RESUMEN
A recent analysis by Kirkland et al. [Kirkland, D., Aardema, M., Henderson, L. and Müller, L. (2005) Evaluation of the ability of a battery of 3 in vitro genotoxicity tests to discriminate rodent carcinogens and non-carcinogens. I. Sensitivity, specificity and relative predictivity. Mutat. Res. 584, 1-256] demonstrated an extremely high false positive rate for in vitro genotoxicity tests when compared with carcinogenicity in rodents. In many industries, decisions have to be made on the safety of new substances, and health risk to humans, without rodent carcinogenicity data being available. In such cases, the usual way to determine whether a positive in vitro genotoxicity result is relevant (i.e. indicates a hazard) for humans is to develop weight of evidence (WoE) or mode of action (MoA) arguments. These are based partly on further in vitro investigations, but usually rely heavily on tests for genotoxicity in one or more in vivo assays. However, for certain product types in the European Union, the use of animals for genotoxicity testing (as well as for other endpoints) will be prohibited within the next few years. Many different examples have been described that indicate DNA damage and genotoxic responses in vitro can arise through non-relevant in vitro events that are a result of the test systems and conditions used. The majority of these non-relevant in vitro events can be grouped under a category of 'overload of normal physiology' that would not be expected to occur in exposed humans. However, obtaining evidence in support of such MoAs is not easy, particularly for those industries prohibited from carrying out in vivo testing. It will become necessary to focus on in vitro studies to provide evidence of non-DNA, threshold or in vitro-specific processes and to discuss the potential for such genotoxic effects to occur in exposed humans. Toward this end, we surveyed the published literature for in vitro approaches that may be followed to determine whether a genotoxic effect observed in vitro will occur in humans. Unfortunately, many of the approaches we found are based on only a few published examples and validated approaches with consensus recommendations often do not exist. This analysis highlights the urgent need for developing consensus approaches that do not rely on animal studies for dealing with in vitro genotoxins.
Asunto(s)
Alternativas a las Pruebas en Animales/métodos , Daño del ADN/efectos de los fármacos , Interpretación Estadística de Datos , Pruebas de Mutagenicidad/métodos , Aneugénicos/toxicidad , Bacterias/efectos de los fármacos , Bacterias/genética , Inhibidores Enzimáticos/toxicidad , Peroxidación de Lípido/efectos de los fármacos , Lisosomas/metabolismo , Mutagénesis/efectos de los fármacos , Desnaturalización Proteica/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Reproducibilidad de los ResultadosRESUMEN
Methyl 2-benzimidazolecarbamate (MBC), diethylstilbestrol (DES) and estradiol were tested with regard to their ability to induce C-mitoses, polyploidies, micronuclei, structural chromosomal aberrations and sister-chromatid exchanges (SCE) in human peripheral lymphocytes in vitro. The compounds did not induce structural chromosomal aberrations either in the presence or absence of metabolic activation. MBC and estradiol were negative in the SCE test. DES induced SCE rates which were not even twice the control level and which were independent of dose and of metabolic activation. All compounds induced C-mitoses, polyploidies and micronuclei. The micronuclei are interpreted as resulting from errors in the anaphase distribution of chromosomes by spindle disturbances rather than from structural chromosomal aberrations.
Asunto(s)
Bencimidazoles/toxicidad , Carbamatos , Dietilestilbestrol/toxicidad , Estradiol/toxicidad , Linfocitos/efectos de los fármacos , Mutación/efectos de los fármacos , Núcleo Celular/efectos de los fármacos , Núcleo Celular/ultraestructura , Aberraciones Cromosómicas , Humanos , Cariotipificación , Linfocitos/ultraestructura , Mitosis/efectos de los fármacos , Poliploidía , Intercambio de Cromátides Hermanas/efectos de los fármacosRESUMEN
Peripheral blood lymphocytes of 77 patients under lithium-therapy were analyzed with respect to structural chromosomal aberrations. As compared to controls not treated with lithium, no elevation of the frequencies of chromosomal aberrations was found in the patients. Comparable investigations may lead to erroneous conclusions if the higher X-ray load of psychiatric patients is not considered.