THE absence of direct toxicity is one of the most remarkable properties of the penicillin molecule; that is to say, the penicillin molecule as we know it and as we should use it. If you try hard enough, you can make it toxic by altering it or abusing it, as I shall try to show later. With this reservation, one can say that penicillin G and the main therapeutic derivatives of 6-aminopenicillanic acid (6-APA) at present in use are virtually non-toxic. By this I mean that these drugs can be given in doses very much larger than those of any comparable biologically-active substance to some animals and to man without disturbing organic function or causing any signs or symptoms suggestive of damage to essential tissue (Table I). In mice, rats and dogs, penicillin G, the phenoxypenicillins, methicillin, the isoxazoles and ampicillin are all tolerated intravenously in doses of 2 g./kg. or more, and in twice that dosage subcutaneously or orally. With some derivatives (e.g. ampicillin) it is difficult to establish a toxic dose within the limits of solubility. Extremely high doses (5 g./kg.) may cause convulsions if given intravenously: this would be equivalent to about half a kilogram by injection or a kilogram by mouth to man! At about half this dose level, the isoxazoles cause transient hypotension but in other respects there is no interference with vital functions. The toxic level in man has never been established but it is known that methicillin and penicillin G can be given intravenously in doses of 20 g. per day for weeks on end, and that ampicillin and the isoxazoles can be given in doses of at least 4 g./day (80 mg. /kg.) without any signs of immediate or delayed toxicity. This means that concentrations of penicillin G and methicillin of 50 mg.% can circulate harmlessly in the blood and tissues; in other words, that penicillin is no more toxic than glucose or urea, and much less toxic than many other physiological substances. When such large doses are being given, it is best to use the sodium salt as the potassium cation can be toxic: 15 mega units of penicillin G supplies 25 mEq. of K+ which may cause cardiac dilation, especially if the heart is already damaged, as in bacterial endocarditis, which is the main disease requiring such high doses. Even the sodium cation may rise if there is any renal impairment and it should be remembered that normal doses of methicillin yield 5-10 mEq. of Na+. Some among you may recall that, in the early days, the toxicity of successively purified batches of crude peni-