Bioensayo de carcinogenicidad en roedores a 2-años: Desempeño, y valores predictivos para múltiples fármacos y otras sustancias de interés

ilustraciones, fotografías a color, gráficas

Autores:: Suarez Torres, Jose Daniel

Tipo de recurso:: Doctoral thesis

Fecha de publicación:: 2022

Institución:: Universidad Nacional de Colombia

Repositorio:: Universidad Nacional de Colombia

Idioma:: spa

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dc.title.spa.fl_str_mv	Bioensayo de carcinogenicidad en roedores a 2-años: Desempeño, y valores predictivos para múltiples fármacos y otras sustancias de interés
dc.title.translated.eng.fl_str_mv	Two-year rodent carcinogenicity bioassay: Performance, and predictive values for several pharmaceuticals and other chemicals of interest
title	Bioensayo de carcinogenicidad en roedores a 2-años: Desempeño, y valores predictivos para múltiples fármacos y otras sustancias de interés
spellingShingle	Bioensayo de carcinogenicidad en roedores a 2-años: Desempeño, y valores predictivos para múltiples fármacos y otras sustancias de interés 610 - Medicina y salud::615 - Farmacología y terapéutica 610 - Medicina y salud::612 - Fisiología humana Carcinogenesis Cáncer Patología Pathology Bioensayo de carcinogénesis a 2-años Carcinogénesis química Toxicología predictiva Farmacología traslacional Rodent carcinogenesis bioassay Rodent carcinogenicity bioassay Regulatory toxicology
title_short	Bioensayo de carcinogenicidad en roedores a 2-años: Desempeño, y valores predictivos para múltiples fármacos y otras sustancias de interés
title_full	Bioensayo de carcinogenicidad en roedores a 2-años: Desempeño, y valores predictivos para múltiples fármacos y otras sustancias de interés
title_fullStr	Bioensayo de carcinogenicidad en roedores a 2-años: Desempeño, y valores predictivos para múltiples fármacos y otras sustancias de interés
title_full_unstemmed	Bioensayo de carcinogenicidad en roedores a 2-años: Desempeño, y valores predictivos para múltiples fármacos y otras sustancias de interés
title_sort	Bioensayo de carcinogenicidad en roedores a 2-años: Desempeño, y valores predictivos para múltiples fármacos y otras sustancias de interés
dc.creator.fl_str_mv	Suarez Torres, Jose Daniel
dc.contributor.advisor.none.fl_str_mv	Ciangherotti Franco, Carlos Eduardo Orozco Sanabria, Camilo Alberto
dc.contributor.author.none.fl_str_mv	Suarez Torres, Jose Daniel
dc.contributor.researchgroup.spa.fl_str_mv	Farmacología y Fisiología Veterinaria
dc.contributor.orcid.spa.fl_str_mv	https://orcid.org/0000-0003-4696-8407
dc.contributor.scopus.spa.fl_str_mv	57210743673
dc.subject.ddc.spa.fl_str_mv	610 - Medicina y salud::615 - Farmacología y terapéutica 610 - Medicina y salud::612 - Fisiología humana
topic	610 - Medicina y salud::615 - Farmacología y terapéutica 610 - Medicina y salud::612 - Fisiología humana Carcinogenesis Cáncer Patología Pathology Bioensayo de carcinogénesis a 2-años Carcinogénesis química Toxicología predictiva Farmacología traslacional Rodent carcinogenesis bioassay Rodent carcinogenicity bioassay Regulatory toxicology
dc.subject.lemb.spa.fl_str_mv	Carcinogenesis Cáncer Patología
dc.subject.lemb.eng.fl_str_mv	Pathology
dc.subject.proposal.spa.fl_str_mv	Bioensayo de carcinogénesis a 2-años Carcinogénesis química Toxicología predictiva Farmacología traslacional
dc.subject.proposal.eng.fl_str_mv	Rodent carcinogenesis bioassay Rodent carcinogenicity bioassay Regulatory toxicology
description	ilustraciones, fotografías a color, gráficas
publishDate	2022
dc.date.accessioned.none.fl_str_mv	2022-12-01T22:59:49Z
dc.date.available.none.fl_str_mv	2022-12-01T22:59:49Z
dc.date.issued.none.fl_str_mv	2022-10-21
dc.type.spa.fl_str_mv	Trabajo de grado - Doctorado
dc.type.driver.spa.fl_str_mv	info:eu-repo/semantics/doctoralThesis
dc.type.version.spa.fl_str_mv	info:eu-repo/semantics/acceptedVersion
dc.type.coar.spa.fl_str_mv	http://purl.org/coar/resource_type/c_db06
dc.type.content.spa.fl_str_mv	Text
dc.type.redcol.spa.fl_str_mv	http://purl.org/redcol/resource_type/TD
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status_str	acceptedVersion
dc.identifier.uri.none.fl_str_mv	https://repositorio.unal.edu.co/handle/unal/82835
dc.identifier.instname.spa.fl_str_mv	Universidad Nacional de Colombia
dc.identifier.reponame.spa.fl_str_mv	Repositorio Institucional Universidad Nacional de Colombia
dc.identifier.repourl.spa.fl_str_mv	https://repositorio.unal.edu.co/
url	https://repositorio.unal.edu.co/handle/unal/82835 https://repositorio.unal.edu.co/
identifier_str_mv	Universidad Nacional de Colombia Repositorio Institucional Universidad Nacional de Colombia
dc.language.iso.spa.fl_str_mv	spa
language	spa
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spelling	Atribución-NoComercial-SinDerivadas 4.0 Internacionalhttp://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccesshttp://purl.org/coar/access_right/c_abf2Ciangherotti Franco, Carlos Eduardobcd2cda7cea4e747de33a9c1a2994eebOrozco Sanabria, Camilo Alberto8924ac60122482414881487d851c8622Suarez Torres, Jose Daniel9463a043c390aee5c523b1f261dbcc62600Farmacología y Fisiología Veterinariahttps://orcid.org/0000-0003-4696-8407572107436732022-12-01T22:59:49Z2022-12-01T22:59:49Z2022-10-21https://repositorio.unal.edu.co/handle/unal/82835Universidad Nacional de ColombiaRepositorio Institucional Universidad Nacional de Colombiahttps://repositorio.unal.edu.co/ilustraciones, fotografías a color, gráficasEl bioensayo de carcinogénesis en roedores a 2-años (RCB), todavía es el estándar de oro preclínico para predecir la carcinogenicidad innata para los humanos de las sustancias. Desde hace 40 años, el RCB es un requisito preclínico del que depende la aprobación gubernamental de la comercialización de una diversidad de sustancias, incluyendo (1) aditivos alimentarios; (2) principios activos de plaguicidas; (3) fármacos de uso crónico en humanos, y (4) fármacos de uso en animales productores de alimentos. Por su antigüedad, y por la necesidad que había en aquella época de implementar con urgencia pruebas preclínicas de toxicidad, el RCB se adoptó sin conocimiento empírico acerca de su desempeño predictivo. No obstante, aún se desconoce exactamente cuál es la sensibilidad y especificidad del RCB hacia los carcinógenos de humanos. Esta tesis doctoral es el producto de una investigación teórica basada en datos experimentales publicados en la literatura. En tal sentido, esta tesis se planteó las siguientes preguntas de investigación. Uno, ¿Cuál es la sensibilidad (SEN) y especificidad (SPEC) del RCB hacia los carcinógenos de humanos? Dos, considerando que la toxicología preclínica tiene un carácter y fines predictivos, ¿Cuál es la probabilidad cuantitativa de que carezcan de carcinogenicidad innata para los humanos, sustancias específicas que ya resultaron negativas en el RCB? Tres, ¿Cuál es la probabilidad cuantitativa de que sean connaturalmente carcinogénicas para los humanos, sustancias específicas que ya resultaron positivas en el RCB? Para responder dichas preguntas, esta tesis expandió y adaptó el marco matemático propuesto por la medicina humana para estimar la sensibilidad (SEN), especificidad (SPEC), y los valores predictivos de los resultados entregados por los exámenes de tamizaje (o cribaje). Como carcinógenos de humanos desde los cuales discernir la SEN del RCB, esta tesis reconoció a las sustancias que tienen suficiente evidencia epidemiológica de carcinogénesis en humanos, según las evaluaciones de la IARC, el U.S. NTP, o la U.S. EPA. En materia de resultados, y en términos de vías de exposición, las vías oral e inhalatoria del RCB exhibieron 95% o más de SEN hacia los carcinógenos de humanos de tipo mutagénico con alta potencia genotóxica. La vía inhalatoria del RCB presentó 88% de SEN hacia los carcinógenos de humanos por inhalación de tipo no-mutagénico. La vía oral del RCB presentó tan sólo 65% de SEN hacia los carcinógenos de humanos por ingestión de tipo no-mutagénico. Como no-carcinógenos de humanos desde los cuales dilucidar la SPEC del RCB, esta tesis reconoció a las sustancias que tienen suficiente evidencia mecanicista de que carecen de carcinogenicidad innata para los humanos (p. ej., evidencia mecanicista en términos de mecanismos de acción farmacológica, o mecanismos de acción toxicológica). Hacia los carcinógenos de humanos por ingestión de tipo no-mutagénico, y basado sólo en no-carcinógenos de humanos con muy bajo potencial de carcinogenicidad en el RCB, esta tesis estimó 95% o más de SPEC para la vía oral del RCB. Con base en las SENs y SPEC mencionadas previamente, y mediante las ecuaciones proporcionadas por (1) la estadística Bayesiana, o (2) por la aproximación desarrollada en esta tesis bajo el nombre de la probabilidad de verosimilitud, encontramos los siguientes resultados adicionales. Primero, 98% de probabilidad de que 52 sustancias específicas sean connaturalmente carcinogénicas para los humanos por ingestión o inyección, entre ellas numerosos fármacos de uso antineoplásico o no-antineoplásico en humanos. Segundo, un 96% de probabilidad de que otras 68 sustancias específicas carezcan de carcinogenicidad innata para los humanos por ingestión, incluyendo varios (1) colorantes de alimentos, medicamentos, y cosméticos; (2) principios activos de productos plaguicidas, y (3) fármacos de uso no-antineoplásico en humanos. De ese modo, esta tesis entregó una amplia discusión, así como numerosas conclusiones y recomendaciones acerca de (1) el desempeño del RCB como modelo para el pronóstico preclínico de la carcinogenicidad innata de las sustancias para los humanos; (2) distintas configuraciones para el RCB (p. ej., en términos de dosis, especies, o vías de exposición de los roedores a las sustancias de prueba); (3) del futuro del RCB en la práctica reguladora; (4) de las aproximaciones probabilísticas como una vía para traducir la relevancia (o insignificancia) clínica de hallazgos preclínicos particulares, y (5) la pertinencia de las predicciones de carcinogenicidad (o de carencia de carcinogenicidad) innata para los humanos, entregada por esta tesis para 120 sustancias específicas. (Texto tomado de la fuente)At the preclinical level, the 2-year rodent carcinogenesis bioassay (RCB) is the gold standard to predict the innate carcinogenicity to humans of substances. For 40 years, the RCB has been a preclinical requirement for the regulatory approval of a variety of chemicals, including (1) food additives; (2) active ingredients of pesticides; (3) pharmaceuticals for chronic use in humans, and (4) for drugs used in food-producing animals. Due to its antiquity, and the need in those days for an urgent deployment of preclinical tests, the RCB was adopted without knowledge of its true predictive performance. Although the RCB is regulatorily in force, the sensitivity and specificity of the RCB towards human carcinogens remain unknown. This doctoral thesis is the product of theoretical research based on experimental data available in the literature. In that respect, this thesis addressed the following research questions. One, what is the sensitivity (SEN) and specificity (SPEC) of the RCB towards human carcinogens? Two, considering the predictive nature and the predictive purpose of preclinical toxicology, what is the numerical probability that specific chemicals that tested negative in the RCB actually lack any carcinogenicity to humans? And third, what is the numerical probability that specific substances that tested positive in the RCB are innately carcinogenic to humans? To answer those questions, this thesis expanded and adapted the mathematical framework used in human medicine to evaluate the sensitivity (SEN), specificity (SPEC), and the predictive value of the results provided by medical screening tests. As human carcinogens (on which to base the SEN of the RCB), we recognized those chemicals with sufficient epidemiological evidence of carcinogenicity in humans, according to the evaluations published by the IARC, the U.S. NTP, or the U.S. EPA. As a result, both the oral and inhalation routes of the RCB showed more than 95% SEN towards human carcinogens with high genotoxic potency. The inhalation route of the RCB displayed 88% SEN towards non-mutagenic human carcinogens by inhalation. Toward non-mutagenic human carcinogens by ingestion, the RCB’s oral route displayed as few as 65% SEN. As human non-carcinogens (from which to elucidate the SPEC of the RCB), this thesis recognized those chemicals with sufficient mechanistic evidence that they lack innate carcinogenicity to humans (e.g., mechanistic evidence in terms of their mechanism of action, their mechanistic toxicology, or their basic pharmacology). Thereby, towards non-mutagenic human carcinogens by ingestion, and based only on human non-carcinogens with scant carcinogenic potential, this thesis estimated a 95% SPEC for the oral route of the RCB. Based on the SENs and SPEC mentioned before, and through the equations provided by (1) the Bayesian statistics, or (2) the method developed here and named the probability of verisimilitude, we found the following additional results. First, a 98% probability that 52 specific chemicals are innately carcinogenic to humans by ingestion or injection, including several pharmaceuticals of either antineoplastic or non-antineoplastic use in humans. Second, a 96% probability that 68 other substances lack innate carcinogenicity to humans by ingestion, including various (1) food, drug, and cosmetic colorants; (2) active ingredients of pesticides, or (3) several pharmaceuticals used in the treatment of human non-neoplastic diseases. Accordingly, this thesis delivered a large discussion, together with numerous conclusions and recommendations about (1) the preclinical performance of the RCB, as an animal testing method to predict the innate carcinogenicity to humans of chemicals; (2) different configurations for the RCB, including aspects such as the rodent species, doses, endpoints, or routes of exposure; (3) the future of the RCB in regulatory policy; (4) the probabilistic approaches used in this thesis, as a mode for translating the clinical relevance (or insignificance) of specific preclinical findings, and (5) the clinical and regulatory implications of the predictions placed by this thesis, about the innate carcinogenicity to humans (or the lack of innate carcinogenicity to humans) of 120 chemicals of either therapeutic or toxicological interest.Convocatoria 757 de 2016 (Crédito Educativo Condonable). Doctorado Nacional. Ministerio de Ciencia, Tecnología e Innovación. República de Colombia.DoctoradoDoctor en Ciencias FarmacéuticasFarmacologíaxx. 167 páginasapplication/pdfspaUniversidad Nacional de ColombiaBogotá - Ciencias - Doctorado en Ciencias FarmacéuticasFacultad de CienciasBogotá, ColombiaUniversidad Nacional de Colombia - Sede Bogotá610 - Medicina y salud::615 - Farmacología y terapéutica610 - Medicina y salud::612 - Fisiología humanaCarcinogenesisCáncerPatologíaPathologyBioensayo de carcinogénesis a 2-añosCarcinogénesis químicaToxicología predictivaFarmacología traslacionalRodent carcinogenesis bioassayRodent carcinogenicity bioassayRegulatory toxicologyBioensayo de carcinogenicidad en roedores a 2-años: Desempeño, y valores predictivos para múltiples fármacos y otras sustancias de interésTwo-year rodent carcinogenicity bioassay: Performance, and predictive values for several pharmaceuticals and other chemicals of interestTrabajo de grado - Doctoradoinfo:eu-repo/semantics/doctoralThesisinfo:eu-repo/semantics/acceptedVersionhttp://purl.org/coar/resource_type/c_db06Texthttp://purl.org/redcol/resource_type/TDIARC (International Agency for Research on Cancer). 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TRIFEXIS - Spinosad and milbemycin oxime tablet (prescribing information from the U.S. NLM DailyMed service [internet]. Silver Spring: U.S. FDA Center for Veterinary Medicine; 2018 [citado Mayo 2022]. Disponible desde: https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=b9e40668-b913-47e2-8cf4-8b3d3d29c6d4&type=displayEMA (European Medicines Agency). Scientific discussion: COMFORTIS (spinosad) (EMEA/V/C/002233) [internet]. Amsterdam: European Medicines Agency, Veterinary Medicines and Product Data Management; 2011 [citado Mayo 2022]. Disponible desde: https://www.ema.europa.eu/en/documents/scientific-discussion/comfortis-epar-scientific-discussion_en.pdfJMPR (Joint FAO/WHO Meeting on Pesticide Residues). Pesticide residues in food – Evaluations 2006. Part II, Toxicological: Cyfluthrin/beta-Cyfluthrin [Internet]. Rome: Joint FAO/WHO Meeting on Pesticide Residues; 2006 [citado Mayo 2022]. 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Part II, Toxicological: Deltamethrin [Internet]. Rome: Joint FAO/WHO Meeting on Pesticide Residues; 2000 [citado Mayo 2022]. Disponible desde: https://inchem.org/documents/jmpr/jmpmono/v00pr04.htm#_00042230U.S. NCI (United States of America National Cancer Institute). Bioassay of ICRF-159 for possible carcinogenicity. Natl Cancer Inst Carcinog Tech Rep Ser. 1978;78:1-113. PMID: 12830219U.S. FDA (United States of America Food and Drug Administration). Questions and Answers regarding Carbadox [internet]. Silver Spring: U.S. FDA Center for Veterinary Medicine; 2022 [citado Mayo 2022]. Disponible desde: https://www.fda.gov/animal-veterinary/product-safety-information/questions-and-answers-regarding-carbadoxMinisterio de Ciencia, Tecnología e Innovación. República de ColombiaPúblico generalLICENSElicense.txtlicense.txttext/plain; charset=utf-85879https://repositorio.unal.edu.co/bitstream/unal/82835/1/license.txteb34b1cf90b7e1103fc9dfd26be24b4aMD51ORIGINAL1125250186.2022.pdf1125250186.2022.pdfTesis de Doctorado en Ciencias Farmacéuticasapplication/pdf2587131https://repositorio.unal.edu.co/bitstream/unal/82835/2/1125250186.2022.pdf686e7bd7c6fd84547433bd575d138a6dMD52THUMBNAIL1125250186.2022.pdf.jpg1125250186.2022.pdf.jpgGenerated Thumbnailimage/jpeg4340https://repositorio.unal.edu.co/bitstream/unal/82835/3/1125250186.2022.pdf.jpgff3363ee6e2277bef39844a98cd1117aMD53unal/82835oai:repositorio.unal.edu.co:unal/828352023-08-11 23:04:29.082Repositorio Institucional Universidad Nacional de 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