458 CHEMICAL AGENTS 



molecular weight as the series is ascended, but at some point the trend 

 is reversed, and higher members of the series are less toxic. All com- 

 pounds of the series, however, appear to act in the same way on cells. 

 Early explanations of this homologous series effect were centered on 

 permeability of the cell to toxicants. It was found that toxicity is 

 correlated in such a series with an oil-water partition coefficient. Since 

 the plasma membrane is in general more permeable to non-polar com- 

 pounds than to polar compounds (84), it was natural to hypothesize 

 that the more lipoid-soluble compounds are more toxic simply because 

 they enter the cell more rapidly. 



The classical paper of Ferguson (104) corrects and expands this 

 limited hypothesis by introducing chemical potential as the index. 

 Essentially, Ferguson's principle states that the biological effectiveness 

 of non-specific poisons is a function of proportional concentration at 

 the site of action. At equilibrium any compound is at the same pro- 

 portional saturation in all phases of the system. Consequently, toxicity 

 is a function, not of bulk concentration in the external phase but of 

 relative concentration or chemical potential. It follows that a sub- 

 stance only sparsely soluble in water will be more active, mole for 

 mole, than a more soluble related compound. Consider compound A, 

 soluble in water to the extent of 1.0 M, and compound B, soluble only 

 to 0.1 M. Ideally, if an 0.05 M solution of B (all phases 50 per cent 

 saturated) exerts a given non-specific effect, compound A will exert the 

 same effect only at 0.5 M, i.e., at 50 per cent of saturation. 



Concrete experimental results are not, of course, so neat. It is a 

 matter of some doubt, for example, whether the chemical activity re- 

 quired for a given biological response is constant or rises slowly as a 

 homologous series is ascended (18, 46). 



Figure 8, taken directly from Ferguson (104), illustrates the principle 

 for the series of aliphatic primary alcohols. As the series is ascended, 

 all the properties — solubility, surface tension lowering, vapor pressure, 

 and oil-water partition coefficient — which depend on chemical poten- 

 tial change simultaneously. So does toxicity. 



It must be emphasized that these considerations do not give specific 

 information as to the site of action. All the constants of Figure 8 are 

 distribution functions. From this we argue that toxicity depends upon 

 a distribution between heterogeneous phases. We can not argue for 

 any one distribution, e.g., that between external solution and proto- 

 plasm. The governing partition could, for example, be that between 

 the medium and the cell surface or that between the non-polar portions 

 of a protein chain and the ambient intracellular medium. Acceptance 

 of Ferguson's principle does not of itself commit us to any particular 



