RESUMEN
Less than 10% of the candidate drug compounds are associated with male reproductive toxicity. Genetic and/or epigenetic information on sperm may be crucial for fetal development. Therefore, developmental toxicity, such as paternally transmitted birth defects, is possible if genetic abnormalities in the male germ line persist and accumulate in the sperm during spermatogenesis. First, this study provides an overview of chemical and male reproductive toxicity, which may lead to developmental toxicity from the perspective of male reproduction. Second, we demonstrate methods for evaluating male reproductive toxicity to anticipate male-mediated developmental toxicity. We developed a novel staining technique for evaluating sperm quality, as well as a noninvasive imaging analysis of male reproductive toxicity. The former is a mammalian male germ cell-specific staining method using reactive blue 2 dye (RB2), as previously confirmed in human sperm, and a method for detecting the early-stage DNA fragmentation in a single nucleus from mouse spermatozoa using single-cell pulsed-field gel electrophoresis. The latter is a new, ready-to-use, and compact magnetic resonance imaging (MRI) platform utilizing a high-field permanent magnet to evaluate male reproductive toxicity. The histopathological analysis supported the suitability of the MRI platform. The present study, for the first time, revealed a rapid, noninvasive evaluation of male reproductive toxicity in vivo using compact MRI. These novel toxicity assessments can help predict male-mediated developmental toxicity, contributing to accelerated drug discovery and drug repositioning.
Asunto(s)
Imagen por Resonancia Magnética , Reproducción , Espermatogénesis , Espermatozoides , Masculino , Animales , Espermatozoides/efectos de los fármacos , Humanos , Ratones , Reproducción/efectos de los fármacos , Espermatogénesis/efectos de los fármacos , Pruebas de Toxicidad/métodos , Fragmentación del ADN , Coloración y Etiquetado/métodosRESUMEN
The presented research introduces the "Cells-on-Particles" integrated aerosol sampling and cytotoxicity testing in vitro platform, which allows for the direct assessment of the biological effects of captured aerosol particles on a selected cell type without the need for extraction or resuspension steps. By utilizing particles with unaltered chemical and physical properties, the method enables simple and fast screening of biological effects on specific cell types, making it a promising tool for assessing the cytotoxicity of particulate matter in ambient and occupational air. Platforms fabricated from cellulose acetate (CA) and poly[ε]caprolactone (PCL) were proven to be biocompatible and promoted the attachment and growth of the human bronchial epithelial cell line BEAS-2B. The PCL platforms were exposed to simulated occupational aerosols of silver, copper, and graphene oxide nanoparticles. Each nanoparticle type exhibited different and dose-dependent cytotoxic effects on cells, evidenced by reduced cell viability and distinct, particle type-dependent gene expression patterns. Notably, copper nanoparticles were identified as the most cytotoxic, and graphene oxide the least. Comparing the "Cells-on-Particles" and submerged exposure ("Particles-on-Cells") testing strategies, BEAS-2B cells responded to selected nanoparticles in a comparable manner, suggesting the developed testing system could be proposed for further evaluation with more complex environmental aerosols. Despite limitations, including particle agglomeration and the need for more replicates to address variability, the "Cells-on-Particles" platform enables effective detection of toxicity induced by relatively low levels of nanoparticles, demonstrating good sensitivity and a relatively simpler procedure compared to standard 2D cell exposure methods.
Asunto(s)
Aerosoles , Supervivencia Celular , Pruebas de Toxicidad , Humanos , Supervivencia Celular/efectos de los fármacos , Línea Celular , Pruebas de Toxicidad/métodos , Cobre/toxicidad , Grafito/toxicidad , Nanopartículas del Metal/toxicidad , Células Epiteliales/efectos de los fármacos , Nanopartículas/toxicidad , Tamaño de la Partícula , Plata/toxicidad , Material Particulado/toxicidad , Poliésteres/toxicidad , Poliésteres/químicaRESUMEN
Microbial toxicity tests play an important role in various scientific and technical fields including the risk assessment of chemical compounds in the environment. There is a large battery of normalized tests available that have been standardized by ISO (International Organization for Standardization) and OECD (Organization for Economic Co-operation and Development) and which are worldwide accepted and applied. The focus of this review is to provide information on microbial toxicity tests, which are used to elucidate effects in other laboratory tests such as biodegradation tests, and for the prediction of effects in natural and technical aqueous compartments in the environment. The various standardized tests as well as not normalized methods are described and their advantages and disadvantages are discussed. In addition, the sensitivity and usefulness of such tests including a short comparison with other ecotoxicological tests is presented. Moreover, the far-reaching influence of microbial toxicity tests on biodegradation tests is also demonstrated. A new concept of the physiological potential of an inoculum (PPI) consisting of microbial toxicity tests whose results are expressed as a chemical resistance potential (CRP) and the biodegradation adaptation potential (BAP) of an inoculum is described that may be helpful to characterize inocula used for biodegradation tests. KEY POINTS: ⢠Microbial toxicity tests standardized by ISO and OECD have large differences in sensitivity and applicability. ⢠Standardized microbial toxicity tests in combination with biodegradability tests open a new way to characterize inocula for biodegradation tests. ⢠Standardized microbial toxicity tests together with ecotoxicity tests can form a very effective toolbox for the characterization of toxic effects of chemicals.
Asunto(s)
Biodegradación Ambiental , Pruebas de Toxicidad , Pruebas de Toxicidad/métodos , Pruebas de Toxicidad/normas , Bacterias/efectos de los fármacos , Bacterias/metabolismo , Organización para la Cooperación y el Desarrollo Económico , Contaminantes Ambientales/toxicidad , Contaminantes Ambientales/metabolismo , Ecotoxicología/métodos , Ecotoxicología/normasRESUMEN
Regulatory guidance for global drug development relies on animal studies to evaluate safety risks for humans, including risk of reproductive toxicity. Weight-of-evidence approaches (WoE) are increasingly becoming acceptable to evaluate risk. A WoE for developmental risk of monoclonal antibodies (mAbs) was evaluated for its ability to retrospectively characterize risk and to determine the need for further in vivo testing based on the remaining uncertainty. Reproductive toxicity studies of 65 mAbs were reviewed and compared to the WoE. Developmental toxicities were absent in 52/65 (80%) mAbs. Lack of toxicity was correctly predicted in 29/52 (56%) cases. False positive and equivocal predictions were made in 9/52 (17%) and 14/52 (27%) cases. For 3/65 (5%) mAbs, the findings were equivocal. Of mAbs with developmental toxicity findings (10/65, 15%), the WoE correctly anticipated pharmacology based reproductive toxicity without any false negative predictions in 9/10 (90%) cases, and in the remaining case (1/10, 10%) an in vivo study was recommended due to equivocal WoE outcome. Therefore, this WoE approach could characterize presence and absence of developmental risk without animal studies. The current WoE could have reduced the need for developmental toxicity studies by 42% without loss of important patient information in the label.
Asunto(s)
Anticuerpos Monoclonales , Anticuerpos Monoclonales/toxicidad , Humanos , Medición de Riesgo , Animales , Pruebas de Toxicidad/métodos , Reproducción/efectos de los fármacos , FemeninoRESUMEN
The mission of the Force Health Protection (FHP) program of the U.S. Air Force (USAF), sustaining the readiness of warfighters, relies on determinations of acceptable levels of exposure to a wide array of substances that USAF personnel may encounter. In many cases, exposure details are limited or authoritative toxicity reference values (TRVs) are unavailable. To address some of the TRV gaps, we are integrating several approaches to generate health protective exposure guidelines. Descriptions are provided for identification of chemicals of interest for USAF FHP (467 to date), synthesis of multiple TRVs to derive Operational Exposure Limits (OpELs), and strategies for identifying and developing candidate values for provisional OpELs when authoritative TRVs are lacking. Rodent bioassay-derived long-term Derived No Effect Levels (DNELs) for workers were available only for a minority of the substances with occupational TRV gaps (19 of 84). Additional occupational TRV estimation approaches were found to be straightforward to implement: Tier 1 Occupational Exposure Bands, cheminformatics approaches (multiple linear regression and novel nearest-neighbor approaches), and empirical adjustment of short term TRVs. Risk assessors working in similar contexts may benefit from application of the resources referenced and developed in this work.
Asunto(s)
Personal Militar , Exposición Profesional , Humanos , Exposición Profesional/normas , Exposición Profesional/prevención & control , Exposición Profesional/efectos adversos , Valores de Referencia , Animales , Medición de Riesgo , Estados Unidos , Nivel sin Efectos Adversos Observados , Pruebas de Toxicidad/normas , Pruebas de Toxicidad/métodos , Sustancias Peligrosas/toxicidadRESUMEN
Allyl alcohol (C3H6O; prop-2-en-1-ol; CAS RN 107-18-6; EINECS 203-470-7) is used as an intermediate/monomer in polymerization reactions producing chemicals/optical resins or as a coupling/cross-linking agent for unsaturated polyester and alkyd resins. Human exposure to allyl alcohol (AA) is restricted to workplace manufacturing facilities where it is used in enclosed systems, which limits release and impact on environmental receptors. To address regulatory questions about possible developmental toxicity, two OECD Guideline studies were conducted. A rat developmental toxicity study found fetal and maternal toxicity, in the form of resorptions and decreased body weight and food consumption, but no teratogenic effects. A rabbit developmental toxicity study was subsequently conducted upon request by the European Chemical Agency in 2011 under the REACH program and likewise reported maternal toxicity in the form of reductions in body weight gain and food consumption, but neither fetal toxicity or teratogenic effects. The results of both studies are presented and compared in this paper. Based on our review of the collective results of these studies, AA is considered non-teratogenic, yet does elicit increased post-implantation loss and reduced fetal body weight, possibly resulting from concomitant maternal toxicity. Based on the results of these studies, a maternal and developmental toxicity No Observed Adverse Effect Level of 10 mg/kg/day was apparent for both species.
Asunto(s)
Nivel sin Efectos Adversos Observados , Propanoles , Animales , Femenino , Conejos , Ratas , Embarazo , Propanoles/toxicidad , Desarrollo Fetal/efectos de los fármacos , Masculino , Pruebas de Toxicidad/métodos , Exposición Materna/efectos adversosRESUMEN
Chemicals are representative environmental factors that affect human health. Recently, external exposure to a chemical of rhododenol (RD) caused chemical leukoderma, an acquired patchy hypopigmentation, in about 20,000 Asian people. The development of a hazard assessment system for accurate determination of leukoderma-inducible chemicals is required for the prevention of such tragedies. Case studies in humans have shown 6 chemicals, including RD, with a constitutive leukoderma-inducible potency and 3 chemicals with a photosensitive but not a constitutive leukoderma-inducible potency. In this study, the 6 positive and 3 negative control chemicals with or without constitutive leukoderma-inducible potencies were investigated by our previously developed in vivo hazard assessment system using tail skin of mice. Based on the results of validation, this study aimed to develop an in vitro hazard assessment system to correctly determine chemicals with a constitutive leukoderma-inducible potency. As expected, external exposure to the 6 positive control chemicals, but not external exposure to the 3 negative control chemicals, resulted in development of constitutive leukoderma in mouse tail skin with a decreased level of skin melanin and decreased number of melanocytes. Moreover, the 6 positive and 3 negative control chemicals were correctly distinguished by the presence or absence of endoplasmic reticulum (ER) stress induction, but not by tyrosinase-dependent cell death or production of reactive oxygen species (ROS), in immortalized normal melanocytes. The hazard assessment system using tail skin could be a solid in vivo tool to reliably determine the chemical potency of a chemical for constitutive leukoderma induction. The hazard assessment system focusing on ER stress induction in normal melanocytes might be a novel and convenient in vitro tool for accurately evaluating chemicals with leukoderma-inducible potencies. Thus, this study contributed to environmentology through the development of a screening system for preventing an environmental factor-related disease.
Asunto(s)
Hipopigmentación , Animales , Ratones , Hipopigmentación/inducido químicamente , Medición de Riesgo , Melanocitos/efectos de los fármacos , Piel/efectos de los fármacos , Estrés del Retículo Endoplásmico/efectos de los fármacos , Melaninas , Humanos , Pruebas de Toxicidad/métodos , ButanolesRESUMEN
Growing restrictions and bans on animal testing for chemical safety assessment under different regulations have led to an increasing use of alternative methods. Read-across is one of the major approaches used for this purpose, which relies on the identification of toxicological hazards of a data-poor or untested (target) chemical from data on other already-tested (source) similar chemicals. This requires the target substance to be first assigned to a group or category of 'similar' chemicals. The 'similarity' may be in terms of structural features alone, or in combination with certain rules that are based on mechanistic and/or toxicological aspects. In this regard, the OECD QSAR toolbox-a major free-access in silico platform-is widely used to derive toxicity predictions for a range of (eco) toxicological endpoints. The Toolbox allows the user to identify a set of similar chemicals (analogues) by computational 'profilers' that incorporate different structural alerts, or a combination of structural alerts and physicochemical and/or toxicokinetic rules relevant to a specific toxicological endpoint. The overall aim of this study was to assess the performance of the in silico profilers provided in the OECD QSAR Toolbox for reliability for identifying chemical analogues for category formation in a number of high-quality databases on mutagenicity, carcinogenicity, and skin sensitisation. The study also aimed to identify the reasons for any limitations in the performance of the profilers, and propose ways to improve their overall accuracy. The results showed that whilst some structural alerts are fit-for-purpose as such within the acceptable limits, others need refinement or a consideration for their possible exclusion from the profiler. Such refinements are imperative for a reliable use of the profilers in read-across and grouping/categorisation for classification, labelling and risk assessment of chemicals.
Asunto(s)
Organización para la Cooperación y el Desarrollo Económico , Relación Estructura-Actividad Cuantitativa , Simulación por Computador , Animales , Pruebas de Toxicidad/métodos , Humanos , Reproducibilidad de los Resultados , Medición de Riesgo/métodosRESUMEN
The aim of embryo-fetal developmental toxicity assessments for pharmaceuticals is to inform potential risk of adverse pregnancy outcome, which has traditionally relied on studies in pregnant animals. Recent updates to international safety guidelines (ICH S5R3) have incorporated information on how to use weight of evidence and alternative assays to reduce animal use while still informing risk of fetal harm. Uptake of these alternative approaches has been slow due to limitations in understanding how alternative assays translate to in vivo effects and then relevance to human exposure. To understand the predictivity of new approach methodologies for developmental toxicity (DevTox NAMs), we used two pharmaceutical examples (glasdegib and lorlatinib) to illustrate the value of DevTox NAMs to complement weight of evidence (WoE) assessments while considering the relationship of concentration-effect levels in NAMs to in vivo studies. The in vitro results generated in a battery of assays (mEST, rWEC, zebrafish, and human based stem cells) confirmed the WoE based on literature and further confirmed by preliminary embryo-fetal development data. The data generated for these two compounds supports integrating DevTox NAMs into the developmental toxicity assessment for advanced cancer indications.
Asunto(s)
Desarrollo Embrionario , Pruebas de Toxicidad , Pez Cebra , Animales , Humanos , Pruebas de Toxicidad/métodos , Desarrollo Embrionario/efectos de los fármacos , Teratógenos/toxicidad , Femenino , Pirazoles/toxicidad , Embarazo , Desarrollo Fetal/efectos de los fármacos , Alternativas a las Pruebas en Animales , Línea Celular , Medición de RiesgoRESUMEN
This study introduces a novel in vitro methodology that employs the 3-D reconstructed tissue model, EpiOcular, to assess the irritation and phototoxicity potential of medical devices and drugs in contact with the eye. Our study evaluated diverse test materials, including medical devices, ophthalmological solutions and an experimental drug (cemtirestat), for their potential to cause eye irritation and phototoxicity. The protocols used in this study with the EpiOcular tissue model were akin to those used in the ultra-mildness testing of cosmetic formulations, which is challenging to predict with standard in vivo rabbit tests. To design these protocols, we leveraged experience gained from the validation project on the EpiDerm skin irritation test for medical devices (ISO 10993-23:2021) and the OECD TG 498 method for photo-irritation testing. The predictions were based on the tissue viability and inflammatory response, as determined by IL-1α release. By developing and evaluating these protocols for medical devices, we aimed to expand the applicability domain of the tests referred to in ISO 10993-23. This will contribute to the standardisation and cost-effective safety evaluation of ophthalmic products, while reducing reliance on animal testing in this field. The findings obtained from the EpiOcular model in the photo-irritation test could support its implementation in the testing strategies outlined in OECD TG 498.
Asunto(s)
Alternativas a las Pruebas en Animales , Ojo , Alternativas a las Pruebas en Animales/métodos , Animales , Ojo/efectos de los fármacos , Dermatitis Fototóxica , Conejos , Equipos y Suministros/efectos adversos , Irritantes/toxicidad , Ensayo de Materiales/métodos , Humanos , Pruebas de Toxicidad/métodos , Soluciones Oftálmicas/toxicidad , Materiales Biocompatibles/toxicidadRESUMEN
Ecological risk assessments of agrochemicals have traditionally depended on in vivo guideline tests using northern bobwhite and mallard to provide relevant endpoints for avian species. However, these studies have limitations, including animal welfare concerns, the time and cost involved, limited potential for extrapolation to more realistic exposure conditions, and the lack of mechanistic understanding. The proof-of-concept work presented a case study for thiamethoxam in three avian species, demonstrating the potential of physiologically based kinetic (PBK) modeling to enable dosimetry extrapolations that inform hazard characterization in risk assessment, and reduce the use of avian testing. The model structure for northern bobwhite and mallard contained ten compartments, while an additional ovulation model was included for chicken in the physiological state of egg-laying. The model was first parameterized and evaluated for chicken and northern bobwhite using in vitro kinetic measurements and in vivo toxicokinetic (TK) data. The chicken model was then extrapolated to mallard based on allometric scaling. The models were then used to map the TK profiles across species by simulating internal dose metrics in different avian toxicology studies. These metrics, including peak blood concentrations (Cmax) and area under the curve (AUC) for blood concentration, were determined for acute, subacute, or chronic toxicity endpoints for mallard and northern bobwhite, enabling a quantitative cross-species and cross-route comparison of dosimetry. The results suggested that the chronic toxicological response of birds exposed to thiamethoxam is highly dependent on internal exposure, while mallard appeared to be more dynamically sensitive to thiamethoxam on an acute oral exposure basis. The case study increases the confidence in using new approach methodologies (NAMs) for interpreting avian toxicity studies and facilitating in vitro-in silico-based ecological risk assessments of agrochemicals.
Asunto(s)
Pollos , Ecotoxicología , Animales , Ecotoxicología/métodos , Medición de Riesgo , Colinus , Tiametoxam , Patos/fisiología , Pruebas de Toxicidad/métodos , Toxicocinética , Agroquímicos/toxicidadRESUMEN
Detecting the toxic effects of chemicals on reproduction and development without using mammalian animal models is crucial in the exploitation of pharmaceuticals for human use. Zebrafish are a promising animal model for investigating pharmacological effects and toxicity during vertebrate development. Several studies have suggested the use of zebrafish embryos for the assessment of malformations or embryo-fetal lethality (MEFL). However, a reproducible protocol as a standard for the zebrafish MEFL test method that fulfills global requests has not been established based on the International Council of Harmonisation (ICH) S5 (R3) guidelines. To establish such a toxicity test method, we developed a new and easy protocol to detect MEFL caused by chemicals, especially those with teratogenic potential, using fertilized zebrafish eggs (embryos) within 5 days of development. Our toxicity test trials using the same protocol in two to four different laboratories corroborated the high inter-laboratory reproducibility. Our test method enabled the detection of 18 out of 22 test compounds that induced rat MEFL. Thus, the prediction rate of our zebrafish test method for MEFL was almost 82% compared with that of rat MEFL. Collectively, our study proposes the establishment of an easy and reproducible protocol for the zebrafish MEFL test method for reproductive and developmental toxicity that meets ICH guideline S5 (R3), which can be further considered in combination with information from other sources for regulatory use.
Asunto(s)
Embrión no Mamífero , Teratógenos , Pruebas de Toxicidad , Pez Cebra , Pez Cebra/embriología , Animales , Pruebas de Toxicidad/métodos , Embrión no Mamífero/efectos de los fármacos , Reproducibilidad de los Resultados , Teratógenos/toxicidad , Guías como Asunto , Ratas , Anomalías Inducidas por Medicamentos/etiología , Desarrollo Embrionario/efectos de los fármacos , Modelos AnimalesRESUMEN
There has been growing emphasis on environmental pollutants, including heavy metals, pesticides, and nanoplastics, owing to the escalating significance of environmental pollution as a major global issue. Various toxicities induced by these compounds have been consistently reported, and many cell lines and animal models have been used in toxicity studies. Zebrafish are one of the most widely used animal models for verifying the toxic effects of environmental pollutants, owing to their many advantages. In this study, we provide brief guidelines for zebrafish maintenance and mating methods, toxicant treatments, survival measurements, and morphological abnormalities.
Asunto(s)
Embrión no Mamífero , Pruebas de Toxicidad , Pez Cebra , Pez Cebra/embriología , Animales , Pruebas de Toxicidad/métodos , Embrión no Mamífero/efectos de los fármacosRESUMEN
Concentrations of microplastics (MPs) were determined in three commonly used zebrafish housing systems to see if their levels could affect the final results of laboratory microplastic-related toxicology tests. MPs have received notable attention in the last few years, and their toxicology tests have also come to the fore. Zebrafish (Danio rerio), kept in fish housing systems, are widely used as models for MPs studies. Most of these systems contain a significant number of parts made of different polymers. As usage and amortization can erode these parts, MPs might appear in the keeping water or the fish body, which may represent a background load and possibly influence the results of microplastic-related toxicological tests. To take representative water samples from systems, two in-situ filtration techniques, a newly developed peristaltic pump-, and a jet pump-driven method were applied. The collected MP particles were analyzed with a Fourier-transform infrared microscope (detection limit 50 µm), and their possible origin was also investigated. The newly developed technique was more sufficient for sampling as it had a higher MPs recovery, especially in the smaller size range. Polyester, polyethylene and polypropylene were the most frequently detected polymers in the examined fish housing systems, the highest detected concentration was 0.31±0.12 particles/liter (0.22±0.16 µg/liter). These values are negligible compared to the literature data reporting enormously high applied MPs concentrations (104 - 2.21 × 108 particles/liter) during toxicology tests. The results also show that some detected MPs did not originate from the systems, their origin was presumed to be external.
Asunto(s)
Microplásticos , Pruebas de Toxicidad , Contaminantes Químicos del Agua , Pez Cebra , Pez Cebra/fisiología , Animales , Microplásticos/toxicidad , Microplásticos/análisis , Contaminantes Químicos del Agua/análisis , Contaminantes Químicos del Agua/toxicidad , Pruebas de Toxicidad/métodos , Vivienda para Animales , Monitoreo del Ambiente/métodosRESUMEN
Experimental systems allowing aerosol exposure (AE) of cell cultures at the air-liquid-interface (ALI) are increasingly being used to assess the toxicity of inhaled contaminants as they are more biomimetic than standard methods using submerged cultures, however, they require detailed characterisation before use. An AE-ALI system combining aerosol generation with a CULTEX® exposure chamber was characterised with respect to particle deposition and the cellular effects of filtered air (typical control) exposures. The effect of system parameters (electrostatic precipitator voltage, air flowrate to cells and insert size) on deposition efficiency and spatial distribution were investigated using ICP-MS and laser ablation ICP-MS, for an aerosol of CeO2 nanoparticles. Deposition varied with conditions, but appropriate choice of operating parameters produced broadly uniform deposition at suitable levels. The impact of air exposure duration on alveolar cells (A549) and primary small airway epithelial cells (SAECs) was explored with respect to LDH release and expression of selected genes. Results indicated that air exposures could have a significant impact on cells (e.g., cytotoxicity and expression of genes, including CXCL1, HMOX1, and SPP1) at relatively short durations (from 10 mins) and that SAECs were more sensitive. These findings indicate that detailed system characterisation is essential to ensure meaningful results.
Asunto(s)
Aerosoles , Humanos , Supervivencia Celular/efectos de los fármacos , Células Epiteliales/efectos de los fármacos , Células Epiteliales/metabolismo , Cerio/toxicidad , Técnicas de Cultivo de Célula , Células Cultivadas , Pruebas de Toxicidad/métodos , Tamaño de la Partícula , Nanopartículas/toxicidad , L-Lactato Deshidrogenasa/metabolismo , Células A549RESUMEN
Nanomaterials are increasingly used in many applications due to their enhanced properties. To ensure their safety for humans and the environment, nanomaterials need to be evaluated for their potential risk. The risk assessment analysis on the nanomaterials based on animal or in vivo studies is accompanied by several concerns, including animal welfare, time and cost needed for the studies. Therefore, incorporating in vitro studies in the risk assessment process is increasingly considered. To be able to analyze the potential risk of nanomaterial to human health, there are factors to take into account. Utilizing in vitro data in the risk assessment analysis requires methods that can be used to translate in vitro data to predict in vivo phenomena (in vitro-in vivo extrapolation (IVIVE) methods) to be incorporated, to obtain a more accurate result. Apart from the experiments and species conversion (for example, translation between the cell culture, animal and human), the challenge also includes the unique properties of nanomaterials that might cause them to behave differently compared to the same materials in a bulk form. This overview presents the IVIVE techniques that are developed to extrapolate pharmacokinetics data or doses. A brief example of the IVIVE methods for chemicals is provided, followed by a more detailed summary of available IVIVE methods applied to nanomaterials. The IVIVE techniques discussed include the comparison between in vitro and in vivo studies, methods to rene the dose metric or the in vitro models, allometric approach, mechanistic modeling, Multiple-Path Particle Dosimetry (MPPD), methods using organ burden data and also approaches that are currently being developed.
Asunto(s)
Nanoestructuras , Nanoestructuras/toxicidad , Medición de Riesgo , Humanos , Animales , Pruebas de Toxicidad/métodosRESUMEN
The aim of the present work is to propose a new quantitative assessment method (FETAX-score) for determining the degree of Xenopus laevis embryo development intended for use in embryotoxicity studies. Inspired by a similar scoring system used to evaluate developmental delays (young-for-age phenotypes) in rat embryos cultured in vitro, the FETAX-score was established by considering seven morphological features (head, naris, mouth, lower jaw, tentacles, intestine, anus) that are easily evaluable in tadpoles during the late stages of development at the conclusion of the test. Given that X. laevis development is temperature-dependent and that temperatures below 14°C and above 26°C are teratogenic, the FETAX-score was tested in embryos maintained at 17, 20, 23 and 26°C. No abnormalities were observed in any group, while the total score was temperature-related, suggesting that the FETAX-score is sensitive to moderate distress that does not influence general morphology. Intestine and anus were the least sensitive structures to temperature variations. To assess the applicability of the FETAX-score in developmental toxicological studies, we evaluated FETAX-score in tadpoles exposed during the morphogenetic period to Ethanol (Eth) at concentrations of 0, 0.25, 0.5, 1, 1.5, and 2â¯% v/v. Gross malformations were observed only in tadpoles from the Eth 2â¯% group. By contrast, data analysis of the other Eth groups showed dose-related reductions in the FETAX-score. Tentacles were the most sensitive structures to Eth-related delays. These results support the use of the FETAX-score to quantitatively assess developmental deviations in FETAX embryotoxicity studies.
Asunto(s)
Embrión no Mamífero , Desarrollo Embrionario , Etanol , Temperatura , Teratógenos , Xenopus laevis , Animales , Xenopus laevis/embriología , Etanol/toxicidad , Embrión no Mamífero/efectos de los fármacos , Embrión no Mamífero/anomalías , Desarrollo Embrionario/efectos de los fármacos , Teratógenos/toxicidad , Larva/efectos de los fármacos , Larva/crecimiento & desarrollo , Pruebas de Toxicidad/métodos , Anomalías Inducidas por MedicamentosRESUMEN
Insect cell lines are finding utility in many areas of biology, but their application as an in vitro tool for ecotoxicity testing has been given less attention. Our study aimed to demonstrate the utility and sensitivity of Sf21 cells to commonly used fungicides: Propiconazole and CuSO4, as well as dimethyl sulphoxide (DMSO) an industrial solvent. Sf21 cells were readily cultured from frozen stocks in 3-4 days and showed utility as an invertebrate in vitro acute toxicity test. The data showed the threshold levels of cell survivability against propiconazole and CuSO4. The EC50 values were 135.1 µM and 3.31 mM respectively. The LOAEL (lowest observed adverse effect level) was ≈ 1 µM for propiconazole and ≈ 10 µM for CuSO4. Culturing of Sf21 cells in media containing the solvent DMSO showed that 0.5% DMSO concentration did not effect cell viability. Sf21 cells are sensitive and useful as a robust ecologically relevant screening tool for acute toxicity testing.
Asunto(s)
Dimetilsulfóxido , Animales , Dimetilsulfóxido/toxicidad , Fungicidas Industriales/toxicidad , Triazoles/toxicidad , Pruebas de Toxicidad Aguda/métodos , Pruebas de Toxicidad/métodos , Línea Celular , Spodoptera/efectos de los fármacos , Células Sf9RESUMEN
Mixture toxicity was determined for 32 binary combinations. One chemical was the non-reactive, non-polar narcotic 3-methyl-2-butanone (always chemical A) and the other was a potentially reactive electrophile (chemical B). Bioluminescence inhibition in Allovibrio fischeri was measured at 15-, 30-, and 45-minutes of exposure for A, B, and the mixture (MX). Concentration-response curves (CRCs) were developed for each chemical and used to develop predicted CRCs for the concentration addition (CA) and independent action (IA) mixture toxicity models. Also, MX CRCs were generated and compared with model predictions using the 45-minute data. Classification of observed mixture toxicity used three specific criteria: 1) predicted IA EC50 vs. CA EC50 values at 45-minutes, 2) consistency of 45-minute MX CRC fit to IA, CA, or otherwise at three effect levels (EC25, EC50 and EC75), and 3) the known/suspected mechanism of toxicity for chemical B. Mixture toxicity was then classified into one of seven groupings. As a result of the predicted IA EC50 being more toxic than the predicted CA EC50, IA represented the greater toxic hazard. For this reason, non-sham MXs having toxicity consistent with CA were classified as being "coincident" with CA rather than mechanistically-consistent with CA. Multiple linear regression analyses were performed to develop equations that can be used to estimate the toxicity of other 3M2B-containing binary mixtures. These equations were developed from the data for both IA and CA, at each exposure duration and effect level. Each equation had a coefficient of determination (r2) above 0.950 and a variance inflation factor <1.2. This approach can potentially reduce the need for mixture testing and is amenable to other model systems and to assays that evaluate toxicity at low effect levels.
Asunto(s)
Aliivibrio fischeri , Butanonas , Aliivibrio fischeri/efectos de los fármacos , Butanonas/toxicidad , Relación Dosis-Respuesta a Droga , Pruebas de Toxicidad/métodosRESUMEN
The production of nanoparticles has recently surged due to their varied applications in the biomedical, pharmaceutical, textile, and electronic sectors. However, this rapid increase in nanoparticle manufacturing has raised concerns about environmental pollution, particularly its potential adverse effects on human health. Among the various concerns, inhalation exposure to nanoparticles poses significant risks, especially affecting the respiratory system. Airway epithelial cells play a crucial role as the primary defense against inhaled particulate matter and pathogens. Studies have shown that nanoparticles can disrupt the airway epithelial barrier, triggering inflammatory responses, generating reactive oxygen species, and compromising cell viability. However, our understanding of how different types of nanoparticles specifically impact the airway epithelial barrier remains limited. Both in vitro cell culture and in vivo murine models are commonly utilized to investigate nanoparticle-induced cellular responses and barrier dysfunction. This review discusses the methodologies frequently employed to assess nanoparticle toxicity and barrier disruption. Furthermore, we analyze and compare the distinct effects of various nanoparticle types on the airway epithelial barrier. By elucidating the diverse responses elicited by different nanoparticles, we aim to provide insights that can guide future research endeavors in assessing and mitigating the potential risks associated with nanoparticle exposure.