Progress in the application of three-dimensional cell culture model in toxicity tests of xenobiotic / 中华预防医学杂志

In the process of xenobiotic toxicity prediction and risk assessment, in vitro cell culture models possess high practical application value. With the rapid development of biological technologies such as three-dimensional (3D) bio-printing, organoid culture and organ-on-a-chip systems, in vitro cell culture models have made great progress. Sharing the similarities in structure, function and the physiological environment with tissues or organs in vivo, hazard identification and dose-response analysis based on 3D cell culture models provide access to more accurate toxicity data as a theoretical basis for risk assessment and risk management of chemicals. This review summarizes the establishment of three typical 3D cell culture models, i.e., human cell line-based co-culture model, 3D-printed scaffold-based cell culture model and organoids, and their application in toxicity tests of xenobiotics.

Dependencia de la dosis en los mecanismos de toxicidad y la evaluación de riesgo en toxicología / Dose-dependent transitions in mechanisms of toxicity and risk assessment in toxicology / Dependencia da dosagem nos mecanismos de toxicidade e avaliagáo de risco em toxicologia

En la Toxicología se presentan desafíos derivados de la complejidad creciente de los escenarios ambientales que condicionan a muchas enfermedades humanas. Cuando se analiza la curva dosis-respuesta tóxica, frecuentemente se hace evidente que pueden existir varios procesos subyacentes para la acción de cualquier xenobiótico sobre un organismo vivo. Es muy probable que los pasos críticos, limitantes en cualquier mecanismo de toxicidad, puedan verse sobrepasados con exposiciones más grandes, señalando esto la emergencia de modos nuevos de injuria tisular a dosis más altas. Por lo tanto, pueden ocurrir transiciones dependientes de la dosis en el mecanismo principal de toxicidad, que tendrían un impacto significativo en la interpretación de la colección de los datos de referencia para la evaluación del riesgo. Una explicación para las relaciones lineales dosis-respuesta en serie es la transición dosis-dependiente entre una secuencia de pasos encadenados mecanística-mente, pasos limitantes de la velocidad saturables en el proceso total, que llevan desde la exposición a la expresión de uno o más modos para la respuesta tóxica. El análisis de estos fenómenos tiene una relevancia muy grande en términos prácticos, esto es, para las consecuencias sobre la regulación del uso y exposición a sustancias peligrosas en distintos ámbitos humanos.

In Toxicology, many challenges arise from the increasing complexity of environmental scenarios conditioning human diseases. When analyzing the toxic dose response, it often becomes apparent that there may be several underlying processes for any xenobiotic action on a living organism. It is likely that the critical steps, limiting in any mechanism of toxicity, may be overwhelmed with increased exposure, indicating the emergence of new forms of tissue injury at higher doses. Therefore, transitions might occur in a dose-dependent manner in the main mechanism for toxicity, having a significant impact on the performance of the collection of baseline data for risk assessment. One explanation for the linear dose-response relationships in series is dose-dependent transition from a sequence of steps chained mechanistically, saturable rate limiting steps in the process, leading from exposition to the expression of one or more forms of toxic response. The analysis of these phenomena has a great relevance in practical terms, that is, to the effects on the regulation of the use and exposure to hazardous substances in different human situations.

Em Toxicologia apresentam-se desafios decorrentes da complexidade crescente dos cenários ambientais que condicionam muitas doengas humanas. Ao analisar a curva dosagem-resposta tóxica frequentemente se torna evidente que podem existir vários processos subjacentes para a agáo de qualquer xenobiótico num organismo vivo. É muito provável que os passos essenciais, limitantes em qualquer mecanismo de toxicidade, possam ser superados com exposigoes maiores, indicando o aparecimento de modos novos de lesáo tissular com doses mais altas. Portanto podem acontecer transigoes que dependam da dosagem no mecanismo principal de toxicidade, que teriam um impacto significativo na interpretagáo da coleta de dados de referencia para a avaliagáo do risco. Uma explicagáo para as relagoes lineares dose-resposta em série é a transigáo dose-dependente entre uma sequencia de passos encadeados mecanicamente, passos limitantes da velocidade saturáveis no processo total, que levam da exposigáo a expressáo de um ou mais modos para a resposta tóxica. A análise desses fenómenos tem grande relevancia em termos práticos, isto é, para as consequencias na regulagáo do uso e exposigáo a substancias perigosas em diferentes ámbitos humanos.

Avaliação antropométrica e exposição a organoclorados em grupo populacional adepto da alimentação semivegetariana / Anthropometric and exposure to organochlorines in population group adept at feeding semivegetariana

O uso indiscriminado de agrotóxicos organoclorados (OC) no controle de vetores transmissores de doenças e no desenvolvimento da agricultura resultou em graves problemas de contaminação ambiental, devido à sua longa persistência no ambiente e nos organismos, constituindo um grande risco à saúde humana. Os OC estão presentes nos alimentos com altoteor lipídico e o consumo de peixe é o principal preditor alimentar. O perfil de distribuição da gordura corporal é um importante determinante dos níveis circulantes de OC, devido a altalipofilicidade destas substâncias e a capacidade de armazenamento no tecido adiposo. A antropometria vem sendo utilizada para avaliar o estado nutricional dos indivíduos e de grupospopulacionais nos diferentes ciclos de vida, e para estudar a relação da exposição à xenobióticos pela dieta. O objetivo do estudo foi determinar os preditores alimentares e antropométricos dos níveis de OC e as bifenilas policloradas (PCB), em 47 adultos não expostos ocupacionalmente,residentes do Estado do Rio de Janeiro e funcionários do Hospital Adventista Silvestre, que segue a alimentação vegetariana. (...). Os resultados encontrados mostram a relação do padrão de distribuição do tecido adiposonesses indivíduos e o risco de morbi-mortalidade, e a associação de parâmetro antropométrico e consumo de frutas e legume com níveis de Endosulfan I, agrotóxico organoclorado com uso ainda permitido na agricultura.

Role of nutrition in toxic injury.

The importance of nutrition in protecting the living organism against the potentially lethal effects of reactive oxygen species and toxic environmental chemicals has recently been realized. This new perspective has prompted re-evaluation of the food constituents of human diet from the point of view of their nutritional adequacy, deficiency and toxicity. The biological antioxidant defense system is an integrated array of enzymes, antioxidants and free radical scavengers. These include glutathione reductase, glutathione-s-transferase, glutathione peroxidase, phospholipid hydroperoxide glutathione peroxidase, superoxide dismutase (SOD) and catalase, together with the antioxidant vitamins C, E and A. The individual components of this system get utilized in various physiological process and for chemoprotection and therefore require replenishment from the diet. Other components of the diet like carbohydrates, proteins and lipids are important for maintaining the levels of various enzymes required in body's defense system providing protection against carcinogens. However, the emerging newer concepts focus on the role of trace elements and other dietary components in antioxidant defense and detoxification mechanisms. Trace elements like Iron, zinc magnesium, selenium, copper, and manganese are some of the elements involved in antioxidant defense mechanisms. Inadequate intake of these nutrients has been associated with ischemic heart disease, arthritis, stroke and cancer, where pathogenic role of free radicals is suggested. Further the importance of diet in the prevention of chemical induced toxicity can not be undetermined. Recent reports on the role of bioflavonoids as antioxidents and their potential use to reduce the risks of coronary heart disease and cancer in human beings have opened a new arena for future research. Induction of the cytochrome P450 isoenzymes by food pyrolysis, mutagens, alcohol and fasting, on the other hand is reported to contribute to chemical toxicity and carcinogenecity. Certain chemicals moieties in the food are mutagenic and carcinogenic.

Biochemical mechanisms in hepatotoxicity: oxidative stress induced by xenobiotics and hormonal changes

Cytotoxicity induced by xenobiotics and hormonal changes is a complex event, comprising primary and secondary mechanisms whose joint operation may lead to irreversible molecular changes associated with cell death. In this respect, alcoholic liver cell necrosis may be conditioned either by the generation of ethanol-derived acetaldehyde leading to covalent binding to biomolecules and derangement of key metabolic functions, the production of hypoxic damage secondary to elevated O2 uptake, impairment of membrane functions upon reduction in membrane fluidity, and/or by the development of oxidative stress. The latter mechanism is involved in the hepatotoxic effects of lindane, involving both early direct actions related to the biotransformation of the insecticide and late adaptive changes derived from cytochrome P-450 induction. Thyroid calorigenesis involving an accelerated rate of O2 consumption in the liver determines an increased oxidative stress status due to higher rates of O2 and/or H2O2 production by microsomal, mitochondrial, and peroxisomal electron transport systems, with diminished antioxidant defenses. Hyperthyroidism-induced liver oxidative stress may be associated with cell injury, altered hepatic functions, and potentiation of toxicity by xenobiotics. Liver oxidative stress may be secondarily exacerbated by neutrophil infiltration and/or alterations in Kupffer cell function. These phagocytes release chemical mediators and respiratory burst-related reactive O2 species upon stimulation in the liver, which are potentially toxic for parenchymal cells. As the different factors underlying oxidative stress and the interrelationships between oxidative stress and other cytotoxic mechanisms become better defined preventive and protective interventions will become more clear.