Regulatory Toxicology and Pharmacology最新文献

In 2022 the World Health Organization (WHO) published updated ‘Toxic Equivalence Factors’ (TEFs) for a wide variety of chlorinated dioxins, dibenzofurans and PCBs [collectively referred to as ‘dioxin-like chemicals’; DLCs) that interact with the aryl hydrocarbon receptor (AHR)]. Their update used sophisticated statistical analysis of hundreds of published studies that reported estimation of ‘Relative Effective Potency’ (REP) values for individual DLC congeners. The weighting scheme used in their assessment of each study favored in vivo over in vitro studies and was based largely on rodent studies. In this Commentary, we highlight the large body of published studies that demonstrate large species differences in AHR-ligand activation and provide supporting evidence for our position that the WHO 2022 TEF values intended for use in human risk assessment of DLC mixtures will provide highly misleading overestimates of ‘Toxic Equivalent Quotients’ (TEQs), because of well-recognized striking differences in AHR ligand affinities between rodent (rat, mouse) and human. The data reviewed in our Commentary support the position that human tissue-derived estimates of REP/TEF values for individual DLC congeners, although uncertain, will provide much better, more realistic estimates of potential activation of the human AHR, when exposure to complex DLC mixtures occurs.

The Modernization of Cosmetics Regulation Act of 2022 (MoCRA) amends the Food, Drug and Cosmetic Act (FDCA), elevating the standard of proof of safety (better known as a “safety standard”) for cosmetics to the standard of a “reasonable certainty … [of] … safe.”a standard equal to that of food ingredients. The standards of the proof of safety differ for various classes of FDA-regulated product categories e.g., cosmetics, dietary supplements, food ingredients and food itself. This manuscript describes the various standards of proof, the essential differences between the standards, key elements required to achieve a particular standard and, compares the standards to more familiar legal terms such as “a preponderance of the evidence” or “beyond reasonable doubt.” The standards of proof for these product categories are also ranked according to increasing threshold for achievement of “safe” status. Lastly, this manuscript suggests how the requirements for the high standard of a “reasonable certainty of safe” (or “reasonable certainty of no harm”) might be met.

Post-market medical device-associated failures and patient problems are reported in Medical Device Reports (MDRs) to the US Food and Drug Administration. Reports are accessible through Manufacturer and User Facility Device Experience (MAUDE), a database including both required and voluntary submissions. We present an overview of >10 million MDRs received from 2011 to 2021. Approximately 92% of reporting issues represent medical device physical or functional failures, categorized from 1704 codes related to medical device integrity or function. ∼8% were coded adverse events (AEs). Patient outcomes are reported via 998 patient codes in 19 medical specialties (cardiovascular, orthopedic, etc.). ∼40% of patient reports indicated “no health consequences”; however, a small number of devices had consistently high AE reports. While overall reports did not exhibit a sex-based dichotomy, ∼9% of the reported AEs occurred more frequently in females, many of which were related to immune effects. The analyses are subject to uncertainties and potential bias based on data available and data selected for analysis. However, such an overview of post-market MDR data, not previously published, fills a gap in understanding medical device issues and patient-based outcomes related to medical device use. Trends identified may be subjects of additional hypotheses, analysis, and research.

ISO 10993-1:2018 describes evaluating the biocompatibility profile of a medical device from a risk-based approach. This standard details the battery of information that should be considered within the assessment of a device, including raw material composition data, manufacturing processes, and endpoint testing. The ISO 10993/18562 series requires worst-case assumptions and exposure scenarios to be used in the evaluation, which may result in an over-estimation of patient safety risk. Currently, biocompatibility assessments evaluate each data set independently, and the consequence of this individualized assessment of exaggerated inputs is potential false alarms regarding patient safety. To evaluate these safety concerns, the ISO standards indicate that professional judgement should be used to estimate patient risk but does not provide guidance on incorporating a holistic review of the data into the risk assessment. Recalibrating these worst-case data to evaluate them in a weight-of-evidence (WoE) approach may provide a more realistic data set to determine actual patient risk. This proposed WoE framework combines understanding data applicability with a method for gauging the strength of data that can provide additional support for the final safety conclusion. Using a WoE framework will allow risk assessors to contextualize the data and utilize it to comprehensively estimate patient safety.

Development of New Approach Methodologies (NAMs) capable of providing a No Expected Sensitization Induction Level (NESIL) value remains a high priority for the fragrance industry for conducting a Quantitative Risk Assesment (QRA) to evaluate dermal sensitization. The in vitro GARDskin assay was recently adopted by the OECD (TG 442E) for the hazard identification of skin sensitizers. Continuous potency predictions are derived using a modified protocol that incorporates dose-response measurements. Linear regression models have been developed to predict human NESIL values. The aim of the study was to evaluate the precision and reproducibility of the continuous potency predictions from the GARDskin Dose-Response (DR) assay and its application in conducting QRA for fragrance materials using a Next Generation Risk Assessment (NGRA) framework. Results indicated that the GARDskin Dose-Response model predicted human NESIL values with a good degree of concordance with published NESIL values, which were also reproducible in 3 separate experiments. Using Isocyclocitral as an example, a QRA was conducted to determine its safe use levels in different consumer product types using a NGRA framework. This study represents a major step towards the establishment of the assay to derive NESIL values for conducting QRA evaluations for fragrance materials using a NGRA framework.

All cosmetics products, including nail care products, must be evaluated for their safety. The assessment of systemic exposure is a key component of the safety assessment. However, data on the exposure, especially via ungual route (nail plate) are limited. Based on the physicochemical properties of human nails and permeability data of topical onychomycosis drugs, the nail plate is considered a good barrier to chemicals. We examine factors impacting penetration of nail care ingredients through the nail plate, including properties of the nails of the ingredients and formulations. The molecular weight, vapor pressure, logP, water solubility, and keratin binding, as well as formulations properties e.g., polymerization of acrylate monomers are considered important factors affecting penetration. To estimate systemic exposure of nail care ingredients through the nail plate, a standardized framework is applied that quantifies the impacts of these properties on penetration with an adjustment factor for each of these influencing properties. All the adjustment factors are then consolidated to derive an integrated adjustment factor which can be used for calculation of the systemic exposure dose for the ingredient. Several case studies are presented to reflect how this framework can be used in the exposure assessment for nail cosmetic products.