Minimal Lethal Dose of various Toxic Substances. 325 



Without further multiplying detailed instances it may be stated that we 

 have obtained the same results on calculation from a variety of published 

 observations on a number of different substances administered by various 

 methods in different animals. Among these substances are sulphate of methyl 

 brucium injected subcutaneously in- the rabbit, and codeine hydrochloride 

 administered by the stomach in the same animal (Oram Brown and Fraser 

 (11) ); sulphate of physostigma given subcutaneously in rabbits (Fraser (12)); 

 morphia and atropine sulphate administered subcutaneously in the rat 

 (Bashford (I'd) ) ; various snake venoms — krait, Enhydrium valakadien, Enhy- 

 dris curtus, cobra — inoculated in rats, rabbits, guinea-pigs, and cats by 

 different observers (Fraser and Elliott (14), Elliott, Siller, and Carmichael 

 (15), Madsen and Noguchi (16), and others); adrenalin both natural and 

 synthetic in the mouse (Schultz (17)) ; tetanus toxin injected subcutaneously 

 in the mouse (Knorr (18) ) ; potassium chloride (KC1) introduced intra- 

 venously in the rabbit (Hald (19) ) ; and caffeine subcutaneously, intraperi- 

 toneally, intravenously, or by the mouth in dogs, cats, rabbits, and guinea-pigs 

 (Salant and Bieger(20) ). 



In view of the conclusions to which the results obtained with all these 

 very diverse toxic agents lead, it seems clear that in animals of different 

 size in any given species the dose required to produce a given effect is related 

 to the surface and blood volume of the animal and not directly to the body 

 weight. That is to say, the smaller individuals require a relatively larger 

 dose than the heavier animals to produce the same effect. 



While we are not prepared to maintain that this constitutes a universal 

 rule to which there are no exceptions, yet it follows from what has been 

 already stated that it possesses a very wide application, and we have not up 

 to the present met with any exception in the case of mammals and birds. 



Accordingly we conclude that if it is desired to administer comparable 

 doses of drugs in warm-blooded animals of different size and weight in any 

 given species, they must be calculated in relation to the body surface. 



It follows from this that if one administers any given toxic substance in 

 doses such as will kill each of the animals employed in about the same period 

 of time, one is now in a position to use animals of various size over a wide 

 range of weight within the same species instead of only animals of one 

 particular size in carrying out experimental work upon toxicity and lethal 

 dosage. One is no longer restricted to the use of carefully selected animals 

 of a given and standard weight, as has hitherto been the case, for example, in 

 all determinations of the strength of toxins as well as in the standardisation 

 of antitoxins. This result will naturally prove of value in facilitating 

 toxicological investigation in very many directions. 



