518 Editor: M. WINITZ 
kg orally or about four times the LD,, dose. Now in regard to the second part of your question 
about the lethal dose required with sheep, the toxicity of dieldrin to sheep is of the same order of 
magnitude as that to rats. Therefore the dosage level used in the present experiment would be 
more than sufficient to kill sheep. The amounts of dieldrin to which a grazing sheep might be 
exposed present no hazard to the sheep or the consumer. 
Wrinitz: With regard to the metabolic response to drug toxicity, several years ago we had 
occasion to carry out studies on ammonia toxicity in rats and found that arginine had a marked 
protective effect against ordinarily lethal doses of ammonia. Thus, when LDgy., doses of ammo- 
nium acetate were administered intraperitoneally to rats, the mortality was 100%. However, 
animals treated either concurrently or prior to such injection with protective doses of L-arginine 
invariably showed 100% survival. These studies were carried out by GULLINO, who is a very 
competent pathologist, and in these studies he used several thousand rats—so the results were 
pretty unequivocal. We subsequently pinned down the mechanism of action of arginine to its 
implication in the 7m vivo KREBs’—HENSELEIT cycle. 
Later we extended these studies to hepatectomized rats. It was found here that ordinarily 
protective doses of L-arginine were completely ineffective in protecting partially hepatectomized 
rats—about 40-70% of the liver was removed—from LDgy., doses of ammonium acetate, even 
after the liver had been permitted to regenerate for several days following its removal. So despite 
the fact that the size of the liver had returned to normal or nearly normal, the liver function had 
not. How tong it takes for liver function to get back to normal—this we don’t know. 
SCHREIER: I may add that in the terminal stages of various liver diseases, arginine, glutamine 
and similar compounds have been tried, but they did not show very much effect. 
The last topic on the agenda is concerned with a discussion of amino acid balance. Although it 
has been very easy to get toxic reactions with different types of amino acids in animals, there 
are very few publications, to my knowledge at least, that have been concerned with such studies 
in human beings. In Marburg, Germany, STAVE recently carried out some studies with cystine 
and found that he could cause kidney damage with this amino acid. Of course, the relation to 
FANCONI’s syndrome is clear. 
Winitz: Evidently, it has been pretty well established that this type of cystinosis is charac- 
terized by a marked deposition of cystine in the tissues. The question now arises as to whether 
the clinical manifestations of the syndrome can be alleviated if the deposition of cystine is pre- 
vented. Well, how can one prevent cystine deposition in the tissues? It seems that we have a 
situation here analogous to that found with phenylpyruvic oligophrenia, where diets are em- 
ployed in which the level of phenylalanine is adjusted upwards to the level just required for 
growth, maintenance and tissue repair, and no higher, since providing higher levels of phenylalanine 
can lead to retardation of growth, mental defects and so on. Would it likewise be possible to 
control the effects of cystinosis by dietary means? 
Recently, we had occasion to set up some studies in which nitrogen-free diets were provided 
to rats. For these studies, chemically defined diets were employed which contained the necessary 
glucose, vitamins, minerals and essential fats, but which contained no amino acids or protein. 
However, we neglected to note that in the process of leaving out the methionine and cystine 
components, we had also left out all traces of dietary sulfur. When we examined the amino acid 
plasma levels of animals that had been fed these diets for about 5 days, we found that, with 
the exception of methionine, the amounts and relative proportions of the free amino acids in the 
plasma were very nearly the same as the fasting amino acid plasma levels—amino acid levels of 
animals fed a complete diet but fasted for 24 hours prior to the removal of the blood sample. 
However, the methionine level of animals on the nitrogen-free and sulfur-free diet was only 
one-third that of the fasted animals. What presumably had happened was that the sulfur needed 
for certain of the essential metabolic processes was being supplied at the expense of the endo- 
genous methionine. 
If we now return to cystinosis, would it not be of interest here to employ nutritionally adequate 
chemically defined diets wherein the methionine component is provided as the sole source of 
dietary sulfur at a level just sufficient for growth, maintenance, tissue repair and conversion to 
the necessary cystine? Excess dietary sulfur for the formation and ultimate deposition of cystine 
in the tissues could thereby be avoided. 
SCHREIER: Dr. WESTALL, would you like to comment on the suggestion of Dr. Wrnttz concerning 
the use of cystine-free diets in FANCONT’s cystinosis? 
WeEsTALL: Well, we haven’t done anything about dietary treatment of this type for cystinosis. 
Unfortunately, free amino acids in England are still very expensive, and we have to make a 
great deal of effort to get amino acids for any particular project of this type. This would seem to 
be a very long-term experiment, and extremely costly. I agree that this is a thing which will have 
to come, because there are a number of diseases now where, if the diagnosis is made early enough, 
you have an extraordinarily good chance of eliminating many of the effects of the metabolic 
block by a protective diet. 
References p. 524 
