RESUMO
Values for reaction-kinetic parameters of electrophiles can be used to predict mutagenic potency. One approach employs the Swain-Scott relationship for comparative kinetic studies of electrophilic agents reacting with nucleophiles. In this way glycidamide (GA), the putatively mutagenic/carcinogenic metabolite of acrylamide, was assessed by determining the rates of reaction with different nucleophiles. The rate constants (kNu) were determined using the "supernucleophile" cob(I)alamin [Cbl(I)] as an analytical tool. The Swain-Scott parameters for GA were compared with those of ethylene oxide (EO). The substrate constants, s values, for GA and for EO were found to be 1.0 and 0.93, respectively. The reaction rates at low values of nucleophilic strength (n=1-3), corresponding to oxygens in DNA, were determined to be 2-3.5 times higher for GA compared to EO. GA was also more reactive than EO towards other nucleophiles (n=0-6.4). The mutagenic potency of GA was determined in Chinese hamster ovary cells (hprt mutations in CHO-AA8 cells per dose unit with gamma-radiation as reference standard). The potency of GA was estimated to be about three mutations per 10(5) cells and mMh corresponding to about 40 rad-equ./mMh. A preliminary comparison of the mutagenic potency (per mMh and as rad-equivalents) of GA and EO shows an approximately seven times higher potency for GA. A higher mutagenic potency of GA compared to EO is compatible with expectation from reaction-kinetic data of the two compounds. The data confirmed that GA is not a strong mutagen, which is in line with what is expected for simple oxiranes. The present study shows the value of cob(I)alamin for the determination of reaction-kinetic parameters and their use for prediction of mutagenic potency.
Assuntos
Compostos de Epóxi/química , Modelos Biológicos , Mutagênicos/química , Mutação , Animais , Linhagem Celular , Cricetinae , Cricetulus , Relação Dose-Resposta a Droga , Compostos de Epóxi/toxicidade , Óxido de Etileno/química , Óxido de Etileno/toxicidade , Cinética , Mutagênicos/toxicidade , Vitamina B 12/químicaRESUMO
Urban air pollution, originating in western countries mainly from automotive engine exhausts, contains thousands of components, many of which are genotoxic, i.e. are putative cancer initiators. Other pollution components, such as NO2 and certain particles, may have cocarcinogenic/promotive effects, at least at higher exposure levels. Cancer risk assessment of this complex mixture has to combine data from the exposure history, from epidemiological studies as well as from animal carcinogenicity tests, and from in vitro studies of fractions and individual components. Data for metabolism and pharmaco-kinetics have also to be considered. A multiplicative linear model is assumed to be valid for cancer initiation at low levels. Attempts are being made to determine the target dose from ultimate carcinogens (reactive metabolites) via macromolecule adduct levels, and to base the risk assessment on the radiation-dose equivalent to the chemical dose. So far this has been possible only for simple alkenes, which are metabolized to epoxides, and indirectly, via benzo(a)pyrene (BaP), for particle-bound polycyclic aromatic hydrocarbons (PAH). The lifetime risk of cancer (all sites) from ethene is estimated accordingly to 1.4 x 10(-4) per microgram m-3, and from PAH to 12 x 10(-4) per ng m-3 BaP. For other components indicated to give risk contribution (NOx, volatile PAH, benzene, aldehydes, butadiene) essential data are lacking and only very rough estimates can be given at this time.
Assuntos
Poluição do Ar/efeitos adversos , Neoplasias/etiologia , Poluentes Atmosféricos/efeitos adversos , Poluentes Atmosféricos/análise , Animais , Exposição Ambiental , Humanos , Modelos Biológicos , Fatores de Risco , População UrbanaRESUMO
The usefulness of data from various sources for a cancer risk estimation of urban air pollution is discussed. Considering the irreversibility of initiations, a multiplicative model is preferred for solid tumors. As has been concluded for exposure to ionizing radiation, the multiplicative model, in comparison with the additive model, predicts a relatively larger number of cases at high ages, with enhanced underestimation of risks by short follow-up times in disease-epidemiological studies. For related reasons, the extrapolation of risk from animal tests on the basis of daily absorbed dose per kilogram body weight or per square meter surface area without considering differences in life span may lead to an underestimation, and agreements with epidemiologically determined values may be fortuitous. Considering these possibilities, the most likely lifetime risks of cancer death at the average exposure levels in Sweden were estimated for certain pollution fractions or indicator compounds in urban air. The risks amount to approximately 50 deaths per 100,000 for inhaled particulate organic material (POM), with a contribution from ingested POM about three times larger, and alkenes, and butadiene cause 20 deaths, respectively, per 100,000 individuals. Also, benzene and formaldehyde are expected to be associated with considerable risk increments. Comparative potency methods were applied for POM and alkenes. Due to incompleteness of the list of compounds considered and the uncertainties of the above estimates, the total risk calculation from urban air has not been attempted here.
Assuntos
Poluição do Ar/efeitos adversos , Neoplasias/induzido quimicamente , Aldeídos/efeitos adversos , Alcenos/efeitos adversos , Animais , Benzeno/efeitos adversos , Humanos , Modelos Biológicos , Compostos Policíclicos/efeitos adversos , Medição de Risco , Saúde da População UrbanaRESUMO
When estimating the absolute risk of cancer, the shape of the dose--response curve in the region of doses where actual exposure of man occurs is of crucial importance. This shape is equally important for the determination of relative risks, as in the comparison of risks from alternative energy sources. Experimental and epidemiological studies are, for various reasons, unable to give sufficiently exact information concerning the dose response in the low dose region. Therefore, the discussion concerning dose--response relationships also has to consider biologically reasonable mechanisms for the origin of tumors.
Assuntos
Carcinógenos , Neoplasias Experimentais , Animais , Relação Dose-Resposta a Droga , Humanos , Concentração Máxima Permitida , RiscoRESUMO
A cancer epidemiologist recently said that "adduct measurement has so far been of little use to epidemiological research." This remark gives us a starting point for the discussion of the purposes of measuring macromolecule adducts that originate from electrophilic compounds or metabolites in humans and animals. Historically, methods for adduct monitoring were developed as a means of determining target doses that, combined with measurements of genotoxic potencies, could be used for risk assessment. With mass spectrometric methods, adducts can be quantified at levels that are thousands of times lower than those in which the cancer incidence associated with this exposure is detectable in disease-epidemiological studies. Furthermore, mass spectrometric techniques permit identification of the chemical structure of the adduct, particularly in the case of hemoglobin adducts. Adduct measurement therefore constitutes not only a means of risk estimation but it may be used as a complement of disease epidemiology in situations in which, for statistical reasons, the risk is too low to be detectable--which does not signify that the risk is acceptably low. It also gives a possibility of identification of the dangerous components in mixed exposures and of the relevant reactive intermediates in cases of complex metabolism.
Assuntos
Exposição Ambiental , Mutagênicos , Biomarcadores , Adutos de DNA , Relação Dose-Resposta à Radiação , Monitoramento Ambiental , Monitoramento Epidemiológico , Humanos , Cinética , Neoplasias/epidemiologia , Neoplasias/etiologia , Padrões de Referência , Medição de RiscoRESUMO
Induction by gamma-radiation, UV radiation or hydroxyurea of RecA gene product synthesis in Escherichia coli, monitored as beta-D-galactosidase in recA-lacZ fusion strains, was shown to be inhibited if 2-mercaptoethylamine (MEA) was added before treatment with the inducing agents. If cysteine (Cys) at low concentrations was added at the same time as MEA it counteracted the action of MEA. The effect of MEA may be described as a competitive inhibition of an inducing or conducting effect of Cys. In E. coli GE499 (uvrA+), complete inhibition by 30-mmol dm-3 MEA of recA induction was associated with about five times higher radio-resistence. Both of these effects of MEA were completely reversed by 0.3-mmol dm-3 Cys. As shown in parallel experiments with E. coli GE500 (uvrA-), these effects of MEA and Cys were shown to be independent of excision-repair proficiency. Treatment of bacteria with MEA and/or Cys was shown not to lead to increased intracellular concentrations of these thiols. Instead, treatment with them appeared to provoke conspicuous increases in glutathione levels, which are, however, probably not directly involved in the studied action of MEA and Cys.
Assuntos
Cisteína/farmacologia , Escherichia coli/metabolismo , Escherichia coli/efeitos da radiação , Regulação Bacteriana da Expressão Gênica/efeitos da radiação , Mercaptoetilaminas/farmacologia , Tolerância a Radiação , Recombinases Rec A/biossíntese , Escherichia coli/efeitos dos fármacos , Hidroxiureia/farmacologia , Cinética , Óperon Lac , Proteínas Recombinantes/metabolismo , beta-Galactosidase/metabolismoRESUMO
Reactive compounds form adducts at several sites in DNA. One of these sites, the phosphate groups, forms phosphotriesters (PTE) which are both chemically stable and little repaired. A measurement of PTE in DNA could therefore be advantageous for the determination of doses in vivo of mutagens/cancer initiators. In this paper, the possibilities of utilizing the weakly alkylating properties of PTE for the transfer of adducts to strong nucleophiles have been investigated. Model compounds, thymidine 3'-[thymidine 5'-(methyl phosphate)], TpMeT, and thymidine 3'-[thymidine 5'-(2-hydroxyethyl phosphate)], TpHOEtT, were incubated with thiosulfate, a relatively strong nucleophile and the formation of dealkylated model PTE, thymidine 3'-(thymidine 5'-phosphate), TpT, was followed by HPLC. Transalkylation to thiosulfate or aniline of methyl PTE in DNA alkylated by [3H]N-methyl-N-nitrosourea was demonstrated. The methyl groups transferred, forming methyl thiosulfate and N-methylaniline, respectively, were determined by HPLC. These experiments demonstrate that it is possible to transfer alkyls from DNA phosphate to nucleophiles. Kinetic aspects of the transalkylation and requirement on nucleophiles for a practically useful method for determination of DNA adducts are discussed. Constants of reaction rates are presented.
Assuntos
Compostos de Anilina/química , Adutos de DNA/química , DNA/química , Nucleotídeos de Desoxiguanina/química , Tiossulfatos/química , Animais , Bovinos , Cromatografia Líquida de Alta Pressão , Metilação de DNA , Remoção de Radical Alquila , Metilnitrosoureia/químicaRESUMO
Cancer initiators (mutagens) present, due to the absence of definable no effect threshold, a special problem in toxicology, requiring a high sensitivity of detection methods. Disease epidemiology aiming at identification of carcinogens and quantification of associated risks has a low resolving power, the detectable incidence or mortality increments being often orders of magnitude larger than those which are of public concern. Other drawbacks of disease epidemiology is the long latency times and the influence of confounders. The use of genetic endpoints as biomarkers suffers from low cause specificity, although this drawback seems to be overcome, partly at least, by emerging methods for determination of mutation spectra at the DNA level. Proximal cancer initiators/mutagens are electrophilic compounds or metabolites that can react with nucleophilic atoms in nucleic acids and proteins. These reactions lead to 'adducts' that can be identified and quantified, e.g. in lymphocytes and erythrocytes in blood samples. The shift from biological observations to chemical analysis permits sufficient sensitivity, and measurement can be done shortly after onset of exposure. The well-defined life span of the adducts to hemoglobin (Hb) offer possibilities of dose calculation and risk estimation. For these reasons the measurement of adducts to Hb and DNA constitutes a powerful epidemiological tool, applications of which has been initiated in work environments and the general environment and also in the search for a priori unknown carcinogens.
Assuntos
Neoplasias/etiologia , Animais , Biomarcadores Tumorais , DNA/metabolismo , Relação Dose-Resposta a Droga , Humanos , Neoplasias/epidemiologia , RiscoRESUMO
Data for relationships between in vivo doses inferred from levels of hemoglobin (Hb) or DNA adducts and administered (by inhalation or injection) doses of ethylene oxide (EO) in mice, rats and humans are reviewed. At low absorbed doses or dose rates these relationships appear to be linear, whereas at higher dose rates deviations from linearity due to saturation kinetics of detoxification and of DNA repair as well as certain toxic effects have to be allowed for. If these factors are taken into consideration, a rather consistent picture is obtained for animal studies, with a variation by less than a factor 2 between estimates of adduct level increments or in vivo dose increments per unit of administered dose. Although the value for in vivo dose per unit of exposure dose (ppm-hour) in humans is uncertain because of unreliable data for the time-weighted average exposure level, the most likely value for this relationship, supported by data for ethene, agrees with data for the rodents. In the animal species testis doses are approximately one-half of the blood doses inferred from Hb adducts.
Assuntos
Adutos de DNA/sangue , Monitoramento Ambiental/métodos , Óxido de Etileno/toxicidade , Testes de Mutagenicidade , Mutagênicos/toxicidade , Administração por Inalação , Animais , Interpretação Estatística de Dados , Relação Dose-Resposta a Droga , Monitoramento Ambiental/normas , Óxido de Etileno/administração & dosagem , Óxido de Etileno/sangue , Óxido de Etileno/metabolismo , Mutação em Linhagem Germinativa , Hemoglobinas/metabolismo , Humanos , Inativação Metabólica , Injeções Intraperitoneais , Masculino , Camundongos , Modelos Genéticos , Testes de Mutagenicidade/métodos , Testes de Mutagenicidade/normas , Mutagênicos/metabolismo , Ratos , Reprodutibilidade dos Testes , Medição de Risco , Especificidade da Espécie , Testículo/efeitos dos fármacosRESUMO
Measurements of adducts formed with blood proteins, particularly haemoglobin, are increasingly being used to monitor human exposures to genotoxic chemicals. Information about the relationships between levels of genotoxic chemicals in the environment, e.g., concentration in the air, and levels of protein adducts in the blood is particularly important in setting safety standards and assessing risks. This paper describes the relationships between level of exposure to alkylating agents and level of haemoglobin adducts, considering the zero-order kinetics of the disappearance of these adducts. For comparison the corresponding relationship for adducts to macromolecules subjected to turnover, with first-order kinetics of disappearance, is described. For chemically stable and unstable adducts different exposure situations are considered: acute, chronic, intermittent and varying exposure levels. It is shown how an optimum solution of the problem of establishing the relationship between long-term exposure at varying levels (e.g., in work environments) and adduct level can be reached. Through mathematical derivations, which are given, expressions applicable to various exposure patterns are obtained and presented.
Assuntos
Alquilação , Substâncias Macromoleculares , Modelos Teóricos , Relação Dose-Resposta a Droga , Exposição Ambiental , Hemoglobinas/metabolismo , Humanos , Fatores de TempoRESUMO
Cysteamine (MEA) is comutagenic to methylnitrosourea (MNU) in E. coli AB 1157 but not in the nonadaptable mutant derivative ada-6 of that strain. The comutagenic action of MEA was eliminated by cysteine at low concentrations, which also lowered mutation frequencies in AB1157 but not in ada-6. In model experiments it was shown that cysteine counteracted the inhibition by MEA of beta-galactosidase induction in both bacterium strains. The comutagenic action of MEA is interpreted as being due to an inhibition of induction of methyltransferase during treatment with MNU.
Assuntos
Cisteamina/farmacologia , Metilnitrosoureia/farmacologia , Proteínas de Bactérias/biossíntese , Depressão Química , Resistência Microbiana a Medicamentos , Sinergismo Farmacológico , Indução Enzimática/efeitos dos fármacos , Escherichia coli/efeitos dos fármacos , Metiltransferases/antagonistas & inibidores , beta-Galactosidase/biossínteseRESUMO
Our earlier finding that the radioprotective action of 2-mercaptoethylamine (MEA) is counteracted by ascorbate suggests a biochemical mechanism of action, which is supported by observations that MEA is not radioprotective in Rec- E. coli strains. In this study we show that MEA inhibits the induction of the recA gene by UV- or gamma-irradiation or by nalidixic acid in Escherichia coli strain GE94, which contains a recA-lacZ fusion. This effect, which may be counteracted by cysteine, indicates that in general MEA inhibits the induction of SOS functions.
Assuntos
Cisteamina/farmacologia , Regulação Bacteriana da Expressão Gênica/efeitos dos fármacos , Protetores contra Radiação/farmacologia , Recombinases Rec A/biossíntese , Cisteamina/antagonistas & inibidores , Cisteína/farmacologia , Escherichia coli/efeitos dos fármacos , Escherichia coli/genética , Escherichia coli/efeitos da radiação , Raios gama , Regulação Bacteriana da Expressão Gênica/efeitos da radiação , Ácido Nalidíxico/farmacologia , Recombinases Rec A/genética , Proteínas Recombinantes de Fusão/biossíntese , Proteínas Recombinantes de Fusão/genética , Raios Ultravioleta , beta-Galactosidase/genéticaRESUMO
The results from assays that describe biological effects of polycyclic aromatic hydrocarbons (PAH) were explored using multivariate methods. Based on the availability of data, 29 PAH were included in the study. Five variables described the carcinogenic potency in rodents of the PAH. Biological effects were assayed using 14 variables. These included bacterial mutagenicity, enhancement and inhibition of bacterial mutagenicity, Ah receptor (AhR) affinity, and induction of enzymes that bioactivate many PAH to proximal bacterial mutagens. A principal components analysis (PCA) showed that the highest correlations with the cancer data were observed for variables describing AhR affinity, whereas bacterial mutagenicity data were poorly correlated with cancer data. When a partial least squares (PLS) regression analysis was applied, only one bacterial mutagenicity variable, but all AhR affinity variables were statistically relevant to describe carcinogenic potency. The latter variables were also correlated with the inhibition of bacterial mutagenicity of benzo[a]pyrene. It was concluded that structural requirements for AhR affinity are the same as those required for metabolism by enzymes that bioactivate benzo(a)pyrene. Negative correlations between mutagenicity and induction of enzymes were observed. The roles of cancer initiation and cancer promotion are discussed regarding the biological properties studied. It is proposed that bacterial mutagenicity reflects the cancer initiation potency, whereas the AhR affinity reflects the promotive effect of some PAH at the high doses applied in rodent carcinogenicity tests. It is thus indicated that initiation and promotion are provoked by different chemical species: reactive metabolites and the parent hydrocarbons, respectively. At doses reflecting a normal human exposure situation the effects of initiation may be more important in the course of chemical carcinogenesis. The mechanisms of cancer initiation and cancer promotion should therefore be studied in more detail for reliable quantitative risk assessments.
Assuntos
Carcinógenos/farmacologia , Hidrocarbonetos Policíclicos Aromáticos/farmacologia , Animais , Testes de Carcinogenicidade , Citocromo P-450 CYP1A1/metabolismo , Citocromo P-450 CYP1A2/metabolismo , Humanos , Sistemas de Informação , Testes de Mutagenicidade , Neoplasias/metabolismo , Hidrocarbonetos Policíclicos Aromáticos/química , Receptores de Hidrocarboneto Arílico/metabolismo , Análise de Regressão , Roedores/metabolismo , Estatística como AssuntoRESUMO
5'-Deoxy-5'-(methylthio)adenosine (MTA) alone and in combination with methionine was found to increase frequencies of background HGPRT mutation and SCE in V79 Chinese hamster cells. The same agents exert a comutagenic action on these effects as well as upon mutation induction in Escherichia coli stain AB1157 (but not in its non-adaptable derivative ada-6) following treatment with N-methyl-N-nitrosourea (MNU). MTA plus methionine also enhanced the lethal action of MNU on hamster cells. The effects observed may tentatively be ascribed to hypomethylation due to inhibition of DNA methylase by MTA.
Assuntos
Adenosina/análogos & derivados , Desoxiadenosinas , Hipoxantina Fosforribosiltransferase/genética , Mutagênicos , Mutação , Troca de Cromátide Irmã/efeitos dos fármacos , Tionucleosídeos/farmacologia , Adenosina/farmacologia , Animais , Linhagem Celular , Cricetinae , Cricetulus , Escherichia coli/efeitos dos fármacos , Escherichia coli/genética , Feminino , Rim , Testes de Mutagenicidade , OvárioRESUMO
Methyl nitrite was tested for mutagenicity in Salmonella typhimurium TA1535. In the first set of experiments, plated bacteria were exposed to methyl nitrite in desiccators both in the absence and presence of a metabolizing system (S9 from Aroclor-pretreated Sprague-Dawley rats). Initial concentrations from 125 to 500 ppm were tested. In all experiments an increased initial concentration gave an increased mutagenic response. The mutagenic effect in the presence of S9 was similar to that in the absence of S9. Owing to difficulties in dose determinations in this type of experiment it could not be decided, unequivocally, whether the mutagenic effect was caused by methyl nitrite or its hydrolysis products. Experiments were therefore carried out in suspension, and the concentrations of methyl nitrite and inorganic nitrite were determined. Treatments with inorganic nitrite were also carried out under similar conditions. From the results of these experiments we concluded that methyl nitrite is mutagenic. Possible mechanisms of action of methyl nitrite are discussed, and it is suggested that mutagenicity may be a general property of alkyl nitrites.
Assuntos
Mutagênicos , Mutação , Nitritos/toxicidade , Animais , Biotransformação , Microssomos Hepáticos/metabolismo , Testes de Mutagenicidade , Ratos , Ratos Endogâmicos , Salmonella typhimurium/efeitos dos fármacosRESUMO
Dose-response relationships and determination of dose of mutagens and carcinogens are summarized and discussed on the basis of conceptual and kinetic aspects. Different dose definitions may be referred to steps in the chain of events from exposure (or emission) to observed effects. A system is applied to show the influence of various processes on the kinetics of the transfers between consecutive steps. The same system illustrates processes influenced by protraction and fractionation of dose, synergists, comutagens/cocarcinogens, heritable factors, etc. The response at a given dose is expected to depend on the product of consecutive transfer functions. An application of general rules of chemical kinetics shows that when a chemical is introduced at a sufficiently low level, all processes affecting the transfers and therefore the transfer functions themselves become first-order, provided the induction status of enzymes and the cell-division rate remain constant. Under the same conditions, dose-response relationships are expected to be linear, i.e. without "safe" thresholds. However, present knowledge of the kinetics of repair at low levels of DNA damage and of the kinetics of induction of repair functions is not enough complete to be decisive. These considerations and the fact that observed dose-response data in some cases indicate the existence of thresholds but in others appear able to reject the threshold hypothesis lead to the conclusion that, generally, dose-response curves are most probably linear down to dose zero. However, certain mutagens/carcinogens give rise to lesions repaired so effectively that quasi-thresholds appear in certain subpopulations or organs.
Assuntos
Mutagênicos/toxicidade , Mutação , Animais , DNA/metabolismo , Reparo do DNA , Relação Dose-Resposta a Droga , Genes/efeitos dos fármacos , Temperatura Alta , Humanos , Matemática , Modelos Genéticos , RiscoRESUMO
Ethylene oxide and propylene oxide are high-volume reactive alkylating agents used primarily as intermediates in the chemical industry. Studies were undertaken to investigate the ability of these alkylating agents to induce chromosomal aberrations, micronuclei and sister-chromatid exchanges in mouse bone marrow cells. The mice were exposed to these chemicals by intraperitoneal injection. The data show that both compounds are effective in inducing chromosomal alterations. Our studies confirm the findings reported by different investigators that ethylene oxide is more cytotoxic than propylene oxide. This difference is to a large extent due to a faster detoxification of propylene oxide than of ethylene oxide.
Assuntos
Medula Óssea/efeitos dos fármacos , Aberrações Cromossômicas , Compostos de Epóxi/toxicidade , Óxido de Etileno/toxicidade , Micronúcleos com Defeito Cromossômico/efeitos dos fármacos , Troca de Cromátide Irmã/efeitos dos fármacos , Animais , Medula Óssea/efeitos da radiação , Medula Óssea/ultraestrutura , Feminino , Camundongos , Doses de RadiaçãoRESUMO
Knowledge of the relationships between exposure levels and levels of hemoglobin adducts are essential when the latter are to be used for exposure monitoring or risk estimation, the hygienic control being based on measurements of exposure. These ratios are mostly very uncertain, mainly due to difficulties of determining the time-weighted average exposure concentration. A solution to this problem has been suggested involving adduct measurement before and after two consecutive periods of about 1 week, the first with absence from exposure, the second with careful measurement of exposure. This model was tested in two smokers who abstained from smoking for one week. Analysis of inhaled ethene and of adducts from ethylene oxide (EO) to N-terminal valine of hemoglobin are compatible with metabolism of 2% of inhaled ethene to EO and a detoxification rate of 1 h-1 of EO.
Assuntos
Etilenos/sangue , Hemoglobinas/metabolismo , Abandono do Hábito de Fumar , Adulto , Idoso , Transporte Biológico , Monitoramento Ambiental/métodos , Óxido de Etileno/sangue , Etilenos/farmacocinética , Feminino , Humanos , Inativação Metabólica , Cinética , Masculino , Modelos Teóricos , ValinaRESUMO
Mutagenicity tests have shown that the potencies of ethylene oxide and other alkylating agents relative to that of low-LET ionising radiation are approximately the same in different biological systems. In the present study this relationship, the radiation-dose equivalence ("rad-equivalence") of doses of genotoxic chemicals, was tested for the induction of tumours in skin and lung of mice using different initiation-promotion protocols. The initiators used were X-rays, ethylene oxide and N-(2-hydroxyethyl)-N-nitrosourea (HOENU). This short-term treatment was followed by treatment with the "promoters" 12-O-tetradecanoylphorbol 13-acetate (TPA) and carbon tetrachloride. Unexpectedly, the animals treated with carbon tetrachloride did not show treatment-related liver tumours, but exhibited precocious death, mostly with lung tumours. According to estimates from in vitro tests the total in vivo dose from exposure to 400 ppm for 4 x 5 h corresponds to 700 rad-equivalents. Although still with great statistical uncertainty, this ratio is supported by the observed time-dependent frequencies of animals with papillomas (in the TPA series) and lung tumours (in the carbon tetrachloride series). Animals treated with HOENU exhibited high incidences of tumours of both these types in approximate agreement with the higher rad-equivalence of the treatments with this compound.
Assuntos
Carcinógenos/toxicidade , Óxido de Etileno/toxicidade , Etilnitrosoureia/análogos & derivados , Neoplasias Induzidas por Radiação , Animais , Testes de Carcinogenicidade , Etilnitrosoureia/toxicidade , Neoplasias Pulmonares/induzido quimicamente , Masculino , Camundongos , Neoplasias Cutâneas/induzido quimicamente , Acetato de Tetradecanoilforbol/farmacologia , Raios XRESUMO
The degree of alkylation of haemoglobin was determined at different times after treatment of mice with one directly active alkylating agent, ethylene oxide, and one agent that requires metabolic activation, dimethylnitrosamine. Because of the random alkylation of red blood cells of various ages and the stability of alkylated haemoglobin, the amount of alkylated amino acids in haemoglobin decreases linearly with time, reaching the value zero after about 40 days, the life-span of erythrocytes in the mouse. This provides a basis for the use of haemoglobin as a monitor for integral doses of genotoxic environmental chemicals.