VOEGTLIN and THOMPSON [1922] have suggested that the toxicity of an arsenical is governed to a large extent by its rate of excretion. Phenylarsenoxide has a high toxicity compared with those of arsenicals used in therapeutics. In an effort to determine to what extent this can be attributed to the degree to which the arsenic-containing molecule is retained in the body, and, in particular, in vital organs, rather than to any specific properties not shared by similar arsenicals, organs and exereta of rabbits were analysed following injection with phenylarsenoxide, mapharsen (m-amino-p;-hydroxyphenylarsenoxide) and with the arsonic acid corresponding to each arsenoxide. This work had to be abandoned without completing the full programme originally planned, but it is thought that the results obtained should be put on record. While further information on certain points would be desirable, the main objective has been attained.A great deal of work has been published on the fate of mapharsen in the body following intravenous injection. The distribution and excretion of arsenic following treatment of dogs with massive doses was studied by Magnuson and Raulston [1941]. Figures for the excretion of mapharsen by dogs have also been given by Gruhzit, Dixon et al. [1936]. In rats, the distribution has been described by Wright et al. [1937] and the excretion by Voegtlin and Thompson [1922]. Excretion figures for mapharsen in man have been reported by Foerster and his co-workers [1935] and by Henning and Kampmeier [1943]. All figures for the excretion of mapharsen are in agreement in suggesting that this is a fairly rapid process, at least half of the arsenic administered being cleared in a week. In man and the dog, in contrast to the rat, more arsenic was found in the freces than in the urine.In a paper received after we had ceased work on this problem, Hogan and Eagle [1944] give an account of a detailed and extensive study of the basis for the varying toxicity of arsenicals. Results are 137
SHORTLY after their discovery of BAL (British Anti-Lewisite, 2:3-dimercaptopropanol), Stocken and Thompson [1946] showed that application of this substance to the skin hastened the excretion of lewisite in rats. Some time later it was found by Eagle [quoted by Walters and Stock, 1945] that injection of BAL led to a more rapid elimination of arsenic in animals poisoned with arsenicals of therapeutic interest.In a previous communication [Chance, Crawford and Levvy, 1945], the fate of arsenic in the body after injection of rabbits with phenylarsenoxide, mapharsen (m-anmino-p-hydroxyphenylarsenoxide) and the corresponding arsenic acids was described. At the same time as these experiments, others were done in which the effect of BAL on the clearance of the two arsenoxides fronm the body was studied, but it has not hitherto been possible to publish the results of the latter. A brief account of the work with BAL is given below. It should be noted that it had to be terminated while still incomplete. EXPERIMENTAL AND RESULTS.The experimental procedure was described in detail in the previous paper [Chance et al., 1945]. BAL was injected subcutaneously as a 5 per cent. (w/v) solution in peanut oil, the dosage being 30 mg./kg. in all cases. Doses of the arsenicals, which were injected intravenously, are given in Table I in terms of elemental arsenic. The table shows the amounts of arsenic in the urine and fieces, expressed as ,ug.As excreted for each mg. As injected. When the animals were sacrificed at the end of the seventh day, the lung, liver, kidneys and gall-bladder were analysed for arsenic. Since, at the most, only traces of arsenic were present, the results are not given in detail. Fig. 1 shows the cumulative daily excretion of arsenic in the urine in experiments 25 to 28. For comparison, figures from the previous paper for the excretion of arsenic in the urine after the injection of a similar dose of each arsenoxide, but in absence of BAL, are also plotted.
The work described in this paper was carried out on behalf of the Ministry of Supply, and preliminary accounts of it were circulated by the Ministry in 1943 and early in 1944. A quantitative investigation was made of various factors concerned in the disappearance of arsenic from the skin after the application of an arsenical vesicant. These factors determine the severity of the local and systemic effects caused by a given amount of a vesicant. Phenyldichloroarsine and lewisite I (,-chlorovinyldichloroarsine) were studied, using rabbits as experimental animals. The amount of arsenic removed from the skin by absorption into the general circulation or evaporation of the vesicant, and the fraction of the residual arsenic which was fixed by combination with skin constituents, were determined at varying periods after applying the vesicant. The effect of varying the amount of vesicant applied to a given area of skin was examined. Stocken & Thompson (1946) had previously found that BAL (British Anti-Lewisite, 2:3-dimercaptopropanol) diminished the amount of arsenic remaining in the skin of rats 48 hr. after contamination with lewisite. Experiments were done to discover the way in which BAL modifies the fate of arsenical vesicants in the skin.EXPERIMENTAL General method8 The vesicants (obtained from the Ministry of Supply) were purified by distillation in vacuo. They were applied to the skin as freely falling drops, measured from the 'burette' devised by Lane (1946) or from the modification of this instrument developed by Levvy (1946). The amounts of liquid to be measured were so very small that they could be delivered accurately only in the form of discrete drops. In using Lane's instrument, it was found convenient to retard the drop rate by applying a negative hydrostatic pressure to the column of vesicant. In experiments with phenyldichloroarsine, two different drop sizes were employed (5 and 0-5 mg.), and in the case of lewisite I, three (4.5, 0 5 and 0-133 mg.). The exact weight of the drop applied in an individual experiment was calculated from the readings given by the instrument at the time, and this figure was used in working out the results. For drops of any one magnitude, the range from experiment to experiment in the calculated figure for the weight was not more than 5% of the mean.The rabbits used ranged in weight from 2 to 3 kg. and were of both sexes. For treatment with the vesicant, an area of skin on the back was freed from fur by clipping closely with scissors. One or more circles, approximately 3 cm. in diameter, were drawn in Indian ink on the skin, as far apart as possible if there were more than one. One drop of vesicant was allowed to fall on to each of these marked out 'spots'. In some cases the spot was immediately covered with a glass vessel, 2 cm. in diam. and 1 cm. in depth, which was firmly attached to the skin with adhesive plaster. Open glass cylinders of the same dimensions were secured to spots which were to be left uncovered so as to prevent the animal from removing the vesicant. The an...
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