Acta pharmacologica et toxicologica最新文献

The possibility to use organs, organelle preparations and biologically active chemicals in toxicity tests and in toxicology will be reviewed. Examples are perfused liver preparations, tissue slices and homogenates, isolated nerve preparations, nerve-muscle preparations, membrane preparations, microsomes, mitochondria, synaptosomes, antibodies and isolated chemical compounds (receptors, enzymes).

Cultured mouse neuroblastoma cells (C1300) may be used as models for nerve cells since they have a number of properties in common with their normal counterparts in vivo. In order to test the possibility of using C1300 cells as alternative to experimental animals when testing for acute toxicity, cells (clone 41A3) were exposed to a number of common chemicals (CH3HgCl, CdCl2,HgCl2 ppDDT, n-butanol, benzene, dioxan, n-propanol, aceton and t-butanol). The toxic effect was quantified by measuring the degree of cell detachment in the cultures. The concentrations of chemicals that caused 25% of the total cell number to detach (TD25) were used for comparison with LD50 values. In spite of the very simplified situation in culture, where the toxicity of a substance is little or not at all influenced by factors like penetration, storage, metabolism and excretion a good correlation (corr. coeff. 0,98) was obtained between TD25 values and LD50 values. Good correlations between in vitro and in vivo tests have also been reported by others. One possible explanation to these findings could be simplified in vivo toxicokinetics of these substances when tested in high doses for general effects like animal death. If so, simple in vitro tests may be used for predicting acute toxicity of certain groups of substances.

It is essential to have an adequate understanding of the acute toxic effects of a new drug. It may not be necessary however to blindly follow the full classical median lethal assay on every occasion. The LD50 was developed to obtain the maximum accuracy from a modest experimental size. The objective of the study and the limitations of the assay should not be overlooked however and undue precision should not be sought. Methodological aspects including species and maximum and minimum doses will be discussed. Other methods and approaches to acute toxicity will be recommended with a more broad approach to acute toxicity than lethality alone.

Does the pharmaceutical industry perform LD50-determinations in animals just because it is required by the authorities or are there any scientific benefits from counting dead animals and calculating and index of lethal toxicity? This is an important question when discussing LD50 and possible alternatives. We will try to answer this question by presenting data and some views collected during almost ten years at a Swedish pharmaceutical company. We will describe how we have made use of the LD50-values in the safety evaluation process. We will compare LD50-values with the dose levels used in longterm toxicity both after single or repeated administration and with therapeutical dose levels in man for different classes of drugs. These data will enable us to demonstrate the value of the LD50-determinations. As we are of the opinion that the LD50-value itself has a limited value for the total safety evaluation of drugs we will look into the possibility of replacing the LD50-determination with something else as an indication of lethal toxicity. In order to minimize the number of animals used and the number of animals dying because of dosing in studies on lethal toxicity we will try to support a proposal to use the maximal nonlethal dose (MNLD) as an indication of lethal toxicity in small animals.

The prediction of the biological activity of chemical compounds by means of mathematical models is discussed. Biological activity of chemicals, including their toxicity on man and other biological organisms and systems, involves too complex phenomena to presently be predictable by fundamental models such as ab initio quantum mechanical models or statistical mechanical models. Hence one takes recourse to semi-empirical and empirical models which relate the variation in chemical structure of chemical compounds to the variation in their measured biological activity, e.g. toxicity in one or several test systems. These models are "calibrated" on series of similar compounds with "known" toxicity, the training set. Thereafter the models can--in fortunate cases--be used to predict the toxicity of compounds which are structurally similar to the training set compounds. The formulation and applicability of semi-empirical and empirical models relating chemical structure to biological activity is discussed. Causes and remedies for commonly encountered fallacies are presented.