EFFECTS OBSERVED IN THE WHOLE ANIMAL 717 



Toxic and Lethal Doses 



Selected data on toxicity are presented in Table 6-10 and provide some 

 comparative assessment of the relative potencies. Although there is a good 

 deal of variability, the average ratio of toxic potencies of the trivalent 

 and pentavalent arsenicals is 58 with regard to intraperitoneal administra- 

 tion to mice (Eagle and Doak, 1951). The variation is mainly among the 

 pentavalents. The trivalent arsenicals are roughly of equivalent toxicities, 

 but possibly the additional factor of reduction increases the variability 

 of pentavalent activity. Such toxic doses should not be construed as accu- 

 rate and invariable because many factors may alter the sensitivity of animals 



The time factor is very important in poisoning by the arsenicals. Thus 

 the LD50 determined at 2 hr may be greatly different from that at 24 hr. 

 In rabbits, arsenite given subcutaneously kills within 10-12 hr at 6.6 mg/kg, 

 within 1 hr at 26 mg/kg, and within 30 min at 66 mg/kg (Morishima, 1900 

 a); in frogs, 20 mg/kg^ kills in 2 days, whereas 300-600 mg/kg kills in around 

 1 hr (Ringer and Murrell, 1878). The susceptibility of mice to arsenite varies 

 with age and sex, and sexual intercourse has been shown to increase resis- 

 tance to arsenite, around 50% greater dose being required in males and 

 25% greater in females, either the cause or the effects falling off with age 

 (Agduhr, 1937). Hormonal levels may also be of importance, hyperthyroid- 

 ism increasing the susceptibility of mice to phenylarsenoxide and neoars- 

 phenamine (Dybing, 1948), and ACTH or adrenal extracts decreasing 

 susceptibility some 35-40% (Beck, 1951). Tumor-bearing animals are some- 

 what more resistant than normals to oxophenarsine; at a certain dose 

 the survival was increased from 26% to 83% (Beck and Gillespie, 1954). 

 This effect is not due to accumulation of the arsenical in the tumor tissue 

 since analyses showed no specific uptake. In connection with the variability 

 of toxic doses, perhaps it is well to remember that AS2O3 often contains 

 very significant amounts of SbaOg, which can contribute to the effects 

 produced, particularly the vascular and gastrointestinal (Harrisson et al., 

 1958). 



The relation of arsenical structure to toxic potency presents many in- 

 triguing problems in interpretation; much of the work has been well summa- 

 rized in the review article of Eagle and Doak (1951). The unsubstituted 

 phenylarsenoxide is highly toxic to all types of cells studied and shows 

 relatively little selective effect on infective parasites. Many phenylarsen- 

 oxides have been examined in an effort to find compounds more selectively 

 parasiticidal (Table 6-11). Ring substituents almost invariably reduce the 

 toxicity. An unfortunate fact preventing satisfactory explanation of varia- 

 tions in activity with structure is the almost complete lack of data on the 

 effects of structural changes on the reactivity of the arsenicals with enzyme 

 systems. In other words, when groups are introduced into the phenylar- 

 senoxide ring, the toxic or parasiticidal activity may be altered due either 



