International Journal of Toxicology最新文献

The U.S. Food and Drug Administration (FDA), Center for Drug Evaluation and Research (CDER), and Office of New Drugs (OND) has continuously encouraged the submission of nonclinical tests utilizing new approach methodologies (NAMs) and sponsor engagement with regulators to optimize NAM utility in supporting the safety and efficacy of new drugs. Previously, we published an FDA/CDER perspective on nonclinical testing strategies, discussed the opportunities and challenges of using NAMs to replace, reduce, and refine animal testing in drug development, and reported gaps and challenges underserved by existing nonclinical testing approaches that CDER Pharmacology/Toxicology reviewers face. Here, we demonstrate how FDA/CDER has historically incorporated NAMs into standard nonclinical assessments, describing how specific tests became validated and internationally accepted alternatives to animal testing for regulatory decision-making. We also provide a CDER/OND Pharmacology/Toxicology reviewer perspective on NAMs submitted to support new drug development, in an effort to provide insight into our experience with NAMs submitted for CDER-regulated products. Furthermore, we provide a CDER/OND Pharmacology/Toxicology reviewer perspective on the future of NAM incorporation into nonclinical development programs for new drugs as scientific technology continues to evolve. Ultimately, we hope that by sharing the FDA/CDER/OND experience with NAMs thus far and providing considerations for refining NAM submissions, we will (1) illustrate our scientific approach to evaluating NAM submissions, (2) reiterate FDA/CDER's steadfast commitment to the 3Rs, and (3) foster confidence in our continued efforts to encourage nonclinical test NAM submissions for regulatory decision-making, while maintaining our mission to protect public health and patients from unintended harm.

Traditional tobacco products are harmful to the body, especially the respiratory system. In recent years, different kinds of novel and emerging nicotine and tobacco products have emerged on the market and are becoming increasingly popular with young people. Some regulatory policies have been implemented, but the public still lacks a systematic understanding of the health risks of these novel products. To provide a summary of these topics to date, we performed a literature review, in which we summarized studies on novel and emerging nicotine and tobacco products in terms of cell models, three-dimensional models, animal models, and population and their potential advantages and disadvantages, which will provide support for the market supervision and policy control and the comprehensive health risks of novel and emerging nicotine and tobacco products to the public.

Drug discovery and development is a complex, lengthy, and expensive process that takes on average 10-15 years and approximately $1-2 billion USD for approval of a new drug. While the studies needed to support clinical development are generally outlined in guidance documents, there is much less guidance on how to translate the nonclinical data into clinical designs. Nonclinical studies are performed to conduct the First-in-Human clinical trial, which is the first major milestone to advance new promising drug candidates, and are conducted primarily to determine the safe dose range for clinical development. Resolving how to move forward, and even when to move forward, requires significant cross-functional collaboration with pathologists, ADME scientists, biologists, and clinical staff. There are many reasons why drug candidates may fail; these could be as simple as insufficient understanding of the nature of the translational process, failure to effectively integrate the data from different pharmacologically relevant species, or erosion of the margin of safety during chronic toxicology studies. The case studies described here were designed to help participants in the 2024 American College of Toxicology (ACT) Continuing Education course "Translational Challenges from Nonclinical to Clinical Program: Case Study Examples" to improve their skills in managing translational challenges from nonclinical to clinical program encountered during drug development.

Sukré™, a highly purified l-arabinose produced from hydrolyzed acacia, has potential uses as a natural sweetener. To evaluate the safety of l-arabinose, a battery of GLP-compliant in vitro and in vivo studies were conducted with Sukré™ (Compound Solutions, Inc, USA). No mortality, morbidity, or adverse effects were observed in a 28-day subchronic toxicity study conducted in rats administered doses up to 7200 mg/kg bw/day Sukré™ by gavage. Thus, the 28-day oral subchronic NOAEL for Sukré™ in male and female Wistar rats was 7200 mg/kg bw/day, the highest dose tested. Furthermore, results of in vitro studies (a bacterial reverse mutation assay, a mammalian chromosomal aberration study, and a mammalian micronucleus study) demonstrate that Sukré™ was non-mutagenic and non-clastogenic. Collectively, these observations indicate that oral consumption of Sukré™ is not of toxicological concern and provide supportive evidence for the safe oral consumption of Sukré™ as an ingredient in foods.

The Expert Panel for Cosmetic Ingredient Safety (Panel) assessed the safety of 16 barley-derived ingredients, most of which are reported to function as skin-conditioning agents in cosmetic products. Industry should continue to use good manufacturing practices to minimize impurities that could be present in botanical ingredients. The Panel reviewed the available data to determine the safety of these ingredients. The Panel concluded that 5 barley-ingredients (i.e., the seed- and sprout-derived ingredients) are safe in cosmetics in the practices of use and concentration described in this safety assessment. However, the Panel also concluded that the available data are insufficient to make a determination of safety for the remaining 11 barley-derived ingredients under the intended conditions of use in cosmetic formulations.

The Expert Panel for Cosmetic Ingredient Safety (Panel) assessed the safety of 9 Zingiber officinale (ginger)-derived ingredients. The majority of these ingredients are reported to function in cosmetics as skin-conditioning agents. The Panel reviewed the available data to determine the safety of these ingredients. Because final product formulations may contain multiple botanicals, each containing similar constituents of concern, formulators are advised to be aware of these constituents and to avoid reaching levels that may be hazardous to consumers. With Zingiber officinale (ginger)-derived ingredients, the Panel was concerned about the presence of potential sensitizers (e.g., citronellol) in cosmetics. Industry should continue to use good manufacturing practices to minimize impurities that could be present in botanical ingredients. The Panel concluded that 8 Zingiber officinale (ginger)-derived ingredients are safe in cosmetics in the present practices of use and concentration described in this safety assessment when formulated to be non-sensitizing. In addition, the Panel concluded that the available data are insufficient to make a determination that Zingiber Officinale (Ginger) Leaf Cell Extract is safe under the intended conditions of use in cosmetic formulations.

The Expert Panel for Cosmetic Ingredient Safety (Panel) assessed the safety of 4 starch phosphates as used in cosmetic formulations. Distarch Phosphate is reported to function in cosmetics as an anticaking agent and binder. Distarch Phosphate Acetate, Hydroxypropyl Starch Phosphate, and Sodium Hydroxypropyl Starch Phosphate are all reported to function as viscosity increasing agents. The Panel considered the available data and concluded that these ingredients are safe in cosmetics in the present practices of use and concentrations described in this safety assessment.

The Expert Panel for Cosmetic Ingredient Safety (Panel) assessed the safety of 8 fatty ethers as used in cosmetic formulations. These ingredients are reported to function in cosmetics as skin conditioning agents. The Panel reviewed the available data to determine the safety of these ingredients, and concluded that these ingredients are safe in cosmetics in the present practices of use and concentrations described in this safety assessment.

The Expert Panel for Cosmetic Ingredient Safety (Panel) reviewed the safety of five Equisetum arvense-derived ingredients as used in cosmetic products; all of these ingredients are reported to function as skin-conditioning agents in cosmetics. Industry should use current good manufacturing practices to minimize impurities that could be present in these botanical ingredients. The Panel reviewed data relevant to the safety of these ingredients in cosmetic formulations, and concluded that the five Equisetum arvense-derived ingredients are safe in cosmetics in the present practices of use and concentration described in this safety assessment.

The Expert Panel for Cosmetic Ingredient Safety (Panel) assessed the safety of 12 Salvia officinalis (Sage)-derived ingredients as used in cosmetic formulations. These ingredients are most commonly reported to function as skin conditioning agents and fragrance ingredients. Because final product formulations may contain multiple botanicals, each containing the same constituents of concern, formulators are advised to be aware of these constituents and to avoid reaching levels that may be hazardous to consumers. With Salvia officinalis (Sage)-derived ingredients, the Panel was concerned about certain terpenes as potential sensitizers. Industry should use current good manufacturing practices to minimize impurities. The Panel reviewed data relevant to the safety of these ingredients in cosmetic formulations, and concluded that 6 of the ingredients (those derived from the leaves and the oil) are safe in cosmetics in the present practices of use and concentrations described in this safety assessment when formulated to be non-sensitizing, and that the data are insufficient to make a determination of safety for the remaining 6 ingredients under the intended conditions of use in cosmetic formulations.