RESUMO
There is an increased need to develop novel alternative approaches to the two-year rodent bioassay for the carcinogenicity assessment of substances where the rodent bioassay is still a basic requirement, as well as for those substances where animal use is banned or limited or where information gaps are identified within legislation. The current progress in this area was addressed in a EURL ECVAM- ESTIV workshop held in October 2016, in Juan les Pins. A number of initiatives were presented and discussed, including data-driven, technology-driven and pathway-driven approaches. Despite a seemingly diverse range of strategic developments, commonalities are emerging. For example, providing insight into carcinogenicity mechanisms is becoming an increasingly appreciated aspect of hazard assessment and is suggested to be the best strategy to drive new developments. Thus, now more than ever, there is a need to combine and focus efforts towards the integration of available information between sectors. Such cross-sectorial harmonisation will aid in building confidence in new approach methods leading to increased implementation and thus a decreased necessity for the two-year rodent bioassay.
Assuntos
Testes de Carcinogenicidade/tendências , Alternativas aos Testes com Animais , Animais , Neoplasias da Mama/induzido quimicamente , Carcinógenos/toxicidade , Conferências de Consenso como Assunto , Europa (Continente) , Feminino , Humanos , Camundongos , Modelos de Riscos Proporcionais , Ratos , Tecnologia/tendências , ToxicogenéticaRESUMO
Throughout the last 50 years, the paradigm for carcinogenicity assessment has depended on lifetime bioassays in rodents. Since 1997, the International Conference on Harmonisation (ICH) S1B has permitted the use of a 2-year rodent bioassay (usually in the rat) and an alternative, genetically modified mouse model to support cancer risk assessment of pharmaceuticals. Since its introduction, it has become apparent that many of the stated advantages of the 6-month Tg mouse bioassay have, in actual fact, not been realized, and the concern exists that an albeit imperfect, 2-year mouse bioassay has been replaced by a similarly imperfect 6-month equivalent. This essay argues strongly that model systems, using cancer as the end point, should be discontinued, and that the recent initiatives, from the Organization for Economic Cooperation and Development and Institute of Peace and Conflict Studies, on "mode of action," "adverse outcome pathways," and "human relevance framework" should be embraced as being risk assessments based upon the available science. The recent suggested revisions to the ICH S1 guidelines, utilizing carcinogenicity assessment documents, go some way to developing a science-based risk assessment that does not depend almost entirely on a single, imperfect, cancer-based end point in nonrelevant animal species.
Assuntos
Bioensaio , Testes de Carcinogenicidade , Animais , Animais Geneticamente Modificados , Bioensaio/história , Bioensaio/métodos , Bioensaio/tendências , Testes de Carcinogenicidade/história , Testes de Carcinogenicidade/métodos , Testes de Carcinogenicidade/tendências , História do Século XX , História do Século XXI , Camundongos , Neoplasias Experimentais , Ratos , Medição de RiscoRESUMO
Most of the current in vitro carcinogenicity assays assess the potential carcinogenic properties of chemicals through the detection of inflicted DNA damage or subsequent chromosome damage and gene mutations. Unfortunately, these assays generally do not provide mechanistic insight into the reactive properties of a chemical. Upon chemical-induced damage of biomolecules, molecular sensors will activate general and damage-specific cellular response pathways that provide protection against the (geno)toxic and potential carcinogenic properties of chemicals. These cellular defense mechanisms include activation of cell-cycle checkpoints, DNA repair systems and induction of apoptosis or necrosis. Visualization of activated cellular-signaling pathways forms a powerful means to readily detect the genotoxic potential of chemical compounds and simultaneously gain insight into their reactive properties. Over the past years, various in vitro reporter assays have been developed that monitor activation of general and more specific cellular-signaling pathways, including the GreenScreen HC and ToxTracker assays. In this review we provide a perspective on how we can exploit activation of cellular signaling pathways to shed light on the mode of action of the chemical exposure and to develop sophisticated mechanism-based in vitro assays for cancer risk assessment.
Assuntos
Testes de Carcinogenicidade/tendências , Carcinógenos/toxicidade , Transdução de Sinais/efeitos dos fármacos , Animais , Humanos , Camundongos , Testes de Mutagenicidade , Medição de RiscoRESUMO
The carcinogenicity (cancer-inducing potential) of pharmaceuticals is an important risk factor for health when considering whether thousands of patients on drug trials or millions/billions of consumers in the marketplace should be exposed to a new drug. Drawing on fieldwork involving over 50 interviews and documentary research spanning 2002-2010 in Europe and the US, and on regulatory capture theory, this article investigates how the techno-regulatory standards for carcinogenicity testing of pharmaceuticals have altered since 1998. It focuses on the replacement of long-term carcinogenicity tests in rodents (especially mice) with shorter-term tests involving genetically-engineered mice (GEM). Based on evidence regarding financial/organizational control, methodological design, and interpretation of the validation and application of these new GEM tests, it is argued that regulatory agencies permitted the drug industry to shape such validation and application in ways that prioritized commercial interests over the need to protect public health. Boundary-work enabling industry scientists to define some standards of public-health policy facilitated such capture. However, as the scientific credibility of GEM tests as tools to protect public health by screening out carcinogens became inescapably problematic, a regulatory resurgence, impelled by reputational concerns, exercised more control over industry's construction and use of the tests, The extensive problems with GEM tests as public-health protective regulatory science raises the spectre that alterations to pharmaceutical carcinogenicity-testing standards since the 1990s may have been boundary-work in which the political project of decreasing the chance that companies' products are defined as carcinogenic has masqueraded as techno-science.
Assuntos
Animais Geneticamente Modificados , Testes de Carcinogenicidade/tendências , Indústria Farmacêutica/organização & administração , Regulamentação Governamental , Camundongos/genética , Animais , Testes de Carcinogenicidade/normas , Indústria Farmacêutica/legislação & jurisprudência , Europa (Continente) , Humanos , Neoplasias/induzido quimicamente , Política , Reprodutibilidade dos Testes , Medição de Risco , Ciência , Estados UnidosRESUMO
Utilizing basic concepts of chemical carcinogenesis and the human relevance framework based on mode of action analysis of animal carcinogens, an alternative is proposed for the two-year bioassay for screening chemicals for potential carcinogenic risk in humans. This model includes short-term screening of chemicals for DNA reactivity, immunosuppressive and, estrogenic activity, and potential increased cell proliferation. Follow-up studies can provide detailed information with regard to dose response and mode of action, with a detailed evaluation of potential relevance to humans. It is no longer appropriate to continue performing two year rodent bioassays.
Assuntos
Bioensaio , Testes de Carcinogenicidade/métodos , Testes de Carcinogenicidade/tendências , Carcinógenos/toxicidade , Proliferação de Células/efeitos dos fármacos , DNA/efeitos dos fármacos , Neoplasias Experimentais/patologia , Animais , Modelos Animais de Doenças , Humanos , Neoplasias Experimentais/induzido quimicamente , Medição de Risco , Roedores , Fatores de TempoRESUMO
With developments in the philosophy behind animal testing for carcinogenicity and toxicity, with increasing emphasis on Mode of Action analysis, the future usefulness of the 2 year rodent carcinogenesis bioassay is in doubt.
Assuntos
Bioensaio , Evolução Biológica , Testes de Carcinogenicidade/métodos , Testes de Carcinogenicidade/tendências , Carcinógenos/toxicidade , Modelos Animais de Doenças , Neoplasias Experimentais/patologia , Animais , Humanos , Camundongos , Neoplasias Experimentais/induzido quimicamente , Ratos , Medição de Risco , Fatores de TempoRESUMO
IMPORTANCE OF THE FIELD: Carcinogenicity and mutagenicity are toxicological end points posing considerable concern for human health. Due to the cost in animal lives, time and money, alternative approaches to the rodent bioassay were designed based on: i) identification of mutations and ii) structure-activity relationships. AREAS COVERED IN THIS REVIEW: Evidence on i) and ii) is summarized, covering 4 decades (1971 - 2010). WHAT THE READER WILL GAIN: A comprehensive, state-of-the-art perspective on alternatives to the carcinogenicity bioassay. TAKE HOME MESSAGE: Research to develop mutagenicity-based tests to predict carcinogenicity has generated useful results only for a limited area of the chemical space, that is, for the DNA-reactive chemicals (able to induce cancer, together with a wide spectrum of mutations). The most predictive mutagenicity-based assay is the Ames test. For non-DNA-reactive chemicals, that are Ames-negative and mutagenic in other in vitro assays (e.g., clastogenicity), no correlation with carcinogenicity is apparent. The knowledge on DNA reactivity permits the identification of genotoxic carcinogens with the same efficiency of the Ames test. Thus, a chemical mutagenic in Salmonella and/or with structural alerts should be seriously considered as a potential carcinogen. No reliable mutagenicity-based alternative tools are available to assess the risk of non-DNA-reactive chemicals.
Assuntos
Alternativas aos Testes com Animais/métodos , Bioensaio/métodos , Testes de Toxicidade/métodos , Alternativas aos Testes com Animais/tendências , Animais , Bioensaio/efeitos adversos , Bioensaio/tendências , Testes de Carcinogenicidade/efeitos adversos , Testes de Carcinogenicidade/métodos , Testes de Carcinogenicidade/tendências , Humanos , Modelos Animais , Testes de Mutagenicidade/métodos , Testes de Mutagenicidade/tendências , Relação Estrutura-Atividade , Testes de Toxicidade/tendênciasRESUMO
The National Toxicology Program (NTP) hosted a workshop, "Animal Models for the NTP Rodent Cancer Bioassay: Strains and Stocks--Should We Switch?" on June 16-17, 2005, at the National Institute of Environmental Health Sciences (NIEHS) in Research Triangle Park, North Carolina. The workshop's objectives were to determine (1) whether the currently used models, the F344/N rat and B6C3F1/N mouse, continue to be appropriate to identify substances that may pose a carcinogenic hazard for humans and (2) whether the NTP should consider conducting cancer bioassays using multiple strains of rats and/or mice to better capture the range of genetic variability. Workshop participants advised the NTP to discontinue using the current F344/N strain due to the recent issues with fertility, seizure activity, and chylothorax and provided several options on how the program should approach identifying and selecting a new rat model. Participants believed that the B6C3F1/N mouse is still appropriate for use by the NTP, but suggested the NTP take steps to better understand and address increases in background rates of liver tumors in this strain. Finally, the participants supported the NTP exploring the use of the multiple strain approach, although they raised many questions concerning data interpretation and feasibility. This article also outlines the NTP's next steps in pursuing the workshop recommendations.
Assuntos
Testes de Carcinogenicidade/tendências , Carcinógenos/toxicidade , Modelos Animais , Neoplasias/induzido quimicamente , Animais , Guias como Assunto , Humanos , Camundongos , Camundongos Endogâmicos , Ratos , Ratos Endogâmicos F344 , Medição de Risco , Especificidade da Espécie , Estados UnidosAssuntos
Biomarcadores Tumorais/metabolismo , Testes de Carcinogenicidade , Carcinógenos/metabolismo , Valor Preditivo dos Testes , Animais , Animais de Laboratório , Testes de Carcinogenicidade/métodos , Testes de Carcinogenicidade/normas , Testes de Carcinogenicidade/tendências , Feminino , Masculino , Camundongos , Preparações Farmacêuticas/normas , Prognóstico , Ratos , Especificidade da Espécie , Fatores de Tempo , Estados Unidos , United States Environmental Protection Agency , United States Food and Drug AdministrationRESUMO
DNA double strand breaks (DSBs) are potentially carcinogenic lesions. The induction of DSBs triggers phosphorylation of histone H2AX. Phosphorylated H2AX, denoted p-H2AX, may be detected immunocytochemically and the intensity of p-H2AX immunofluorescence (IF) reveals the frequency of DSBs. Using this assay we tested whether the exposure of A549 human pulmonary adenocarcinoma cells to tobacco smoke, and normal human bronchial epithelial cells (NHBE) to tobacco smoke condensate, induces DSBs. Cellular p-H2AX IF and DAPI fluorescence of individual cells were measured by laser scanning cytometry (LSC). Exposure of A549 cells to tobacco smoke and NHBE cells to smoke condensate led to H2AX phosphorylation in both a time and dose dependent manner. The maximal rate of H2AX phosphorylation was seen during the initial 4h of cell treatment. At high doses (50 microg/ml of smoke condensate), H2AX phosphorylation continued to increase for up to 24h. No differences in the level of H2AX phosphorylation were apparent between cells in G(1) vs S vs G(2)/M phase of the cell cycle in response to treatment with smoke condensate. The data provide strong evidence that exposure of A549 cells to tobacco smoke or NHBE cells to smoke condensate rapidly induces DSBs in these cells. The present assay to detect and measure DSBs induced by tobacco products complements other mutagenicity assays and may be applied to test potential carcinogens in other products.
Assuntos
Adenocarcinoma/metabolismo , Carcinógenos/análise , Histonas/metabolismo , Neoplasias Pulmonares/metabolismo , Nicotiana/metabolismo , Fumaça/análise , Adenocarcinoma/química , Adenocarcinoma/patologia , Brônquios/química , Brônquios/citologia , Brônquios/metabolismo , Testes de Carcinogenicidade/tendências , Linhagem Celular Tumoral , Quebra Cromossômica/genética , Dano ao DNA/genética , Células Epiteliais/química , Células Epiteliais/metabolismo , Histonas/imunologia , Humanos , Imuno-Histoquímica/métodos , Neoplasias Pulmonares/química , Neoplasias Pulmonares/patologia , FosforilaçãoRESUMO
Use of laboratory animals to identify carcinogenic potential of chemicals, mixtures, and other agents has a modern history of greater than 40 years from which much useful scientific and public health information can be derived. While laboratory animals differ from humans in some respects that may affect responses to hazardous exposures, use of such models is based on experimental evidence indicating that there are more genetic, genomic, physiological, biochemical, and metabolic similarities than differences among mammalian species. Issues of concordance of responses between rodent species and between rodents and humans as well as repeatability and site-specificity are important considerations in evaluating laboratory animal carcinogenicity results. Variables in experimental design such as animal strain, diet, route of exposure, and study, duration as well as single-site versus multisite carcinogenic responses all influence interpretation and intelligent use of study data. Similarities and differences in site-specific laboratory animal and corresponding human cancers should also be considered in study evaluation. Recent attempts to explore genetically engineered mice and to humanize the mouse for more relevant identification of carcinogen hazard identification have yielded mixed results. In the end we are confronted by the realization that virtually all animal cancer models are useful but imperfect surrogates for humans. Assuming the percentage of chemicals currently in commerce that are estimated to be potent animal or human carcinogens is quite low, the task of identifying agents with significant carcinogenic potential is daunting and important. The biological conundrum of scientific debate regarding the relevance of carcinogenicity studies in laboratory animals is likely to continue. Nonetheless public health considerations must take precedence when deciding human safety issues.
Assuntos
Neoplasias Experimentais , Neoplasias/prevenção & controle , Animais , Testes de Carcinogenicidade/métodos , Testes de Carcinogenicidade/tendências , Transformação Celular Neoplásica , Humanos , Neoplasias Hepáticas/etiologia , Neoplasias Hepáticas/patologia , Camundongos , Camundongos Transgênicos , Valor Preditivo dos Testes , Especificidade da EspécieRESUMO
Almost all new drugs must be tested for carcinogenicity at some point during their development, and ultimately, a lifetime in vivo assay, usually in rodents, must be performed. Many in vitro assays of carcinogenicity have been developed for use before short- or long-term in vivo testing in order to remove from the development stream those drugs that are likely to produce tumors in vivo. This review discusses in vitro assays that are required by the International Conference on Harmonization, followed by a discussion of in vitro carcinogenicity assays, which are currently in use, but are not specifically required. The concluding section is devoted to a discussion of high-throughput compatible carcinogenicity screens and potential human cell-based high-throughput compatible screens with reference to future methods in silico.
Assuntos
Testes de Carcinogenicidade/métodos , Testes de Carcinogenicidade/tendências , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Ensaios de Seleção de Medicamentos Antitumorais/tendências , Testes de Mutagenicidade/métodos , Testes de Mutagenicidade/tendências , Animais , Química Farmacêutica , HumanosRESUMO
This perspective is based upon the data presented at the International Life Sciences Institute (ILSI), Health and Environmental Sciences Institute Workshop on the Evaluation of Alternative Methods for Carcinogenicity Testing (ILSI Workshop). It is important to understand that all models discussed at the Workshop have limitations and that they are not designed to be employed as stand-alone assays. Although they may have other, appropriate applications. I do not recommend use of the SHE cell assay and the Tg.AC model for the regulatory purposes of a safety assessment. In my view, the neonatal mouse, p53+/-, XPA-/-, XPA-/- and p53+/-, and the rasH2 models can, as a component of an overall assessment, provide information on potential carcinogenicity of a chemical that is appropriate for consideration in a regulatory context. Generally, these models exhibit the ability to detect genotoxic compounds. In most cases these compounds would be detected in a standard battery of genotoxicity tests and, therefore, quite often the use of an alternative is not necessary. Actually, I believe that a bioassay in rats will suffice most of the time, that is, in my view, a routine bioassay in mice is not necessary. Specific circumstances where data obtained from one of the "recommended" alternative models might be helpful are discussed. With regard to lessons for the future, there is a particular need for models that are responsive to chemicals that exhibit a nongenotoxic mode of action. Additionally, new models will continue to be developed and their half-life will likely be substantially shorter than the time required for traditional validation. The development of enhanced paradigms for validation should be a priority so that improved safety assessment decisions can be made more quickly. However, while evaluating and validating such models, it is important to consider the fundamental issues, for example, rational dose selection, evaluation of mode of action in the context of dose-response relationships including the existence of thresholds and secondary mechanisms, and species-to-species extrapolation. The alternatives to carcinogenicity testing project was a very major undertaking. In addition to the valuable information provided, it serves to illustrate the value of cooperation between academia, government, and industry. Furthermore, the involvement of the International Life Sciences Institute as the overall organizing, facilitating umbrella was crucial for the success of the project.
Assuntos
Alternativas aos Testes com Animais/métodos , Testes de Carcinogenicidade/métodos , Carcinógenos/toxicidade , Modelos Animais de Doenças , Neoplasias Experimentais/induzido quimicamente , Academias e Institutos , Alternativas aos Testes com Animais/tendências , Animais , Testes de Carcinogenicidade/tendências , Humanos , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Neoplasias Experimentais/patologia , Política Pública , Ratos , Medição de Risco , Sociedades Científicas , Especificidade da Espécie , Estados Unidos , United States Food and Drug AdministrationRESUMO
The results of the present study have advanced dramatically the database on transgenic mouse abbreviated carcinogenicity bioassay models. As such, it will provide a secure foundation for future evaluations of these assays and for their eventual validation as models for the prediction of possible human carcinogens. Based upon the results derived from the present study, it is suggested that 5 areas require discussion as a prelude to the further evaluation of existing models and the future evaluation of new models. First, there is the need to agree a standard list of calibration chemicals to be studied and to derive agreement on optimal bioassay group sizes, statistical methods, and exposure periods. Second, general agreement must be reached regarding the classes/types of known rodent carcinogens so that it is acceptable for the new models to find negative, by implication, those rodent carcinogens considered not to pose a carcinogenic hazard to humans. Third, current understanding of mechanisms of carcinogenesis should be integrated into the evaluation of new bioassay models. Fourth, any changes made to the standard rodent carcinogenicity bioassay protocol will require compromises being made, and these should be commonly owned between interested parties in order to reduce the number of regional/agency-specific carcinogenicity testing schemes. Fifth, a mechanism needs to be developed by which assays can be adopted or rejected for use in the routine bioassay of chemicals. In the absence of such initiatives the increasing number of new bioassay models will come to exist along side of the standard 2-species bioassay, and this may potentially lead to confusion regarding the true future role of these assays.
Assuntos
Testes de Carcinogenicidade/métodos , Carcinógenos/toxicidade , Modelos Animais de Doenças , Neoplasias Experimentais/induzido quimicamente , Alternativas aos Testes com Animais , Animais , Testes de Carcinogenicidade/tendências , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Neoplasias Experimentais/genética , Neoplasias Experimentais/patologia , RatosRESUMO
The International Life Sciences Institute Alternative Carcinogenicity Testing (ILSI ACT) Workshop concluded with a panel discussion that addressed the framework issue of the appropriate application of alternative models to human cancer risk assessment. This discussion encompassed both technical issues relating to the level of understanding of these models and their output as well as issues relating to the regulatory acceptance of these data. Although there were many different perspectives represented by the panelists, there was also significant consensus on many broad issues. This article focuses on several key areas of emphasis that were addressed by panelists and are considered critical issues for future discussions and evaluations.
Assuntos
Testes de Carcinogenicidade/métodos , Carcinógenos/toxicidade , Modelos Animais de Doenças , Neoplasias Experimentais/induzido quimicamente , Academias e Institutos , Alternativas aos Testes com Animais , Animais , Testes de Carcinogenicidade/tendências , Humanos , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Neoplasias Experimentais/genética , Neoplasias Experimentais/patologia , Ratos , Medição de Risco , Sociedades CientíficasRESUMO
Twenty-one chemicals were evaluated by standardized protocols in 6 mouse models that have been sugggested as alternatives to the 2-year mouse bioassay. Included were genotoxic and nongenotoxic chemicals, carcinogens and noncarcinogens, immunosuppressive and estrogenic agents, peroxisome proliferators, and chemicals producing cancer in rodents by other mechanisms. Mice were sacrificed at the end of 6 to 12 months, depending on the model. Standardized histopathology, biostatistical analyses, and criteria for overall evaluation of the results were employed. The TgAC transgenic (dermal and oral administration), the Tg-rasH2 transgenic, the heterozygous p53 gene knockout, the homozygous XPA and homozygous XPA-heterozygous p53 gene knockout, and the neonatal mouse models were evaluated. The chemicals were also evaluated in the in vitro SHE assay. Comparison of the results between the various in vivo models suggest that they might have usefulness as screening bioassays for hazard identification for potential human carcinogens. They have the benefits of being quicker, less expensive, and involve fewer animals than the traditional 2-year mouse bioassay. They do not appear to be overly sensitive. However, they do not definitively distinguish between genotoxic and nongenotoxic carcinogens, and they do not have 100% specificity for identifying human carcinogens. Like the 2-year bioassay, the results from these models need to be evaluated in conjunction with other information on a chemical in an overall weight-of-evidence, integrated analytical approach to assess risk for human exposures.
Assuntos
Testes de Carcinogenicidade/métodos , Carcinógenos/toxicidade , Modelos Animais de Doenças , Mutagênicos/toxicidade , Neoplasias Experimentais/induzido quimicamente , Alternativas aos Testes com Animais , Animais , Testes de Carcinogenicidade/tendências , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Neoplasias Experimentais/genética , Neoplasias Experimentais/patologia , Ratos , Reprodutibilidade dos Testes , Medição de Risco , Sensibilidade e EspecificidadeRESUMO
In the sixties of the last century it was realized that many human cancers are caused by environmental carcinogens and that the best way how to reduce cancer is first to identify in environment chemical carcinogens and second to prevent people from being exposed to such carcinogens. Epidemiological studies are probably the only way to confirm human carcinogenesis, however, this approach is so retrospective that carcinogens can be identified only after many victims have appeared. Carcinogenicity testing in long-term, medium-term, and short-term studies is therefore the only way for the prospective identification of possible human carcinogens. End-points of interest in a carcinogenicity study are primarily preneoplastic and neoplastic changes, but also include degree of malignancy, time to tumor appearance, multiplicity of (pre)neoplasia, and occurence of metastases. Long-term bioassays are designed and conducted to detect all of these end-points. Medium-term bioassays are mainly based on the detection of putative preneoplastic lesions and short-term tests can provide very important information concerning genotoxic effects of studied compounds.
Assuntos
Testes de Carcinogenicidade/métodos , Carcinógenos Ambientais/toxicidade , Neoplasias/induzido quimicamente , Animais , Animais Geneticamente Modificados , Testes de Carcinogenicidade/tendências , Modelos Animais de Doenças , Humanos , Testes de Mutagenicidade/métodos , Testes de Mutagenicidade/tendências , Fatores de TempoRESUMO
Prevention of human cancer in the future will depend on using the results of epidemiologic and animal studies and strategies to minimize exposure. Changes are occurring in the area of animal testing and research that potentially represent significant steps toward reducing our dependence on the traditional 2-year bioassay as our primary tool for identification of chemical carcinogens and management of risk. Efforts to prevent cancer would be enhanced by more attention to describing modes of action so that the development of tumors would not be the only basis for predicting carcinogenic potential. These markers might also serve for early detection of cancer at a stage more amenable to treatment. What carcinogens do we want to detect through animal tests in the future? Whether the goal is to identify weak or potent carcinogens, or both, there will still be a need for 2-year bioassays, but hopefully for confirmatory rather than screening purposes.
Assuntos
Testes de Carcinogenicidade , Neoplasias , United States Food and Drug Administration , Animais , Testes de Carcinogenicidade/métodos , Testes de Carcinogenicidade/tendências , Humanos , Neoplasias/epidemiologia , Neoplasias/prevenção & controle , Gestão de Riscos , Estados UnidosRESUMO
At the present time, karyology and tumorigenicity are applied to primary, diploid, and continuous cell systems in an uneven and inappropriate manner, largely for historical reasons. It is a significant anomaly that such rigorous requirements are applied only to diploid cells when, of all three cell types, they represent the category with the least potential problems. During the 1992 presidential campaign in the U.S., a very direct and telling slogan was used to the advantage of Mr. Clinton: <
Assuntos
Testes de Carcinogenicidade/tendências , Técnicas de Cultura de Células/tendências , Cariotipagem , Animais , Humanos , Cariotipagem/métodos , Cultura de VírusRESUMO
Transgenic mouse modelling has proved to be a powerful approach to explore the various steps involved in spontaneous and induced carcinogenesis. Some of the multitude of models currently available have the potential to become a substitute for the expensive, long-term rodent bioassay to predict carcinogenicity of environmental compounds. Here, we review the progress in the development and use of transgenic mouse models specifically for the purpose of carcinogenicity and mutagenicity testing.