RESUMEN
Ionising radiation has been used for over a century for peaceful purposes, revolutionising health care and promoting well-being through its application in industry, science, and medicine. For almost as long, the International Commission on Radiological Protection (ICRP) has promoted understanding of health and environmental risks of ionising radiation and developed a protection system that enables the safe use of ionising radiation in justified and beneficial practices, providing protection from all sources of radiation. However, we are concerned that a shortage of investment in training, education, research, and infrastructure seen in many sectors and countries may compromise society's ability to properly manage radiation risks, leading to unjustified exposure to or unwarranted fear of radiation, impacting the physical, mental, and social well-being of our peoples. This could unduly limit the potential for research and development in new radiation technologies (healthcare, energy, and the environment) for beneficial purposes. ICRP therefore calls for action to strengthen expertise in radiological protection worldwide through: (1) National governments and funding agencies strengthening resources for radiological protection research allocated by governments and international organisations, (2) National research laboratories and other institutions launching and sustaining long-term research programmes, (3) Universities developing undergraduate and graduate university programmes and making students aware of job opportunities in radiation-related fields, (4) Using plain language when interacting with the public and decision makers about radiological protection, and (5) Fostering general awareness of proper uses of radiation and radiological protection through education and training of information multipliers. The draft call was discussed with international organisations in formal relations with ICRP in October 2022 at the European Radiation Protection Week in Estoril, Portugal, and the final call announced at the 6th International Symposium on the System of Radiological Protection of ICRP in November 2022 in Vancouver, Canada.
Asunto(s)
Protección Radiológica , Humanos , Radiación Ionizante , Canadá , Agencias InternacionalesRESUMEN
The International Commission on Radiological Protection (ICRP) has embarked on a process to review and revise the current System of Radiological Protection ('the System'). To stimulate discussion, the ICRP published two open-access articles: one on aspects of the System that might require review, and another on research that might improve the scientific foundation of the System. Building on these articles, the ICRP organized a Workshop on the Future of Radiological Protection as an opportunity to engage in the review and revision of the System. This digital workshop took place from 14 October-3 November 2021 and included 20 live-streamed and 43 on-demand presentations. Approximately 1500 individuals from 100 countries participated. Based on the subjects covered by the presentations, this summary is organized into four broad areas: the scientific basis, concepts and application of the System; and the role of the ICRP. Some of the key topics that emerged included the following: classification of radiation-induced effects; adverse outcome pathway methodologies; better understanding of the dose-response relationship; holistic and reasonable approaches to optimization of protection; radiological protection of the environment; ethical basis of the System; clarity, consistency and communication of the System; application of the System in medicine and application of the principles of justification and optimization of protection.
Asunto(s)
Traumatismos por Radiación , Protección Radiológica , Humanos , Agencias Internacionales , Traumatismos por Radiación/prevención & control , Protección Radiológica/métodosRESUMEN
The International Commission on Radiological Protection's (ICRP) system to protect the living components of the environment is designed to provide a broad and practical framework across different exposure situations. The framework recognises the need to be able to demonstrate an adequate level of protection in relation to planned exposure situations, whilst also providing an ability to manage existing and emergency situations in an appropriate way. In all three exposure situations, the release of radionuclides into the natural environment leads to exposures of non-human biota (wildlife), as well as having the potential for exposures of the public. How the key principles of the ICRP system of radiological protection apply in each of these exposure situations will be discussed. Using examples, we will demonstrate how the overall approach provides a mechanism for industry to assess and demonstrate compliance with the environmental protection objectives of relevant (national) legislation, and to meet stakeholder expectations that radiological protection of the environment is taken into consideration in accordance with international best practice. However, several challenges remain, and these will be discussed in the context of the need for additional guidance on the protection of the environment.
Asunto(s)
Conservación de los Recursos Naturales/estadística & datos numéricos , Agencias Internacionales/estadística & datos numéricos , Protección Radiológica/normas , Biota , Humanos , Dosis de Radiación , Monitoreo de Radiación/estadística & datos numéricosRESUMEN
The International Commission on Radiological Protection (ICRP) recognises three types of exposure situations: planned, existing, and emergency. In all three situations, the release of radionuclides into the natural environment leads to exposures of non-human biota, as well as the potential for exposures of the public. This paper describes how the key principles of the ICRP system of radiological protection apply to non-human biota and members of the public in each of these exposure situations. Current work in this area within ICRP Task Group 105 is highlighted. For example, how simplified numeric criteria may be used in planned exposure situations that are protective of both the public and non-human biota. In emergency exposure situations, the initial response will always be focused on human protection; however, understanding the potential impacts of radionuclide releases on non-human biota will likely become important in terms of communication as governments and the public seek to understand the exposures that are occurring. For existing exposure situations, there is a need to better understand the potential impacts of radionuclides on animals and plants, especially when deciding on protective actions. Understanding the comparative impacts from radiological, non-radiological, and physical aspects is often important in managing the remediation of legacy sites. Task Group 105 is making use of case studies of how exposure situations have been managed in the past to provide additional guidance and advice for the protection of non-human biota.
Asunto(s)
Dosis de Radiación , Exposición a la Radiación/prevención & control , Protección Radiológica/normas , Liberación de Radiactividad Peligrosa/prevención & control , Radioisótopos/análisis , Animales , Humanos , Agencias Internacionales , Plantas/efectos de la radiación , Traumatismos por Radiación/prevención & controlRESUMEN
Australia's regulatory framework has evolved over the past decade from the assumption that protection of humans implies protection of the environment to the situation now where radiological impacts on non-human species (wildlife) are considered in their own right. In an Australian context, there was a recognised need for specific national guidance on protection of non-human species, for which the uranium mining industry provides the major backdrop. National guidance supported by publications of the Australian Radiation Protection and Nuclear Safety Agency (Radiation Protection Series) provides clear and consistent advice to operators and regulators on protection of non-human species, including advice on specific assessment methods and models, and how these might be applied in an Australian context. These approaches and the supporting assessment tools provide a mechanism for industry to assess and demonstrate compliance with the environmental protection objectives of relevant legislation, and to meet stakeholder expectations that radiological protection of the environment is taken into consideration in accordance with international best practice. Experiences from the past 5-10 years, and examples of where the approach to radiation protection of the environment has been well integrated or presented some challenges will be discussed. Future challenges in addressing protection of the environment in existing exposure situations will also be discussed.
Asunto(s)
Conservación de los Recursos Naturales/métodos , Monitoreo de Radiación , Protección Radiológica/métodos , Australia , HumanosRESUMEN
To investigate differences in the frictional behavior between initially bare rock surfaces of serpentinite and powdered serpentinite ("gouge") at subseismic to seismic slip rates, we conducted single-velocity step and multiple-velocity step friction experiments on an antigorite-rich and lizardite-rich serpentinite at slip rates (V) from 0.003 m/s to 6.5 m/s, sliding displacements up to 1.6 m, and normal stresses (σn ) up to 22 MPa for gouge and 97 MPa for bare surfaces. Nominal steady state friction values (µnss) in gouge at V = 1 m/s are larger than in bare surfaces for all σn tested and demonstrate a strong σn dependence; µnss decreased from 0.51 at 4.0 MPa to 0.39 at 22.4 MPa. Conversely, µnss values for bare surfaces remained â¼0.1 with increasing σn and V. Additionally, the velocity at the onset of frictional weakening and the amount of slip prior to weakening were orders of magnitude larger in gouge than in bare surfaces. Extrapolation of the normal stress dependence for µnss suggests that the behavior of antigorite gouge approaches that of bare surfaces at σn ≥ 60 MPa. X-ray diffraction revealed dehydration reaction products in samples that frictionally weakened. Microstructural analysis revealed highly localized slip zones with melt-like textures in some cases gouge experiments and in all bare surfaces experiments for V ≥ 1 m/s. One-dimensional thermal modeling indicates that flash heating causes frictional weakening in both bare surfaces and gouge. Friction values for gouge decrease at higher velocities and after longer displacements than bare surfaces because strain is more distributed. KEY POINTS: Gouge friction approaches that of bare surfaces at high normal stressDehydration reactions and bulk melting in serpentinite in < 1 m of slipFlash heating causes dynamic frictional weakening in gouge and bare surfaces.
RESUMEN
Non-peptidomimetic renin inhibitors of the piperidine type represent a novel structural class of compounds potentially free of the drawbacks seen with peptidomimetic compounds so far. Synthetic optimization in two structural series focusing on improvement of potency, as well as on physicochemical properties and metabolic stability, has led to the identification of two candidate compounds 14 and 23. Both display potent and long-lasting blood pressure lowering effects in conscious sodium-depleted marmoset monkeys and double transgenic rats harboring both the human angiotensinogen and the human renin genes. In addition, 14 normalizes albuminuria and kidney tissue damage in these rats when given over a period of 4 weeks. These data suggest that treatment of chronic renal failure patients with a renin inhibitor might result in a significant improvement of the disease status.
Asunto(s)
Antihipertensivos/farmacología , Piperidinas/farmacología , Renina/antagonistas & inhibidores , Animales , Presión Sanguínea/efectos de los fármacos , Humanos , Piperidinas/síntesis química , Insuficiencia Renal/tratamiento farmacológico , Renina/farmacologíaRESUMEN
The identification, synthesis and activity of a novel class of piperidine renin inhibitors is presented. The most active compounds show activities in the picomolar range and are among the most potent renin inhibitors ever identified.
Asunto(s)
Piperidinas/farmacología , Renina/antagonistas & inhibidores , Sitios de Unión , Humanos , Modelos Moleculares , Estructura Molecular , Piperidinas/química , Piperidinas/metabolismo , Proteínas Recombinantes/antagonistas & inhibidores , Proteínas Recombinantes/metabolismo , Renina/metabolismoRESUMEN
Piperidine renin inhibitors with heterocyclic core modifications or hydrophilic attachments show improved physical properties (lower lipophilicity, improved solubility). Tetrahydroquinoline derivative rac-30 with a molecular weight of 517 and a log D(pH 7.4) of 1.9 displays potent and long lasting blood pressure lowering effects after oral administration to sodium depleted conscious marmosets.
Asunto(s)
Antihipertensivos/química , Piperidinas/química , Renina/antagonistas & inhibidores , Animales , Antihipertensivos/farmacología , Callithrix , Relación Dosis-Respuesta a Droga , Humanos , Piperidinas/farmacología , Proteínas Recombinantes/antagonistas & inhibidoresRESUMEN
BACKGROUND: The aspartic proteinase renin catalyses the first and rate-limiting step in the conversion of angiotensinogen to the hormone angiotensin II, and therefore plays an important physiological role in the regulation of blood pressure. Numerous potent peptidomimetic inhibitors of this important drug target have been developed, but none of these compounds have progressed past clinical phase II trials. Limited oral bioavailability or excessive production costs have prevented these inhibitors from becoming new antihypertensive drugs. We were interested in developing new nonpeptidomimetic renin inhibitors. RESULTS: High-throughput screening of the Roche compound library identified a simple 3, 4-disubstituted piperidine lead compound. We determined the crystal structures of recombinant human renin complexed with two representatives of this new class. Binding of these substituted piperidine derivatives is accompanied by major induced-fit adaptations around the enzyme's active site. CONCLUSIONS: The efficient optimisation of the piperidine inhibitors was facilitated by structural analysis of the renin active site in two renin-inhibitor complexes (some of the piperidine derivatives have picomolar affinities for renin). These structural changes provide the basis for a novel paradigm for inhibition of monomeric aspartic proteinases.
Asunto(s)
Ácido Aspártico Endopeptidasas/antagonistas & inhibidores , Piperidinas/farmacología , Renina/antagonistas & inhibidores , Fluoresceína , Biblioteca de Genes , Glutatión/metabolismo , Histidina/metabolismo , Humanos , Biosíntesis de Proteínas , Proteínas/genética , Proteínas ras/metabolismoRESUMEN
We describe here Ro 46-8443, the first non-peptide endothelin ETB receptor selective antagonist. It displays up to 2000-fold selectivity for ETB receptors both in terms of binding inhibitory potency and functional inhibition. The observed parallel rightward shift of concentration-response curves with different antagonist concentrations is consistent with a competitive binding mode. Since R0 46-8443 selectively inhibits ETB receptor mediated responses, it is a valuable tool for clarifying the role of ETB receptors in pathology.
Asunto(s)
Antagonistas de los Receptores de Endotelina , Pirimidinas/farmacología , Sulfonamidas/farmacología , Animales , Ácido Araquidónico/metabolismo , Unión Competitiva , Células CHO , Membrana Celular/metabolismo , Cricetinae , Humanos , Técnicas In Vitro , Microsomas/metabolismo , Estructura Molecular , Contracción Muscular/efectos de los fármacos , Unión Proteica , Pirimidinas/metabolismo , Ratas , Receptor de Endotelina B , Receptores de Endotelina/metabolismo , Receptores de Péptidos/antagonistas & inhibidores , Receptores de Péptidos/metabolismo , Proteínas Recombinantes/metabolismo , Sulfonamidas/metabolismo , Vasoconstricción/efectos de los fármacos , Vasoconstrictores/metabolismo , Venenos de Víboras/metabolismoRESUMEN
The authors describe here the pharmacological properties of bosentan, a new nonpeptide mixed antagonist of endothelin (ET) receptors, obtained by structural optimization of the less potent Ro 46-2005 [Ro 46-2005 (4-tert-butyl-N-[6-(2-hydroxyethoxy)-5-(3-methoxy-phenoxy)-4-pyrimidinyl ]-benzenesulfonamide]. Bosentan (Ro 47-0203, 4-tert-butyl-N-[6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2,2'-bipyr imidin-4-yl]-benzenesulfonamide) competitively antagonized the specific binding of [125I]-labeled ET-1 on human smooth muscle cells (ETA receptors) with a Ki of 4.7 nM and on human placenta (ETB receptors) with a Ki of 95 nM. It also inhibited the binding of selective ETB ligands on porcine trachea. Contractions induced by ET-1 in isolated rat aorta (ETA) and by the selective ETB agonist sarafotoxin S6C in rat trachea were competitively inhibited by bosentan (pA2 = 7.2 and 6.0, respectively), as was the endothelium-dependent relaxation to sarafotoxin S6C in rabbit superior mesenteric artery (pA2 = 6.7). The binding of 40 other peptides, prostaglandins, ions and neurotransmitters was not significantly affected by bosentan, which shows its specificity for ET receptors. In vivo, bosentan inhibited the pressor response to big ET-1 both after i.v. and oral administration, with a long duration of action and no intrinsic agonist activity. It also inhibited the depressor and pressor effect of ET-1 and sarafotoxin S6C. Thus, bosentan is the most potent orally active antagonist of ET receptors described so far. Its pharmacological profile makes bosentan a potentially useful drug in the management of clinical disorders associated with vasoconstriction.
Asunto(s)
Antagonistas de los Receptores de Endotelina , Sulfonamidas , Administración Oral , Secuencia de Aminoácidos , Animales , Unión Competitiva , Bosentán , Células CHO/efectos de los fármacos , Cricetinae , Humanos , Técnicas In Vitro , Insectos , Radioisótopos de Yodo , Cinética , Masculino , Datos de Secuencia Molecular , Conejos , Ratas , Ratas Endogámicas WKY , Ratas Wistar , Receptores de Endotelina/clasificación , Receptores de Endotelina/metabolismo , Receptores de Endotelina/fisiología , Sensibilidad y Especificidad , PorcinosRESUMEN
Since its discovery, endothelin-1 has attracted considerable scientific interest because of its extremely potent and long-lasting vasoconstrictor effect and its binding to G-protein-coupled receptors. Plasma concentrations of endothelin-1 are low and its release by endothelial cells is polarized towards the basolateral side, suggesting that it is a paracrine factor and not a hormone. Consequently, the effect of injected endothelin-1 may not reflect the effect of endogenous endothelin-1. In contrast, blockade of the action of endogenous endothelin-1 using receptor antagonists should be a valuable means of investigating its physiological and pathological effects. We report here evidence for the pathophysiological role of endothelin-1 as brought by the first synthetic orally active nonpeptide antagonist of endothelin receptors, Ro 46-2005.