Regulatory Toxicology and Pharmacology最新文献

Naturally occurring radioactive materials, particularly radon (²²²Rn) gas, can accumulate in carbonated beverages through source water and carbonation processes, potentially exposing consumers through ingestion and inhalation pathways. This investigation measured ²²²Rn activity concentrations and physicochemical parameters in 25 commercially available non-alcoholic carbonated beverages from Iraqi Kurdistan and evaluated associated radiological health risks. ²²²Rn concentrations ranged between 20.4 and 48.5 mBq/L, averaging 34.0 mBq/L. All measurements remained considerably below drinking water reference limits established by USEPA (11,100 mBq/L), WHO (100,000 mBq/L), and UNSCEAR (40,000 mBq/L). Physicochemical analysis revealed pH values of 2.2-4.5, electrical conductivity of 603-2622 μS/cm, total dissolved solids of 515-2250 mg/L, and Brix values of 0.4-12.3%. Calculated annual effective doses for adults, considering both ingestion and inhalation routes, stayed well beneath the WHO reference level of 100 μSv/y. Excess lifetime cancer risk values were approximately three orders of magnitude lower than USEPA's acceptable threshold. Statistical analysis showed no significant correlations between ²²²Rn concentrations and physicochemical properties. These non-alcoholic carbonated beverages present negligible radiological health risks to consumers. However, periodic monitoring of ²²²Rn concentrations in commercial beverages and continued surveillance of source water quality remain recommended to ensure ongoing compliance with safety standards and maintain public health protection.

Skin sensitization is a key endpoint for the safety assessment of topical consumer products. Ingredients with the potential to act as skin sensitizers differ markedly in their threshold for induction but can be used safely if their potency is characterized and exposure remains within an appropriate margin of safety. To this end, the fragrance industry co-developed Quantitative Risk Assessment (QRA) which starts with the No-Expected-Sensitization-Induction-Level (NESIL). Historically, QRA relies on a weight of evidence approach based on animal data, human confirmatory tests and read across. To allow an approach based solely on New Approach Methodologies (NAMs), the International Dialogue for the Evaluation of Allergens (IDEA) initiative, developed an extended Reference Chemical Potency List (RCPL) integrating human and animal data to derive potency values (PV). Here, we use PVs to evaluate the suitability of quantitative NAMs, including Defined Approaches (DAs), to derive a Point-of-Departure (NAM-PoD) for skin sensitization potency assessment. Evaluation of NAM-PoD derived by SARA-ICE DA, Regression DA and GARDskin dose-response assay (GSDR), indicates that the sensitization potency of fragrance chemicals can be reliably predicted using each approach. Through comparison of NAM-PoDs with in vivo human sensitization thresholds, NAM-specific adjustment factors were derived to convert NAM-PoDs into NAM-NESILs for QRA.

Microplastics (MPs) pollution is a growing environmental issue due to excessive plastic use and improper waste disposal. While early studies focused on MPs in aquatic and terrestrial ecosystems, recent research has expanded to include air quality. This comprehensive narrative review examines MP concentrations in both indoor and outdoor air, highlighting that poorly ventilated indoor spaces have the highest levels of MPs, while good ventilation helps reduce pollution. Factors such as humidity and precipitation decrease MP concentrations through particle deposition, while temperature, wind, and environmental conditions influence their dispersion and persistence. Effective management of environmental conditions and ventilation design is essential to reduce human exposure to MPs. MPs in indoor and outdoor environments show distinct characteristics. Indoor MPs are mostly small (<30 μm), transparent or black, and mainly appear as fibers, originating from textiles, carpets, and furniture. Outdoor MPs are more diverse, often found as fragments and composed of polymers like polystyrene (PS), polyethylene (PE), and polyethylene terephthalate (PET). Human exposure to MPs occurs primarily through inhalation and ingestion, with indoor environments posing higher risks due to particle accumulation and prolonged human presence. Fine MPs (<10 μm, especially ≤2.5 μm) can penetrate deep into the lungs, causing inflammation, oxidative stress, and systemic toxicity. Ingestion through dust is particularly concerning for infants and toddlers. Despite increasing evidence of health risks, the lack of standardized methods and regulatory limits highlights the urgent need for harmonized exposure assessment and targeted public health interventions. By synthesizing existing literature, this review provides a qualitative assessment of the current state of knowledge, identifies key research gaps, and discusses implications for future policy and exposure mitigation strategies.

Selecting first-in-human (FIH) doses for immunomodulators presents significant challenges. Conservative approaches, which rely on the minimal anticipated biological effect level (MABEL), emphasize safety but often result in sub-therapeutic starting doses. These doses limit patients' benefit in severe diseases and prolong dose escalation. To address these limitations, we previously introduced a refined integrative approach from an expert working group. This commentary highlights key enhancements of this refined framework for FIH dose selection, including a revised decision tree, industry case studies, and pharmacokinetic/pharmacodynamic (PK/PD) modeling. This approach allows for careful consideration of immunomodulator mechanisms of action and balances risk-benefit profiles. The case studies illustrate the utility of these strategies. Furthermore, the commentary discusses how emerging concepts like Model-Informed Drug Development (MIDD) and quantitative systems pharmacology (QSP) models can inform and potentially strengthen FIH starting dose selection, aiming to optimize the balance between patient safety and therapeutic efficacy in early-phase trials (148 words).

Nitrosamines (NAs) are a diverse class of mutagenic impurities encompassing both small molecules and structurally complex drug-related NAs, referred to as nitrosamine drug substance-related impurities (NDSRIs). NAs display a broad range of carcinogenic potential, from high carcinogenic potency to being weak or even non-carcinogenic. In vitro Ames tests, conducted with both rat and hamster liver-induced S9, and in vivo transgenic rodent (TGR) mutation assays have been used by pharmaceutical sponsors for hazard identification of NDSRIs. A comparative analysis of Ames tests and TGR results for 33 NDSRIs was performed and revealed an accuracy of 79% between the overall mutagenic calls in the two assays. For NDSRIs with positive TGR results, mutagenic potency estimates were calculated and compared to NAs with robust carcinogenicity and TGR dose-response data. Results from these NAs demonstrated a strong correlation between carcinogenic potency (TD₅₀) and TGR mutagenic potency (BMDL₅₀) (r² = 0.95), which supports the use of TGR data for both hazard identification and acceptable intake (AI) determination. By integrating quantitative risk assessment tools with TGR assays, this work contributes to a more robust framework for evaluating NA-associated risks.

Most accelerated approvals for oncology drugs have been granted, few studies have characterized the regulatory outcomes of non-oncology drugs within this framework. To examine regulatory outcome and approval timelines of non-oncology drug indications, a cross-sectional analysis was performed using the Food and Drug Administration's accelerated approval database from 1992 to 2024. Among 328 accelerated approval indications, 98 (30 %) were for non-oncology drugs. Overall, 63/98 (64 %) were converted to full approval with systemic anti-infectives accounting for 50 %. Among the 77 (79 %) original indications, 55 (71 %) were converted to full approval, compared to only 8 (38 %) of the 21 supplemental indications. The median times to accelerated approval and convert to full approval for all non-oncology indications were 7.9 (IQR, 5.9-10.0) and 38.8 (IQR, 22.5-63.9) months, respectively. The median time to accelerated approval was 6.8 (IQR, 5.9-10.0) months for 90 (92 %) chemical drug indications and 8.6 (IQR, 7.9-11.0) for 8 (8 %) biologic drug indications; conversion to full approval took 38.8 (IQR, 22.8-63.8) and 42.6 (IQR, 21.3-100.6) months, respectively. Accelerated approvals for non-oncology biologic drug indications took significantly longer than those for oncology biologic indications (8.6 vs. 6.0 months; p = 0.003). These findings underscore the importance of enhanced regulatory oversight and continued post-marketing evaluation to confirm the clinical benefits of non-oncology drugs approved via the accelerated pathway.

Exposure to 'metabolic disrupting chemicals' (MDCs) are increasingly implicated in obesity, diabetes and/or fatty liver disease; indeed, these metabolic changes may play a role in the global metabolic disorders' epidemic. To better assess and manage the health risks of MDCs, improved hazard identification is needed. This review describes how current in vivo OECD Test Guidelines (TGs) can better capture MDC effects. The biological and clinical evidence to support the inclusion of promising human relevant biomarkers, blood parameters, endpoints and relevant tissues for MDCs for potential inclusion in OECD TGs is documented. Current clinical chemistry routine requirements could be utilised further, and the additional assessment of relevant hormones such as a decrease in adiponectin, increase in resistin and leptin, which impact satiety, could be additionally included. Additionally, assessment of fatty tissue distribution in alert animals and insulin resistance, is recommended, and histological parameters in relation to the different types of adipose tissue. How specific biomarkers and endpoints could be incorporated into OECD mammalian in vivo assays, and how they can be included in the EU strategy for Endocrine Disrupting Chemicals identification and the forthcoming update to the OECD Guidance Document on the Testing and Assessment of Endocrine Disruption chemicals, are discussed.

Imidacloprid is a neonicotinoid insecticide that was first registered in the early 1990's, with global registrations that include agricultural, residential and veterinary uses. In 2001, Bayer reported a developmental neurotoxicity (DNT) study with imidacloprid that complied with U.S. EPA and OECD guidelines to support global registrations. The report concluded that there were slight effects in the offspring at the highest dietary level related to general or acute (neuro)-toxicity and no evidence of DNT at any dose; however, the European Food Safety Authority (EFSA) questioned certain findings at the high dose and whether the study established a clear NOAEL. More recently, the Jai Research Foundation (JRF) independently conducted a guideline-compliant DNT study with imidacloprid for other registrants, with elements incorporated into the study design to facilitate comparison with the Bayer study that could address these issues. This paper examines the findings from both studies, in the context of an updated literature review, to address regulatory uncertainty and persistent claims from non-governmental organizations that imidacloprid is a developmental neurotoxicant. The present analysis supports the interpretation that differences in brain measurements at the high dose in the Bayer study were incidental and unrelated to treatment and that imidacloprid is not a developmental neurotoxicant.