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1.
Crit Rev Toxicol ; 50(1): 72-95, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-32133908

RESUMO

The European Centre for Ecotoxicology and Toxicology of Chemicals (ECETOC) organized a workshop "Hazard Identification, Classification and Risk Assessment of Carcinogens: Too Much or Too Little?" to explore the scientific limitations of the current binary carcinogenicity classification scheme that classifies substances as either carcinogenic or not. Classification is often based upon the rodent 2-year bioassay, which has scientific limitations and is not necessary to predict whether substances are likely human carcinogens. By contrast, tiered testing strategies founded on new approach methodologies (NAMs) followed by subchronic toxicity testing, as necessary, are useful to determine if a substance is likely carcinogenic, by which mode-of-action effects would occur and, for non-genotoxic carcinogens, the dose levels below which the key events leading to carcinogenicity are not affected. Importantly, the objective is not for NAMs to mimic high-dose effects recorded in vivo, as these are not relevant to human risk assessment. Carcinogenicity testing at the "maximum tolerated dose" does not reflect human exposure conditions, but causes major disturbances of homeostasis, which are very unlikely to occur at relevant human exposure levels. The evaluation of findings should consider biological relevance and not just statistical significance. Using this approach, safe exposures to non-genotoxic substances can be established.


Assuntos
Testes de Carcinogenicidade/métodos , Carcinógenos/toxicidade , Carcinógenos/classificação , Ecotoxicologia , Humanos , Medição de Risco/métodos
2.
Regul Toxicol Pharmacol ; 108: 104444, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31433998

RESUMO

One of the important tasks of the German Senate Commission for the Investigation of Health Hazards of Chemical Compounds in the Work Area (known as the MAK Commission) is in the evaluation of a potential for carcinogenicity of hazardous substances at the workplace. Often, this evaluation is critically based on data on carcinogenic responses seen in animal studies and, if positive tumor responses have been observed, this will mostly lead to a classification of the substance under investigation into one of the classes for carcinogens. However, there are cases where it can be demonstrated with a very high degree of confidence that the tumor findings in the experimental animals are not relevant for humans at the workplace and, therefore, the MAK Commission will not classify the respective substance into one of the classes for carcinogens. This paper will summarize the general criteria used by the MAK Commission for the categorization into "carcinogen" and "non-carcinogen" and compare this procedure with those used by other national and international organizations.


Assuntos
Poluentes Ocupacionais do Ar/classificação , Carcinógenos/classificação , Guias como Assunto , Poluentes Ocupacionais do Ar/toxicidade , Animais , Carcinógenos/toxicidade , Alemanha , Órgãos Governamentais , Humanos , Agências Internacionais , Neoplasias/induzido quimicamente , Doenças Profissionais/induzido quimicamente , Exposição Ocupacional , Medição de Risco , Especificidade da Espécie
3.
Toxicol Sci ; 169(1): 14-24, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-30649495

RESUMO

We developed an integrated, modular approach to predicting chemical toxicity relying on in vitro assay data, linkage of molecular targets to disease categories, and software for ranking chemical activity and examining structural features (chemotypes). We evaluate our approach in a proof-of-concept exercise to identify and prioritize chemicals of potential carcinogenicity concern. We identified 137 cancer pathway-related assays from a subset of U.S. EPA's ToxCast platforms. We mapped these assays to key characteristics of carcinogens and found they collectively assess 5 of 10 characteristics. We ranked all 1061 chemicals screened in Phases I and II of ToxCast by their activity in the selected cancer pathway-related assays using Toxicological Prioritization Index software. More chemicals used as biologically active agents (eg, pharmaceuticals) ranked in the upper 50% versus lower 50%. Twenty-three chemotypes are enriched in the top 5% (n = 54) of chemicals; these features may be important for their activity in cancer pathway-related assays. The biological coverage of the ToxCast assays related to cancer pathways is limited and short-term assays may not capture the biology of some key characteristics. Metabolism is also minimal in the assays. The ability of our approach to identify chemicals with cancer hazard is limited with the current input data, but we expect that our approach can be applied with future iterations of ToxCast and other data for improved chemical prioritization and characterization. The novel approach and proof-of-concept exercise described here for ranking chemicals for potential carcinogenicity concern is modular, adaptable, and amenable to evolving data streams.


Assuntos
Carcinógenos/toxicidade , Transformação Celular Neoplásica/induzido quimicamente , Mineração de Dados , Bases de Dados de Compostos Químicos , Neoplasias/induzido quimicamente , Toxicologia/métodos , Animais , Carcinógenos/química , Carcinógenos/classificação , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/imunologia , Transformação Celular Neoplásica/patologia , Regulação Neoplásica da Expressão Gênica , Humanos , Estrutura Molecular , Neoplasias/genética , Neoplasias/imunologia , Neoplasias/patologia , Estudo de Prova de Conceito , Medição de Risco , Fatores de Risco , Transdução de Sinais , Relação Estrutura-Atividade
4.
Regul Toxicol Pharmacol ; 103: 124-129, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30660801

RESUMO

Developments in the understanding of the etiology of cancer have undermined the 1970s concept that chemicals are either "carcinogens" or "non-carcinogens". The capacity to induce cancer should not be classified in an inflexible binary manner as present (carcinogen) or absent (non-carcinogen). Chemicals may induce cancer by three categories of mode of action: direct interaction with DNA or DNA replication including DNA repair and epigenetics; receptor-mediated induction of cell division; and non-specific induction of cell division. The long-term rodent bioassay is neither appropriate nor efficient to evaluate carcinogenic potential for humans and to inform risk management decisions. It is of questionable predicitiveness, expensive, time consuming, and uses hundreds of animals. Although it has been embedded in practice for over 50 years, it has only been used to evaluate less than 5% of chemicals that are in use. Furthermore, it is not reproducible because of the probabilisitic nature of the process it is evaluating combined with dose limiting toxicity, dose selection, and study design. The modes of action that lead to the induction of tumors are already considered under other hazardous property categories in classification (Mutagenicity/Genotoxicity and Target Organ Toxicity); a separate category for Carcinogenicity is not required and provides no additional public health protection.


Assuntos
Carcinogênese/induzido quimicamente , Carcinógenos/classificação , Carcinógenos/farmacologia , Animais , Testes de Carcinogenicidade , Carcinógenos/toxicidade , Humanos , Reprodutibilidade dos Testes
5.
Bull Cancer ; 106(7-8): 665-677, 2019.
Artigo em Francês | MEDLINE | ID: mdl-30551793

RESUMO

Since 2008, cancer became the first cause of death in France, exceeding cardiovascular diseases. The part of occupational cancers is close to 5% of all cancers but may still be widely underestimated. The detection of occupational cancer risk factors remains complicated. Indeed, most occupational risk factors are also present in the general environment. Thus far, 36 substances and 13 activities have been classified as carcinogenic (Group 1) and 37 substances and 6 activities have been classified as probably carcinogenic (Group 2A) by the International Agency for Research on Cancer (IARC). The most common cancer site is the lung, followed by bladder and skin (except melanoma). The most frequently observed occupational exposure was chemicals, building and construction, mining, metal production and coal transformation. Thus far, preventive actions are mandatory in occupational health in France, and are about occupational exposure monitoring, protection of vulnerable populations and reinforced medical supervision. Research must be continued to improve the knowledge on occupational carcinogens, in order to better protect the health of workers.


Assuntos
Neoplasias/etiologia , Doenças Profissionais/etiologia , Carcinógenos/classificação , Carcinógenos/toxicidade , França/epidemiologia , Humanos , Neoplasias/epidemiologia , Neoplasias/prevenção & controle , Doenças Profissionais/epidemiologia , Doenças Profissionais/prevenção & controle , Exposição Ocupacional/efeitos adversos , Fatores de Risco
6.
Toxicol Pathol ; 47(1): 82-92, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30585133

RESUMO

The 6-month Tg.rasH2 mouse carcinogenicity model provides an acceptable alternative to the 2-year carcinogenicity study in CD-1 mice. However, key questions related to the use of this model for testing antisense oligonucleotides (ASOs) include the similarity in the biologic response between mouse strains and the feasibility of using data from the CD-1 mouse to set doses and dose schedules for a Tg.rasH2 carcinogenicity study. To evaluate the potential strain differences, four distinct 2'- O-(2-methoxyethyl) ASOs were administered to CByB6F1 (wild type), Tg.rasH2 (hemizygous), and CD-1 mice. There were no meaningful differences in clinical signs, body weight, food consumption, or serum chemistry and hematology parameters. Histopathology evaluation indicated little to no difference in the spectrum or magnitude of changes present. The cytokine/chemokine response was also not appreciably different between the strains. This was consistent with the similarity in ASO concentration in the liver between the mouse strains tested. As the class effects of the ASOs were not meaningfully different between CD-1, CByB6F1, or Tg.rasH2 mice, data from nonclinical studies in CD-1 mice can be used for dose selection and expectation of effect in the Tg.rasH2 mouse.


Assuntos
Carcinógenos/toxicidade , Genes ras , Oligonucleotídeos Antissenso/toxicidade , Oligorribonucleotídeos/toxicidade , Testes de Toxicidade , Animais , Sequência de Bases , Carcinógenos/classificação , Carcinógenos/farmacocinética , Citocinas/sangue , Feminino , Hemizigoto , Masculino , Camundongos Endogâmicos ICR , Camundongos Transgênicos , Oligonucleotídeos Antissenso/classificação , Oligonucleotídeos Antissenso/farmacocinética , Oligorribonucleotídeos/classificação , Oligorribonucleotídeos/farmacocinética , Tamanho do Órgão/efeitos dos fármacos , Especificidade de Órgãos , Especificidade da Espécie , Fatores de Tempo , Distribuição Tecidual , Testes de Toxicidade/métodos , Testes de Toxicidade/normas
7.
Braz. j. pharm. sci ; 55: e18217, 2019. tab, graf
Artigo em Inglês | LILACS | ID: biblio-1011649

RESUMO

The International Agency for Research on Cancer (IARC) placed the most widely used herbicide glyphosate (GLY) into the category 2A (probably carcinogenic to humans), a classification questioned by experts from academia and industry. This article critically appraised the epidemiological and experimental data that led the IARC working group (WG) to consider GLY a probable human carcinogen and the ensuing controversy. An association of GLY with non-Hodgkin lymphoma was suggested by some observational studies. A non-causal explanation for this weak association, however, cannot be excluded. Contrary to WG's view, long-term rodent assays yielded no convincing evidence that GLY is carcinogenic. The mechanistic evidence remains elusive as well. Bacterial reverse mutation tests (including tester strains sensitive to oxidative mutagens) were clearly negative, and so were rodent genotoxicity assays by oral route. Tests with mammalian cells in vitro yielded conflicting results at high (cytotoxic) concentrations of GLY-based formulations. Conflicting results were also obtained when high doses of GLY-based herbicides were administered to rodents by the intraperitoneal route. Such high doses are unlikely to be attained in realistic scenarios of exposure. Finally, the IARC classification is based on a conjectural hazard, and rational public health interventions must be based on estimated risks.


Assuntos
Animais , Masculino , Feminino , Camundongos , Ratos , Praguicidas/toxicidade , Carcinógenos/classificação , Herbicidas/análise , Técnicas In Vitro/instrumentação , Estudos Epidemiológicos , Epidemiologia Experimental , Genotoxicidade/prevenção & controle
8.
Toxicol Appl Pharmacol ; 356: 99-113, 2018 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-30048669

RESUMO

Chemicals induce liver cancer in rodents through well characterized adverse outcome pathways (AOPs). We hypothesized that measurement of molecular initiating events (MIEs) and downstream key events (KEs) in liver cancer AOPs in short-term assays will allow early identification of chemicals and their associated doses that are likely to be tumorigenic in the liver in two-year bioassays. We tested this hypothesis using the rat in vivo TG-GATES study data to measure MIEs (genotoxicity, cytotoxicity, AhR, CAR, ER, PPARα) and associated KEs (oxidative stress, cell proliferation, liver to body weights) across 77 chemicals that could be linked to doses with previously established effects on rat liver tumor induction. Gene expression biomarkers for MIEs generally considered to be rodent specific and human irrelevant (CAR, PPARα) and for MIEs that would be considered of greater risk at human relevant exposures (ER, AhR) were built using microarray comparisons from the livers of rats treated with prototypical activators of the receptors. The genotoxicity biomarker, also a potentially human relevant MIE, was comprised of 7 p53-responsive genes known to be induced upon DNA damage. The ability of the biomarkers to accurately predict MIE activation ranged from 91% to 98%. The Toxicological Priority Index (ToxPi) was used to rank chemicals based on their ability to activate MIEs/KEs. Chemicals administered at tumorigenic doses clearly gave the highest ranked scores. Our AOP-directed approach could be used in short term assays to identify chemicals and their doses that would be predicted to cause liver tumors in rats.


Assuntos
Rotas de Resultados Adversos , Testes de Carcinogenicidade/métodos , Carcinógenos/toxicidade , Neoplasias Hepáticas Experimentais/induzido quimicamente , Animais , Biomarcadores Tumorais/metabolismo , Peso Corporal/efeitos dos fármacos , Carcinógenos/classificação , Dano ao DNA/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Neoplasias Hepáticas Experimentais/patologia , Tamanho do Órgão/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley
9.
Carcinogenesis ; 39(4): 614-622, 2018 04 05.
Artigo em Inglês | MEDLINE | ID: mdl-29562322

RESUMO

Smith et al. (Env. Health Perspect. 124: 713, 2016) identified 10 key characteristics (KCs), one or more of which are commonly exhibited by established human carcinogens. The KCs reflect the properties of a cancer-causing agent, such as 'is genotoxic,' 'is immunosuppressive' or 'modulates receptor-mediated effects,' and are distinct from the hallmarks of cancer, which are the properties of tumors. To assess feasibility and limitations of applying the KCs to diverse agents, methods and results of mechanistic data evaluations were compiled from eight recent IARC Monograph meetings. A systematic search, screening and evaluation procedure identified a broad literature encompassing multiple KCs for most (12/16) IARC Group 1 or 2A carcinogens identified in these meetings. Five carcinogens are genotoxic and induce oxidative stress, of which pentachlorophenol, hydrazine and malathion also showed additional KCs. Four others, including welding fumes, are immunosuppressive. The overall evaluation was upgraded to Group 2A based on mechanistic data for only two agents, tetrabromobisphenol A and tetrachloroazobenzene. Both carcinogens modulate receptor-mediated effects in combination with other KCs. Fewer studies were identified for Group 2B or 3 agents, with the vast majority (17/18) showing only one or no KCs. Thus, an objective approach to identify and evaluate mechanistic studies pertinent to cancer revealed strong evidence for multiple KCs for most Group 1 or 2A carcinogens but also identified opportunities for improvement. Further development and mapping of toxicological and biomarker endpoints and pathways relevant to the KCs can advance the systematic search and evaluation of mechanistic data in carcinogen hazard identification.


Assuntos
Testes de Carcinogenicidade/métodos , Carcinógenos/classificação , Neoplasias/induzido quimicamente , Animais , Humanos
10.
Regul Toxicol Pharmacol ; 86: 157-166, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28274811

RESUMO

The International Agency for Research on Cancer (IARC) has formulated 10 key characteristics of human carcinogens to incorporate mechanistic data into cancer hazard classifications. The analysis used glyphosate as a case example to examine the robustness of IARC's determination of oxidative stress as "strong" evidence supporting a plausible cancer mechanism in humans. The IARC analysis primarily relied on 14 human/mammalian studies; 19 non-mammalian studies were uninformative of human cancer given the broad spectrum of test species and extensive use of formulations and aquatic testing. The mammalian studies had substantial experimental limitations for informing cancer mechanism including use of: single doses and time points; cytotoxic/toxic test doses; tissues not identified as potential cancer targets; glyphosate formulations or mixtures; technically limited oxidative stress biomarkers. The doses were many orders of magnitude higher than human exposures determined in human biomonitoring studies. The glyphosate case example reveals that the IARC evaluation fell substantially short of "strong" supporting evidence of oxidative stress as a plausible human cancer mechanism, and suggests that other IARC monographs relying on the 10 key characteristics approach should be similarly examined for a lack of robust data integration fundamental to reasonable mode of action evaluations.


Assuntos
Carcinógenos/classificação , Glicina/análogos & derivados , Agências Internacionais , Neoplasias/induzido quimicamente , Estresse Oxidativo , Animais , Carcinógenos/toxicidade , Glicina/administração & dosagem , Glicina/toxicidade , Humanos
11.
Regul Toxicol Pharmacol ; 88: 291-302, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28119000

RESUMO

For the proper regulation of a carcinogenic material it is necessary to fully understand its mode of action, and in particular whether it demonstrates a threshold of effect. This paper explores our present understanding of carcinogenicity and the mechanisms underlying the carcinogenic response. The concepts of genotoxic and non-genotoxic and threshold and non-threshold carcinogens are fully described. We provide summary tables of the types of cancer considered to be associated with exposure to a number of carcinogens and the available evidence relating to whether carcinogenicity occurs through a threshold or non-threshold mechanism. In light of these observations we consider how different regulatory bodies approach the question of chemical carcinogenesis, looking in particular at the definitions and methodologies used to derive Occupational Exposure Levels (OELs) for carcinogens. We conclude that unless proper differentiation is made between threshold and non-threshold carcinogens, inappropriate risk management measures may be put in place - and lead also to difficulties in translating carcinogenicity research findings into appropriate health policies. We recommend that clear differentiation between threshold and non-threshold carcinogens should be made by all expert groups and regulatory bodies dealing with carcinogen classification and risk assessment.


Assuntos
Carcinogênese , Carcinógenos/toxicidade , Neoplasias/induzido quimicamente , Carcinógenos/classificação , Humanos , Exposição Ocupacional , Medição de Risco
12.
Regul Toxicol Pharmacol ; 83: 66-80, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-27871870

RESUMO

Perfluoroalkyls are stable synthetic chemicals, able to repel oils, fats and water. These compounds have been used in the manufacturing of products such as Teflon®, lubricants, paints, fire-fighting foams, coatings for pans, carpets, clothes, and paperboard for packaging, among others. It is believed that populations are exposed constantly to them. Its regulation in the world is under development and several controversies are in the course of litigation. One occupational study shows bladder cancer risk. This paper intends to review scientific information on the most critical perfluoroalkyl compound and proposes a procedure to get a cancer-risk categorization which PFOS can cause to populations. METHODS: As a guiding axis, we used the IARC process for developing monographs of carcinogenic risks. We used the SIGN guides for evaluating the quality of studies in human populations; and finally, we used the Squire method for evaluating studies in laboratory animals. Inadequate evidence of carcinogenicity was found in human studies mainly due to chance, threshold effect and confounders. In experimental animal studies, inadequate evidence of carcinogenicity was found in view of the number of affected species, different types of neoplasms, dose-response relationship and genotoxicity found in in-vivo and in-vitro studies. In this proposal, we concluded that cancer risk for PFOS, according to the IARC method, is not classifiable as carcinogenic to humans (group 3).


Assuntos
Ácidos Alcanossulfônicos/toxicidade , Carcinógenos/toxicidade , Transformação Celular Neoplásica/induzido quimicamente , Poluentes Ambientais/toxicidade , Fluorcarbonetos/toxicidade , Neoplasias/induzido quimicamente , Doenças Profissionais/induzido quimicamente , Terminologia como Assunto , Ácidos Alcanossulfônicos/classificação , Animais , Testes de Carcinogenicidade , Carcinógenos/classificação , Transformação Celular Neoplásica/genética , Relação Dose-Resposta a Droga , Poluentes Ambientais/classificação , Fluorcarbonetos/classificação , Humanos , Testes de Mutagenicidade , Neoplasias/epidemiologia , Neoplasias/genética , Doenças Profissionais/genética , Exposição Ocupacional/efeitos adversos , Saúde do Trabalhador , Medição de Risco , Fatores de Risco
13.
Regul Toxicol Pharmacol ; 82: 158-166, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27780763

RESUMO

Classification schemes for carcinogenicity based solely on hazard-identification such as the IARC monograph process and the UN system adopted in the EU have become outmoded. They are based on a concept developed in the 1970s that chemicals could be divided into two classes: carcinogens and non-carcinogens. Categorization in this way places into the same category chemicals and agents with widely differing potencies and modes of action. This is how eating processed meat can fall into the same category as sulfur mustard gas. Approaches based on hazard and risk characterization present an integrated and balanced picture of hazard, dose response and exposure and allow informed risk management decisions to be taken. Because a risk-based decision framework fully considers hazard in the context of dose, potency, and exposure the unintended downsides of a hazard only approach are avoided, e.g., health scares, unnecessary economic costs, loss of beneficial products, adoption of strategies with greater health costs, and the diversion of public funds into unnecessary research. An initiative to agree upon a standardized, internationally acceptable methodology for carcinogen assessment is needed now. The approach should incorporate principles and concepts of existing international consensus-based frameworks including the WHO IPCS mode of action framework.


Assuntos
Testes de Carcinogenicidade/métodos , Carcinógenos/classificação , Carcinógenos/toxicidade , Terminologia como Assunto , Alternativas aos Testes com Animais , Animais , Bioensaio , Relação Dose-Resposta a Droga , Humanos , Reprodutibilidade dos Testes , Medição de Risco , Especificidade da Espécie
14.
Food Chem Toxicol ; 97: 141-149, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27597133

RESUMO

The carcinogenicity prediction has become a significant issue for the pharmaceutical industry. The purpose of this investigation was to develop a novel prediction model of carcinogenicity of chemicals by using a naïve Bayes classifier. The established model was validated by the internal 5-fold cross validation and external test set. The naïve Bayes classifier gave an average overall prediction accuracy of 90 ± 0.8% for the training set and 68 ± 1.9% for the external test set. Moreover, five simple molecular descriptors (e.g., AlogP, Molecular weight (MW), No. of H donors, Apol and Wiener) considered as important for the carcinogenicity of chemicals were identified, and some substructures related to the carcinogenicity were achieved. Thus, we hope the established naïve Bayes prediction model could be applied to filter early-stage molecules for this potential carcinogenicity adverse effect; and the identified five simple molecular descriptors and substructures of carcinogens would give a better understanding of the carcinogenicity of chemicals, and further provide guidance for medicinal chemists in the design of new candidate drugs and lead optimization, ultimately reducing the attrition rate in later stages of drug development.


Assuntos
Teorema de Bayes , Testes de Carcinogenicidade/métodos , Carcinógenos/classificação , Carcinógenos/toxicidade , Modelos Estatísticos , Neoplasias/induzido quimicamente , Animais , Carcinógenos/química , Simulação por Computador , Bases de Dados de Compostos Químicos , Ratos
15.
Regul Toxicol Pharmacol ; 81: 89-105, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27480961

RESUMO

The aim of this paper is to compare results from inhalation studies with those from intraperitoneal and intrapleural tests, where available, for a number of fibrous and particulate test materials. The objective is to determine how well intraperitoneal/intrapleural studies predict the pathological responses observed in more standard in vivo studies of pulmonary toxicity, with a particular focus on carcinogenicity. Published toxicity data was obtained for a number of materials including asbestos, wollastonite, MMVFs (including glass fibres, stone wools and RCF), silicon carbide whiskers, potassium octatitanate, quartz, kevlar, polypropylene and titanium dioxide. For some of the fibrous material reviewed, there is conformity between the results of intraperitoneal and inhalation tests such that they are either consistently positive or consistently negative. For the remaining fibrous materials reviewed, intraperitoneal and inhalation tests give different results, with positive results in the intraperitoneal test not being reflected by positive inhalation results. It is suggested that the intraperitoneal test can be used to exonerate a dust or fibre (because if negative in the intraperitoneal test it is extremely unlikely to be positive in either inhalation or intratracheal tests) but should not be used to positively determine that a dust or fibre is carcinogenic by inhalation. We would argue against the use of intraperitoneal tests for human health risk assessment except perhaps for the purpose of exoneration of a material from classification as a carcinogen.


Assuntos
Testes de Carcinogenicidade , Carcinógenos/toxicidade , Poeira , Exposição por Inalação/efeitos adversos , Neoplasias Pulmonares/induzido quimicamente , Pulmão/efeitos dos fármacos , Material Particulado/toxicidade , Peritônio/efeitos dos fármacos , Pleura/efeitos dos fármacos , Testes de Toxicidade/métodos , Animais , Carcinógenos/classificação , Humanos , Injeções Intraperitoneais , Pulmão/patologia , Neoplasias Pulmonares/patologia , Material Particulado/classificação , Peritônio/patologia , Pleura/patologia , Reprodutibilidade dos Testes , Medição de Risco
17.
Regul Toxicol Pharmacol ; 77: 54-64, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-26879462

RESUMO

A recent research article by the National Center for Computational Toxicology (NCCT) (Kleinstreuer et al., 2013), indicated that high throughput screening (HTS) data from assays linked to hallmarks and presumed pathways of carcinogenesis could be used to predict classification of pesticides as either (a) possible, probable or likely rodent carcinogens; or (b) not likely carcinogens or evidence of non-carcinogenicity. Using independently developed software to validate the computational results, we replicated the majority of the results reported. We also found that the prediction model correlating cancer pathway bioactivity scores with in vivo carcinogenic effects in rodents was not robust. A change of classification of a single chemical in the test set was capable of changing the overall study conclusion about the statistical significance of the correlation. Furthermore, in the subset of pesticide compounds used in model validation, the accuracy of prediction was no better than chance for about three quarters of the chemicals (those with fewer than 7 positive outcomes in HTS assays representing the 11 histopathological endpoints used in model development), suggesting that the prediction model was not adequate to predict cancer hazard for most of these chemicals. Although the utility of the model for humans is also unclear because a number of the rodent responses modeled (e.g., mouse liver tumors, rat thyroid tumors, rat testicular tumors, etc.) are not considered biologically relevant to human responses, the data examined imply the need for further research with HTS assays and improved models, which might help to predict classifications of in vivo carcinogenic responses in rodents for the pesticide considered, and thus reduce the need for testing in laboratory animals.


Assuntos
Bioensaio , Testes de Carcinogenicidade/métodos , Carcinógenos/toxicidade , Ensaios de Triagem em Larga Escala , Neoplasias/induzido quimicamente , Praguicidas/toxicidade , Animais , Carcinógenos/classificação , Simulação por Computador , Técnicas de Apoio para a Decisão , Relação Dose-Resposta a Droga , Humanos , Camundongos , Modelos Estatísticos , Razão de Chances , Praguicidas/classificação , Ratos , Reprodutibilidade dos Testes , Medição de Risco , Especificidade da Espécie , Fatores de Tempo
18.
Arch Toxicol ; 90(9): 2215-2229, 2016 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26525393

RESUMO

The assessment of the carcinogenic potential of chemicals with alternative, human-based in vitro systems has become a major goal of toxicogenomics. The central read-out of these assays is the transcriptome, and while many studies exist that explored the gene expression responses of such systems, reports on robustness and reproducibility, when testing them independently in different laboratories, are still uncommon. Furthermore, there is limited knowledge about variability induced by the data analysis protocols. We have conducted an inter-laboratory study for testing chemical carcinogenicity evaluating two human in vitro assays: hepatoma-derived cells and hTERT-immortalized renal proximal tubule epithelial cells, representing liver and kidney as major target organs. Cellular systems were initially challenged with thirty compounds, genome-wide gene expression was measured with microarrays, and hazard classifiers were built from this training set. Subsequently, each system was independently established in three different laboratories, and gene expression measurements were conducted using anonymized compounds. Data analysis was performed independently by two separate groups applying different protocols for the assessment of inter-laboratory reproducibility and for the prediction of carcinogenic hazard. As a result, both workflows came to very similar conclusions with respect to (1) identification of experimental outliers, (2) overall assessment of robustness and inter-laboratory reproducibility and (3) re-classification of the unknown compounds to the respective toxicity classes. In summary, the developed bioinformatics workflows deliver accurate measures for inter-laboratory comparison studies, and the study can be used as guidance for validation of future carcinogenicity assays in order to implement testing of human in vitro alternatives to animal testing.


Assuntos
Carcinógenos/toxicidade , Biologia Computacional , Perfilação da Expressão Gênica , Túbulos Renais Proximais/efeitos dos fármacos , Ensaio de Proficiência Laboratorial , Fígado/efeitos dos fármacos , Toxicogenética/métodos , Transcriptoma/efeitos dos fármacos , Carcinógenos/classificação , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Regulação da Expressão Gênica/efeitos dos fármacos , Estudo de Associação Genômica Ampla , Humanos , Túbulos Renais Proximais/metabolismo , Fígado/metabolismo , Variações Dependentes do Observador , Análise de Sequência com Séries de Oligonucleotídeos , Reprodutibilidade dos Testes , Medição de Risco , Fatores de Tempo , Fluxo de Trabalho
20.
Chem Res Toxicol ; 28(8): 1636-46, 2015 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-26198647

RESUMO

It is widely accepted that in chemical carcinogenesis different modes-of-action exist, e.g., genotoxic (GTX) versus nongenotoxic (NGTX) carcinogenesis. In this context, it has been suggested that oxidative stress response pathways are typical for NGTX carcinogenesis. To evaluate this, we examined oxidative stress-related changes in gene expression, cell cycle distribution, and (oxidative) DNA damage in human hepatoma cells (HepG2) exposed to GTX-, NGTX-, and noncarcinogens, at multiple time points (4-8-24-48-72 h). Two GTX (azathriopine (AZA) and furan) and two NGTX (tetradecanoyl-phorbol-acetate, (TPA) and tetrachloroethylene (TCE)) carcinogens as well as two noncarcinogens (diazinon (DZN, d-mannitol (Dman)) were selected, while per class one compound was deemed to induce oxidative stress and the other not. Oxidative stressors AZA, TPA, and DZN induced a 10-fold higher number of gene expression changes over time compared to those of furan, TCE, or Dman treatment. Genes commonly expressed among AZA, TPA, and DZN were specifically involved in oxidative stress, DNA damage, and immune responses. However, differences in gene expression between GTX and NGTX carcinogens did not correlate to oxidative stress or DNA damage but could instead be assigned to compound-specific characteristics. This conclusion was underlined by results from functional readouts on ROS formation and (oxidative) DNA damage. Therefore, oxidative stress may represent the underlying cause for increased risk of liver toxicity and even carcinogenesis; however, it does not discriminate between GTX and NGTX carcinogens.


Assuntos
Carcinógenos/classificação , Fígado/patologia , Estresse Oxidativo , Carcinógenos/toxicidade , Dano ao DNA , Células Hep G2 , Humanos , Espécies Reativas de Oxigênio/análise , Fatores de Tempo
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