Benzaldehyde

In October 2010 the National Organic Standards Board recommended that engineered nanomaterials (ENMs) be prohibited from food products bearing the U.S. Department of Agriculture’s coveted Organic label.1 If the department adopts the recommendation, ENMs will find themselves in the same officially taboo category as genetically modified organisms when it comes to organic foods—nanotechnology-enabled innovations like flavor- and texture- enhancing ingredients and shelf life– extending packaging will be off the menu. Prior to issuing its recommendation, the board received thousands of public comments and petition signatures supporting the ban and virtually none opposing it. Although an official decision could take years, supporters are confident the recommendation will be adopted, and it will go down as one of the first lines drawn in the sand when it comes to the reach of this relatively new and potentially transformative technology in the American marketplace. Nanotechnology-enabled products are quietly proliferating on U.S. store shelves, despite nagging questions about the safety of synthetic nanoparticles and the products that contain them. “[I]n our regulation of food and most consumer products, we don’t implement the precautionary principle. Things go to market before we know whether or not they’re really safe for human beings over the long term,” says Alexis Baden-Mayer, a lawyer with the Organic Consumers Association, an advocacy group, who attended the meeting and campaigned for the ban. Baden-Mayer and other observers perceive a distinct lack of public awareness about how common ENMs are becoming in the market-place, and she hopes discussion among consumers of organic products will help change that. “Consumers don’t know much about nanotechnology, and the first time they may hear about it is now when they learn that the organic regulations are going to prohibit [it],” she says. The International Organization for Standardization defines a nanomaterial as a material with any external dimension between 1 and 100 nm.2 (By comparison, a double strand of DNA is about 2 nm thick.) Nanoparticles, which have been the focus of most nanotoxicology studies to date,3 are one subset of nanomaterials. Nanoparticles include structures of various shapes, such as nanotubes, nanowires, quantum dots, and fullerenes. They also occur naturally in substances like air, smoke, and sea spray, and “incidental” nanoparticles are created during processes such as combustion and food milling, churning, freezing, and homogenization. (Naturally occurring and incidental nanoparticles were not included in the National Organic Standards Board’s recommendation to ban ENMs.) Nanotechnology—the deliberate synthesis and manipulation of nanomaterials—began in the 1980s. Today thousands of ENMs are manufactured in a kaleidoscope of substances, shapes, and sizes for use in a wide range of products and industrial processes that take advantage of their novel physical, thermal, optical, and biological properties. These properties may be determined by the ENM’s chemical composition, size or shape, crystal structure, solubility, adhesion (the force that holds the nanoparticle components together), or surface chemistry, charge, or area.3 Industry analysts have been forecasting “game-changing” advances as a result of nanotechnology in renewable energy, computers, communications, pollution cleanup, agriculture, medicine, and more.4 Clothing, sunscreens, cosmetics, sporting equipment, batteries, food packaging, dietary supplements, and electronics are just a few of the types of nanotechnology-enabled goods in use by U.S. consumers. But safety questions arise around the nanoparticles in some of these products. The novel biological and physical properties of some ENMs pose unique challenges to comprehensive safety research, and investigators are working to figure out just how hazardous they might be to people, wildlife, and the environment. Compared with larger particles, nanoparticles’ tiny size means tissues may take them up more readily. It also can give them an unusual ability to travel throughout the body, including into cells and cell nuclei, and across the placenta and the blood–brain barrier, as demonstrated in rodent studies.5,6 No cases of human illness or death have been definitively attributed to ENMs. However, a number of researchers and consumer and environmental advocates have warned that the abundant unknowns make it necessary to proceed with caution lest we repeat the history of asbestos, polychlorinated biphenyls, the insecticide DDT, and other innovations that seemed valuable when they were introduced, proceeded with little oversight, and ultimately caused major health or environmental problems.

Five non-nutritive sweeteners (NNS) are currently approved for use in the United States as food additives by the Food and Drug Administration (FDA): acesulfame-K, aspartame, neotame, saccharin, and sucralose; stevia glycosides (principally rebaudioside A) are also permitted for use based on a GRAS (generally recognized as safe) petition submitted to the FDA. The daily intake of each NNS by children and adults in the United States is well below the acceptable daily intake (ADI) set by the FDA. The ADI is the amount that can be consumed daily for life without health or safety concern. The FDA approval process for new food additives (including GRAS) includes the generation and submission of extensive safety databases in animals and humans. Nutritive and NNS initiate sweet taste in the mouth by binding to the same sweet-taste receptor, located on the cell membrane of taste bud cells. The oral sweet-taste receptor consists of two membrane-associated proteins coupled to an intracellular G-protein. The variety of molecules that taste sweet (nutritive and non-nutritive) bind to different parts of these membrane proteins. The same sweet-taste receptor is also found on enteroendocrine cells of the small intestine. Both nutritive and NNS bind to these receptors and can cause the release of hormones involved in glucose homeostasis. The sweet-taste receptor is also found on pancreatic, insulin-secreting beta cells, and while not mediating glucose-induced insulin secretion, can promote insulin secretion in vitro in the presence of high (non-physiologic) concentrations of NNS. Unlike nutritive sweeteners (NS), the ingestion of NNS by fasting humans does not elevate plasma concentrations of the hormones secreted by enteroendocrine or pancreatic beta cells. NNS ingestion may enhance some of these responses to NS when both are ingested together, but the effects thus far reported are not consistent among studies. The body of epidemiologic evidence exploring for associations between NNS use and body weight gain is not convincing; moreover, epidemiologic studies cannot prove causality. Active intervention studies in which NNS are covertly substituted for NS in the diet for extended periods of time (e.g., up to 18 months in children) show that NNS do not cause weight gain or obesity.

*These authors contributed to the devlopment and review of this manuscript but are unable to endorse the request for NIH funding. On Sept. 20, 2011, the American Association for Cancer Research (AACR) released its inaugural AACR Cancer Progress Report to commemorate the

The US Food and Drug Administration (FDA) has premarket review authority over food additives, but a food manufacturer may, according to the legislation, intentionally add a substance to human food or animal food without their premarket review or approval if the substance is generally recognized, among qualified experts, to be safe under the conditions of its intended use. Generally recognized as safe (GRAS) implies that the current scientific community agrees on the adequacy of how data is generated. This system has come under public pressure because of doubts as to its efficiency and the FDA's recent GRAS rule is part of the response. The FDA guidance for testing food additives, known as the "Redbook", is about two decades old. Work toward a new "Redbook" is on the way, but the US Grocery Manufacturer Association (GMA) also has initiated the development of an independent standard on how to perform GRAS determinations. This review of the current guidance shows a very rigorous system for higher concern levels, but also many waiving options. Opportunities and challenges for safety evaluations of food additives are discussed. Where scientific progress has allowed improving existing and adapting new methods, these should be adopted to improve product safety and animal welfare. The continuous adaptation of such improved methods is therefore needed. Especially, there are opportunities to embrace developments within the toxicity testing for the 21st century movement and evidence-based toxicology approaches. Also, the growing understanding of the limitations of traditional tests needs to be considered.

Clinical Prioritization of Antispike Monoclonal Antibody Treatment of Mild to Moderate COVID-19

The safety and regulatory process for low calorie sweeteners in the United States

Under the Federal Food, Drug, and Cosmetic Act (FFDCA), food ingredients that are generally recognized as safe (GRAS) by qualified experts, (either based on scientific principles or because they have had a history of safe consumption in food) are exempt from mandatory premarket approval. Those that are not GRAS are defined as “food additives” under the FFDCA and are subject to premarket review and approval by the Food and Drug Administration (FDA) before they can be used in food. Before any new color additive can be marketed, a manufacturer must first petition the FDA for its approval. Since enactment of the Dietary Supplement Health and Education Act (DSHEA) of 1994, certain dietary ingredients used in dietary supplements are exempt from the definition of food additive and are instead subject to the provisions of DSHEA.

Effective immunization programs have markedly diminished the incidence of vaccine-preventable diseases. As a result, there now exists in society a lower awareness of the actual risks associated with the diseases themselves and a greater prominence of the potential risks of adverse effects associated with vaccines.Concern regarding public reactions to new vaccine safety issues may place pressure on policymakers and/or health care providers to act quickly in response to new information. However, this concern must be tempered by the necessary caution required to assess the intended and unintended risks and benefits of any action undertaken. The interplay of these potentially competing demands is well illustrated by the recent safety concern involving the use of thimerosal in vaccines.Thimerosal is a mercury-containing compound that has been widely used as an antimicrobial agent in vaccines for over 60 years. Human exposure to mercury may have potentially significant health consequences. By mid-1999, the Food and Drug Administration (FDA) had discovered that children could be exposed to an amount of mercury from vaccines that exceeded 1 of 3 existing federal safety thresholds. After this realization, the organized medical and public health communities in the United States became involved in a series of urgent and intense discussions to determine an appropriate response to the issue. This manuscript describes and analyzes the process that led to the July 7, 1999, joint American Academy of Pediatrics (AAP)/US Public Health Service (PHS) statement on thimerosal,1 with the goal of suggesting improvements for managing similar vaccine safety concerns in the future.We conducted structured interviews with over 15 individuals involved in the discussions and negotiations leading to the joint AAP/PHS statement on thimerosal. The individuals represented both the governmental agencies and nongovernmental organizations involved, including the FDA, the Environmental Protection Agency (EPA), the Centers for Disease Control and Prevention (CDC), the National Vaccine Program Office (NVPO), the AAP, and the American Academy of Family Physicians (AAFP). Interviews were conducted through face-to-face meetings or by telephone between January and April 2001. Table 1 lists the individuals interviewed who allowed their identities to be published.The development and implementation of immunization policy in the United States is a cooperative effort among many entities in the public and private sectors (Table 2).The concern over thimerosal in vaccines originated from a confluence of independent events, 1 informal and 1 formal, within the FDA. In the spring of 1998, some individuals within the FDA's Center for Biologics Evaluation and Research (CBER) began to informally consider the increased number of recommended vaccines and the amount of substances, such as mercury, contained in them to which vaccine recipients were exposed. Available literature to help quantify their concern was limited.The formal identification of thimerosal as a concern arose through the FDA's efforts to comply with the Food and Drug Administration 2Modernization Act.2 As mandated by Congress, Section 413(a) of the Act required the FDA to compile a list of drugs and foods that contain "intentionally introduced" mercury compounds and to provide a quantitative and qualitative analysis of these compounds within 2 years of the Act's enactment.The FDA's previous formal review of thimerosal in biological products had occurred in 1976. The convergence of concerns over mercury in vaccines that occurred within the CBER beginning in April 1998 prompted the agency to reassess the risks of thimerosal.3One of the steps of this risk assessment was to investigate the potential exposure of humans to thimerosal in vaccines. Based on the information submitted by industry and FDA internal data, the CBER determined that thimerosal was present in over 30 licensed vaccines in the United States.4,5 The amount of mercury by weight present in each of these vaccines was calculated. The CBER then referred to the recommended childhood immunization schedule to determine the amount of mercury to which young children may be exposed. Of the vaccines that a child could receive in the first 2 years of life, those that contained thimerosal were the 2 available formulations of the hepatitis B vaccine and some formulations of the diphtheria-tetanus-acellular pertussis and Haemophilus influenzae type b vaccines. Looking at cumulative exposure over the first 6 months of life, an infant 6 months old who received all recommended vaccine doses on schedule could be exposed to up to 187.5 μg of mercury.Another step in the risk assessment process was to determine whether thimerosal actually constituted a true health risk; that is, whether there were data demonstrating that this amount of mercury could be potentially harmful to children. To identify whether there were any known health risks from exposure to thimerosal, the CBER conducted a literature review and queried the Vaccine Adverse Event Reporting System, a national surveillance system for voluntarily reported adverse events associated with vaccines. The CBER found that at low doses, thimerosal has been associated with rare hypersensitivity reactions, such as persistent skin sensitization at the site of vaccination. At very high doses (ie, 1000 times higher than levels found in vaccines), thimerosal has been reported to cause neurologic and renal toxicity.An early assessment of the health risks of all forms of mercury by the World Health Organization (WHO) found that insufficient information was available to perform risk calculations for human exposure to ethyl mercury compounds, the type of mercury contained in thimerosal.6 However, the WHO did note that the limited data available suggested that ethyl mercury was probably less hazardous than methyl mercury, because it is metabolized faster in the body.The WHO and 3 US governmental agencies—the FDA, the EPA, and the Agency for Toxic Substances and Disease Registry (ATSDR)—had developed independent guidelines for safe exposure to methyl mercury (Table 3).7–10 Because no guidelines exist for ethyl mercury exposure, the FDA used the guidelines for safe exposure to methyl mercury as a guide for determining whether the mercury (ethyl) dose from thimerosal in vaccines approached a level of concern or health risk.The existence of 3 differing US federal guidelines for methyl mercury was a source of confusion and contention in determining the appropriate response to concern regarding thimerosal in vaccines. Each agency developed their guidelines for different purposes. The most conservative of these guidelines was the level established by the EPA to serve as a warning of mercury in the environment to trigger additional investigation. The ATSDR guideline is set below levels that might cause an adverse health impact in those most sensitive to a particular substance. The FDA guidelines were developed as safe limits for long-term consumption of food contaminated with mercury, particularly fish, which is the main exposure route of humans to methyl mercury. No guidelines were available to assess the risk of exposure in bolus doses by intramuscular injection.Nevertheless, the existing methyl mercury guidelines were the best information available at the time for assessing risk from ethyl mercury exposure. The CBER calculated exposure limits for each of these guidelines based on the average weight at various percentiles in female infants between birth and 26 weeks of age (Table 4). Based on these calculations, the CBER determined that potential exposure to mercury from the recommended childhood vaccines in the first 6 months of life could exceed the EPA methyl mercury guideline, but not the ATSDR, FDA, or WHO guidelines. However, the CBER was unable to determine with certainty whether exposure to thimerosal in vaccines was harmful.In April 1999, results from the preliminary risk assessment were discussed at an internal FDA meeting, and participants realized that there was a clear need for additional data. The CBER began to consult with toxicologists both within the FDA and at the National Center for Environmental Health, and several vaccine researchers, including Neal Halsey, MD, Director of the Institute for Vaccine Safety at Johns Hopkins University. The FDA also initiated discussions with vaccine manufacturers regarding the need to develop thimerosal-free vaccines.3Dr Halsey was invited by the FDA to an internal meeting in mid-June 1999 where he was asked to provide feedback on the results of their preliminary risk assessment regarding thimerosal. On learning of the FDA data, and personally verifying the calculations of the levels of mercury to which children could be exposed, he believed that the issue warranted serious concern and urgent action. At the time, Dr Halsey was soon to complete his term as Chair of the AAP Committee on Infectious Diseases (COID). Dr Halsey previously worked within the CDC's immunization program and had been a member of the Advisory Committee on Immunization Practices (ACIP). As such, he had extensive experience and professional relationships within the US immunization policymaking arena. Beginning around June 24, 1999, Dr Halsey informed many of these contacts of his concern regarding the potential health effects of thimerosal and the results of the FDA's preliminary risk assessment. After notifying the Director of the CDC's National Immunization Program, Dr Halsey met with CDC personnel at the National Immunization Conference on June 25. He also informed several other individuals, including the incoming Chair of the COID, the Chair of the ACIP, and a member of the AAP Board of Directors. In addition to his concern regarding the potential health effects of mercury exposure in infants, Dr Halsey expressed the need for urgent action on the issue because the FDA was planning to send a letter to vaccine manufacturers in the beginning of July 1999 regarding the need to remove thimerosal from vaccines, at which point the information about thimerosal would become public. He believed that publicity surrounding this issue, without action on the part of the PHS and/or the AAP, could result in long-term damage to public confidence in the national immunization system.After Dr Halsey informed these initial contacts of his concerns regarding thimerosal, conversations began to occur among the parties. The Interagency Vaccine Group (IAG) held a conference call on June 28 and reviewed the information from the FDA's preliminary risk assessment. After this call, the IAG formed a special workgroup to address the thimerosal issue. CDC immunization officials also conferred with the AAP, vaccine companies, and internal CDC toxicologists.Significant differences of opinion surfaced regarding the accuracy of the exposure and risk-assessment information concerning thimerosal, its importance, and the need for any immediate discussion or action.To quickly bring representatives of several organizations involved in immunization policymaking together to discuss the issue, a meeting was organized by Dr Halsey and Dr Cooper for June 30, 1999, at the AAP offices in Washington, DC. The selection of the venue for this meeting was deliberate. The initial course of action for the government normally would have been for the ACIP and the National Vaccine Advisory Committee (NVAC) to meet to discuss the issue. However, governmental advisory boards are required by the Federal Advisory Committee Act to provide adequate public notice of meetings and publish meeting agendas in the Federal Register. Given how quickly some individuals believed a meeting should occur, it was not possible to officially convene these advisory bodies in such a short time frame. By having an informal meeting at the offices of the AAP, a frank discussion of the scientific and biological veracity of all available information could take place without delay. As a result, however, this meeting precluded the formal involvement of the ACIP and the NVAC.Drs Cooper and Halsey developed a list of invitees, which included representatives of the CDC, FDA, EPA, AAP, vaccine manufacturers, and toxicologic consultants. An initial goal of the meeting was to achieve consensus on a course of action, as many believed that public presentation of differing views would likely confuse practitioners and parents, and potentially undermine confidence in the national immunization system.At the meeting, FDA representatives shared the results of their preliminary risk assessment, outlining what was known and unknown about the issue and describing the difficulties in determining whether the level of mercury in vaccines should be of concern. Because of the complexities in interpreting the data regarding the potential risk of harm from thimerosal, there was disagreement among the parties present as to its significance. Disagreements existed between organizations, within organizations, and among the toxicologists present at the meeting. Some participants believed strongly that the potential threat to health from thimerosal was significant; others believed that there was no clear evidence that thimerosal was harmful, particularly when compared with the clear health risks of delaying childhood vaccines. The 2 AAP committees represented at the meeting, the COID and the Committee on Environmental Health, were in sharp disagreement on this point. There was also a varied sense of exigency, with some participants believing that urgent action was required, whereas others thought the process should slow down to include other parties in the discussion and address perceived significant gaps in the scientific data. Actions proposed by participants at the meeting ranged from immediately stopping administration of all vaccines containing thimerosal to children under 6 months of age to encouraging vaccine manufacturers to expedite the elimination of thimerosal from vaccines.An overriding concern expressed by all parties at the meeting was the need to maintain the public's trust in the US immunization system by striking the appropriate balance between acknowledgment of the potential risk of harm from thimerosal and the actual risk of harm from not immunizing against vaccine-preventable diseases.It became clear during the June 30, 1999 meeting that no consensus would be reached that day regarding an appropriate course of action. Sharp disagreements regarding the clinical significance of thimerosal exposure were not resolved. Specific individuals who felt most strongly regarding the potential health risk of thimerosal exposure stated that they would independently make public statements if their respective organizations did not support their contentions. The meeting concluded with all participants agreeing that no statement would be released by any individual or organization until after the July 4th weekend, and that discussions between the PHS and the AAP would continue in an attempt to achieve a unified public statement. Leadership in both the AAP and the PHS believed that releasing a joint public statement was crucial for preserving the public's trust in the immunization system.PHS officials in the CDC and elsewhere believed that vaccine manufacturers should be encouraged to expedite the elimination of thimerosal from vaccines, but did not want to make any changes to the childhood immunization schedule. However, CDC officials also felt strongly that it would be in the best interests of the national immunization system and the public's trust for a statement to be developed jointly with the AAP. This prompted David Satcher, MD, PhD, the US Surgeon General and Assistant Secretary for Health, to be involved in the negotiations.After the June 30 meeting, there was significant debate within the AAP as to the appropriate course of action to be taken. Over the next several days, there was constant reconsideration and revision of positions taken among both individuals and committees.On review of available information and opinions, the AAP Board of Directors decided to put forth the position in their negotiations with the PHS that the birth dose of the hepatitis B vaccine be temporarily delayed. They considered the risk of disease to be low except for infants of HBsAg-positive mothers. The Board of Directors believed that hospitals should already have procedures in place to determine the hepatitis B status of mothers and treat the infants of HBsAg-positive status mothers appropriately.Other parties were informally involved in the discussions leading to the joint statement. The AAFP did not think the issue warranted such urgency and believed that the health effects data for methyl mercury on which the EPA guidelines were based were questionable.Many conference calls, meetings, and sharing of draft statements occurred within and between the AAP and the PHS over the course of the July 4, 1999 holiday weekend. The Surgeon General held several discussions with the AAP president to negotiate a compromise position. Although they were extremely concerned about both the short- and long-term consequences of delaying administration of the hepatitis B vaccine, PHS officials agreed to the recommendation to present a unified position to the public.The joint statement was officially released in the late afternoon of July 7, 1999,11 and was published in the MMWR Morbidity and Mortality Weekly Report on July 9, 1999.1First and foremost, it is clear that all parties involved in this process acted in the manner they believed was in the best interest of children in the United States. Even parties that differed most strongly never doubted the intent or purpose of those with whom they disagreed.Only 2 weeks transpired between the time that leaders of the major national organizations involved in US immunization policy learned about the issue of thimerosal in vaccines and the release of the joint AAP/PHS statement. During that time, these individuals and their organizations worked diligently to develop a response that they believed balanced the potential risk from exposure to thimerosal with the actual risk of vaccine-preventable disease and would ensure continued public confidence in the nations' immunization system. Considering the complexity of the information available and the gaps in information relevant to specific concerns, it is not surprising there was significant disagreement regarding the potential risk associated with thimerosal. To some, the process could be considered a success, in that compromise was reached and the "crisis" was addressed. However, others have publicly the that the recommendation to the birth dose of hepatitis B vaccine practitioners and put infants at risk for hepatitis B vaccine as to that the process was a of how not to public health of the IAG would have first learned of the thimerosal issue from FDA who would have informed the of its review of the thimerosal in vaccines. In this however, an individual of the government was the first to many of these soon the FDA should have is a of as is how information should have been other parties. The FDA was to an issue with the IAG when there were many surrounding the potential health risks In the FDA must be sensitive to issues to any under its IAG is to among federal agencies with vaccine issues through meetings and other To the IAG must achieve a balance between that are informed of and agencies to data to other parties the information is released to the public. such to be there must be confidence among the parties that their all from and shared efforts with each the must be as independent and to its of this issue is to ensure that the and of the are not under the or perceived or of any the through the that serious be by the Office of the Secretary for Health and Human to the of the of the including the of and the of meeting that occurred at the AAP offices in Washington, on June 30, 1999, was a in the discussions leading to the joint statement. the of this type of meeting and the in which it was organized was for the AAP, the of action was of the of the Board of are as to the of who or was concern expressed from many was the of vaccine industry representatives at the meeting. The meeting occurred the time of the vaccine safety in Congress, and in a environment in which of between industry and immunization policymakers had been Some participants at the meeting believed that having industry representatives at a meeting could have this may also have the of some meeting the of the vaccine industry to a immunization system be Vaccine manufacturers a of vaccine development and and their in different of immunization policy is concern is that some parties did not in this meeting such as the AAFP or representatives of hospitals that would be by the in the hepatitis B the of the 2 federal immunization advisory the ACIP and the did not in the initial thimerosal because of the perceived of the Federal Advisory Committee Act on meetings on very short The CDC and the have reviewed the and have found that exist for meetings on an to the birth dose of hepatitis B vaccine was not taken by any to the the risk of thimerosal exposure with the known risk of of hepatitis B disease was for However, in some leading to the joint AAP/PHS of the potential impact of delaying the birth dose of the hepatitis B vaccine did not receive some in of stopping the birth dose of hepatitis B vaccine, there was acknowledgment of the potentially significant of the of hospitals the the for this policy to these or the of procedures for determining the hepatitis B status of mothers. There to be effort to the existing literature on the impact of changes in immunization and the times for the of there was an confidence by some in the of hospitals to all mothers for hepatitis B status previous had of such of the impact of the joint statement on infant hepatitis B are now beginning to be have that some hospitals all with hepatitis B vaccine, including those to HBsAg-positive possible is the of information or of the recommendation by hospitals and Because of the of appropriate for and the hepatitis B status of this in policy has led to the of at 1 infant from hepatitis have also that many hospitals have not to doses of the hepatitis B vaccine the of thimerosal-free The of the first dose of hepatitis B vaccine at birth is illustrated by a recent that that children who received the first dose at birth were likely to complete the hepatitis B times of regarding immunization that all parties involved to the short- and long-term intended and unintended consequences of their proposed This type of analysis could take the of the and structured risk assessment process used by other government such as the of the major issues concern and urgency among all parties was the manner in which the would the issue. over the accuracy of in and for vaccine issues in is well However, an overriding issue is the of how should concern over the time of for public or individual health with policymaking must balance concern over the risk of public regarding safety issues with concern over the to ensure that information be to the public.The FDA the safety and of products they are for use and the process of a constant of products available to However, the of thimerosal an to FDA In the when thimerosal was for use in this there were limited available to assess for the of there is no for the FDA to vaccine with is in to some other federal such as the In was that be by the EPA years. Because no such process has been for the FDA, thimerosal not In for a containing mercury, the of most concern is on system At this time, the FDA has no for of the products it the FDA not have a to identify the cumulative amount of thimerosal, which children would receive over the course of the recommended immunization schedule. Each vaccine was for use as an independent agent and the amount of thimerosal contained in each individual vaccine no concern. was when the cumulative amount from all the vaccines contained in the recommended immunization schedule was calculated that concern that should consider to the FDA the to perform of vaccine In that the FDA its and the FDA develop a for of the cumulative amount of to which individuals may be exposed as a result of specific federal of the issues to all parties involved was the existence of differing federal for exposure to mercury from the EPA, the FDA, and the Although each agency had a different purpose in a specific safety the that there was no clear federal consensus on this issue was This allowed different parties to the discussion to over to support their federal agencies that have differing safety for exposure to specific to develop a federal consensus on safe exposure levels determine under which the different guidelines are to be than 1 federal is each agency should be with the for determining a different safety AAP is an organization for its to the of the health and of children. the internal debate that place within the AAP on this issue involved disagreement on the course of action that would be of to the children of the United AAP Board of Directors to its committees for and information regarding specific issues on which it must set However, the exists that the course of within the was in some than the Board of Directors on this issue from specific individuals were to the they may have represented the of the AAP is very that all be to maintain use of this in times of This help ensure that the consensus of than specific individuals, are to help guide the AAP Board of Directors regarding policy have on a of immunization The of these has been and At point efforts have been to information of those involved in immunization policy and in the or review of from the Institute of are now to in such committees for of and having their publicly and public if have the potential to cause significant and professional involvement of leading in the on childhood vaccines were to soon after the June 30, 1999, meeting at the AAP As such, concern over the manner in which any action or might be perceived in this type of environment a of concern and over many this was perceived as a course of action under by a process not in the best interests of the immunization system or children. This also to the development of a and the to act in interviewed but not of the parties involved in this As such, have an and assessment of the events that place in late June and early July However, there exists the that some information may not have been In these interviews were conducted 2 years after this process there may be some of the information process that in the in immunization as a result of concern to thimerosal was and Although there are significant differences of opinion regarding the of the the immunization system in the United States and was by the Program for and Health,

Universal hepatitis B vaccination in adults aged 19–59 years: Updated recommendations of the advisory committee on immunization practices—United States, 2022

Propylene glycol (PG) là một chất phụ gia hiện đang được sử dụng rộng rãi làm dung môi, chất giữ ẩm, chất chống đông trong thực phẩm, dược phẩm và mỹ phẩm. Năm 1982, PG được FDA (Food and Drug Administration) xếp vào nhóm GRAS (Generally Recognized As Safe - được công nhận là an toàn), nhưng ngày càng có nhiều ghi nhận và báo cáo về độc tính của PG. Do đó, trong nghiên cứu này chúng tôi sử dụng mô hình ruồi giấm để đánh giá mức độ ảnh hưởng của PG đến sức khoẻ và khả năng sinh sản. Kết quả nghiên cứu cho thấy ruồi phơi nhiễm với PG nồng độ 1%, tuổi thọ giảm 89,7% ở con cái và 86,7% ở ruồi đực khi so với nhóm chứng. Nồng độ PG 0,5% làm giảm mạnh khả năng sinh sản đến 39,74% so với nhóm chứng. Đồng thời, nồng độ PG 0,1% làm giảm biểu hiện gen thụ thể liên quan đến estrogen - ERR (Estrogen-related receptor) rõ rệt từ 10 ngày đến 30 ngày tuổi. Trong khi, nồng độ PG 0,02% và 0,2% đều làm tăng biểu hiện gen ERR ở 10 ngày tuổi và giảm biểu hiện ở 20 ngày tuổi. Vào thời điểm 30 ngày tuổi, biểu hiện ERR tăng ở nồng độ 0,02% nhưng giảm ở nồng độ 0,2%. Biểu hiện gen thụ thể ecdysone - EcR (ecdysone receptor) ở nhóm nghiên cứu tăng gấp 10 lần so với nhóm chứng ở cả 3 nồng độ PG vào thời điểm 10 ngày tuổi. Nhưng biểu hiện của EcR lại giảm rõ rệt tại thời điểm 20 và 30 ngày tuổi ở nồng độ 0,1% và 0,2% PG. Từ các kết quả cho thấy, Propylene glycol làm giảm tuổi thọ và tác động đến thụ thể hormon sinh sản trên mô hình ruồi giấm, và đây cũng là gợi ý cho việc mở rộng nghiên cứu cho đánh giá các chất phụ gia khác đối với sức khoẻ con người.

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High Prescription Drug Prices and the Influence of the Food and Drug Administration

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Despite remarkable progress in cancer treatment, drug resistance remains a significant issue for prostate cancer, breast cancer, and others. Disulfiram (DSF), an alcohol-aversion drug, has been repurposed for cancer treatment and overcome drug resistance. DSF and copper ions form a copper diethyldithiocarbamate (Cu-DSF) complex which has a potent anticancer activity. However, the poor aqueous solubility of Cu-DSF creates a significant formulation challenge, and there is no formulation available for clinical use. We developed a S tabilized M etal I on L igand Nanocompl e x ( SMILE ) technology to prepare Cu-DSF nanoparticle (NP) formulations where in situ formed DSF-Cu NPs were stabilized by an optimal amount of stabilizers ( e.g. poly(ethylene glycol)-poly(lactide)). The SMILE technology involves a novel formulation design and an innovative preparation process using a 3D-printed microfluidic device. After optimizing the protocol, we can prepare Cu-DSF NPs with size in the sub-100 nm range which are suitable for intravenous injection and can target solid tumors through enhanced permeability and retention (EPR) effects. Cu-DSF NPs prepared with SMILE method showed high drug loading efficiency (above 90%) and high drug concentration (at least 2 mg/mL). The drug concentration of Cu-DSF NPs developed in our study was much higher than those in micelle NP formulations prepared with the classical film-dispersion method. Since we used generally recognized as safe (GRAS) excipients approved by the US Food and Drug Administration (FDA) or other excipients with well-recognized safety profiles, the developed NP formulations will have less regulatory hurdle for FDA approval. Because of the novel preparation process and unique formulation design, the SMILE technology can produce Cu-DSF NPs on a large scale and thus paved the way for its mass production and commercialization. We also determined the anticancer effects of Cu-DSF NPs with multiple assays including MTT assay, colony-forming assay, calcein-AM/propidium iodide staining, and others. Cu-DSF NPs showed excellent anticancer activity against various prostate cancer and breast cancer cells as well as drug-resistant cancer cells. In summary, we developed a novel SMILE method to prepare Cu-DSF NP formulations which could address drug delivery and formulation challenges of DSF-based chemotherapy and facilitate the clinical translation. Citation Format: Wu Chen, Wen Yang, Landon F. Stewart, David T. Coombs, Jianzhong Shen, Pengyu Chen, Feng LI. Develop novel nanoparticle formulations of disulfiram copper for cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3626.