III.—Statistics.
§ 20. The number of deaths from poison (whether accidental, suicidal, or homicidal), as compared with other forms of violent, as well as natural deaths, possesses no small interest; and this is more especially true when the statistics are studied in a comparative manner, and town be compared with town, country with country.
The greater the development of commercial industries (especially those necessitating the use or manufacture of powerful chemical agencies), the more likely are accidents from poisons to occur. It may also be stated, further, that the higher the mental development of a nation, the more likely are its homicides to be caused by subtle poison—its suicides by the euthanasia of chloral, morphine, or hemlock.
Other influences causing local diversity in the kind and frequency of poisoning, are those of race, of religion, of age and sex, and the mental stress concomitant with sudden political and social changes.
In the ten years from 1883-1892, there appear to have died from poison, in England and Wales, 6616 persons, as shown in the following tables:—
DEATHS FROM POISON IN ENGLAND AND WALES DURING THE TEN YEARS 1883-92.
Although so large a number of substances destroy life by accident or design, yet there are in the list only about 21 which kill about 2 persons or above each year: the 21 substances arranged in the order of their fatality are as follows:—
| Actual deaths in ten years ending 1892. | |
|---|---|
| Caustic potash | 19 |
| Poisonous fungi | 23 |
| Aconite | 59 |
| Mercury | 60 |
| Belladonna | 76 |
| Sulphuric acid | 93 |
| Ammonia | 98 |
| Chlorodyne | 102 |
| Alcohol | 108 |
| Arsenic | 110 |
| Chloroform | 113 |
| Vermin-killer | 127 |
| Chloral | 127 |
| Phosphorus | 155 |
| Cyanide of potassium | 166 |
| Strychnine | 201 |
| Nitric acid | 204 |
| Prussic acid | 260 |
| Carbolic acid | 762 |
| Lead | 1043 |
| Opiates | 1324 |
In each decade there are changes in the position on the list. The most significant difference between the statistics now given and the statistics for the ten years ending 1880, published in the last edition of this work, is that in the former decade carbolic acid occupied a comparatively insignificant place; whereas in the ten years ending 1892, deaths from carbolic acid poisoning are the most frequent form of fatal poisoning save lead and opiates.
§ 21. The following table gives some German statistics of poisoning:—
TABLE SHOWING THE ADMISSIONS INTO VARIOUS MEDICAL INSTITUTIONS[30] IN BERLIN OF PERSONS SUFFERING FROM THE EFFECTS OF POISON DURING THE THREE YEARS 1876, 1877, 1878.
[30] Viz., the Königl. Charité, Allg. Städtisches Krankenhaus, Städtisches Baracken-Lazareth, Bethanien, St. Helwög’s-Lazarus, Elisabethen-Krankenhaus, Augusta Hospital, and the Institut für Staatsarzneikunde.
| Males. | Females. | Total. | |||
|---|---|---|---|---|---|
| Charcoal Vapour, | 77 | 78 | 155 | ||
| Sulphuric Acid, | 24 | 54 | - | 93 | |
| Hydrochloric Acid, | 4 | 4 | |||
| Nitric Acid, and Aqua Regia, | 7 | ... | |||
| Phosphorus, | 13 | 28 | 41 | ||
| Cyanide of Potassium, | 29 | 3 | - | 38 | |
| Prussic Acid, | 5 | 1 | |||
| Oxalic Acid, and Oxalate of Potash, | 11 | 8 | 19 | ||
| Alcohol, | 12 | 2 | 14 | ||
| Arsenic, | 7 | 5 | 12 | ||
| Morphine, | 8 | 1 | - | 12 | |
| Opium, | 2 | 1 | |||
| Potash or Soda Lye, | 2 | 6 | 8 | ||
| Chloral, | 3 | 4 | 7 | ||
| Chloroform, | 4 | 2 | 6 | ||
| Sewer Gas, | 5 | ... | 5 | ||
| Strychnine, | ... | 4 | 4 | ||
| Atropine, | 1 | 2 | 3 | ||
| Copper Sulphate, | 1 | 2 | 3 | ||
| Nitrobenzol, | 2 | ... | 2 | ||
| Carbolic Acid, | ... | 2 | 2 | ||
| Chromic Acid, | 1 | 1 | 2 | ||
| Burnt Alum, | ... | 1 | 1 | ||
| Ammonium Sulphide, | 1 | ... | 1 | ||
| Datura Stramonium, | ... | 1 | 1 | ||
| Petroleum, | ... | 1 | 1 | ||
| Benzine, | 1 | ... | 1 | ||
| Ether, | 1 | ... | 1 | ||
| Prussic Acid and Morphine, | 1 | ... | 1 | ||
| Prussic Acid and Chloral, | 1 | ... | 1 | ||
| Turpentine and Sal Ammoniac, | ... | 1 | 1 | ||
| 223 | 212 | 435 | |||
Suicidal Poisoning.—Poisons which kill more than one person suicidally each year are only 19 in number, as follows:—
In the ten years ending 1880, suicidal deaths from vermin-killers, from prussic acid, from cyanide of potassium, and from opiates were all more numerous than deaths from phenol, whereas at present phenol appears to be the poison most likely to be chosen by a suicidal person.
Criminal Poisoning.
§ 22. Some useful statistics of criminal poisoning have been given by Tardieu[31] for the 21 years 1851-1871, which may be summarised as follows:—
[31] Étude Médico-Légale sur l’Empoisonnement, Paris, 1875.
It hence may be concluded, according to these statistics of criminal poisoning, that of 1000 attempts in France, either to injure or to destroy human life by poison, the following is the most probable selective order:—
| Arsenic, | 331 |
| Phosphorus, | 301 |
| Preparations of Copper, | 183 |
| The Mineral Acids, | 54 |
| Cantharides, | 35 |
| Strychnine, | 14 |
| Opiates, | 12 |
| Mercurial preparations, | 9 |
| Antimonial preparations, | 6 |
| Cyanides (that is, Prussic Acid and Potassic Cyanide), | 5 |
| Preparations of Iron, | 5 |
This list accounts for 955 poisonings, and the remaining 45 will be distributed among the less used drugs and chemicals.
IV.—The Connection between Toxic Action and Chemical Composition.
§ 23. Considerable advance has been made of late years in the study of the connection which exists between the chemical structure of the molecule of organic substances and physiological effect. The results obtained, though important, are as yet too fragmentary to justify any great generalisation; the problem is a complicated one, and as Lauder Brunton justly observes:—
“The physiological action of a drug does not depend entirely on its chemical composition nor yet on its chemical structure, so far as that can be indicated even by graphic formula, but upon conditions of solubility, instability, and molecular relations, which we may hope to discover in the future, but with which we are as yet imperfectly acquainted.”[32]
[32] Introduction to Modern Therapeutics, Lond., 1892. 136.
The occurrence of hydroxyl, whether the substance belong to the simpler chain carbon series or to the aromatic carbon compounds, appears to usually endow the substance with more or less active and frequently poisonous properties, as, for example, in the alcohols, and as in hydroxylamine. It is also found that among the aromatic bodies the toxic action is likely to increase with the number of hydroxyls: thus phenol has one hydroxyl, resorcin two, and phloroglucin three; and the toxic power is strictly in the same order, for, of the three, phenol is least and phloroglucin most poisonous.
Replacing hydrogen by a halogen, especially by chlorine, in the fatty acids mostly produces substances of narcotic properties, as, for instance, monochloracetic acid. In the sulphur compounds, the entrance of chlorine modifies the physiological action and intensifies toxicity: thus ethyl sulphide (C2H5)2S is a weak poison, monochlorethyl sulphide C2H5C2H4ClS a strong poison, and dichlorethyl sulphide C4H8Cl2S a very strong poison: the vapour kills rabbits within a short time, and a trace of the oil applied to the ear produces intense inflammation of both the eyes and the ear.[33]
[33] V. Meyer, Ber. d. Chem. Ges., XX., 1725.
The weight of the molecule has an influence in the alcohols and acids of the fatty series; for instance, ethyl, propyl, butyl, and amyl alcohols show as they increase in carbon a regular increase in toxic power; the narcotic actions of sodium propionate, butyrate, and valerianate also increase with the rising carbon. Nitrogen in the triad condition in the amines is far less poisonous than in the pentad condition.
Bamberger[34] distinguishes two classes of hydrogenised bases derived from α and β naphthylamine, by the terms “acylic” and “aromatic.” The acylic contains the four added hydrogens in the amidogen nucleus, the aromatic in the other nucleus, thus
[34] Ber., xxii. 777-778.
α Naphthylamine.
β Naphthylamine.
Acylic tetrahydro-α Naphthylamine.
Aromatic tetrahydro-β Naphthylamine.
α Naphthylamine.
β Naphthylamine.
Acylic tetrahydro-α Naphthylamine.
Aromatic tetrahydro-β Naphthylamine.
The acylic β tetrahydro-naphthylamine, the β tetrahydroethylnaphthylamine, and the β tetrahydromethylnaphthylamine all cause dilatation of the pupil and produce symptoms of excitation of the cervical sympathetic nerve; the other members of the group are inactive.
§ 24. The result of replacing hydrogen by alkyls in aromatic bodies has been studied by Schmiedeberg and others; replacing the hydrogen of the amidogen by ethyl or methyl, usually results in a body having a more or less pronounced narcotic action. The rule is that methyl is stronger than ethyl, but it does not always hold good; ortho-amido-phenol is not in itself poisonous, but when two hydrogens of the amidogen group are replaced by two methyls thus—
the resulting body has a weak narcotic action.
It would naturally be inferred that the replacement of the H in the hydroxyl by a third methyl would increase this narcotic action, but this is not so: on the other hand, if there are three ethyl groups in the same situation a decidedly narcotic body is produced.
The influence of position of an alkyl in the aromatic bodies is well shown in ortho-, para- and meta-derivatives. Thus the author proved some years ago that with regard to disinfecting properties, ortho-cresol was more powerful than meta-; meta-cresol more powerful than para-; so again ortho-aceto-toluid is poisonous, causing acute nephritis; meta-aceto-toluid has but feeble toxic actions but is useful as an antipyretic; and para-aceto-toluid is inactive.
In the trioxybenzenes, in which there are three hydroxyls, the toxic action is greater when the hydroxyls are consecutive, as in pyrogallol, than when they are symmetrical, as in phloroglucin.
Pyrogallol.
Phloroglucin.
Pyrogallol.
Phloroglucin.
The introduction of methyl into the complicated molecule of an alkaloid often gives curious results: thus methyl strychnine and methyl brucine instead of producing tetanus have an action on voluntary muscle like curare.
Benzoyl-ecgonine has no local anæsthetic action, but the introduction of methyl into the molecule endows it with a power of deadening the sensation of the skin locally; on the other hand, cocethyl produces no effect of this kind.
Drs. Crum Brown and Fraser[35] have suggested that there is some relation between toxicity and the saturated or non-saturated condition of the molecule.
[35] Journ. Anat. and Phys., vol. ii. 224.
Hinsberg and Treupel have studied the physiological effect of substituting various alkyls for the hydrogen of the hydroxyl group in para-acetamido-phenol.
Para-aceto-amido-phenol when given to dogs in doses of 0.5 grm. for every kilogr. of body weight causes slight narcotic symptoms, with slight paralysis; there is cyanosis and in the blood much methæmoglobin.
In men doses of half a gramme (7·7 grains) act as an antipyretic, relieve neuralgia and have weak narcotic effects.
The following is the result of substituting certain alkyls for H in the HO group.
(1) Methyl.—The narcotic action is strengthened and the antipyretic action unaffected. The methæmoglobin in the blood is somewhat less.
(2) Ethyl.—Action very similar, but much less methæmoglobin is produced.
(3) Propyl.—Antipyretic action a little weaker. Methæmoglobin in the blood smaller than in para-acetamido-phenol, but more than when the methyl or ethyl compound is administered.
(4) Amyl.—Antipyretic action decreased.
The smallest amount of toxicity is in the ethyl substitution; while the maximum antipyretic and antineuralgic action belongs to the methyl substitution.
Next substitution was tried in the Imid group. It was found that substituting ethyl for H in the imid group annihilated the narcotic and antipyretic properties. No methæmoglobin could be recognised in the blood.
Lastly, simultaneous substitution of the H of the HO group by ethyl and the substitution of an alkyl for the H in the NH group gave the following results:—
Methyl.—In dogs the narcotic action was strengthened, the methæmoglobin in the blood diminished. In men the narcotic action was also more marked as well as the anti-neural action. The stomach and kidneys were also stimulated.
Ethyl.—In dogs the narcotic action was much strengthened, while the methæmoglobin was diminished. In men the antipyretic and anti-neural actions were unaffected.
Propyl.—In dogs the narcotic action was feebler than with methyl or ethyl, and in men there was diminished antipyretic action.
Amyl.—In dogs the narcotic action was much smaller.
From this latter series the conclusion is drawn that the maximum of narcotic action is obtained by the introduction of methyl and the maximum antipyretic action by the introduction of methyl or ethyl. The ethyl substitution is, as before, the less toxic.[36]
[36] Ueber die physiologische Wirkung des p-amido-phenol u. einiger Derivate desselben. O. Hinsberg u. G. Treupel, Archiv f. Exp. Pathol. u. Pharm., B. 33, S. 216.
The effect of the entrance of an alkyl into the molecule of a substance is not constant; sometimes the action of the poison is weakened, sometimes strengthened. Thus, according to Stolnikow, dimethyl resorcin, C6H4(OCH3)2, is more poisonous than resorcin C6H4(OH)2. Anisol C6H5OCH3, according to Loew, is more poisonous to algæ, bacteria, and infusoria than phenol C6H5OH. On the other hand, the replacement by methyl of an atom of hydrogen in the aromatic oxyacids weakens their action; methyl salicylic acid
is weaker than salicylic acid
.
Arsen-methyl chloride, As(CH3)Cl2, is strongly poisonous, but the introduction of a second methyl As(CH3)2Cl makes a comparatively weak poison.
§ 25. In some cases the increase of CO groups weakens the action of a poison; thus, in allantoin there are three carbonyl (CO) groups; this substance does not produce excitation of the spinal cord, but it heightens muscular irritability and causes, like xanthin, muscular rigidity; alloxantin, with a similar structure but containing six carbonyl groups, does not possess this action.
Allantoin.
Alloxantin.
Allantoin.
Alloxantin.
§ 26. A theory of general application has been put forward and supported with great ability by Oscar Loew[37] which explains the action of poisons by presuming that living has a different composition to dead albumin; the albumin of the chemist is a dead body of a definite composition and has a stable character; living albumin, such as circulates in the blood or forms the protoplasm of the tissues, is not “stable” but “labile”; Loew says:—“If the old idea is accepted that living albumin is chemically the same substance as that which is dead, numerous toxic phenomena are inexplicable. It is impossible, for instance, to explain how it is that diamide N2H4 and hydroxylamine NH2OH are toxic, even with great dilution, on all living animals; whilst neither of those substances have the smallest action on dead plasma or the ordinary dissolved passive albumin, there must therefore be present in the albumin of the living plasma a grouping of atoms in a “labile” condition (Atomgruppirungen labiler Art) which are capable of entering into reactions; such, according to our present knowledge, can only be the aldehyde and the ketone groups. The first mentioned groups are more labile and react in far greater dilution than the latter groups.”
[37] Ein natürliches System der Gift-Wirkungen, München, 1893.
Loew considers that all substances which enter into combination with aldehyde or ketone groups must be poisonous to life generally. For instance, hydroxylamine, diamide and its derivatives, phenylhydrazine, free ammonia, phenol, prussic acid, hydric sulphide, sulphur dioxide and the acid sulphites all enter into combination with aldehyde.
So again the formation of imide groups in the aromatic ring increases any poisonous properties the original substance possesses, because the imide group easily enters into combination with aldehyde; thus piperidine (CH2)5NH is more poisonous than pyridine (CH)5N; coniine NH(CH2)4CH-CH2-CH2CH3, is more poisonous than collidine N(CH)4C-CH-(CH3)2; pyrrol (CH)4NH than pyridine (CH)5N; and amarin,[38]
, than hydrobenzamide
.
[38] Th. Weyl (Lehrbuch der organischen Chemie) states (p. 385) that amarin is not poisonous, but Baccheti (Jahr. d. Chemie, 1855) has shown that 250 mgrms. of the acetate will kill a dog, 80 mgrms. a guinea-pig; and that it is poisonous to fishes, birds, and frogs: hydrobenzamide in the same doses has no effect.
If the theory is true, then substances with “labile” amido groups, on the one hand, must increase in toxic activity if a second amido group is introduced; and, on the other, their toxic qualities must be diminished if the amido group is changed into an imido group by the substitution of an atom of hydrogen for an alkyl.
Observation has shown that both of these requirements are satisfied; phenylenediamine is more poisonous than aniline; toluylenediamine more poisonous than toluidine. Again, if an atom of hydrogen in the amido (NH2) group in aniline be replaced by an alkyl, e.g. methyl or ethyl, the resulting substance does not produce muscular spasm; but if the same alkyl is substituted for an atom of hydrogen in the benzene nucleus the convulsive action remains unaffected.
If an acidyl, as for example the radical of acetic acid, enter into the amido group, then the toxic action is notably weakened; thus, acetanilide is weaker than aniline, and acetylphenylhydrazine is weaker than phenylhydrazine. If the hydrogen of the imido group be replaced by an alkyl or an acid radical, and therefore tertiary bound nitrogen restored, the poisonous action is also weakened.
In xanthin there are three imido groups; the hydrogen of two of these groups is replaced by methyl in theobromin; and in caffein the three hydrogens of the three imido groups are replaced by three methyls, thus:—
Xanthin.
Theobromin.
Xanthin.
Theobromin.
Caffein.
and experiment has shown that theobromin is weaker than xanthin, and caffein still weaker than theobromin.
Loew[39] makes the following generalisations:—
[39] Ein natürliches System der Gift-Wirkungen, München, 1893.
1. Entrance of the carboxyl or sulpho groups weakens toxic action.
2. Entrance of a chlorine atom exalts the toxic character of the catalytic poisons (Loew’s catalytic poisons are alcohols, ether, chloroform, chloral, carbon tetrachloride, methylal, carbon disulphide and volatile hydrocarbons).
3. Entrance of hydroxyl groups in the catalytic poisons of the fatty series weakens toxic character; on the other hand, it exalts the toxicity of the substituting poisons. (Examples of Loew’s class of “substituting” poisons are hydroxylamine, phenylhydrazine, hydric cyanide, hydric sulphide, aldehyde, and the phenols.)
4. A substance increases in poisonous character through every influence which increases its power of reaction with aldehyde or amido groups. If, for example, an amido or imido group in the poison molecule be made more “labile,” or if thrice linked nitrogen is converted into nitrogen connected by two bands, whether through addition of water or transposition (umlagerung) or if a second amido group enters, the poisonous quality is increased. Presence of a negative group may modify the action.
5. Entrance of a nitro group strengthens the poisonous character. If a carboxyl or a sulpho group is present in the molecule, or if, in passing through the animal body, negative groups combine with the poison molecule, or carboxyl groups are formed in the said molecule; in such cases the poisonous character of the nitro group may not be apparent.
6. Substances with double carbon linkings are more poisonous than the corresponding saturated substances. Thus neurine with the double linking of the carbon of CH2 is more poisonous than choline; vinylamine than ethylamine.
Neurine.
Choline.
Neurine.
Choline.
Vinylamine.
Ethylamine.
Vinylamine.
Ethylamine.
§ 27. M. Ch. Michet[40] has investigated the comparative toxicity of the metals by experiments on fish, using species of Serranus, Crenolabrus, and Julius. The chloride of the metal was dissolved in water and diluted until just that strength was attained in which the fish would live 48 hours; this, when expressed in grammes per litre, he called “the limit of toxicity.”
[40] “De la Toxicité comparée des différents Métaux.” Note de M. Ch. Michet. Compt. Rend., t. xciii., 1881, p. 649.
The following is the main result of the inquiry, by which it will be seen that there was found no relation between “the limit of toxicity” and the atomic weight.
TABLE SHOWING THE RESULTS OF EXPERIMENTS ON FISH.
| No. of Experiments. | Metal. | Limit of Toxicity. | |
|---|---|---|---|
| 20. | Mercury, | ·00029 | |
| 7. | Copper, | ·0033 | |
| 20. | Zinc, | ·0084 | |
| 10. | Iron, | ·014 | |
| 7. | Cadmium, | ·017 | |
| 6. | Ammonium, | ·064 | |
| 7. | Potassium, | ·10 | |
| 10. | Nickel, | ·126 | |
| 9. | Cobalt, | ·126 | |
| 11. | Lithium, | ·3 | |
| 20. | Manganese | ·30 | |
| 6. | Barium, | ·78 | |
| 4. | Magnesium, | 1 | ·5 |
| 20. | Strontium, | 2 | ·2 |
| 5. | Calcium, | 2 | ·4 |
| 6. | Sodium, | 24 | ·17 |