The subject of murder, and especially the use of poison, is one I have returned to. Always fascinating, and always deadly.

Cover image of New Scientist published 19 December 1985 Whatever happened to Arsenic?
Famed as a fatal poison, its historical role as tonic and medicine is less well known. Today it keeps a low profile, though it makes important contributions to semi-conductors and as a treatment for leukemia.

For centuries, arsenic has led a double life.

John Emsley

Published: 19/26 December 1985

Popular myth greatly exaggerates arsenic's power to kill. For centuries, it was the perfect poison, although it is much less toxic than many organic chemicals. It was undetectable, and the poisoner needed relatively little of it - less than a quarter of a gram - in order to kill his or her victim. The symptoms of arsenic poisoning are easy to mistake for other ailments and the poison is reasonably easy to administer. So-called white arsenic, arsenic trioxide, was the form commonly used. This is not very soluble in water, but enough will dissolve in a glass of wine to do the job.

Arsenic's notoriety began in the Middle Ages. The German Dominican scholar and alchemist, Albertus Magnus (1193–1280), is usually credited with its discovery. Since then, kings, popes and emperors have suffered at its hands just as much as unwanted spouses, lovers and children whose names are now forgotten. Only when chemistry emerged from the shadows of alchemy in the middle of the 18th century, did the secrecy surrounding arsenic gradually disappear. Research into its chemical analysis in the 1830s made it possible to measure minute traces of arsenic. The golden age of arsenic murders dawned and was not to set for another 120 years.

Today, the chemist's and biochemists views of arsenic are changing. Perhaps we have misjudged arsenic: it may be essential to animal life; and, contrary to a long-established prejudice, it may not be responsible for cancer of the skin and lung. However, before we allow it out on parole, we shall look over its probation officer's reports and its criminal records in more detail.

The average person, weighing 70 kilograms, contains about 10 milligrams of arsenic. The liver continually extracts this element, converting it mainly to dimethylarsinic acid, (CH3)2AsO2H, which passes out in the urine. This methylated version of arsenic has only 1 per cent of the toxicity of inorganic arsenic, As3+, and as the liver carries out the conversion rapidly, it manages to protect the body to some extent. We continually replenish the arsenic in our bodies from our diet. Arsenic is widespread in the environment-in soil, in natural spring waters and in the sea, at a concentration of about 0.024 parts per million (ppm). Everything we eat contains some arsenic: some foods contain a lot. Marine organisms, such as shellfish and crustaceans and the fish that feed upon them, can have relatively high arsenic levels. Whitstable oysters, for example, contain 3.7 ppm of arsenic. Mussels can have up to 120 ppm and prawns as much as 175 ppm. Plaice, which feed upon shellfish, have a level of 4 ppm of arsenic. Though some species have come to terms with large amounts of this element in their bodies, most organisms find it tolerable only in minute quantities. Any more, and it acts as a poison.

Nevertheless, Walter Mertz and Forrest Nielsen of the US Department of Agriculture believe that arsenic is an essential component of animal life. Nielsen's researches have shown that chickens, goats and rats deprived of arsenic suffer stunted growth until the element reappears in their diet, when they return to normal. Why arsenic is necessary is not yet clear, but it appears to influence the metabolism of the essential amino acid arginine, and the vital metals zinc and manganese, Arsenic also stimulates the production of haemoglobin. This may provide a clue to its role, and explain why doctors used to prescribe it as a treatment for anaemia.

Arsenic, in small doses, is not detrimental to health. A little above the ordinary dietary intake may do no harm and may even do some good. Could its arsenic content explain why steamed plaice is so popular as a food for invalids? Why have medicines down the centuries included arsenic in their ingredients?

Several natural spring waters probably owe their tonic effects, if not their curative properties, to arsenic. The mineral waters of Vichy contain 2 mg of sodium arsenate per litre, and others contain much more. Most spa waters, however, contain very little arsenic. Legend has it that the father of medicine, the great Hippocrates (460–377 BC), used the arsenic sulphide ore, realgar (As4S4), as a remedy for sores. This ties in with arsenic's known efficacy in skin conditions. Doctors have used arsenic compounds to treat rheumatism, arthritis. asthma, malaria. tuberculosis, diabetes and venereal diseases. It was administered medicinally as Fowler's solution (potassium arsenite – see Box 1), Donovan's solution (arsenic iodide) and de Valagin's solution (arsenic trichloride), as well as in various pills.

Box 1. Dr Fowler and the Tasteless Ague and Fever Drops

From the 18th century onwards, people took arsenic medicinally in the form of Dr Fowler's solution or Liquor Arsenicalis, as it was called. The solution contained arsenic trioxide dissolved in potassium carbonate solution, and flavoured with lavender extract to prevent misuse, Fowler's solution contained the equivalent of 10 mg of arsenic trioxide per cubic centimetre - a 1 per cent weight-for-volume solution. Invalids took a few drops of this medicine diluted with water.

Dr Thomas Fowler developed his solution in the 1780s. He worked at Stafford Infirmary where, together with the apothecary Mr Hughes. he analysed a patent medicine that was known as Tasteless Ague and Fever Drops. Fowler was impressed by the effect this medicine had on patients in the hospital. The two men discovered that the active ingredient was arsenic. Together, they devised their own recipe using arsenic trioxide and potassium carbonate, which they knew as white arsenic and potash. Fowler introduced arsenic into medicine with his treatise entitled Medical Reports of the Effect of Arsenic in the Cure of Agues, Remitting Fevers and Periodic Headaches, which he published in 1786. This work made him famous. Fowler's arsenical solution became widely used, and remained in pharmacopoeias for 150 years. In the 19th century, its use spread beyond the purely medicinal and it became popular as a supposed aphrodisiac and as tonic for "tired" businessmen.

Arsenic in these remedies was not really a drug in the modern sense. Nevertheless, one of the earliest effective drug treatments - Salvarsan, the first cure for syphilis - contained arsenic. The German chemist Paul Ehrlich discovered Salvarsan in 1909 alter systematically screening hundreds of compounds containing arsenic. He reasoned that it should be possible to find an arsenical chemical that would poison the syphilis but not the host. Test-compound number 606 fitted that bill, hence the drug's alternative name, arsphenamine (606). Variants of this drug remained in use until the advent of penicillin in the l940s.

Hand-in-hand with arsenics use in medicine went the awful suspicion that arsenic caused skin cancer. It has been implicated ever since, even though experiments on animals have never borne this out. Epidemiological surveys among groups of people exposed to high levels of arsenic in the environment have shown a higher incidence of cancer, but these surveys have never been entirely free of other factors that could be the cause. Arthur Furst of the University of San Francisco has recently argued that arsenic is not a carcinogen; or at least if it is, it must act in a manner completely different from any other chemical that initiates cancer. What arsenic might do is to stimulate the growth of cancer once it is established.

Arsenic is known to be very good at promoting growth in animals: farmers use a compound containing it to help to fatten their pigs and poultry. This compound is called 3-nitro-4-hydroxyphenylarsonic acid, or roxarsone. Scientists discovered this chemical's ability to stimulate growth after it was tested as a treatment for the debilitating disease coccidiosis in chickens. Roxarsone is now used widely, particularly in the US. Pigs and hens fed roxarsone put on only about 3 per cent more weight, but this extra meat more than offsets the cost of the special feed. The animal excretes the arsenic very rapidly, so when the farmer discontinues the doped feed a few days before slaughter. the residual amount of arsenic in the animals' tissue falls rapidly to an acceptable 1 ppm or less.

Arsenic also stimulates human growth, another reason why 19th-century medics prescribed tonics containing arsenic for convalescent patients. The revelation that the peasants of the Styrian Alps of Austro-Hungary took arsenic trioxide as a tonic amazed Victorian society. Eating arsenic, it was said, conferred plumpness and a fresh complexion in women, and improved breathing at high altitudes in men. Some individuals were said to take as much as 250 mg a week regularly for years. They could consume such a large dose only because they worked up to it gradually - a single dose of this size would almost certainly kill a normal person. Taking arsenic had its drawbacks, however. Arsenic in the body opposes the action of another mineral, iodine, which is essential to the thyroid gland. A deficiency of iodine causes the thyroid to swell, a condition known as goitre: many Styrian peasants had this disease. Cretinism - dwarfism and mental retardation from birth, arising from a shortage of thyroid hormone - also affected many of their children.

Normally, arsenic is very toxic in anything but minute doses. The smallest dose of arsenic trioxide to which death has been attributed was 130 mg. Two doses of 100 mg have proved fatal, and a dose of 200–250 mg would kill most people. However. some people would take three daily doses of Fowler's solution regularly. without toxic symptoms appearing. This represents a daily intake of 60 mg, or about 400 mg a week. Of those who ate arsenic, some even reported taking doses of 400 mg of solid arsenic trioxide, twice a week.

If a normal person takes a dose of about 100 mg of arsenic, the first symptom to appear is vomiting. This may start within 15 minutes or may be delayed by up to 12 hours, depending on the amount of food in the stomach at the time the arsenic was eaten. The presence of food delays absorption of the poison. Unfortunately, vomiting starts too late to be of much use. Later the body's main mechanism of rejection becomes diarrhoea, which starts after about 12 hours and continues to exhaustion. The arsenic that has entered the blood stream presents the greatest danger and, though efficient, the liver needs at least two days to remove the poison. Death may occur within 36 hours, although some poor souls lingered on for 96 hours. Rapid death leaves a lot of arsenic in the liver, but the longer the victim survived, the greater the chance of the murderer escaping the gallows.

Mrs Florence Maybrick's husband clung on for three days, by which time the level of arsenic in his body was quite low. However, the forensic scientists of 1889 had no trouble in finding arsenic in his medicines and on a jug that Florence had used for preparing the invalid's food. That evidence, and the large quantity of white arsenic and arsenic flypapers in her bedroom, brought her under suspicion, The court found her guilty, but commuted the sentence of death to imprisonment because of doubt that the amount of arsenic in her husband could have killed him.

Arsenic trioxide was the compound popular with poisoners. It is almost tasteless, and what taste it has is slightly sweet. Although the trioxide is not very soluble in water, a saturated solution can easily convey a fatal dose. A 100 ml volume of cold water, about a teacupful, can dissolve 1800 mg; the same volume of hot water will dissolve twice this amount. In water, arsenic trioxide behaves as a weak acid, arsenious acid (H3AsO3), and it is possible to make salts of this acid. Although most of these are less soluble than the trioxide itself some - such as sodium and potassium arsenites - are much more soluble and therefore much more poisonous. These were the forms once used in the manufacture of flypapers.

In Victorian times, there were two kinds of flypaper - the sticky type, which trapped the fly by its legs, and the paper type, which you moistened in a saucer of water, and which poisoned the fly that sampled it. To make the liquid attractive, the flypaper included sugar, but the manufacturers also added a bittering agent, quassia, and a brown colouring agent, to prevent accidental or deliberate misuse.

By soaking such a flypaper in water, a would-be poisoner could extract most of the soluble arsenites within a few hours, obtaining a tea-coloured solution. A typical flypaper contained 150–400 mg of soluble arsenic salts, so this source of poison was potentially the most lethal, provided that it could be administered without arousing suspicion. Strong tea or coffee, Bovril or brandy offered the best cover for extract of flypaper.

Although the ancient Greeks, Romans and Chinese knew of arsenic ores, it was the alchemists who were the instigators of its chemistry. The extreme secrecy of these mediaeval chemists may have been in part due to the terrible realisation of what they were playing with, Petrus Oponus (1250–1303) described both arsenic and its parent ore, realgar, as deadly poisons. The first recorded attempt at murder using arsenic trioxide was one made (unsuccessfully) against King Charles VI of France in 1384.

Arsenic trioxide, known originally as arsenic sublimate and then as white arsenic, reigned as the queen of poisons for several centuries, protected by its failure to be detected in cup and corpse. The Borgias certainly used it and gave it their own code name, "cantrella". The Borgia Pope, Alexander VI, under whose disgraceful pontificate (1492–1503) his children Cesare and Lucrezia flourished, may have been a victim of poison himself. At a party in August 1503, the Pope and Cesare were taken ill. Rumour had it that they had consumed food and wine prepared by themselves with the intention of poisoning their host. Although Cesare survived, the Pope died a few days later.

The Borgias were amateurs compared to some subsequent poisoners. The most notorious practitioner of the art was Toffana of Sicily. She concocted a potion that she distributed under the name of "Manna of St Nicholas", calling it after a holy water of the day. It became better known as Aqua Toffana. Ostensibly it was a cosmetic - many ladies of 17th-century Italy no doubt used it as such. Its effective ingredient was arsenic; tradition has it that it sent at least 500 people, including two popes, to early graves. Toffana began her career in Palermo in about 1650 and moved to Naples in 1659, where she built up her organisation for the underground distribution of her aqua in rather the same way that drug peddling is organised today. She operated successfully through a network of secret agents for over 50 years. She was eventually arrested and strangled at the instigation of the authorities in 1709.

The French equivalent of Toffana was a woman known by the name of La Voison. Her speciality was a powder composed of arsenic trioxide and vegetable poisons. This powder became known as poudre de succession since it reputedly allowed many heirs to titles and wealth to succeed to their estate at an early age. La Voison and her accomplices were eventually arrested and executed. In her heyday, La Voison was consulted by Madame de Montespan, Louis XIV's mistress, who turned to her for a love philtre to help her to regain the king's wandering affections.

Chemistry as a science really began to bloom only about l750 - about the time that it was first instrumental in securing a conviction in a case of poisoning by arsenic. In 1752, Mary Blandy, acting on the instructions of her lover, fed her father arsenic trioxide. After a few attempts she eventually killed him, but not before he realised what she was doing. Her father's love for his daughter was such that his main concern during his final days was not that he would die but that Mary should not hang for his murder. Public anger at her behaviour, however, led to her trial on a charge of murder. The poison she had used was a white powder, and a Dr Addington identified it. He showed that four tests performed on a sample of the powder gave exactly the same results as the tests performed on a sample of white arsenic. The forensic evidence helped to convince the jury that Mary had poisoned her father. She was convicted and hanged.

Arsenic really came into its own as an accidental as well as a deliberate poison in the 19th century. For instance, people used the dye, copper arsenite, discovered in 1775 and commonly known as Scheele's green. This substance may also have led to the strange death of the emperor Napoleon on St Helena in 1821.

The rumour that Napoleon died of poisoning by arsenic has more than a grain of truth in it. Neutron-diffraction analysis of his hair has shown levels of arsenic that are 13 times higher than normal. One theory that the cause was wallpaper-dye was put forward by David Jones (New Scientist, vol 96, p 101). A sample of wallpaper from Long- wood House on St Helena, where Napoleon lived, was discovered by Shirley Bradley of Norfolk; analysis showed it contained arsenic. The emperor lived on St Helena for six years and both he and his domestic staff often complained of ill health, blaming the house's chronic dampness for their troubles. Indirectly they were right; the damp encouraged mould which in tum produced volatile trimethylarsine.

Confectioners even used Scheele's green for colouring ornamental confectionery. After a banquet in London in 1848, several of the guests took such decorations home for their families, many of whom died as a result. Another accidental mass poisoning occurred 10 years later, in November 1858 in Bradford, when over 200 people were taken seriously ill after eating peppermint lozenges sold in the local market. These sweets had been adulterated by arsenic trioxide that had been mistaken for powdered calcium sulphate, This harmless material normally made up to 25 per cent of the weight of these cheap sweets. Some of the lozenges contained 1000 mg of arsenic trioxide, four times the fatal dose. Two boys died within four hours of eating them. During the following week, another 18 people died.

Poisoning affected 6000 people in Manchester in 1900 and 1901. Seventy people died. The culprit was beer that contained 15 ppm of arsenic. The glucose used for brewing the beer contained arsenic at a level of several hundred parts per million. It had been produced from sugar in a process using sulphuric acid containing 1.4 per cent arsenious acid. The acid was contaminated because it had been produced from iron pyrites with a high arsenic content.

The Royal Commission on Arsenic Poisoning in Beer, set up after the Manchester disaster, reported its findings in 1902. The government immediately introduced stringent controls over the amount of arsenic in glycerine, glucose, malt, treacle and beer. Legal limits permitted no more than 0.01 grain of arsenic per pound or gallon, which in current units is 0.14 ppm.

The last large-scale poisoning involving arsenic in Britain took place in 1943 at a student hostel in St Andrews. Many students were taken ill and two died from eating sausages made from meat containing arsenic trioxide. One batch of sausages contained as much as 650 mg each. The last conviction in Britain for murder by arsenic was that of a US Sergeant, Marcus Marymont, in 1958. He poisoned his wife, Mary. His reluctance to have a post-mortem performed on his wife's body made the medical authorities suspicious. They sent tissue for analysis, and arsenic was discovered. Marymont had got the arsenic from the US Air Force base at Sculthorpe in Norfolk where he was stationed. He poisoned his wife after she had discovered that he was having an affair with another woman. The court sentenced him to life imprisonment. Neutron activation analysis of Mrs Marymont's hair showed regular bands of arsenic at weekly intervals, indicating that her husband had tried several times to poison her when home on leave.

The traditional method of forensic analysis for arsenic used to be the Marsh test (see Box 2). This test was sensitive enough to confirm and measure a microgram of arsenic. Today, neutron activation or X-ray fluorescence analysis allows us to measure levels of arsenic to many times this sensitivity, though, luckily, we rarely need to detect arsenic in corpses these days. We need to monitor arsenic levels in the environment much more often. Such stringent precautions surround arsenic that very few people are exposed to it, though we come into increasing contact with materials that contain it. Many special glasses now contain arsenic and the electronics industry uses arsenic in several ways: gallium arsenide, for example, finds its way into lasers that operate at room temperature, solar cells, light-emitting diodes, and so on. Certain salts, such as lead arsenate, are still used as speciality pesticides in the US. One rapidly expanding application is in wood preservatives, a use where British research has made a contribution.

Box 2. The acid test for arsenic

The marsh test was the traditional method of forensic analysis for arsenic. James Marsh, the chemist employed at the Woolwich Arsenal, was the first person to devise an accurate and sensitive method of detecting arsenic in minute quantities.

The stimulus to develop a new test was the acquittal of John Bodle, who was charged with the murder of his grandfather, George Bodle, in 1832. Bodle subsequently admitted to the crime and sold his story to the newspapers. At the trial, Marsh had been asked to show the presence of arsenic in some suspect coffee and in the organs of the dead man. He used the standard test of the time, which was to show that a yellow precipitate of arsenic sulphide formed when hydrogen sulphide gas was bubbled into a solution containing arsenic. Unfortunately, the bright yellow precipitate discolours with time and the jury was not impressed with the forensic exhibits. Bodle went free. Marsh then set to work to devise a test For arsenic that would provide unquestionable proof with results that jurors could observe. In 1836, he described his method in the Edinburgh Philosophical Journal.

The first requisite of the test was to heat samples of suspect tissue with strong acid that destroyed the organic material, thus making the arsenic contained in it soluble. The next step in the Marsh test, as it became known, was to convert the arsenic in solution into arsine gas, AsH3, by reacting it with hydrogen generated within the solution from metallic zinc and acid. When the arsine gas passes through a heated glass tube, it decomposes to arsenic, which condenses on the cooler part of the tube to form a mirror. The amount of arsenic was measured by comparing the mirror with standard mirrors of known weight.

What is our final judgment on arsenic? Because it has been well behaved for the past 25 years, should we forget its 500 years of criminal behaviour? Even assuming it is essential, should we let it free again? Probably not. Arsenic will never purge its past.