Safety evaluation test system

A.1(X)6. All auxiliary systems associated with the reactor process system and the experimental facilities, such as compressed air, process sampling and equipment and floor drainage systems, shall be discussed in this section. The discussion should include the design bases, a system description, a safety evaluation, testing and inspection requirements, and instrumentation requirements. 

Also, the test procedure (protocol) is fundamental because it allows comparing results from different laboratories and from different experimental sets. Moreover, selected test protocol could affect the interpretation of the results, the information content and its application in the safety evaluation process, as stated by Frazer if the biological system is exposed to a test chemical for 24 h and the endpoint assay is immediately conducted, the data produced would be most relevant to the acute toxicity of the test material. If, on the other hand, the system is exposed to material for 24 h and the system is cultured in the absence of the test material for additional 48 h before the endpoint assay is conducted, the data would be more relevant to recovery from toxicity rather than acute toxicity [7]. 

This section discusses how the interpretation, evaluation, and correlation of test results from bench-scale equipment can be integrated into an approach to inherent process safety involving reactive systems. 

In addition to rodent studies, regulatory guidelines for pharmaceuticals require that repeated dose safety studies of up to nine months (in the United States, six months elsewhere) in duration be conducted in a nonrodent species. The most commonly used nonrodent species is the dog, followed by the monkey and pig. Another nonrodent model used to a limited extent in systemic safety evaluation is the ferret. The major objectives of this chapter are (1) to discuss differences in rodent and nonrodent experimental design, (2) to examine the feasibility of using the dog, monkey, pig, and ferret in safety assessment testing, and (3) to identify the advantages and limitations associated with each species. 

Some would say that this is the current state of the art. Much of the necessary library could be assembled from test systems that have been extensively evaluated and have already undergone extensive validation (Gad, 2000, 2001). Three critical steps must be taken for the eventual fulfillment of these objectives (1) acceptance of a scientific approach to the problem of safety assessment (2) development of an operative validation and acceptance process for new test procedures (3) clear enunciation of an acceptance criterion for new test designs by regulatory authorities. 

It has become necessary to question the use of in vivo safety evaluation studies in animals because of the pressure from society to reduce the use of live animals in medical research. Consequently, there has been an increase in the exploration and use of various in vitro systems in toxicity testing. The current philosophy is embodied in the concept of the three R s replacement, reduction, and refinement. Thus if possible, live animals should be replaced with alternatives. If this is not possible, then measures should be adopted to reduce the numbers used. Finally, research workers should also refine the methods used to ensure greater animal welfare and reduction in distress and improve the quality of the data derived, if possible. 

No clear guidelines exist for the appropriate use of performance impairment test systems for work eligibility. There is general agreement that in situations in which worker or public safety is potentially influenced by a worker s performance, impairment test systems are justified. However, no clear criteria for identifying safety issues are available.9 The use of such tests as a means of managing worker productivity is less universally accepted, and if used as an employee evaluation criterion, such tests should be given careful scrutiny. 

Delta, a commercial performance impairment testing system produced by the Essex Corporation, was derived from the Automated Portable Test System (APTS) evaluation system, which, in turn, was based on the work of the Performance Evaluation Tests for Environmental Research Program (PETER), a jointly sponsored U.S. Navy and NASA program designed to identify measures of human cognitive, perceptual, and motor abilities that would be sensitive to environmental perturbations that are associated with decrements in safety and productivity. 

All human circulating metabolites that account for >10% of the administered dose or systemic exposure (whichever is less) and that were not present at sufficient levels to permit adequate evaluation during nonclinical animal studies should be considered for additional safety/ toxicological testings. 

The results of in vitro experiments, however, are important in alerting the toxicologist to potential toxic effects that may be expected in whole animals, or indicating the likely potency of the chemical. They might show that a potential drug is not worth further development, perhaps in comparison with others being developed. For these reasons, the use of in vitro tests will increase in the safety evaluation of all chemicals. But in vitro tests cannot replace evaluation of the effect of a chemical on the whole animal, where possible adverse effects to each organ and system, and the interactions between them, are studied. As we shall see later in the chapter, this is necessary for risk assessment, where the toxic effect that occurs at the lowest dose level in vivo is used. 

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