Safety assessments data selection

The next step, given that no relevant data can be found from any literature sources or from any internal files (and that it has been determined what data are needed or most likely to allow selection of desirable candidate compounds), is to perform appropriate predictive tests. The bulk of this section addresses the specifics of performing such evaluations using in vitro models. Before considering how to design, develop the components of, and conduct such a testing program, we must first consider how the practice of safety assessment came to its current state of acceptance and utilization of such tests. 

Study Type. Metabolic and pharmacokinetic data from a rodent species and a nonrodent species (usually the dog) used for repeat dose safety assessments (14 days, 28 days, 90 days or six months) are recommended. If a dose dependency is observed in metabolic and pharmacokinetic or toxicity studies with one species, the same range of doses should be used in metabolic and pharmacokinetic studies with other species. If human metabolism and pharmacokinetic data also are available, this information should be used to help select test species for the full range of toxicity tests, and may help to justify using data from a particular species as a human surrogate in safety assessment and risk assessment. 

There are numerous calorimeters available on the market Nevertheless, only a relatively restricted choice may be used for the determination of the data required for safety assessment. These are essentially selected for their robustness with... 

Figure 9.1 Proposed rank ordering of methods informing species selection for safety assessment of biopharmaceuticals. Various methods used for selecting pharmacologically relevant species for toxicological studies of biopharmaceuticals are presented, ordered (top to bottom) by the extent to which the data might impact the decision on which species to use. In cases where the methods are further discussed in this chapter, the relevant figure/table numbers are provided. These types of analyses may also be used for creating data packages for small molecules, although not typically for species selection.

When relevant human data are available, the 0-fo d factor for intcrspecics variability may not be necessary. However, relatively few parameters are studied in humans in the assessment of pesticide safety, and data on carcinogenicity, reproduction, and chronic effects are rarely available, Consequently, JMPR rarely utilizes safety factors as low as 10-fold. ADIs of selected OP and CM pesticides are summarized in Table 2. 

In the early stages of preclinical development, metabolite profiling is performed using in vitro systems from animal and human, mainly to identify potential species-dependent metabolism early in the development process and to support the selection of the animal species employed in safety assessment studies. As the compound moves further into development, in vivo animal ADME studies are performed. The compound is usually dosed into a rodent and nonrodent species along with an efficacy model. Metabolism data from the animal studies are then used in species selection for safety assessment to insure that all expected human metabolic transformations will be represented in the animal models used in the safety study. 

A key danger in the retrospective approach is to fall into the trap of conveniently building the safety argument around selective evidence which happens to be at hand. To do so runs the risk of forcing the safety case to articulate an artificially rosy picture of the world. It can be easy to assume that a much-loved system that has been in operation for many years must be intrinsically safe. That is not to say that it is unsafe but one should actively question whether the data which happens to be available can truly and objectively substantiate the safety case s claims. In some circumstances it may be appropriate to undertake the hazard assessment in a virtual vacuum of operational knowledge perhaps involving personnel who are somewhat removed from its day-to-day business. In this way appropriate controls can be developed and more objectively be tested to determine whether they can be traly validated. 

VII.25-VII.27], and efforts have been made to validate computational methods using data selected from these compendiums [VII.27-VII.29]. The measured isotopic data that are available for validation are limited. Of farther concern is the fact that the database of fission product measurements is a small subset of the actinide measnrements. In addition, the cross-section data for fission product nuclides have had much less scrutiny over broad energy ranges than most actinides of importance in INF. Fission prodncts can provide 20-30% of the negative reactivity from bumup, yet the uncertainties in their cross-section data and isotopic predictions reduce their effectiveness in safety assessments with bnmnp credit. 

Biodistribution and safety assessment during preclinical development requires both in vitro and in vivo studies. Biocompatibility of nanoparticles can be determined by in vitro cytotoxicity testing on cell lines. In vitro studies also facilitate the revelation of biochemical mechanisms under controlled conditions not achievable by in vivo studies. The rationale underlying the selection of in vitro assays to provide meaningful efficacy and safety data on nanoparticle is detailed in the literature. However, it is in vivo biodistribution and toxicity studies that determine safety for clinical trials, and all preclinical characterization studies must necessarily include in vivo determination of a nanoparticles biodistribution and toxicity in animal tests. FDA provides detailed guidelines for biodistribution and safety assessment of drug formulations in vivo using animal models and specific consideration for nanoparticle samples are reviewed elsewhere. ... 

Obviously the ultimate use of a sufficiently reliable methodology for safety assessment is to judge whether the safety levels offered by a facility lie within those which are judged acceptable by society and which, therefore, have been embodied in national licensing requirements. In earlier project phases, however, an assessment of the potential influence of numerous specific project choices on achievable safety is an invaluable decision aid. For this reason, iterative safety assessment is also performed to rank conceptual facility designs, to structure data-collection programmes in laboratory and field, to provide input for site-selection, to guide R D work and to optimise the selection of specific combinations of safety barriers in the repository. 

After the site selection phase, if it is established that there is a potential for flooding or for serious erosion at a site, a detailed study should be undertaken to detect the reference mechanism for site flooding and, therefore, to define the relevant design basis flood for the plant. A similar study should be carried out within the framework of a safety assessment of the plant. In this latter option, the data from the site monitoring system which has been in operation since the preliminary phase of site evaluation should have the highest priority. 

The concept of risk assessment requires a profound understanding of food dynamics and technological conditions that may impact the risk levels of certain hazardous compounds. It requires that scientific information and data are collected to underpin conclusions about risk levels. Risk assessment can be used to scientifically underpin the selection of hazards that must be covered by a quality or safety assurance system (e.g., HACCP) that will improve the reliability of the system. 

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