Test system definitions

Hazard identification is defined as tlie process of determining whetlier human exposure to an agent could cause an increase in the incidence of a health condition (cancer, birtli defect, etc.) or whetlier exposure to nonliumans, such as fish, birds, and otlier fonns of wildlife, could cause adverse effects. Hazard identification cliaracterizes tlie liazard in terms of tlie agent and dose of the agent. Since tliere are few hazardous chemicals or hazardous agents for wliich definitive exposure data in humans exists, tlie identification of health hazards is often characterized by the effects of health hazards on laboratory test animals or other test systems. ... 

German water authorities adopted a permit system for effluent emission where the requirements are based on fish toxicity [195]. Daphnia, algae, and luminescent bacteria are including for a screening additionally to the fish test. In this scheme the fish test Goldoifo Leuciscus idus) is stiU considered to be the only test producing definitive results. 

The definitions are for those words and phrases that the reader encounters in the regulations. Examples include quality assurance unit, raw data, reference substance, sponsor, study, study director, test substance, test system, testing facility. See Box 7.4 for these definitions. 

In most instances the test system will be self-evident (e.g., the animal to which the test article is administered or applied). Studies with micro-organisms, however, sometimes present difficulty in defining the test system. In the case of the Ames test, for example, the test system is not merely the colonies of salmonella or yeast, but includes in addition the culture medium, metabolic activation agent (if any), biotin, histidine, and buffer (if any). The last sentence of the definition makes it clear that untreated control groups also meet the definition of test system even though a test or control article is not administered or applied to such groups. 

In most instances the specimens will be self-evident (e.g., samples of blood, plasma, serum, urine, spinal fluid, aqueous humor, organs, tissues, and tissue fractions that are taken from a test system with the intention of performing an examination or analysis). In other instances the definition may not be as clear. For example, the assay plates used in the mammalian cell transformation assay and the mammalian point mutation assay are considered specimens even though they bear many of the attributes of a test system. For these assays, the originally plated cells plus media and excipients are the test system. After treatment with the test or... 

In the absence of definitive human data, risk assessment may have to depend on the results of cancer bioassays in laboratory animals, short-term tests, or other experimental methods. Hence the following issues must be addressed under such circumstances the ability of the test system to predict risks for man (quantitatively as well as qualitatively) the reproducibility of test results the influence of species differences in pharmacokinetics, metabolism, homeostasis, repair rates, life span, organ sensitivity, and baseline cancer rates extrapolation across dose and dose rates, and routes of exposure the significance of benign tumors fitting models to the data in order to characterize dose-incidence relationships and the significance of negative results. 

Utility tests. By definition, these are actual food formulations copying accepted food preparations. As mentioned above, when Model Tests are designed, the range of products undergoing the test should be wide enough to include some failures. In some cases, a Utility Test is employed that substitutes objective evaluation systems for sensory ones. This reduces the time of the test and its cost. However, only those objective tests previously found to be well correlated with sensory tests should be employed. Eventually a sensory test has to be performed. No food product should be marketed without a final utility test employing subjective evaluations. 

For retrospective validation, emphasis is put on the assembly of appropriate historical records for system definition, controls, and testing. Existing systems that are not well documented and do not demonstrate change control and/or do... 

We have redefined "test facility", we have redefined "study". The next definition has to do with the living system that is undergoing the test. Up to now this has been traditionally rodents, dogs and primates. By using the term "test system" and defining "test system" as that to which the test substance is applied, we can now include soil, rodents, primates, bacteria and so on. I will not go into the specific proposed changes.in the text but you will see the emphasis in the text below which highlights the titles of certain sections ... 

Many of you have expressed an interest in a format for your master schedule. Figure 1 depicts the format Mobay Chemical Corp. uses. It is self explanatory and covers the items required in the GLP regulations (test substance test system nature of study study initiation date current status sponsor identity, if explicable and name of study director). For a contract laboratory, the sponsor s identity must appear on the master schedule sheet for each study listed. There are several terms that require definition. In... 

Because of the wide spectrum of activity shown by amines, definitive conclusions concerning structure-activity relationships cannot be made at this time. However, studies using single test systems reveal that the most active silylated amines contain the silicon atom in a y position relative to the nitrogen, as shown in partial structures 12 and 13 (55, 56). Some examples of compounds containing these groupings are found in Tables I and II. The silylated benzhydryl ethers (Section II,F) and sila-tranes (Section III,C) also contain this type of grouping. 

The first and very important part of any plan is the exact definition of the aim, as explained in the previous chapter. This is followed by a list or sequence of major tasks or sections which each must be accomplished in order to achieve the aim. Since these major sections each define critical steps of the project, success criteria or objectives for each of these must be described and agreed. These objectives should specifically address known or potential difficulties (in our example the purity of antigen that is needed, the required test systems, etc.) and should be defined as exactly as possible at this stage and updated when necessary. The definition of objectives requires a reasonable knowledge of the subject and should thus be discussed and agreed with the specialists in these fields and with those who have to meet these objectives. 

Implementation of the software design commences once the design is finalized. Sandpit (prototyping of application functionality) and development facilities are required to support system definition and development. A validation environment to perform qualification testing and a live environment completes the system development and operational architecture. 

The lack of adequate data. Including test results, and limitations in the test systems used preclude a definitive assessment of the genotoxlc potential of BZ, scopolamine, and atropine. Only through further studies can a conclusion be reached about the genotoxlc potential of these chemicals. 

The EPA GEPs for both the TSCA and the FIFRA have basically the same definitions for control substances and reference substances. A control substance means any chemical substance or mixture, or any other material other than a test substance, feed, or water, that is administered to the test system in the course of a study for the purpose of establishing a basis for comparison with the test substance for chemical or biological measurements. A reference substance means any chemical substance or mixture, or analytical standard, or material other than a test substance, feed, or water, that is administered to or used in analyzing the test system in the course of a study for the purposes of establishing a basis for comparison with the test substance for known chemical or biological measurements. ... 

From a practical point of view, there are several additional criteria that the ideal test should meet. Alternatives to current in vivo test systems basically should be designed to evaluate the observed toxic response in a manner as closely predictive of the outcome of interest in humans as possible. In addition, the test should be fast enough so that the turnaround time for a given test chemical is reasonable for the intended purpose (very rapid for a screen and timely for a definitive test). The speed of the test and the ability to conduct tests on several chemicals simultaneously will determine the overall productivity. The test should be inexpensive so that it is economically competitive with current testing practices. Finally, the technology should be easily transferred from one laboratory to another without excessive capital investment (relative to the value of the test performed) or the need for special skills for test implementation. 

The chemical properties and hence the chemical structure of a compound definitely determine its participation in the partial processes making up the various phases of action. The relationship of structure to action is therefore a fundamental characteristic of the action of pharmaca. The apparent absence of such a relationship can only be due to deficient methods of investigation and to the multiplicity and complexity of the processes involved. The structure-action relationship will be found to emerge more clearly if it is studied with regard to particular part-processes such as those involved in pharmacon metabolism, in pharmacon distribution, and in pharmacodynamics. Such a study involves the use of simple, isolated test systems. 

Another issue is reproducibility. The formulation may work perfectly in an in vitro test system, but the dosage form requires aerosolization, and lung deposition is a function of the characteristics of the aerosol (dose, mass concentration, droplet/particle size, etc.) and the nature of the inspiratory maneuver, a factor that the patient has control over. These factors can influence performance to a far greater extent than can be built into a particle, and thus the term controlled does not seem a defensible objective for pulmonary delivery. The vagaries of the deposition profile and of the amount that will deposit also imply that sustaining a certain drug concentration is a difficult proposition, but the loosest definition extended release, seems an acceptable goal within the boundaries set by the clearance mechanisms. 

Whereas acceptance criteria are used to check functioning of in vitro methods, performance standards are used to compare two or more results from different in vitro methods. Such a comparison is often critical in the validation stages when validation bodies are carrying out validation projects, but can be also important when users have to make decisions to use novel test systems or other essential components in the in vitro method. When using standards (such as definition/description standards, physical standards or methodological standards), results from two or more similar and/or different methods may be compared if the same standard(s) was included in all the methods. Acceptance criteria may be met for individual methods, but if standards are not included in the experimental design, there will be no way to compare the different data and result sets when used to test items. 

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