Regulatory Toxicology and Pharmacology最新文献

{"title":"Evaluating dermal absorption of perfluorooctanoic acid (PFOA) and implications for other per- and polyfluoroalkyl substances (PFAS)","authors":"Andrew Yeh ,&nbsp;Robyn L. Prueitt ,&nbsp;Laura E. Kerper ,&nbsp;Barbara D. Beck","doi":"10.1016/j.yrtph.2024.105766","DOIUrl":"10.1016/j.yrtph.2024.105766","url":null,"abstract":"<div><div>To date, only four studies directly measured dermal absorption kinetics of perfluorooctanoic acid (PFOA) in human skin. Reported kinetic parameters spanned two to five orders of magnitude, demonstrating the need to determine the causes of variability and identify the most appropriate dermal absorption factors for use in exposure assessments. We evaluated the reliability and physiological relevance of studies that measured PFOA fractional absorption, steady-state flux (J_ss), and dermal permeability coefficient (K_p). We verified whether the reported kinetic parameters were measured under appropriate conditions (<em>i.e.</em>, fractional absorption under finite dose conditions, and J_ss and K_p under infinite dose conditions). We recommend the following values measured at the approximate pH of the skin, and in aqueous solvents or relevant consumer product matrices, for use as provisional values in PFOA exposure assessments: 1.6% fractional absorption under finite dose conditions, and 0.132 μg/cm²-hr and 0.000044 cm/h for J_ss and K_p, respectively, under infinite dose conditions. Using the recommended absorption factors, we estimated PFOA exposures in children from soil and water <em>via</em> dermal and ingestion routes. Our results indicate low dermal absorption of PFOA relative to ingestion, and low dermal absorption is expected for per- and polyfluoroalkyl substances (PFAS) with physicochemical properties similar to PFOA.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"156 ","pages":"Article 105766"},"PeriodicalIF":3.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142865335","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Rodent estrous cycle pattern: Harmonizing the cycle evaluation and interpretation","authors":"Shivakumar Holalagoudar ,&nbsp;Susan Kisielewski ,&nbsp;Austin Martini ,&nbsp;Kamin Johnson ,&nbsp;Anne-Laure Leoni ,&nbsp;Corinna Demminger ,&nbsp;Sonja Brosel","doi":"10.1016/j.yrtph.2024.105768","DOIUrl":"10.1016/j.yrtph.2024.105768","url":null,"abstract":"<div><div>The estrous cycle is a sensitive endpoint from an endocrine disruptor perspective and is included in rodent reproductive toxicity studies. In this paper, the methods for estrous cycle timing and different approaches followed by testing laboratories for evaluating the days of the estrous cycle were reviewed. No major differences are identified for counting 4-day estrous cycle. However, when extended episodes of estrus (E) stages occur, the cycle counting differs between testing laboratories potentially resulting in misinterpretation and inaccurate outcome. Appearance of extended episodes of two to three E in an estrous cycle need explanation. Therefore, the following are proposed, 1) follow OECD guidance document for normal 4/5 day cycles, 2) recommends an update of the OECD document as in the current one it is unclear for a 5-day cycle ending with Proestrus(P) followed by episode(s) of estrus(E), 3) two episodes of E after P in a 5-day cycle and three consecutive episodes of E should be considered abnormal, and 4) stages prior to first E of the first cycle or after last E (last P of a 5-day) of last cycle should not be assumed a complete cycle. Additionally, call for collaboration is made to harmonize the cycle counting approach.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"156 ","pages":"Article 105768"},"PeriodicalIF":3.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142882850","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploring the link: DNA methylation and kidney injury markers in farmers exposed to glyphosate-surfactant herbicides","authors":"Supakit Khacha-ananda,&nbsp;Unchisa Intayoung,&nbsp;Kanyapak Kohsuwan,&nbsp;Klintean Wunnapuk","doi":"10.1016/j.yrtph.2024.105765","DOIUrl":"10.1016/j.yrtph.2024.105765","url":null,"abstract":"<div><div>Glyphosate-surfactant herbicides (GSH), widely used herbicides, have raised concerns about their potential nephrotoxic effects. Despite extensive studies, the safety of GSH remains debatable. This study aimed to determine if occupational exposure to GSH causes detectable changes in renal injury biomarkers—specifically DNA methylation, KIM-1, TIMP2, and IGFBP7—in farmers regularly exposed to these chemicals. Two urine samples, pre-task (0-h) and post-task (24-h), were collected to analyze these biomarkers. No significant immediate changes were observed post-exposure, possibly due to personal protective equipment use. Moderate positive correlations were found between IGFBP7 and KIM-1, and IGFBP7 and TIMP2, suggesting early kidney injury. About 50% of subjects had a biomarker ratio greater than 1, indicating increased levels of IGFBP7, TIMP2, and KIM-1 after GSH exposure. This indicates that farmers who regularly spray GSH are at high risk of exposure, potentially leading to significant renal injury. Further long-term studies are needed to assess the chronic effects and validate these biomarkers for monitoring renal health in populations exposed to glyphosate.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"156 ","pages":"Article 105765"},"PeriodicalIF":3.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142865347","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Control of N-nitrosamine impurities in drug products: Progressing the current CPCA framework and supporting the derivation of robust compound specific acceptable intakes","authors":"David J. Ponting ,&nbsp;Andreas Czich ,&nbsp;Susan P. Felter ,&nbsp;Susanne Glowienke ,&nbsp;James S. Harvey ,&nbsp;Raphael Nudelman ,&nbsp;Joerg Schlingemann ,&nbsp;Stephanie Simon ,&nbsp;Graham F. Smith ,&nbsp;Andrew Teasdale ,&nbsp;Robert Thomas","doi":"10.1016/j.yrtph.2024.105762","DOIUrl":"10.1016/j.yrtph.2024.105762","url":null,"abstract":"<div><div>The carcinogenic potency categorisation approach (CPCA) has recently been introduced by health authorities. In this model, structural features from recent literature, industry proposals, and analyses performed by health authorities, provide a rapid assessment of the potential acceptable intake (AI) for a nitrosamine impurity. As with other screening regulatory values (such as the ICH M7 Threshold of Toxicological Concern), the CPCA is conservative and can be considered a <em>de minimis</em> risk management framework. In cases where a nitrosamine drug substance-related impurity (NDSRI) is present below the CPCA limit, the framework provides resolution from a toxicological perspective (i.e., no further toxicology studies are required). Where an NDSRI is above the CPCA limit, the framework provides for the initiation of additional activities (i.e., the CPCA is not the only possible limit). Read-across approaches are described in both the CPCA and M7 guidance and can provide a limit with more specific applicability than the general model. The use of available experimental data (<em>in vitro</em> or <em>in vivo</em>), is valuable in order to provide an even more specific limit. The CPCA provides a framework; however, data should permit changing the AI from initial structural assessment, based on increasing data, to ultimately increase precision of the AI.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"156 ","pages":"Article 105762"},"PeriodicalIF":3.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142814074","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Unraveling Caco-2 cells through functional and transcriptomic assessments","authors":"Ye Eun Jeong,&nbsp;Katherine Shea,&nbsp;Kevin A. Ford","doi":"10.1016/j.yrtph.2025.105771","DOIUrl":"10.1016/j.yrtph.2025.105771","url":null,"abstract":"<div><div>The static Caco-2 monolayer is an extensively utilized model for predicting the permeability of small molecules during the drug development process. While these cells can differentiate and develop key functional and morphological features that emulate human enterocytes, they do not fully replicate the complexity of human intestinal physiology. In this study, we investigated functional and morphological aspects of Caco-2 cells, alongside their transcriptomic profiles, with a particular emphasis on genes encoding drug-metabolizing enzymes and drug transporters. We found that Caco-2 cells not only established a robust and bio-relevant permeable intestinal barrier but also demonstrated functional maturity and differentiation in the intestinal epithelium, substantiated by the activities of important enzymes and an efflux transporter. However, our targeted gene expression analyses revealed that substantial disparities were found in mRNA transcript levels among Caco-2 cells and human biopsy samples. These findings highlight that, although Caco-2 cells are valuable for assessing the passive transport of drugs, their accuracy for predicting active transport or small intestinal drug metabolism is constrained by their transcriptomic divergence from human intestinal tissues. This study highlights the importance of understanding the Caco-2 model's inherent limitations and provides insights that could inform its appropriate application in drug development and regulatory decision-making.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"156 ","pages":"Article 105771"},"PeriodicalIF":3.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142979724","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Quantifying the effect of human interindividual kinetic differences on the relative potency value for riddelliine N-oxide at low dose levels by a new approach methodology","authors":"F. Widjaja-van den Ende ,&nbsp;M.A.J.S. van Boekel ,&nbsp;C. Davis ,&nbsp;S. Wesseling ,&nbsp;I.M.C.M. Rietjens","doi":"10.1016/j.yrtph.2024.105767","DOIUrl":"10.1016/j.yrtph.2024.105767","url":null,"abstract":"<div><div>Pyrrolizidine alkaloid N-oxides (PA-N-oxides) are predominant in plants and herbal foods, and are converted to pyrrolizidine alkaloids (PAs) upon consumption, leading to toxicity. The effect of interindividual kinetic differences on the relative potency values of PA-N-oxides compared to their PAs (REP_{PANO to PA}) was studied, with riddelliine N-oxide (RIDO) and riddelliine (RID) as model compounds. <em>In vitro</em> kinetic data measured in incubations with 30 fecal and 25 liver S9 donor samples showed high variation across individuals, where the interindividual variability was captured with Bayesian multilevel regression. The distributions of influential PBK model parameters were used as input for physiologically based kinetic (PBK) modeling combined with Monte Carlo (MC) simulations to calculate the probability distribution of REP_{RIDO to RID} values. At low dose levels, interindividual differences were shown to be a factor that influences the REP_{RIDO to RID} value while neither dose nor endpoint used plays a role. The distribution of the REP_{RIDO to RID} value ranged from 0.71 to 0.97 (95th percentile) with a mean value of 0.87. The approach described enables determination of interindividual REP_{PANO to PA} values at low dose levels, which are not accessible in <em>in vivo</em> experiments quantifying the REP_{PANO to PA}value.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"156 ","pages":"Article 105767"},"PeriodicalIF":3.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142877848","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Global regulatory considerations and practices for tumorigenicity evaluation of cell-based therapy","authors":"Dehu Dou ,&nbsp;Jing Lu ,&nbsp;Jinhui Dou ,&nbsp;Yan Huo ,&nbsp;Xinjiang Gong ,&nbsp;Xuefeng Zhang ,&nbsp;Xijing Chen","doi":"10.1016/j.yrtph.2024.105769","DOIUrl":"10.1016/j.yrtph.2024.105769","url":null,"abstract":"<div><div>Cell-based therapy, as a “living drug”, possesses inherent complexity and heterogeneity. Tumorigenicity evaluation is a crucial aspect of safety assessment for cell-based therapies. Stem cell-based therapies such as hESCs and hiPSCs, may contain residual undifferentiated cells in final product, which have a high potential for proliferation and differentiation, posing a risk of tumor formation in vivo. Additionally, the source, phenotype, differentiation status, proliferative capacity, ex vivo culture conditions, ex vivo processing methods, injection site, and route of administration also influence the tumorigenicity risk of the cells. Tumorigenicity evaluation needs to consider the complexity of design and multifactorial influences. Through the analysis and summary of partial existing marketed and under-development products, combined with practical experience, it is found that there are many differences in requirements and practices related to cell tumorigenicity globally. Regulatory requirements also vary, and guidance and support for applicants’ declaration requirements in different regions need to be considered in conjunction with product characteristics and regulatory considerations. This article comprehensively summarizes the requirements of tumorigenicity from main regulatory agencies. Currently, there is no unified global regulatory consensus on technical implementation guide, measures for quantitation or standardization have not been established for evaluation systems. However, based on regulatory requirements and industry practice summaries, through literature research and analysis of tumorigenicity strategy of representative marketed products, the basic focus, and evaluation strategies for tumorigenicity assessment have been preliminarily clarified, providing a reference for the tumorigenicity design of variety of cell-based therapy products.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"156 ","pages":"Article 105769"},"PeriodicalIF":3.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142915356","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The dual endothelin A and angiotensin II type 1 receptor antagonist sparsentan (FILSPARI®) exhibits a safe nonclinical male fertility toxicity profile","authors":"Patricia W. Bedard ,&nbsp;Francesca Pretto ,&nbsp;Sima Patel ,&nbsp;Celia Jenkinson ,&nbsp;Tacey White ,&nbsp;Donald E. Kohan","doi":"10.1016/j.yrtph.2024.105770","DOIUrl":"10.1016/j.yrtph.2024.105770","url":null,"abstract":"<div><div>Marketed endothelin receptor antagonists (ERAs) have been associated with testicular tubular atrophy and decreases in male animal fertility in chronic toxicity studies in rats and dogs. Consistent with these findings, reduced sperm count has been observed in the clinical setting and is considered a potential class risk with chronic administration of ERAs. In contrast, no such effects on male animal fertility are noted with angiotensin II type 1 receptor blocker (ARB) treatment. Sparsentan (FILSPARI®) is a novel single molecule dual antagonist that antagonizes both the endothelin type A and angiotensin II type 1 receptors. We explored whether the reproductive toxicology profile of this dual endothelin angiotensin antagonist is more like that of marketed ERAs or ARBs. A full package of repeat dose general toxicity, juvenile toxicity, carcinogenicity, and reproductive and developmental toxicity studies was completed with sparsentan. A thorough review of the results from these studies has shown no evidence of effects of sparsentan on spermatogenesis or testicular histopathology. The overall conclusion of this assessment is that sparsentan is not toxic to the testes or the spermatogenic process and is more like ARBs than ERAs in its male fertility toxicity profile.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"156 ","pages":"Article 105770"},"PeriodicalIF":3.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142915360","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Toxicological evaluation of vanadium and derivation of a parenteral tolerable intake value for medical devices","authors":"Charlotte E. Laupheimer ,&nbsp;Yana Kolianchuk ,&nbsp;Rex E. FitzGerald ,&nbsp;Martin F. Wilks ,&nbsp;Arne Jaksch","doi":"10.1016/j.yrtph.2024.105732","DOIUrl":"10.1016/j.yrtph.2024.105732","url":null,"abstract":"<div><div>Vanadium is used in alloys, batteries as well as catalyst and is a known impurity in medical devices and pharmaceuticals. The present work describes the calculation of a parenteral tolerable intake (TI) for vanadium by chronic exposure in implantable medical devices per ISO 10993–17:2023, the applicable standard. The 2023 update of ISO 10993-17 [1] introduces new uncertainty factors (UFs) for calculating a TI. Therefore, we noted differences between the ISO guidance and the ICH Q3D guidance on Permissible Daily Exposure (PDE) for parental elemental pharmaceutical impurities. We derived a TI of 0.20 μg V/kg/day based on the updated ISO guidance, and a PDE of 0.24 μg V/kg/day based on ICH guidance. The latter is considered a more realistic estimate.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"156 ","pages":"Article 105732"},"PeriodicalIF":3.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142547051","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Use of alternatives to animal testing for Environmental Safety Assessment (ESA): Report from the 2023 EPAA partners’ forum","authors":"Jose V. Tarazona ,&nbsp;Ana Fernandez-Agudo ,&nbsp;Ondrej Adamovsky ,&nbsp;Marta Baccaro ,&nbsp;Natalie Burden ,&nbsp;Bruno Campos ,&nbsp;Björn Hidding ,&nbsp;Karen Jenner ,&nbsp;David John ,&nbsp;Katia Lacasse ,&nbsp;Adam Lillicrap ,&nbsp;Delina Lyon ,&nbsp;Samuel K. Maynard ,&nbsp;Amelie Ott ,&nbsp;Veronique Poulsen ,&nbsp;Mike Rasenberg ,&nbsp;Katrin Schutte ,&nbsp;Marta Sobanska ,&nbsp;James R. Wheeler","doi":"10.1016/j.yrtph.2025.105774","DOIUrl":"10.1016/j.yrtph.2025.105774","url":null,"abstract":"<div><div>Environmental Safety Assessments (ESA) are mandatory for several regulatory purposes and are an important component of stewardship/sustainability initiatives. Fish testing is used for assessing chemical toxicity and bioaccumulation potential; amphibians are included in some jurisdictions and their use is increasing to assess endocrine disruption. Alternative methods are becoming more available, covering the principles of the 3Rs (i.e., replacing, reducing and refining animal tests), but their regulatory incorporation is still limited. A cross-sector review by the European Partnership for Alternative Approaches to Animal Testing (EPAA), discussed the status and priorities for accelerating the adoption of non-animal approaches in ESA. The lack of an internationally agreed definition for “animal testing” was recognized as a challenge. For example, testing with vertebrate embryos up to specific developmental stages is a suitable refinement alternative only in some jurisdictions. Invertebrate testing offers refinement alternatives to develop tiered approaches using vertebrate testing as a last resort. Aquatic ESA was identified as a common need by all sectors and regulatory areas, while terrestrial ESA is particularly relevant for agrochemicals. The standardization and validation of some alternative methods as OECD test guidelines (TGs) for fish acute toxicity and fish bioaccumulation have not yet triggered the expected replacement in regulatory settings. Priority actions in these areas are needed to generate confidence in the regulatory use of the available OECD TGs designed as alternatives, including the identification of applicability domains and guidance/decision-trees for integrating different lines of evidence. Case studies under the OECD Integrated Approaches to Testing and Assessment (IATA) program could facilitate further global regulatory uptake. Replacement of fish chronic toxicity testing is more complex and less advanced. A dual approach was suggested, in the short-term, exploring lines of evidence that, alone or in combination, could identify when further fish testing is not needed. The second phase should focus on the application of the 3Rs in those cases where chronic information is needed. Another area of increasing interest is endocrine disruption. It represents a challenge but also an opportunity for implementing mechanistic non-animal methods, in addition to integrate human and ESA. This requires a step-by-step approach with continuous dialogue to ensure that technical developments will address regulatory needs. The review also agreed that the long-term aspiration is a new ESA paradigm, mapping the protection goals and providing connectivity between the chemical legislation and environmental protection policies.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"156 ","pages":"Article 105774"},"PeriodicalIF":3.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143041489","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}