X. TOXICITY 51 



croaso in the size of the thyroid gland and a reduced oxygen consuinptioii. 

 It does not cause significant alterations in the blood picture. 



The chronic oral toxicity of PAliA led in the diet in an amount cal- 

 culated to furnish 2 g. per kilogram of body weight has been studied in 

 rats hy I'liton and Zaiafonetis.-' This dose is approximately live times that 

 ordinarily atlministered as a therapeutic dose in man. After the animals 

 had received the PABA-containing diet for months, complete autopsies 

 were done and ti.ssue sections examined. Xo significant pathological changes 

 were observed with the exception of histological alterations in the thyroid. 

 These thyroid changes consisted of a reduction in the amount and eosino- 

 philia of intrafollicular colloid associated with epithelial hypertrophy and 

 hyperplasia. Xo hepatotoxic effects were observed. 



Ershoff ^ has fed purified diets containing 1 or 2 % of PABA or 1 % of 

 PABA and 1 % of inositol to female rats. X^o adverse effects on growth or 

 reproduction were noted in the animals fed these diets for a number of 

 months. Lactation was poor, but this was observed on unsupplemented 

 control diets as well and could not be ascribed, therefore, to PABA. 



B. IN HUMAN BEINGS 



Studies bj^ Strauss and Finland^ have shown that large amounts of 

 PABA may be administered orally to human beings without untoward 

 effects. One patient received 2 g. of PABA at 3-hour intervals for 12 hours. 

 Another patient was given PABA at 2-hour intervals over a o2-hour period 

 during which time 29 g. was ingested. Later the same patient received 33 

 g. of PABA over a 66-hour period. Thus in less than two \veeks this patient 

 received over 62 g. of PABA. 



With the advent of PABA for the treatment of rickettsial diseases, 

 amounts of this compound of the order of 25 to 30 g. per day have been 

 administered orally to hundreds of patients. Concerning the toxicity of 

 PABA in the treatment of rickettsial diseases, Cruickshank and Mitchell*^ 

 state: "Xo record of pathological changes caused by the drug in human 

 .subjects has been found, although the pathology of two fatal cases of 

 t>T3hus, treated with it, is said to have been studied".^ 



On the other hand, Cruickshank and MitchelP were the first to note 

 toxicity when they observed two cases of acute rheumatic fever and one of 

 arthritis in children who were treated with PABA where the outcome was 



* A. C. Upton and C. J. D. Zarafonetis, Proc. Soc. Exptl. Biol. Med. 75, 450 (1950). 



« B. H. Ershoff, Proc. Soc. Expll. Biol. Med., 63, 479 (1946). 



' E. Strauss and M. Finland, Am. J. Med. Sci. 201, 730 (1941). 



« A. H. Cruickshank and G. W. Mitchell, Jr., Bull. Johns Hopkins Hasp. 88. Jll 



(1951). 

 8 .\. Yeomans. J. C. Snyder, E. S. Murray, C. J. D. Zarafonetis, and R. S. Ecke, 



J. Am. .Med. Assoc. 126, 349 (1944). 



