A TOXICOLOGICAL STUDY OF SOME ALCOHOLS, WITH ESPECIAL REFERENCE TO ISOMERS

Transcription

1 A TOXICOLOGICAL STUDY OF SOME ALCOHOLS, WITH ESPECIAL REFERENCE TO ISOMERS DAVID I. MACHT From the Pharmacological Laboratory, the Johns Hopkins University Received for publication May 25, 1920 The comparative pharmacological, and, more particularly, toxicological, properties of various alcohols have been the sub-. ject of investigations on the part of many authors. The work on the subject has, for the most part, been confined to the first five members of the aliphatic series, and almost entirely to the primary alcohols in the cases in which several isomers are known. The most significant and important observation on the comparative pharmacology of these alcohols was made as early as Richardson, in 1869, stated, in the Medical Times and Gazette, volume 2, page 705, that the toxicity of the alcohols belonging to the fatty acid series increased in proportion to their molecular weight. This observation, known as Richardson s law, has been confirmed and amplified by all the later observers. Among the most important investigators along these lines may be mentioned Dujardin-Baumetz (1), Joifroy and Servaux (2), Picaud (3), and Baer (4), who studied the comparative lethal doses; while Efron (5), Schneegans and v. Mering (6), Breyer (7), Dold (8), Kuno (9) and others investigated the effects of the various alcohols on special organs. Dujardin-Baumetz and Audige found the toxicity of ethyl, propyl, butyl and amyl alcohols to be in the ratio of 1.0, 2.0, 4.2 and 5.2, respectively. According to these authors, the toxicity of methyl alcohol was found to be about the same or slightly higher than that of ethyl. Most authors, however, find that in acute experiments methyl alcohol is less poisonous than ethyl alcohol. Thus, Joifroy found the relation between 1 THE JOUR. OP PHARM. AND EXPER. THERAP., VOL. XVI, NO. 1

2 2 DAVID I. MACHT the lethal doses of alcohol-methyl, ethyl, propyl, butyl and amyl-to be expressed by the ratios 0.46, 1.0, 3.5, 8.0 and Picaud gives the following figures for the same relationship: 0.66, 1.0, 1.0, 3.0 and According to Baer, the ratios are s follows: 0.8, 1.0, 2.0, 3.0 and 4.0. It will be noted that according to the last three authors, the toxicity of the various alcohols increases in proportion to their molecular weight. The actual figures obtained by various observers are different, according to the methods of administration. Some injected the drugs intravenously, which is, on the whole, the most satisfactory method I 4 mmtnmvn #{163}ystIe I- S731 e,7e 7- FIG. 1. FROG S HEART SUSPENSION PREPARATION A, Perfusion with propyl alcohol 1 per cent in Locke; B, perfusion with isopropyl alcohol 1 per cent in Locke. of studying the lethal doses for acute toxic experiments. This is the method, as is well known, now employed for standardizing the digitalis bodies. Dujardin-Baumetz found the same relation-. ship to hold good after administering the alcohols by stomach. Efron (1885) studied the pharmacological action of the various alcohols on nerve and muscle. This author found that Richardson s law applies also to the behavior of these organs. All the alcohols produce a more or less marked primary excitation, followed by paralysis, and the relative toxicity increases with the molecular weight. Schneegans and v. Mering found the

3 TOXICOLOGICAL STUDY OF SOME ALCOHOLS 3 narcotic action of the various alcohols to follow more or less Richardson s law. Picaud studied the effects of various alcohols on fishes, amphibians and other animals. Dold studied the comparative effects of the various alcohols on the frog s heart, while Hermeter investigated the effects of the same on the mammalian heart. All these authors found a relationship between the toxicities to be very much in accordance with Richardson s earlier observations. Further work by Kuno on mam- FIG. 2. FROG S HEART SUSPENSION PREPARATION N, Normal contractions; systole, down; lb., isobutyl alcohol 0.5 per cent; B, butyl alcohol 0.5 per cent. malian hearts, by Breyer 011 motor nerves and ciliated epithelium, by F#{252}hner (10) on the eggs of the sea-urchin, by Blumenthal (11), and by Verzar (12), all corroborated, broadly speaking, the original law enunciated by Richardson. The chief exception noted was that by Blumenthal, who claimed that methyl alcohol is more poisonous than ethyl. Many other interesting pharmacological facts concerning the various alcohols may be found in Professor Abel s monograph on the subject (13).

4 4 DAVID I. MACHT a L Q I-. L 0 II c. - a 0H a z H I- a 0. a H a r -

5 TOXICOLOGICAL STUDY OF SOME ALCOHOLS 5 While the comparative physiological effects of the primary, or normal, alcohols have been studied extensively, very little, indeed, is known concerning the pharmacological action of the secondary alcohols. The present author became interested in this subject in connection with a study of isopropyl alcohol, which he has undertaken at the suggestion of Prof. Ira Remsen. In order to obtain a comprehensive idea of the toxicological effects of isopropyl alcohol, the author made experiments with primary alcohols, on the one hand, and secondary alcohols, on the other. The compounds studied were the following: Methyl alcohol, ethyl alcohol, propyl alcohol, isopropyl alcohol, butyl alcohol, isobutyl alcohol, amyl alcohol, isoamyl alcohol, and, to some extent also, benzyl alcohol. The first investigation undertaken by the author was to determine the lethal doses of the various alcohols. For this purpose the cat method was employed. This method, which is extensively followed for the testing of various drugs, is now recognized as the most convenient method of assaying digitalis and other heart drugs. It consists, briefly, in injecting into the vein of a cat, under light ether anesthesia, at regular intervals of time, a solution of the drug to be tested. The amount of the drug necessary to kill the cat, expressed in terms of its weight, is the lethal dose. In performing the experiment, care is taken to note the form of death produced-whether through paralysis of the heart, paralysis of the respiratory center, etc. It was found, on testing methyl, ethyl, propyl, butyl, and amyl alcohols, that their toxicity increased, broadly speaking, with their molecular weight. In other words, Richardson s law was found to hold good. In the experiments performed, 1 and 5 per cent solution of the various alcohols were made in physiological saline, and injected rather rapidly, but at regular intervals of time (2 cc. per minute). The figures obtained are shown in the subjoined table. It will be noted that while the absolute fatal doses may be different from those obtained by other authors (due to the rapidity of administration and concentration of the solution), Richardson s law was confirmed completely.

6 6 DAVID 1. MACHT Following the injections of the primary alcohols just mentioned, the lethal dosage of the secondary alcohols was determined by the same method, and the figures compared with those obtained in case of the normal propyl, butyl and amyl alcohols. It was found, in case of the three groups of isomers, that the primary or normal alcohols were always more toxic than the secondary, or the isopropyl, isobutyl and isoamyl alcohols. After studying the lethal dosage of the various compounds mentioned above, a comparative study of their solutions on the isolated frog s heart was undertaken. It was interesting to find that on this isolated organ Richardson s law held good, and, TABLE I ALCOHOL CONCENTRATION INJECTED LETHAL KflO DOSE WEIGHT LETHAL DOSE RATIO IN TERMS ETHYL ALCOHOL per cent cc. cc. Methyl Ethyl Propyl Butyl Amy! Isopropyl Isobutyl Isoamyl Benzy! furthermore, that in every case the normal alcohols were more toxic than the secondary ones, as illustrated by the curves. In order to test the curious relationship between the normal and secondary alcohols further, observations were made on their action on isolated plain muscle. It was found that in case of the ureter, which, in many respects, as has been shown by the author elsewhere, is the most convenient smooth muscle organ for quantitative comparisons, the same relationship held good (14). In every case the primary alcohol paralyzed the smooth muscle more quickly than the secondary ones. Inasmuch as the author was especially interested in the properties of isopropyl alcohol, some special studies were made

7 TOXICOLOGICAL STUDY OF SOME ALCOHOLS 7 with that compound. The toxicity of isopropyl alcohol through inhalation was compared with that of methyl and ethyl alcohols. This was studied on rats. The animals were confined in a chamber containing an open vessel, suitably screened off, filled with the above alcohols, so that the air of the chamber was saturated with their fumes. It was found that methyl alcohol quickly killed the rats, the latter succumbing in a day or two. LtLUJkLLLL A FIG. 4. PIG s URETER NP., Normal propyl alcohol 1:500; IF., isopropyl alcohol 1:C0 Ethyl alcohol proved also fatal to the animals, after exposure to its fumes for several days in a warm room. Rats confined in a chamber containing an open vessel with isopropyl alcohol, in a wtarin room, were very little affected, and were found to be apparently in normal health after a week s exposure. No blindness or defects in vision were noted after exposure of the rats to the fumes of isopropyl alcohol in these experiments. The peculiar relationship between the primary and secondary alcohols noted by the author has not been described elsewhere.

8 8 DAVID I. MACHT It is interesting to note, however, that the properties of one of the isomers, namely, isopropyl alcohol, have been investigated by Efron. That author found that isopropyl alcohol is less depressant that the normal propyl alcohol for nerve fibers, and his observations harmonize with the findings of the present investigation. It will be seen that a comparative study of the various alcohols reveals the fact, on the one hand, that their toxicity increases jv.j3. #{182}6 L. fl I.(. I $ $ $3 $ 3 343$ 33333,, $ $ $1 I $ I $ 3$ $ $ $ $ $ $ $ $ Fio. 5. Pic s URETER N.B., Norma! butyl alcohol 1 per cent, paralyzed after three closes 1 cc. each in 30 cc. Locke. No response to epinephrin after that. lb., Isobutyl alcohol 1 per cent, contraction inhibited after 4 cc. but still revived by epinephrin. with their molecular weight, and, on the other hand, that the normal propyl, butyl and arnyl alcohols are more toxic than the isopropyl, isobutyl and isoamyl alcohols, as revealed by studies of the killing dose for cats, by experiments on isolated frog hearts, and by observations on the contractions of isolated plain muscle.

9 TOXICOLOGICAL STUDY OF SOME ALCOHOLS 9 Furthermore, it should be noted that the lethal (loses obtained in this investigation are those for acute intoxications. This is important to bear in mind in connection, especially, with wood alcohol. Methyl alcohol is known to be extremely poisonous, and is regarded as a more violent poison than grain alcohol. This is true only in respect to its remote effects, as commonly seen when it is taken by mouth. When introduced into the alimentary canal, wood alcohol acts not as such, but exerts its most deleterious effects through its decomposition products, jjjjjiftuljjjlumjjjujjjk ia L FIG. 6. PIG S URETER A., Amy! alcohol 1 per cent; l.a., isoaniyl alcohol 1 per cent especially formaldehyde and formic acid. It is these secondary products that render wood alcohol more poisonous than ethyl alcohol, when taken by mouth. When injected into the vein, however, and acting acutely upon the heart and the brain, methyl alcohol is considerably less toxic than ethyl alcohol. It is interesting to compare this difference between the immediate and remote or indirect effects of methyl alcohol with the immediate and secondary, or remote, effects of benzyl alcohol. Benzyl alcohol, which the present author has shown to be a

10 10 DAVID I. MACHP valuable local anesthetic, is a comparatively little toxic drug (15). The lethal dose of benzyl alcohol, as obtained by intravenous injections of its solutions, is, however, very much greater than the toxic dose of it, when administered even in pure form and undiluted by mouth. Indeed, the author has not been able to kill dogs by administering even large quantities of benzyl alcohol through the stomach tube. The difference between the intravenous and oral administrations of the drug is due to the metabolism of benzyl alcohol and its excretion in the form of hippuric acid, when taken by mouth. SUMMARY 1. The toxicity of the normal alcohols-methyl, ethyl, butyl and amyl-increases with their place in the aliphatic series, as indicated by the lethal dosage for cats, and by their effects on isolated frogs hearts and plain muscle preparations. 2. The secondary propyl, butyl and amyl alcohols were found to be less toxic than the corresponding primary alcohols. 3. In discussing the toxicity of alcohols, a distinction should l)e made between the acute or immediate, and the secondary or remote effects of the drugs, as is well illustrated by the studies on methyl and benzyl alcohols. REFERENCES (1) DtJJARDIN-BAUMETZ: Comp. R. Acad., 1875 and Also, Recherches experiinentales sur la puissance toxique des alcohols, Paris, (2) JOFFROY ET SERVAUX: Arch. d. Med. et d Anat. Path., 1895, vii, 569. (3) PicAun: Comp. R., 1897, cxxiv, 830. (4) BAER: Diss. 1erlin, (5) EFRON: Pfluger s Archiv, 1885, xxxvi, 467. (6) SCHNEEGANS AND V. MERLNG Therap. Monatsheft.e, 1892, 327. (7) BREYER: Pfluger s Archiv, xcix, 481. (8) D0LD: Pfluger s Archiv, 1906, cxii, 600. (9) KuNo: Arch. Exp. Path. u. Pharmakol., 1913, lxxiv, 399; 1914, lxxvii, 206. (10) FiJUNER: Arch. Exp. Path. u. Pharmakol., 1904, Ii, 1. (11) BLUMENTHAL: PfiUger s Archiv, 1896, lxxii, 513. (12) VERZAR: Pfluger s Archiv, 1909, cxxv, 398. (13) ABEL: Physiological Aspects of the Liquor Problem, ii, 1903, 1. (14) rv1.cht: Pharmacology of the Ureter. Numerous papers in Jour. Pharmacol. & Exp. Therap. (15) Micuv: Jour. Pharmacol. & Exp. Therap., 1918, xi, 263.