missing in uvr A and uvr B mutant cells. The K-region epoxide phenanthrene-9,10-oxide was ineffective in all E. coli strains tested. In contrast to the K-region epoxides which where found active only in wild type cells, 1,2,3,4-diepoxybutane and the 6,7-epoxides of the tumor promoter TPA (12-O-tetradecanoyl-phorbol-13-acetate) elicited DNA repair in uvrA, uvrB mutant cells as well. Enzymic activities catalyzing particular repair steps were identified by determining a) repair polymerization and b) size reduction of denatured DNA. A) An easily quantifiable effect in E. coli wild type cells was epoxide-induced repair polymerization. None of the K-region epoxides tested stimulated DNA repair synthesis in uvrA, uvrB mutant cells, indicating that the uvrA-, uvrB-controlled UV-endonuclease initiated excision repair by cleaving epoxide-damaged DNA. 1,2,3,4-Diepoxybutane and the TPA-6,7-oxides induced DNA repair polymerization in uvr-deficient cells, although to a lesser extent than in wild type cells, suggesting the involvement of uvr-independent incision steps. None of the epoxides induced repair polymerization in a mutant (polA107) lacking the 5'--3'exonucleolytic activity of DNA polymerase I (exonuclease VI). The absence of any repair polymerization in the polA107 mutant indicates that the exonuclease VI plays a central role in removing epoxide-damaged nucleotides. As evidenced by greatly reduced levels of repair polymerization measured in polA1 cells, DNA polymerase I was the main polymerizing enzyme. b) As a consequence of treatment with 7-methyl-benz[a]anthracene-5,6-oxide, DNA from wild type cells, contrary to uvrA mutant cells, showed size reduction after denaturation and sedimentation in alkaline sucrose gradients. This is explained by repair-specific endonucleolytic cleavage of damaged DNA. The incision required the presence of ATP indicating that functional UV-endonuclease needs ATP as a cofactor.

Carcinogens↗
PubMed1976

Cell cycle-related hormone carcinogen interaction during chemical carcinogen induction of nodule-like mammary lesions in organ culture.

The immature mammary glands of BALB/c female mice were treated with 7,12-dimethylbenz[a]anthracene (DMBA), 2 micrograms/ml, or 3-methylcholanthrene (10 micrograms/ml) for a 24-hr period at different times during the inital six days of lobuloalveolar growth in hormone-supplemented organ culture. Nodule-like alveolar lesions (NLAL) were detectable in 80% of the glands treated with DMBA (40% in 3-methylcholanthrene-treated glands) in the presence of insulin + prolactin + aldosterone + cortisol in the medium. No NLAL were present in dimethyl sulfoxide-treated control glands cultivated with the same hormones. The hormone combination insulin + prolactin + cortisol was unfavorable for NLAL induction by DMBA, and the combination of aldosterone + insulin + prolactin was only moderately conducive. Thus, the presence of cortisol with insulin + prolactin + aldosterone enhances NLAL incidence of mammary cells by DMBA. The highest incidence was found in glands that were treated with DMBA for 24 hr between the third and fourth day of culture, the period corresponding to the onset of the second wave of DNA synthesis in the gland. Cytotoxicity of DMBA was pronounced between 24 and 48 hr, when a high frequency of cells were in DNA synthesis, and survival of the cells after the cytotoxic effect of DMBA appeared to play a role in NLAL incidence. This suggests that DMBA-induction of NLAL in mammary glands in organ culture involves a complex carcinogen-hormone-cell cycle interaction. We emphasize that, although NLAL morphologically resembles the hyperplastic alveolar nodules of mouse mammary gland in vivo, the abilitity of NLAL to produce typical hyperactive alveolar outgrowth and mammary tumor after transplantation iv vivo remains to be determined.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1978

Detection of mutagenicity of the colon carcinogen 1,2-dimethylhydrazine by the host-mediated assay and its correlation to carcinogenicity.

Mutagenic potential of 1,2-dimethylhydrazine (DMH) was investigated in the host-mediated assay with mice used as hosts. This assay revealed potent mutagenicity of this colon carcinogen for Salmonella typhimurium G46. The mutagenicity of DMH was inhibited by pretreatment of mice with disulfiram. In addition, mouse strain and sex differences influenced the mutation induction by DMH: Mutation induction was significantly lower in C57BL/6 mice than in outbred ICR mice of either sex and was generally higher in male than in females of either C57BL/6 or ICR mice.

Animals↗
PubMed1976

The metabolic activation of the carcinogen 1'-hydroxysafrole in vivo and in vitro and the electrophilic reactivities of possible ultimate carcinogens.

Administration of [2',3'-3H]-1'-hydroxysafrole to rats or mice resulted in the formation of hepatic DNA-, ribosomal RNA-, and protein-bound 3H derivatives. Alkaline digestion of the 3H-protein released 0.1 to 0.3% of the 3H as a derivative that was identified as 3'-methylmercaptoisosafrole by its cochromatography in five solvent systems with the synthetic compound. 1'-Hydroxysafrole was metabolized at a low rate by rat and mouse liver cytosols in a 3'-phosphoadenosine 5'-phosphosulfate-dependent reaction to a derivative (presumably the sulfuric acid ester) that was captured by its reaction with RNA. Likewise, 1'-hydroxysafrole was oxidized at a low rate by rat and mouse liver microsomes to 1'-hydroxysafrole-2',3'-oxide in a reduced nicotinamide adenine dinucleotide phosphate-dependent reaction. Both of these electrophilic metabolites are candidate ultimate carcinogenic derivatives of 1'-hydroxysafrole. The electrophilic reactivities of various safrole derivatives with nucleosides were determined to be in the order of 1'-oxosafrole greater than 1'-acetoxysafrole greater than 1'-acetoxysafrole-2',3'-oxide greater than 1'-hydroxysafrole-2',3'-oxide greater than safrole-2',3'-oxide greater than or equal to 1'-oxosafrole-2',3'-oxide. The major reactions were generally observed with guanosine. A major reaction product of 1'-acetoxysafrole and guanosine 5'-monophosphate yielded 3'-hydroxyisosafrole under very mild acidic conditions. These data further substantiate the previous characterization of this reaction product as O-6-(isosafrol-3'-yl)guanylic acid. The syntheses of 1'-oxosafrole, 2',3'-dehydrosafrole, [2',3'-3H]-1'-hydroxysafrole, and the 2',3'-oxed.

Acetyltransferases↗
PubMed1975

Investigations on the carcinogenic burden by air pollution in man. XIII. Assessment of the contribution of passenger cars to air pollution by carcinogenic polycylic hydrocarbons.

A total of 100 passenger cars were tested with regard to the amount of polycyclic aromatic hydrocarbons (PAH) emitted during the EUROPA-Test (E.-Test, simulate city driving; 4 times 195 s). As determined by frequency of registration, the 20 most common car models were chosen. Each model was represented by 5 cars. The total amount of selected 14 PAH emitted by all test vehicles during an E.-test is in the range of 1-16 mg. As can be seen from the average of fuel consumption (409.4 g/E.-test) and benzo(a)pyrene emission (41.6 mug/E.-test), 1000 kg of burned fuel yield 101 mg of benzo(a)pyrene. Based on the consumption of gasoline in 1973 in West Germany (18508200 tons), an annual amount of 1.85 tons of benzo(a)pyrene is produced by gas engine vehicles. However, the biological effect of the automobile exhaust is still larger because it contains additional carcinogenic PAH. - A statistical evaluation of the results shows that different car models can not be distinguish by their PAH emission. When evaluating individual vehicles after 5 repeated E.-tests, the margin of error for any single PAH is between 6.3-10.9% (variation coefficient) for this car. A larger margin of error is obtained by pooling 5 different vehicles of the same model.

Air Pollutants↗
PubMed1977

Oncogenic interaction of carcinogenic and non-carcinogenic polycyclic aromatic hydrocarbons in mice.

To evaluate possible interactions between PAH occurring in automobile exhaust condensates with regard to their tumour forming potency, the following experiments were performed. Six different doses of benzo[a]pyrene (3-100 microgram) and of dibenzo]a,h]anthracene (2-75 microgram) and mixtures thereof were tested subcutaneously on female NMRI mice. In addition, mixtures of 10 non-carcinogenic hydrocarbons were applied: benzo[e]pyrene, benzo[a]anthracene, phenanthrene, anthracene, pyrene, fluoranthene, chrysene, perylene, benzo[ghi]perylene and coronene. Mixtures of all 12 PAH were also applied. The proportion of PAH in all mixtures used was the same as in automobile exhaust condensates; benzo[a]pyrene was used as reference substance. The most important results were as follows: 1. Small doses of dibenzo[a,h]anthracene have a greater tumour promoting effect than do comparable doses of benzo[a]pyrene. Increased doses increase the effect of benzo[a]pyrene more than that of dibenzo[a,h]anthracene. 2. The mixture of benzo[a]pyrene and dibenzo[a,h]anthracene is 1.4 time more active than dibenzo[a,h]anthracene alone. 3. The mixture of all PAH has a lower efficacy than dibenzo[a,h]anthracene alone, amounting to only 0.03 that of dibenzanthracene; however, the activity of dibenzo[a,h]anthracene within the mixture of the 12 PAH increases by a factor of 3.1. 4. The activity of a mixture of dibenzo[a,h]anthracene and benzo[a]pyrene depends to about 40% on dibenzo[a,h]anthracene; and that of 12 PAH to 30% on dibenzo[a,h]anthracene alone or to 80% on a mixture of dibenzo[a,h]anthracene and benzo[a]pyrene.

Animals↗
PubMed1977

Chromosomal effects of carcinogens and non-carcinogens on WI-38 after short term exposures with and without metabolic activation.

The human diploid fibroblast culture, WI-38 was analyzed for chromosomal damage after 24 h exposures to benzo(a)pyrene (BP), 3-methylcholanthrene (MCA), n-methyl-n'-nitrosoguanidine (MNNG), 4-nitroquinoline-1-oxide (4NQO), pyrene and caffeine. A low concentration of 4NQO (0.15 micron) and MNNG (1.9 micron) produced breakage and exchange figures. A relatively high concentration of caffeine (1300 micron) caused breakage. The other compounds (BP, MCA and pyrene) caused little or no increase in damage above the control levels. A 1-h pulse exposure of WI-38 cells to BP (40 micron) in the presence of a rat liver homogenate supernate (S-9) resulted in damage significantly greater than the untreated cells or cells treated with BP alone. 4NQO (0.25 micron) produced exchange figures after a similar 1-h exposure, but this effect was eliminated by the S-9. A much higher concentration of caffeine (10,300 micron) was required to cause breakage greater than control levels after a one hour exposure. The results indicate a possible short term in vitro human cell system for distinguishing carcinogens, procarcinogens, and noncarcinogens.

4-Nitroquinoline-1-oxide↗