PT  - JOURNAL ARTICLE
AU  - RALPH B. HOGAN
AU  - HARRY EAGLE
TI  - THE PHARMACOLOGIC BASIS FOR THE WIDELY VARYING TOXICITY OF ARSENICALS
DP  - 1944 Jan 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 93--113
VI  - 80
IP  - 1
4099  - http://jpet.aspetjournals.org/content/80/1/93.short
4100  - http://jpet.aspetjournals.org/content/80/1/93.full
SO  - J Pharmacol Exp Ther1944 Jan 01; 80
AB  - 1. In a series of phenyl arsenoxides varying twenty-fold in toxicity, the amount of each (acid-substituted compounds excepted) bound by red blood cells in vitro was in proportion to its systemic toxicity. 2. A similar variation was found in the amount of arsenical bound by the circulating red blood cells immediately after intravenous injection. The non-toxic compounds were not bound to the same degree as toxic compounds, and left the blood stream at a faster rate. 3. The amount of arsenic remaining in the liver and kidney 24 or 48 hours after the intravenous injection of arsenoxides or arsonic acids was proportional to their toxicity. 4. The rate of excretion of phenyl arsenoxides (acid-substituted compounds excepted) was also a function of their toxicity. The non-toxic compounds, not bound by body cells, were excreted rapidly; while the toxic compounds were excreted slowly, in inverse proportion to their toxicity. 5. At dosages which produced equivalent toxic effects (the LD50 level), tryparsamide, phenyl arsonic acid and phenyl arsenoxide resulted in comparable tissue levels, despite a 500-fold difference in absolute arsenic dosage. 6. It is therefore suggested that the varying systemic toxicity of arsenicals is primarily determined by the varying degree to which they are bound by, and thus block, essential functional groups in vital organs. The chemical nature of these groups is discussed in the text. 7. Acid-substituted phenyl arsenoxides are only an apparent exception to this generalization. Although fairly toxic, they were bound to only a minimal degree by red blood cells in vitro or in vivo. After intravenous injection, they were at first excreted rapidly, as much as 40 per cent appearing in the urine in one hour. The excretion was, however, abruptly curtailed after approximately four hours; and death in white mice injected at the LD50 level was characteristically delayed as compared with death resulting from other phenyl arsenoxides. It seems probable that most acid-substituted phenyl arsenoxides are not toxic as such, consistent with their lack of affinity for red blood cells, and their initially rapid excretion. The sudden curtailment of urinary excretion, and the delayed death of mice, suggest that they are converted by the body to other compounds which can combine with vital chemical groupings in the tissues, and which are toxic by virtue of that combination.