A testing procedure is described for the assessment of the toxicological response (e.g., acute toxicity or mutagenicity) of any combination and number of chemical, physical, and biological agents, with no more effort for a particular combination than for a single agent. The method provides a simple, sensitive, and quantitative index of synergism, antagonism, and additivity, and it has been demonstrated experimentally in rats by determining the acute lethality of combinations of cadmium, mercury, and lead salts. In a combination of two metal salts, the dose of one metal of the pair was fixed at or near the no-effect level while the dose of the second metal was increased until the entire dose-response curve was obtained. To evaluate interactions of the three metals, the previous pair of metals were kept fixed at their combined extrapolated LD1 level, and the third metal was increased. The statistical treatment of the data employed a computer program that did not involve probit transformations, but rather the approximate linear relationship between the fractional response and the logarithm of the dose. A particular combination could be synergistic, antagonistic, or additive, depending on the relative doses employed. Generally, a combination was synergistic when the most toxic member was present at or near its LD1 dose in the presence of the much less toxic member; the same combination was protective when the least toxic member was present at or near its LD1 dose. The results clarify apparently contradictory reports regarding the biological effects of metal combinations. The application of the testing procedure to combinations of mutagens is described, and an example is cited involving, for a particular bacterial mutagen, a combination of N-methyl-N'-nitro-N-nitrosoguanidine with ethylmethanesulfonate.
dizing f3-hydroxybutyrate. Furthermore, active exchange of the K+ bound to the mitochondrial membrane fragments coupled to respiration has been demonstrated with K42 as a tracer. It is inhibited by cyanide or dinitrophenol, demonstrating' that the binding of the potassium to the digitonin fragments is linked to electron transport and phosphorylation mechanisms. However, ATP cannot substitute for respiration in causing binding of radioactive K+. Since the preparations have relatively insignificant capacity to bind Na+ under any conditions, this active potassium-binding mechanism of the mitochondrial membrane appears to be selective.These experiments demonstrate that the digitonin fragments may provide an important lead for investigation of the molecular mechanisms involved in active transport; further work on identification of the binding sites for K+ is in progress. ConclusionAlthough the membrane fragments are still highly organized, they are considerably less complex than intact mitochondria and thus relatively free of extraneous side reactions not relevant to oxidative phosphorylation and of structural "compartmentation" of pools of dizing f3-hydroxybutyrate. Furthermore, active exchange of the K+ bound to the mitochondrial membrane fragments coupled to respiration has been demonstrated with K42 as a tracer. It is inhibited by cyanide or dinitrophenol, demonstrating' that the binding of the potassium to the digitonin fragments is linked to electron transport and phosphorylation mechanisms. However, ATP cannot substitute for respiration in causing binding of radioactive K+. Since the preparations have relatively insignificant capacity to bind Na+ under any conditions, this active potassium-binding mechanism of the mitochondrial membrane appears to be selective.These experiments demonstrate that the digitonin fragments may provide an important lead for investigation of the molecular mechanisms involved in active transport; further work on identification of the binding sites for K+ is in progress. ConclusionAlthough the membrane fragments are still highly organized, they are considerably less complex than intact mitochondria and thus relatively free of extraneous side reactions not relevant to oxidative phosphorylation and of structural "compartmentation" of pools of intermediates. With the information gained on these preparations, still less organized portions of the complex enzymatic machinery may soon be dissociated and studied separately, toward the ultimate goal of demonstrating the mechanism of oxidative phosphorylation.These investigations are being carried out with full appreciation of the eventuality that such classical approaches to reconstruction applied to the highly integrated and structure-dependent respiratory chain and its energy-coupling mechanisms may never succeed to the same extent or in the same way as they have for other metabolic cycles which occur by interaction of essentially soluble enzymes, because of a possible necessity for special polymolecular arrangements to direct protein-protein ...
On Estimating the Constants of the ' Multi-Hit ' Curve Using a Medium Speed Digital Computer. j-By SYLVANCS !l . TYLER, &l.sC., and RfERLIN H. DIPERT, icI.sC.
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