Safety assessment of food and feed from biotechnology-derived crops employing RNA-mediated gene regulation to achieve desired traits: A scientific review

Gene expression can be modulated in plants to produce desired traits through agricultural biotechnology. Currently, biotechnology-derived crops are compared to their conventional counterparts, with safety assessments conducted on the genetic modification and the intended and unintended differences. This review proposes that this comparative safety assessment paradigm is appropriate for plants modified to express mediators of RNA-mediated gene regulation, including RNA interference (RNAi), a gene suppression mechanism that naturally occurs in plants and animals. The molecular mediators of RNAi, including long double-stranded RNAs (dsRNA), small interfering RNAs (siRNA), and microRNAs (miRNA), occur naturally in foods; therefore, there is an extensive history of safe consumption. Systemic exposure following consumption of plants containing dsRNAs that mediate RNAi is limited in higher organisms by extensive degradation of ingested nucleic acids and by biological barriers to uptake and efficacy of exogenous nucleic acids. A number of mammalian RNAi studies support the concept that a large margin of safety will exist for any small fraction of RNAs that might be absorbed following consumption of foods from biotechnology-derived plants that employ RNA-mediated gene regulation. Food and feed derived from these crops utilizing RNA-based mechanisms is therefore expected to be as safe as food and feed derived through conventional plant breeding.     

Regulatory status quo and prospects for biosurfactants in pharmaceutical applications

The concept of going ‘green’ and ‘cold’ has led to utilizing renewable resources for the synthesis of microbial biosurfactants that are both patient and eco-friendly. In this review, we shed light on the potential and regulatory aspects of biosurfactants in pharmaceutical applications and how they can significantly contribute to novel concepts for the Coronavirus 2019 (COVID-19) vaccine and future treatment. We emphasize that more specific guidelines should be formulated to regulate the approval of biosurfactants for human use. It is also crucial to implement a risk-based approach from the early research and development (R&D) phase in addition to establishing more robust standardized techniques and assays to evaluate the characteristics of biosurfactants.     

CRISPR,animals, and FDA oversight: Building a path to success

Technological advances, such as genome editing and specifically CRISPR, offer exciting promise for the creation of products that address public health concerns, such as disease transmission and a sustainable food supply and enable production of human therapeutics, such as organs and tissues for xenotransplantation or recombinant human proteins to treat disease. The Food and Drug Administration recognizes the need for such innovative solutions and plays a key role in bringing safe and effective animal biotechnology products to the marketplace. In this article, we (the Food and Drug Administration/Center for Veterinary Medicine) describe the current state of the science, including advances in technology as well as scientific limitations and considerations for how researchers and commercial developers working to create intentional genomic alterations in animals can work within these limitations. We also describe our risk-based approach and how it strikes a balance between our regulatory responsibilities and the need to get innovative products to market efficiently. We continue to seek input from our stakeholders and hope to use this feedback to improve the transparency, predictability, and efficiency of our process. We think that working together, using appropriate science- and risk-based oversight, is the foundation to a successful path forward.     

Rotavirus vaccination compliance and completion in a Medicaid infant population

We examined completion and compliance rates of rotavirus (RV) vaccination according to the recommendations of the Advisory Committee on Immunization Practices (ACIP) and the Food and Drug Administration approved Prescribing Information (PI) for Rotarix^® (RV1, GlaxoSmithKline Vaccines) and RotaTeq^® (RV5, Merck and Co.) among infants under one year of age covered by Medicaid programs. Healthcare claims data from state Medicaid programs that constituted the Truven Health MarketScan^® Multi-State Medicaid Database were retrieved from May 2008–June 2012. Infants were grouped under PI and ACIP cohorts based on the dosing regimens followed. The overall compliance per PI (n = 673,956) and ACIP (n = 695,612) recommendations were 24.5% and 28.2%, respectively; completion rates were 30.3% and 32.6%, respectively. In the PI cohort, infants who received RV1 had significantly higher compliance as compared with infants who received RV5 (65.2% vs. 31.3%; p < 0.0001); completion rates among infants receiving RV1 and RV5 were 65.3% and 46.4%, respectively (p < 0.0001). In the ACIP cohort, compliance with RV1 was significantly higher than RV5 (68.8% vs. 45.9%; p < 0.0001) as was the overall completion rate (73.5% vs. 48.8%; p < 0.0001). While compliance is increasing year over year, overall compliance of RV vaccines is suboptimal, with over 40% of eligible infants unvaccinated in both populations. The 2-dose RV vaccine showed better completion rates and higher compliance than the 3-dose RV vaccine in the United States. Public health initiatives focusing on suboptimal compliance and completion rates of RV vaccination in the Medicaid population could improve these metrics, thereby offering protection against RV infection.     

Management Options for Irritable Bowel Syndrome

Irritable bowel syndrome (IBS) is associated with diverse pathophysiologic mechanisms. These mechanisms include increased abnormal colonic motility or transit, intestinal or colorectal sensation, increased colonic bile acid concentration, and superficial colonic mucosal inflammation, as well as epithelial barrier dysfunction, neurohormonal up-regulation, and activation of secretory processes in the epithelial layer. Novel approaches to treatment include lifestyle modification, changes in diet, probiotics, and pharmacotherapy directed to the motility, sensation, and intraluminal milieu of patients with IBS. Despite recent advances, there is a need for development of new treatments to relieve pain in IBS without deleterious central or other adverse effects.     

Clinical Implications of Clonal Hematopoiesis

Clonal hematopoiesis (CH)—an expansion of blood cells derived from a single hematopoietic stem cell—is a defining feature of hematologic cancers, but recently CH was also found to be a frequent consequence of aging. When aging-associated CH results from acquisition of a somatic mutation in a driver gene associated with leukemia, and this mutation is present at a variant allele frequency of at least 0.02 (2%) yet the patient does not meet World Health Organization diagnostic criteria for a hematologic neoplasm, this state is termed clonal hematopoiesis of indeterminate potential (CHIP). CHIP is present in approximately 10% to 15% of people older than 70 years and more than 30% by age 85 years and represents a precursor state for neoplasia akin to monoclonal gammopathy of undetermined significance. Recently, CHIP was unexpectedly found to be an important risk factor for cardiovascular events, with accumulating evidence supporting a mechanism of accelerated atherogenesis as a result of vascular inflammation driven by clonally derived monocytes/macrophages. Risk factors for CHIP include aging, male sex, cigarette smoking, and a common germline variant in the telomere-associated gene TERT. Clonal hematopoiesis can also occur after cytotoxic chemotherapy or radiotherapy for a solid tumor, after hematopoietic stem cell transplant, in the context of aplastic anemia, or after induction chemotherapy for acute leukemia; in each setting, CH has distinct clinical implications. This review summarizes recent studies of CH and CHIP and outlines challenges in clinical management of affected patients.     

Safety assessment for octadecyl 3-(3,5-di-tert-butyl-4-hydroxyphenyl)-propionate (CAS Reg. No. 2082-79-3) from use in food contact applications

Octadecyl 3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate (CAS Reg. No. 2082-79-3), currently marketed as Irganox 1076 (I-76), is a sterically hindered phenolic antioxidant used in a variety of organic substrates, including those used in the manufacture of food contact articles. In 2012, the US Food and Drug Administration (USFDA), Office of Food Additive Safety (OFAS), initiated a post-market re-evaluation of the food contact applications of I-76. This project aimed to ensure that current dietary exposures from the use of I-76 in food contact articles are accurately captured and the safety assessment considered all relevant and available toxicological information. To accomplish these aims, the USFDA reviewed the available toxicological studies and chemistry information on food contact applications of I-76. Based on this in-depth analysis, a NOAEL of 64 mg/kg-bw/d (female rats) from a chronic rat study and a cumulative estimated dietary intake (CEDI) of 4.5 mg/p/d, was used to calculate a margin of exposure (MOE) of ∼850. We concluded that the previous and current exposure levels provide an adequate margin of safety (MOS) and remain protective of human health for the regulated uses.     

美国FDA在应急医药产品应急准备中的职能分析

目的:对美国流行病和灾害性应急准备系列法案中美国食品药品监督管理局(FDA)职能定位进行分析,为我国政府部门的应急职能设计提供参考。方法:采取法案内容分析法,了解FDA在应急医药产品准备中的职能定位。结果:FDA在医药产品应急准备的根本职能是促进突发事件中应急医药产品的开发和使用的可获得性,包括发布医药产品的应急指导和安全警示信息,负责授权医药产品紧急使用权、延长医药产品保存期限及预置职能。结论:应重视国家级应急准备工作,完善应急准备的配套法律体系,准确定位"应急医药产品的应急预案",加强应急医药产品的应急信息化管理,建设应急医药产品的快速调剂和使用机制。