EFFECTS IN THE WHOLE ANIMAL 507 



are exerted by higher doses and it has been noted that animals killed by 

 the quinones are often in a state of rigor or "stiff as boards" (Ames, 1948), 

 suggesting a direct production of contracture such as is seen in isolated 

 muscle. Several investigators have observed pulmonary edema and this 

 may point to an effect on the lung capillaries, particularly as petechial 

 hemorrhages and other signs of vascular damage have been recorded. 

 The renal damage reported in acute poisoning may be in part vascular but 

 changes in the tubular cells indicate a direct toxic effect, which would 

 not be surprising. Hemolysis may occur and is probably due to a direct 

 effect on the erythrocytes, since it occurs in vitro, and methemoglobinemia 

 may contribute to the lowering of the oxygen- carrying capacity of the blood. 

 The cause of death has been a debatable point and there have been propo- 

 nents for both respfratory and circulatory failure, the former being in 

 numerical superiority. However, the evidence for respiratory failure in 

 most cases has been only the observation that breathing stops almost 

 simultaneously with the death of the animal. In one instance it was noted 

 that the heart continues to beat for several minutes after cessation of the 

 respiration (Shimkin, 1941), but terminal ventricular fibrillation has also 

 been observed. 



The most serious effects of the prolonged administration of the quinones 

 are related mainly to the blood and hematopoietic tissues. Direct effects 

 on the erythrocytes to favor hemolysis with the production of icterus ap- 

 parently unassociated with liver damage may occur, although some fatty 

 degeneration of both the liver and the kidney has been noted. A direct effect 

 on the bood-forming tissues can lead to a generalized anemia, or more spe- 

 cifically a granulopenia or agranulocytosis. In certain instances, particularly 

 with the naphthoquinones, hypoprothrombinemia and hemorrhagic states 

 may be induced. Animals may not gain as much weight as normally, or 

 may lose weight, and several investigators have stated that the animals 

 may die without marked symptoms but exhibiting anorexia and inanition. 

 There may be effects on the endocrine balance, including thyroid hyper- 

 plasia, and frequently either a depigmentation of the hair or production of 

 abnormal coloration. The pattern of chronic poisoning depends so much 

 on the dosage level and the species that little more of a general nature can 

 be said. No recent reviews on quinone toxicity are available, but the fol- 

 lowing general references are recommended: Ellinger (1923), Oettel (1936), 

 Supniewski et al. (1936), Ansbacher et al. (1942), Marquardt et al. (1947), 

 and Seifter (1948). 



Toxic and Lethal Doses in Animals 



A few representative doses are presented in Table 5-5 and from these 

 values some general conclusions, which may or may not prove to be valid, 

 can be drawn. The sensitivities of the various species are, in descending 



