Acta pharmacologica et toxicologica最新文献

The nature of the LD50 test and its central place in the conceptual development of pharmacology is reviewed. The results of the test and possible uses are outlined. Some guidelines are set out for the development of alternatives to LD50 tests. Some circumstances are suggested in which it seems likely that some form of the test will continue to be required. It is concluded that the problem of replacing the LD50 test with apparently more elegant methods is part of the larger and more fundamental problem of bringing science to the study and regulation of toxicology.

Relatively little work has been done on the development of cell culture and other models to assess the acute toxicity of chemicals. Many of the present shortcomings have already been addressed in earlier presentations but will be summarized by the author. The parameters necessary for an appropriate model of acute toxicity will be discussed and the difference between testing for specific and general effects will be highlighted. Some possible future research directions and research needs will be discussed.

The safety evaluation of new chemicals involves a range of investigations, including acute and sub-acute toxicity testing, long-term toxicity testing, studies on mutagenicity, carcinogenicity, and reproductive toxicity, and special investigations involving the interaction of the chemical under test with particular parts of the body, such as the skin or the nervous system. We shall consider the potential role of differentiated cell and organ culture in toxicity testing, and the criteria available for assessing cell viability, damage, and death, with a view to establishing whether such methods could be used for determining the relative acute toxicities of chemicals. We shall also consider methods for studying the effects of chemicals on general and specific aspects of cell structure and function, including liver cell and organ cultures both as primary targets themselves susceptible to damage and as providers of metabolically activated compounds able to affect other cells and tissues.

In order for in vitro alternatives for acute toxicity testing to emerge, it will be necessary to stage a clearly-defined strategy. The strategy, with its intermediate objectives and proximal decision points, could serve as the basis for validation of the in vitro tests to be used as components of a test battery for assessment of general cytotoxicity and for the evaluation of impairment of differentiated function. An approach for the evaluation of potential neurotoxic agents is presented and could serve as a model for the evaluation of potential ocular, hepatic, and other toxins.

The objective of any experimenter should be to obtain the maximum amount of useful information in the most economical manner possible. In this context, 'useful' means study both of the principal or anticipated actions of the compound under examination, and also detection of additional responses to it. For efficient evaluation, including greater statistical rigour, a continuous or graded response and quantitative measurement is preferable, although much can be done by simply analysis of the presence or absence of responses, even if these are complex or dependent upon subjective criteria. Consistency of experimental conditions, and of diagnostic criteria are essential, whether in single, exploratory or comparative tests. Acute toxicity tests, like other experiments, should be designed pragmatically, therefore, confirming to the properties of the substance under examination, but also with general or holistic coverage, albeit less specific, to detect unanticipated actions. Greater or lesser weight may be given to these two classes of method, depending on whether the test is done as part of a general screen of a previously unknown substance, or as a specific control measure done to assay one particular property. Extrapolation of the results to man or other species is only possible with the caution proper to any experiment done under restricted and highly artificial conditions, but the value of acute toxicity data has often been shown by experience gained in man.