Basis For Extrapolation Of Data Research Articles

Inhibition, reactivation and aging kinetics of highly toxic organophosphorus compounds: Pig versus minipig acetylcholinesterase

Organophosphorus compound-based (OP) chemical warfare agents (nerve agents) represent a continuing threat to military forces and the civilian population. OPs act primarily by inhibiting acetylcholinesterase (AChE), the standard treatment for which includes AChE reactivators (oximes) in combination with antimuscarinic drugs. In the last decades, the efficacy of oximes has been investigated mostly in small animal models. In order to increase the predictive value of animal studies it is desirable to measure numerous physiological and biochemical parameters. This is difficult in small animals. Large animal models fulfil these requirements and swine are increasingly being used in toxicology studies. Swine breeds generally show considerable variability in different characteristics which may be minimised by the use of specially bred minipigs which have a known genetic background and health status. A comparative study was, therefore, initiated to investigate the kinetic properties of the White Landrace pig and Göttingen minipig AChE in respect of inhibition by the pesticide paraoxon; the nerve agents cyclosarin, VX and VR; the reactivation of inhibited AChE by oximes (obidoxime, pralidoxime and HI 6); and the aging and spontaneous reactivation of inhibited AChE. The determination of the respective kinetic constants found similarities between pig and minipig AChE which showed marked differences in comparison with human AChE values. This has to be considered in designing meaningful models for the investigation of oxime efficacy in pig or minipig experiments. The generated data indicate comparable kinetic properties of pig and minipig AChE and may provide a kinetic basis for extrapolation of data from pig studies to humans.

Analysis of inhibition, reactivation and aging kinetics of highly toxic organophosphorus compounds with human and pig acetylcholinesterase

Organophosphorus compounds (OP) are in wide spread use as pesticides and highly toxic OP may be used as chemical warfare agents (nerve agents). OP inhibit acetylcholinesterase (AChE), therefore, standard treatment includes AChE reactivators (oximes) in combination with antimuscarinic agents. In the last decades, the efficacy of oximes has been investigated in various animal models, mostly in rodents. However, extrapolating animal data to humans is problematical because of marked differences between rodents and humans concerning the toxicokinetics of nerve agents, the pharmacokinetics of antidotes and the AChE enzyme kinetics. In order to improve the understanding of species differences and to enable a more reliable extrapolation of animal data to humans a study was initiated to investigate the effect of highly toxic nerve agents, i.e. VX, Russian VX (VR) and Chinese VX (CVX), with human and pig erythrocyte AChE. Hereby, the rate constants for the inhibition of AChE by these OP ( k i) and for the spontaneous dealkylation ( k a) and reactivation ( k s) of OP-inhibited AChE as well as for the oxime-induced reactivation of OP-inhibited AChE by the oximes obidoxime, 2-PAM, HI 6, HLö 7 and MMB-4 were determined. Compared to human AChE pig AChE showed a lower sensitivity towards the investigated OP. Furthermore, a slower spontaneous dealkylation and reactivation of pig AChE was recorded. The potency of the investigated oximes was remarkably lower with OP-inhibited pig AChE. These data may contribute to a better understanding of species differences and may provide a kinetic basis for extrapolation of data from pig experiments to humans.

The solubility of stabilizing additives in polypropylene

The solubilities of several groups of common stabilizing additives have been measured in polypropylene over a range of temperatures. Regular solution theory is shown to give a good basis for extrapolation of data but cannot predict solubilities. Structural effects on solubility are discussed. The solubility of an additive is dependent upon intrinsic properties (melting point and heat of fusion) and upon interactions with the polymer and both may be equally important.

Biochemical and Physiological Approaches in Ecotoxicology

Ecotoxicology is an interdisciplinary science that deals with the fate and adverse effects of chemicals on ecosystems. A well-balanced assessment of the adverse effects of chemical pollutants in the environment therefore, should be based on studies integrating analytical, toxicological and ecological information. Ecological and analytical information on pollutants are usually obtained from -'field' studies, while toxicological information is mostly obtained from laboratory studies with a limited number of experimental animals (rats, mice, quail, fish, Daphnia, etc.). As the abiotic and biotic environment in the field is very different from that in a laboratory study, it is impossible to predict or explain the effects in a field situation from effects observed in the laboratory. As a consequence, it is almost impossible to establish more than only an empirical relationship between concentrations in the environment or tissues and ecological effects. A large gap in the dose-effect chain still remains to be explained. The gap between field and laboratory studies can be lessened by a better understanding of the mode of fate and action of chemicals in the organism on one hand, and an improved knowledge of relevant physiological processes on the other. The integration of knowledge on physiology and mode of action of chemicals may provide relevant and sensitive parameters to monitor the toxic action of chemicals under 'field' conditions. Studying these parameters in the same species under laboratory and under field conditions may also significantly improve the validity of extrapolation of toxicity data to effects in the field. The use of more or less universal parameters, which can be measured in a wide range of species, can provide a key to the understanding why a certain species is, and another species is not, vulnerable to the toxic action of a chemical. We therefore recommend that when studying the toxicity mechanism of chemicals suspected of causing adverse ecological effects, particular attention should be given to potential interference in biochemical/endocrinological control mechanisms of physiological processes that are important for the survival of populations, such as growth, reproduction, energy utilization and osmoregulation. Such studies should be performed on laboratory animals, and on wildlife species under laboratory and semi-field conditions (Fig. 1). Sensitive toxicity parameters may thus be obtained in a retrospective way, and tested in field experiments. These parameters subsequently can be used in a prospective way as biological effect monitors in an early warning system under field conditions. This approach would also provide a better basis for extrapolation of data obtained under laboratory conditions to field situations, and of data obtained for one species to other species. We realize that such an approach requires detailed knowledge and experience in various disciplines. In many instances this cannot be met by individual researchers, but rather should be tackled by groups of researchers specialized in the different research areas. This proposal is therefore also a plea for setting up joint collaborative studies between different institutions crossing national borders.