- Email: [email protected]
THE BIOLOGICAL ESTIMATION OF TOXICITY.
567 as
the best for infants.
In adults
lipo-vaccines
tute of Medical Research.
The task has been found
(e.g., oily suspensions of streptococci or pneumococci) unexpectedly complex. The determination as to may be administered through a fine curved cannula what shall be regarded as a lethal dose is the first inserted into the trachea, the dosage being similar step-shall it be one which kills any animal, every to that recommended for hypodermic administration. animal, or some intermediate proportion ? Again, Dr. Rosenthal concludes that while vaccine therapy even when a characteristic curve relating doses of has long passed the experimental stage in the treat- the standard preparation to death-rate in mice had ment of broncho-pneumonia, the problem of the been determined, how could a test be devised that best composition of vaccines has yet to be solved, would discriminate sharply between those samples
and this must involve much further work on the which conformed to the standard within reasonable part played by various organisms in pulmonary limits-say, 20 per cent.-and those whose toxicity inflammations. Meanwhile he maintains that ignor- was still higher ? The work was further complicated ance and sloth alone are responsible for the prevalent not only by the suspicion of variations in sensitiveness individual animals, but by the possibility neglect of therapeutic measures of the highest value. between of variations due to age, strain, parentage, dietetic history, sexual development, seasonal changes, and sex. Not even weight could be excluded, though THE BIOLOGICAL ESTIMATION OF TOXICITY. the test dosage given was in milligrammes per THE assumption that the efficacy of organic arsenical gramme weight of the experimental animals, for it preparations varies directly with their toxicity has was discovered that small immature mice had more its origin in the circumstances which followed the resistance than mature ones, whose resistance production in this country, during and after the diminished only up to a certain age. It was found eventually that errors could be to war, of batches of novarsenobenzene (neosalvarsan). It will be remembered that British manufacturers some extent eliminated by choosing mice within found the details set out in the patent specificationsI narrow limits of body-weight-between 18 and 20 g.to be inadequate, and had to rely on the ingenuity of the same strain and kept and fed under similar These precautions having been taken, of their technical advisers to supplement them. At conditions. the request of the Board of Trade the Medical Research various samples were tested for toxicity against the Council devised biological tests to ensure that the standard preparations, and an investigation into the products on the market were suitable for clinical tests in current use in various countries was made. use. After various experiments, an empirical basis The British test hitherto performed is criticised as for testingwas found. Only such batches were lacking sharp discrimination, since of batches 50 per passed as were tolerated by at least four out of five cent. more toxic than the standard only two-thirds mice in an intravenous dose of 0-3 mg. per gramme of the samples are rejected. The German test involves The .of body-weight. Using this method it was dis- an inconveniently large number of mice. - covered that the preparations submitted for testing Japanese test is more lenient than either, but this fell into two well-marked groups. One group leniency is neutralised if, as Prof. Hata, of Tokyo, resembled the original German product in appear- believes, the Japanese mice have a lower resistance ance, solubility, lack of stability when exposed to than European strains. The official American test air, and toxicity. The other group was much more is on rats and not on mice. In the light of all soluble and stable and far less toxic, and for all these this information the onerous task of framing an The final demand reasons achieved a popularity with practitioners improved test was undertaken. which became disturbing when reports began to of this new test is for a survival of at least 50 per cent. of 30 mice weighing 18 to 20 g. injected with mome in from reliable sources criticising the potency of the material. A test for therapeutic efficacy then 7-6 mg. per mouse of the sample under examination. became necessary and was adapted from one developed The test is conducted in three stages, so that those The substances were injected into the samples which are practically certain of acceptance n America. veins of mice experimentally infected with the or rejection are eliminated after the preliminary test trypanosome T. equiperdum, the minimum curative on ten mice ; thus as many as 30 mice are needed dose being arbitrarily fixed as that which caused only for the doubtful samples submitted to further disappearance of the organisms from the circulating test. Since the details of this method were worked blood at a period of 72 hours after the injection. out, the International Conference held at Frankfort By this means it was found that the more stable, in 1928 has agreed to recommend a 20 per cent. less toxic batches of material were inferior in thera- excess of toxicity as the limit of tolerance. This is a peutic value to the older preparations. Clinical trials standard less rigid than was contemplated, but can be met by altering the dose given to each mouse from on syphilitic patients with surface lesions confirmed the results obtained on mice. The manufacturers were for- 7-6 mg. to 7-2 mg. Emphasis is laid on the fact that the tunately able to remedy the defect when their atten- true function of the international standard preparation was called to it, but the variations made obvious tion is to test the sensitiveness of the mice which the desirability, which has since been confirmed, of are being used to assess unknown samples, and to imposing an official control of potency as well as provide a basis of comparison between the effects of freedom from toxicity. Meanwhile the creation of of tests carried out on different species of animals. internationally valid standards under the direction Finally, in a note on the need for a therapeutic test, of the Health Organisation of the League of Nations it is recorded that one batch of material of such high has ensured that a substance of uniform strength toxicity that it would not have passed any test was and toxicity is available for comparison. The Inter- found to have very small therapeutic activity. The national Conference on Biological Standards, which conclusion is that while toxicity and efficacy may met in Geneva in September, 1925, laid down tests show a certain parallelism within a limited range of for potency and toxicity, but was unable to prescribe samples of a particular manufacture, it is still iiecesthe limits of permissible variation from normal sary to maintain independent tests for both properties values, since evidence as to the accuracy with in relation to a common standard. which either property could be estimated was lacking. The fact that this intricate work is concerned only An attempt to furnish this evidence as regards the with the toxicity of one preparation shows what toxicity of one substance, novarsenobenzene, has difficulties lie in the way of a controlled pharmaIt has hitherto resembled now been made, under the general direction of Dr. cology of biologicals. H. H. Dale, by a group of workers2 in the Depart- the Carrollian game of croquet where flamingoes as ment of Biological Standards of the National Insti- mallets hit hedgehog balls which have been only too
1 THE LANCET. 1922, i., 779. 2 Special Report Series, No. 128. Reports on Biological Standards, II. Toxicity Tests for Novarsenobenzene (Neosalvarsan). By Florence M. Durham, J. H. Gaddum, and J. E.
Marchal. H.M. Stationery Office. Pp. 40.
9d.
likely to influence the direction of motion by The business of eliminating own individuality. or allowing for the variables is well in hand, and provided that the game is not required to be played on the old system of rules, there is no reason why their
568 it should not be organised on a plan that all nations Miss Durham and her colleagues have can follow. made a valuable contribution to this end.
STERILITY IN WOMEN. THE haphazard methods generally employed for the relief of sterility are rapidly being replaced by scientific investigation and rational treatment. It is essential that the medical man should be able to advise his patients from accurate knowledge of the character of the operation required, the prospect of pregnancy following such an operation, and the entailed. To the principals the unavoidable ofrisk the operation depends on their desire importance to become parents and it is only right that a fair statement of the prospects should be laid before them. Henry Schmitz has lately made a careful survey of the literature of this subject, and though his paper contains no original work, his analysis of 118 papers is certainly worthy of notice. He points out that salpingography was first practised by W. H. Cary who described his method in 1914. After this, little seems to have been done until 1. C. Rubin in 1920 published his results of tubal inflation by means of oxygen. Since then, methods of filling the tubes with opaque substances have been revived. Lipiodol, the substance now most commonly employed on account of its harmless properties, was introduced
scheme of study which he would be prepared to undertake and his itinerary should stimulate the applicant to the intensive study of different aspects of preventive medicine, while successful applicants will have a splendid opportunity of playing their part in helping towards that international reciprocity in medicine, the value of which, and, indeed, whose advent depends upon the clear vision and practical work of its votaries. Applications should be made by letter before March 25th to the clerk of the Chadwick Trustees, 204, Abbey House, Westminster, a
London, S.W.1, stating name, qualifications, age, and proposed object of study or research accompanied by copies of testimonials and evidence of
previous
work undertaken
or
published.
THE next social evening at the Royal Society of Medicine will be held on Wednesday, March 20th, when the President and Lady Dawson will receivethe guests at the Society’s house in Wimpole-street. The reception will begin at 8.30 P.M., and at 9.15 Dr. Leonard Williams will give an illustrated address on
Napoleon III.
____
THE Minister of Health of the National Government of the Republic of China, Hsueh-Tu-Pi, has invited Sir Arthur Newsholme, Dr. Louis Rajchman, Secretary of the League of Nations Health Organisation, and to gynaecological practice in 1925 by Sidney Foradike Dr. Victor G. Heiser, of the United States Public who has shown that it is absorbed from the peritoneal Health Service, to form an International Advisory cavity without producing any reaction. Some of Council to assist his Ministry. the most recent work in this country is to be found in his book, " Sterility in Women," which gives a clear account of the information to be got by the to record the death of Viscount Finlay intelligent use of gas for inflation of the Fallopian of WE regret British member of the Permanent Court Nairn, tubes and the radiographic evidence obtainable by the injection of lipiodol into the uterus. Schmitz of Arbitration at The Hague, and sometime Lord finds that in 371 cases of salpingostomy reported by Chancellor of England. The eldest son of William 13 authors, pregnancy supervened in about 8-4 per Finlay, F.R.C.P., of Edinburgh, he followed at first cent. He lays stress on the fact that if there is to his father’s profession and graduated in medicine be any hope of success the mucosa of the tube must at Edinburgh University before being called to the be intact. The treatment in these d71 cases seems to Bar in 1867. The viscounty descends to his only include every type of plastic operation on the tube, son, Sir William Finlay, judge of the High Court of and we suggest that when the operation consists Justice. merely of freeing adhesions and opening out intact THE Thirteenth International Congress of Ophthalfimbriae, some word other than salpingostomy should be used to describe it. Forsdike thinks that the mology will be held at Amsterdam and The Hague prospect of patency being maintained is poor if the from Sept. 5th to 13th. The main subjects of disoperation involves more interference than this. cussion will be the Etiology and Non-operative Cases of pregnancy following resection and reimplanta- Treatment of Glaucoma, the International Campaign tion of a tube into the uterus are quoted, but probably against Trachoma, and the Diagnosis of Suprasellar this operation is very rarely successful. Both Forsdike Tumours, whilst among other topics to be reported and Schmitz mention the occurrence of pregnancy on are methods of examining visual acuity, perimetry, I after the grafting of the ovaries into the uterine determination of axis in astigmatism, examination of the sense of light, standardisation of rules for the cornua but neither gives any opinion on the value of examination of railway employees and other workers, the operation. During the next few years further advances will and the ophthalmological study necessary for physicians and specialists. Besides the official sessions no doubt be made in the investigation and treatment of sterility. It is to be hoped that accurate statistics and receptions a programme has been arranged of all cases treated and the clinical details of the allowing for excursions and sight-seeing. The secreoperative procedure will be given, as well as a record tary of the Dutch National Committee is Prof. W. P. C. Z3eman, Wilhelminagasthuis, Amsterdam. of subsequent pregnancies. ____
TRAVELLING SCHOLARSHIPS. WOMEN’S HoSPITALS.-The erection of the new THE Chadwick Trustees are inviting applications Joint Hospital for Women at Liverpool, towards the cost of for two travelling scholarships of MOO a year tenable which .8101,000 has been subscribed, will shortly be begun.for one year to be awarded next July, one in sanitary Redlands Hospital for Women (the Glasgow Women’s Private Hospital), which is staffed and managed by women, science and the other in municipal engineering. The last year treated 557 patients, and is in serious need of candidates must be British subjects between the ages extension. of 25 and 30 who have graduated in a British univerWESTERN OPHTHALMIC HOSPITAL.-At the first sity. These facts have already been announced in our columns, and it may be well to indicate that annual meeting in the new premises in Broad-street, scholarships to enable students and post-graduates Holborn, held last week, it was stated that, the new hospital to obtain wider knowledge conducive to international being nearly thrice the size of the old one, the cost of mainbe almost trebled and would amount to relations in medical science are all too few, so that the tenance awould at least. About .6120,000 had been raised, .820,000 year the Chadwick Trustees by opportunity presented but to clear off debt and provide for the increased cost of to members of younger should make a wide appeal working a further 1:50,000 was needed. The Guild of the medical profession. The fact that the applicant Gratitude, formed two years ago by the out-patients, is required to submit for the approval of the Trustees numbering 11,000 members, has collected B2500.
the best for infants.
In adults
lipo-vaccines
tute of Medical Research.
The task has been found
(e.g., oily suspensions of streptococci or pneumococci) unexpectedly complex. The determination as to may be administered through a fine curved cannula what shall be regarded as a lethal dose is the first inserted into the trachea, the dosage being similar step-shall it be one which kills any animal, every to that recommended for hypodermic administration. animal, or some intermediate proportion ? Again, Dr. Rosenthal concludes that while vaccine therapy even when a characteristic curve relating doses of has long passed the experimental stage in the treat- the standard preparation to death-rate in mice had ment of broncho-pneumonia, the problem of the been determined, how could a test be devised that best composition of vaccines has yet to be solved, would discriminate sharply between those samples
and this must involve much further work on the which conformed to the standard within reasonable part played by various organisms in pulmonary limits-say, 20 per cent.-and those whose toxicity inflammations. Meanwhile he maintains that ignor- was still higher ? The work was further complicated ance and sloth alone are responsible for the prevalent not only by the suspicion of variations in sensitiveness individual animals, but by the possibility neglect of therapeutic measures of the highest value. between of variations due to age, strain, parentage, dietetic history, sexual development, seasonal changes, and sex. Not even weight could be excluded, though THE BIOLOGICAL ESTIMATION OF TOXICITY. the test dosage given was in milligrammes per THE assumption that the efficacy of organic arsenical gramme weight of the experimental animals, for it preparations varies directly with their toxicity has was discovered that small immature mice had more its origin in the circumstances which followed the resistance than mature ones, whose resistance production in this country, during and after the diminished only up to a certain age. It was found eventually that errors could be to war, of batches of novarsenobenzene (neosalvarsan). It will be remembered that British manufacturers some extent eliminated by choosing mice within found the details set out in the patent specificationsI narrow limits of body-weight-between 18 and 20 g.to be inadequate, and had to rely on the ingenuity of the same strain and kept and fed under similar These precautions having been taken, of their technical advisers to supplement them. At conditions. the request of the Board of Trade the Medical Research various samples were tested for toxicity against the Council devised biological tests to ensure that the standard preparations, and an investigation into the products on the market were suitable for clinical tests in current use in various countries was made. use. After various experiments, an empirical basis The British test hitherto performed is criticised as for testingwas found. Only such batches were lacking sharp discrimination, since of batches 50 per passed as were tolerated by at least four out of five cent. more toxic than the standard only two-thirds mice in an intravenous dose of 0-3 mg. per gramme of the samples are rejected. The German test involves The .of body-weight. Using this method it was dis- an inconveniently large number of mice. - covered that the preparations submitted for testing Japanese test is more lenient than either, but this fell into two well-marked groups. One group leniency is neutralised if, as Prof. Hata, of Tokyo, resembled the original German product in appear- believes, the Japanese mice have a lower resistance ance, solubility, lack of stability when exposed to than European strains. The official American test air, and toxicity. The other group was much more is on rats and not on mice. In the light of all soluble and stable and far less toxic, and for all these this information the onerous task of framing an The final demand reasons achieved a popularity with practitioners improved test was undertaken. which became disturbing when reports began to of this new test is for a survival of at least 50 per cent. of 30 mice weighing 18 to 20 g. injected with mome in from reliable sources criticising the potency of the material. A test for therapeutic efficacy then 7-6 mg. per mouse of the sample under examination. became necessary and was adapted from one developed The test is conducted in three stages, so that those The substances were injected into the samples which are practically certain of acceptance n America. veins of mice experimentally infected with the or rejection are eliminated after the preliminary test trypanosome T. equiperdum, the minimum curative on ten mice ; thus as many as 30 mice are needed dose being arbitrarily fixed as that which caused only for the doubtful samples submitted to further disappearance of the organisms from the circulating test. Since the details of this method were worked blood at a period of 72 hours after the injection. out, the International Conference held at Frankfort By this means it was found that the more stable, in 1928 has agreed to recommend a 20 per cent. less toxic batches of material were inferior in thera- excess of toxicity as the limit of tolerance. This is a peutic value to the older preparations. Clinical trials standard less rigid than was contemplated, but can be met by altering the dose given to each mouse from on syphilitic patients with surface lesions confirmed the results obtained on mice. The manufacturers were for- 7-6 mg. to 7-2 mg. Emphasis is laid on the fact that the tunately able to remedy the defect when their atten- true function of the international standard preparation was called to it, but the variations made obvious tion is to test the sensitiveness of the mice which the desirability, which has since been confirmed, of are being used to assess unknown samples, and to imposing an official control of potency as well as provide a basis of comparison between the effects of freedom from toxicity. Meanwhile the creation of of tests carried out on different species of animals. internationally valid standards under the direction Finally, in a note on the need for a therapeutic test, of the Health Organisation of the League of Nations it is recorded that one batch of material of such high has ensured that a substance of uniform strength toxicity that it would not have passed any test was and toxicity is available for comparison. The Inter- found to have very small therapeutic activity. The national Conference on Biological Standards, which conclusion is that while toxicity and efficacy may met in Geneva in September, 1925, laid down tests show a certain parallelism within a limited range of for potency and toxicity, but was unable to prescribe samples of a particular manufacture, it is still iiecesthe limits of permissible variation from normal sary to maintain independent tests for both properties values, since evidence as to the accuracy with in relation to a common standard. which either property could be estimated was lacking. The fact that this intricate work is concerned only An attempt to furnish this evidence as regards the with the toxicity of one preparation shows what toxicity of one substance, novarsenobenzene, has difficulties lie in the way of a controlled pharmaIt has hitherto resembled now been made, under the general direction of Dr. cology of biologicals. H. H. Dale, by a group of workers2 in the Depart- the Carrollian game of croquet where flamingoes as ment of Biological Standards of the National Insti- mallets hit hedgehog balls which have been only too
1 THE LANCET. 1922, i., 779. 2 Special Report Series, No. 128. Reports on Biological Standards, II. Toxicity Tests for Novarsenobenzene (Neosalvarsan). By Florence M. Durham, J. H. Gaddum, and J. E.
Marchal. H.M. Stationery Office. Pp. 40.
9d.
likely to influence the direction of motion by The business of eliminating own individuality. or allowing for the variables is well in hand, and provided that the game is not required to be played on the old system of rules, there is no reason why their
568 it should not be organised on a plan that all nations Miss Durham and her colleagues have can follow. made a valuable contribution to this end.
STERILITY IN WOMEN. THE haphazard methods generally employed for the relief of sterility are rapidly being replaced by scientific investigation and rational treatment. It is essential that the medical man should be able to advise his patients from accurate knowledge of the character of the operation required, the prospect of pregnancy following such an operation, and the entailed. To the principals the unavoidable ofrisk the operation depends on their desire importance to become parents and it is only right that a fair statement of the prospects should be laid before them. Henry Schmitz has lately made a careful survey of the literature of this subject, and though his paper contains no original work, his analysis of 118 papers is certainly worthy of notice. He points out that salpingography was first practised by W. H. Cary who described his method in 1914. After this, little seems to have been done until 1. C. Rubin in 1920 published his results of tubal inflation by means of oxygen. Since then, methods of filling the tubes with opaque substances have been revived. Lipiodol, the substance now most commonly employed on account of its harmless properties, was introduced
scheme of study which he would be prepared to undertake and his itinerary should stimulate the applicant to the intensive study of different aspects of preventive medicine, while successful applicants will have a splendid opportunity of playing their part in helping towards that international reciprocity in medicine, the value of which, and, indeed, whose advent depends upon the clear vision and practical work of its votaries. Applications should be made by letter before March 25th to the clerk of the Chadwick Trustees, 204, Abbey House, Westminster, a
London, S.W.1, stating name, qualifications, age, and proposed object of study or research accompanied by copies of testimonials and evidence of
previous
work undertaken
or
published.
THE next social evening at the Royal Society of Medicine will be held on Wednesday, March 20th, when the President and Lady Dawson will receivethe guests at the Society’s house in Wimpole-street. The reception will begin at 8.30 P.M., and at 9.15 Dr. Leonard Williams will give an illustrated address on
Napoleon III.
____
THE Minister of Health of the National Government of the Republic of China, Hsueh-Tu-Pi, has invited Sir Arthur Newsholme, Dr. Louis Rajchman, Secretary of the League of Nations Health Organisation, and to gynaecological practice in 1925 by Sidney Foradike Dr. Victor G. Heiser, of the United States Public who has shown that it is absorbed from the peritoneal Health Service, to form an International Advisory cavity without producing any reaction. Some of Council to assist his Ministry. the most recent work in this country is to be found in his book, " Sterility in Women," which gives a clear account of the information to be got by the to record the death of Viscount Finlay intelligent use of gas for inflation of the Fallopian of WE regret British member of the Permanent Court Nairn, tubes and the radiographic evidence obtainable by the injection of lipiodol into the uterus. Schmitz of Arbitration at The Hague, and sometime Lord finds that in 371 cases of salpingostomy reported by Chancellor of England. The eldest son of William 13 authors, pregnancy supervened in about 8-4 per Finlay, F.R.C.P., of Edinburgh, he followed at first cent. He lays stress on the fact that if there is to his father’s profession and graduated in medicine be any hope of success the mucosa of the tube must at Edinburgh University before being called to the be intact. The treatment in these d71 cases seems to Bar in 1867. The viscounty descends to his only include every type of plastic operation on the tube, son, Sir William Finlay, judge of the High Court of and we suggest that when the operation consists Justice. merely of freeing adhesions and opening out intact THE Thirteenth International Congress of Ophthalfimbriae, some word other than salpingostomy should be used to describe it. Forsdike thinks that the mology will be held at Amsterdam and The Hague prospect of patency being maintained is poor if the from Sept. 5th to 13th. The main subjects of disoperation involves more interference than this. cussion will be the Etiology and Non-operative Cases of pregnancy following resection and reimplanta- Treatment of Glaucoma, the International Campaign tion of a tube into the uterus are quoted, but probably against Trachoma, and the Diagnosis of Suprasellar this operation is very rarely successful. Both Forsdike Tumours, whilst among other topics to be reported and Schmitz mention the occurrence of pregnancy on are methods of examining visual acuity, perimetry, I after the grafting of the ovaries into the uterine determination of axis in astigmatism, examination of the sense of light, standardisation of rules for the cornua but neither gives any opinion on the value of examination of railway employees and other workers, the operation. During the next few years further advances will and the ophthalmological study necessary for physicians and specialists. Besides the official sessions no doubt be made in the investigation and treatment of sterility. It is to be hoped that accurate statistics and receptions a programme has been arranged of all cases treated and the clinical details of the allowing for excursions and sight-seeing. The secreoperative procedure will be given, as well as a record tary of the Dutch National Committee is Prof. W. P. C. Z3eman, Wilhelminagasthuis, Amsterdam. of subsequent pregnancies. ____
TRAVELLING SCHOLARSHIPS. WOMEN’S HoSPITALS.-The erection of the new THE Chadwick Trustees are inviting applications Joint Hospital for Women at Liverpool, towards the cost of for two travelling scholarships of MOO a year tenable which .8101,000 has been subscribed, will shortly be begun.for one year to be awarded next July, one in sanitary Redlands Hospital for Women (the Glasgow Women’s Private Hospital), which is staffed and managed by women, science and the other in municipal engineering. The last year treated 557 patients, and is in serious need of candidates must be British subjects between the ages extension. of 25 and 30 who have graduated in a British univerWESTERN OPHTHALMIC HOSPITAL.-At the first sity. These facts have already been announced in our columns, and it may be well to indicate that annual meeting in the new premises in Broad-street, scholarships to enable students and post-graduates Holborn, held last week, it was stated that, the new hospital to obtain wider knowledge conducive to international being nearly thrice the size of the old one, the cost of mainbe almost trebled and would amount to relations in medical science are all too few, so that the tenance awould at least. About .6120,000 had been raised, .820,000 year the Chadwick Trustees by opportunity presented but to clear off debt and provide for the increased cost of to members of younger should make a wide appeal working a further 1:50,000 was needed. The Guild of the medical profession. The fact that the applicant Gratitude, formed two years ago by the out-patients, is required to submit for the approval of the Trustees numbering 11,000 members, has collected B2500.