Morphological and Chemical Mechanisms of Elongated Mineral Particle Toxicities

Much of our understanding regarding the mechanisms for induction of disease following inhalation of respirable elongated mineral particles (REMP) is based on studies involving the biological effects of asbestos fibers. The factors governing the disease potential of an exposure include duration and frequency of exposures; tissue-specific dose over time; impacts on dose persistence from in vivo REMP dissolution, comminution, and clearance; individual susceptibility; and the mineral type and surface characteristics. The mechanisms associated with asbestos particle toxicity involve two facets for each particle's contribution: (1) the physical features of the inhaled REMP, which include width, length, aspect ratio, and effective surface area available for cell contact; and (2) the surface chemical composition and reactivity of the individual fiber/elongated particle. Studies in cell-free systems and with cultured cells suggest an important way in which REMP from asbestos damage cellular molecules or influence cellular processes. This may involve an unfortunate combination of the ability of REMP to chemically generate potentially damaging reactive oxygen species, through surface iron, and the interaction of the unique surfaces with cell membranes to trigger membrane receptor activation. Together these events appear to lead to a cascade of cellular events, including the production of damaging reactive nitrogen species, which may contribute to the disease process. Thus, there is a need to be more cognizant of the potential impact that the total surface area of REMP contributes to the generation of events resulting in pathological changes in biological systems. The information presented has applicability to inhaled dusts, in general, and specifically to respirable elongated mineral particles

Recent progress in scenario development for the WIPP

The US Department of Energy (DOE) is preparing to request the US Environmental Protection Agency to certify compliance with the radioactive waste disposal standards found in 40 CFR Part 191 for the Waste Isolation Pilot Plant (WIPP). The DOE will also need to demonstrate compliance with a number of other State and Federal standards and, in particular, the Land Disposal Restrictions of the Resource Conservation and Recovery Act (RCRA), 40 CFR Part 268. Demonstrating compliance with these regulations requires an assessment of the long-term performance of the WIPP disposal system. Re-evaluation and extension of past scenario development for the WIPP forms an integral part of the ongoing performance assessment (PA) process

Scenario development for the Waste Isolation Pilot Plant: Building confidence in the assessment

Scenario developments is part of the iterative performance assessment (PA) process for the Waste Isolation Pilot Plant (WIPP). Scenario development for the WIPP has been the subject of intense external review, and is certain to be the subject of continued scrutiny as the project proceeds toward regulatory compliance. The principal means of increasing confidence is this aspect of the PA will be through the use of a systematic and thorough procedure toward developing the scenarios and conceptual models on which the assessment is to be based. Early and ongoing interaction with project reviewers can assist with confidence building. Quality of argument and clarity of presentation in PA will be of key concern. Appropriate tools are required for documenting and tracking assumptions, through a single assessment phase, and between iterative assessment phases. Risks associated with future human actions are of particular concern to the WIPP project, and international consensus on the principles for incorporation of future human actions in assessments would be valuable

The Assessment of Future Human Actions at Radioactive Waste Disposal Sites: An international perspective

For some deep geological disposal systems, the level of confinement provided by the natural and engineered barriers is considered to be so high that the greatest long-term risks associated with waste disposal may arise from the possibility of future human actions breaching the natural and/or engineered barrier systems. Following a Workshop in 1989, the OECD Nuclear Energy Agency established a Working Group on Assessment of Future Human Actions (FHA) a Radioactive Waste Disposal Sites. This Group met four times in the period 1991--1993, and has extensively reviewed approaches to and experience of incorporating the effects of FHA into long-term performance assessments (PAs). The Working Group`s report reviews the main issues concerning the treatment of FHA, presents a general framework for the quantitative, consideration of FHA in radioactive waste disposal programmes, and discusses means in reduce the risks associated with FHA. The Working Group concluded that FHA must be considered in PAs, although FHA where the actors were cognizant of the risks could be ignored. Credit can be taken for no more than several hundred years of active site control; additional efforts should therefore be taken to reduce the risks associated with FHA. International agreement on principles for the construction of FHA scenarios would build confidence, as would further discussion concerning regulatory policies for judging risks associated with FHA

Regulatory basis for the Waste Isolation Pilot Plant performance assessment

The Waste Isolation Pilot Plant (WIPP) is the first operational repository designed for the safe disposal of transuranic (TRU) radioactive waste from the defense programs of the US Department of Energy (DOE). The US Environmental Protection Agency (EPA) is responsible for certifications and regulation of the WIPP facility for the radioactive components of the waste. The EPA has promulgated general radioactive waste disposal standards at 40 CFR Part 191. and WIPP-specific criteria to implement and interpret the generic disposal standards at 40 CFR Part 194. In October 1996. the DOE submitted its Compliance Certification Application (CCA) to the EPA to demonstrate compliance with the disposal standards at Subparts B and C of 40 CFR Part 191. This paper summarizes the development of the overall legal framework for radioactive waste disposal at the WIPP, the parallel development of the WIPP performance assessment (PA), and how the EPA disposal standards and implementing criteria formed the basis for the CCA WIPP PA. The CCA resulted in a certification in May 1998 by the EPA of the WIPP'S compliance with the EPA's disposal standard, thus enabling the WIPP to begin radioactive waste disposal

How B cell receptor repertoire sequencing can be enriched with structural antibody data

Next-generation sequencing of immunoglobulin gene repertoires (Ig-seq) allows the investigation of large-scale antibody dynamics at a sequence level. However, structural information, a crucial descriptor of antibody binding capability is not collected in Ig-seq protocols. Developing systematic relationships between the antibody sequence information gathered from Ig-seq and low-throughput techniques such as X-ray crystallography could radically improve our understanding of antibodies. The mapping of Ig-seq datasets to known antibody structures can indicate structurally, and perhaps functionally, uncharted areas. Furthermore, contrasting naïve and antigenically challenged datasets using structural antibody descriptors should provide insights into antibody maturation. As the number of antibody structures steadily increases and more and more Ig-seq datasets become available, the opportunities that arise from combining the two types of information increase as well. Here we review how these data types enrich one another and show potential for advancing our knowledge of the immune system and improving antibody engineering