RESISTANCE TO THE ARSENICALS 765 



significant resistance in microorganisms. Kuhs et al. (1939) succeeded in 

 producing tolerance to the organic arsenicals in rats, rabbits, and dogs, 

 but did not succeed with arsenite; furthermore, the animals which were 

 resistant to oxophenarsine, tryparsamide, or carbarsone were not resis- 

 tant to arsenite. The resistance factors were only 1.2-3 so that tolerance 

 was slight although definite. Five to eight intravenous injections weekly 

 over several weeks were required to induce this degree of tolerance, the 

 dosage being increased slightly during this time. Norris and Elliott (1945) 

 subjected rats to daily intraperitoneal injections of arsenite at levels not 

 depressing growth or causing toxicity; at the end of 3 weeks, the dosage 

 could be raised significantly (to levels normally toxic in 1 hr) and the char- 

 acteristic hypothermia no longer occurred. It was proved that the tolerance 

 is not due to alteration in the absorption from the peritoneal region, and 

 it is known that the fraction of arsenical excreted by the kidney in the 

 tolerant animal is the same as in normals. Bunting and Longley (1940) 

 reasoned that since the kidneys suffer arsenical damage, some change 

 might be observable in resistant animals. Rats were given increasing intra- 

 venous doses of tryparsamide for a month, at which time they were receiving 

 50% more than the dose just tolerated by normal animals. The kidneys 

 initially showed a coagulative type of necrosis, especially in the convoluted 

 tubules; regeneration occurred and, by the fifth week after the highest dose, 

 there was no observable necrosis and the tubules were lined with mature 

 epithelial cells. These regenerated cells are thus quite resistant to trypar- 

 samide inasmuch as high doses no longer produce evidence of necrosis. 



Mechanism of the Resistance 



The resistance could develop as a direct adaptation to the presence of 

 the arsenical, or could be the result of selection from an initial hetero- 

 geneous population, or could appear by selection of mutants arising during 

 the exposure. The first explanation is the most likely but over long periods 

 selection may also play a role. At least there are experiments which seem 

 to exclude selection in some cases. For example, arsphenamine-resistant 

 trypanosomes have been derived from a single cell, excluding selection 

 from an original varying population; furthermore, resistance can be induced 

 when exposure is only during periods when no growth or division is occurring 

 (bound arsenical might, of course, be carried into the growth phase). The 

 marked rapidity of the development of resistance in some cases also argues 

 for a direct adaptation. In the development of high resistance, however, 

 selection may occur, as indicated by Schueler et al. (1947), who found the 

 sensitivity distribution curves for low-resistance and high-resistance 

 strains not to overlap. The ability of low-resistance strains to revert to 

 normal, whereas high-resistance strains seem very stable also points to 

 some selection. The rate at which resistant organisms lose their resistance 



