Toxicology in general

Toxicology in general

Classification

Toxicological substances (including medicines) can be classified according to the following:

·              chemical characteristics, for example organic, inorganic

·              mode of action, for example corrosive, irritant

·              target organ, for example lungs, heart

·              intended use, for example solvent, insecticide

·              field of use, for example agricultural, industrial

·              origin, for example plant, bacterial, fungal

Factors affecting toxicity

A poison is a substance which, when absorbed by a living organism, results in harm or death. There are many thousands of substances occurring naturally or in synthesised form that exhibits this property. Medicines or even beverages, if used in excess or inappropriately, can result in poisoning. Furthermore, two innocuous substances could, after administration, combine and so have a harmful synergistic effect.

Poisoning can be acute, subacute or chronic and its intensity as well as its signs and symptoms can vary from person to person, appearing dramatically and suddenly or as vague discomfort over a long time. It may also vary in the same individual at different times.

The intensity and nature of the reaction to a poison often becomes an important issue in court. The many variables which need to be considered when attempting to solve this problem are best expressed as a functional equation: 

Intensity of the reaction ranges from the most insignificant to death.

Dose is the amount administered and the frequency of administration.

Rate of absorption will be influenced by the route of administration, that is whether by mouth, intravenously, per vagina, per rectum, or by inunction (rubbing in) or inhalation.

Rate of elimination may be accelerated by vomiting, diarrhoea or accelerated metabolic pathways such as in people addicted to the particular substance or habitually exposed to it in the workplace. Both absorption and elimination may be delayed by a variety of medicines in use at the relevant time. The converse is equally true.

The specific properties of the subject include hypersensitivity, various diseases, as well as the inherent biological variability of living material even in the same population group, and expressed graphically as an S-shaped curve when dose is plotted against percentage response in the group at each varying dose level.

The physico-chemical nature of the poison (solid, gaseous, liquid, soluble) is also an important variable in the equation.

The difference between a therapeutic and a lethal dosage

As already stated in the explication of the formula, the response to a given dose is not always the same in all individuals. Some individuals may show the same reaction at a lower dose than another individual will show at a significantly higher dose. This is due to specific features, which not only differ from individual to individual, but can also differ in the same individual from day to day. In other words, there are interpersonal as well as intrapersonal differences in the reaction to a given dose. This reaction can be represented graphically by a sigmoid or S-shape (fig 11.1).

The therapeutic dose where 50% of individuals will experience the therapeutic effect is also known as the ED50 (``effective dose''). The dose where 50% of indiduals will die, is called LD50 (``lethal dose''). If a specific toxic effect other than death is used, it is called TD50 (``toxic dose''). The closer these doses are to one another, the higher the risk for toxic reactions. The concept of the minimum lethal dose or MLD has been debated at length. It is obvious from the sigmoid curve that we could say that the drug could not have caused the individual's death if the level is lower than the MLD. The contrary, however, is not possible; if an individual's blood level is somewhere along this curve, it is not possible to state whether the individual indeed died due to the effect of the drugs or substance. The higher the level of the substance, the greater the chances that it could have played a role.

Poisoning

How is poisoning proved?

Poisoning can be proved from the symptoms and signs displayed by the victim during his lifetime, together with a chemical analysis to test for the presence of a particular poison or its metabolites in the vomit, bodily excretions, and blood, or by determining specific target-organ changes. At a post-mortem examination internal organs and tissues can be removed from the body for chemical analysis.

If the poison is taken by mouth, it must (after absorption from the gut) pass to the liver. The liver can destroy the poison or modify it, or the poison can damage the liver. This can lead to symptoms and signs indicating liver disorder, but often there is no clinical evidence to indicate whether the damage is due to disease or poisoning. There could for example, be jaundice (a yellow colouring of the skin, internal organs and tissues) because the ability of the liver to handle the bile pigments could be sufficiently disrupted to push the bile back into the blood. This is one of the ways in which jaundice can originate regardless whether by disease or by a poison. One can now understand why the liver is often one of the organs sent for chemical analysis in a case of suspected poisoning.

After passing through the liver the poison reaches the heart and then goes to the brain and all the other organs and tissues of the body. It is eventually eliminated in the sweat, urine and the faeces. This is why the kidneys (which produce the urine) are also often sent for analysis in the case of a deceased, or the urine in the case of a living person.

The stomach and its contents can also be removed at a post-mortem examination for analysis or, in the living patient, vomit can be examined. Inspection of stomach contents can reveal recognisable items, for example portions of the swallowed capsules which contained medicines, fragments of the coloured wing cases of the beetles responsible for cantharadin (Spanish fly) poisoning, et cetera. Some poisons have a greater affinity for certain tissues. For example, arsenic is deposited in the hair and the nails, and hair and nail clippings thus could provide evidence not only of this form of poisoning, but also of the approximate period of time during which the arsenic was ingested, because the tempo at which hair and nails grow is known. So, if these specimens are analysed in sections along the length of the hair (or nails), the likely time of ingestion of the poison can be determined.

In 1955 a lock of Napoleon's hair was shown to contain arsenic. It was hinted that this might purposely have been administered by his captors during the latter part of his life on St Helena. He experienced health problems after the Russian debacle, and evidence suggests that since arsenic was commonly prescribed as a tonic at the time, this probably was the source of the arsenic.

If heavy metal poisons are found in tissues they should be evaluated carefully, and the possibility that they may represent environmental contamination before and after death must be carefully considered. In certain parts of South Africa the soil is heavily contaminated by arsenic, and the presence of arsenic in the hair or nails of exhumed bodies may mean no more than post-mortem contamination of these tissues.

Post-mortem examinations seldom reveal any characteristic signs which can be attributed to a particular poison. One of the few notable exceptions is the bright, cherry-red colour of the blood in carbon-monoxide poisoning, due to the formation of a special blood pigment called carboxyhaemoglobin (COHb). Another example is the staining and destruction of the skin around the lips and of the lining of the mouth, the gullet and the stomach, produced by corrosive acids or caustic alkalis.

It is sometimes claimed that acute arsenic poisoning produces characteristic haemorrhages beneath the inner lining of the left ventricle of the heart. However, this is also seen in cases of death due to other causes. Therefore, although such haemorrhages are not peculiar to arsenic poisoning only, they may well arouse the suspicion of arsenic poisoning (in the absence of any other satisfactory explanation for its appearance in the heart  -   see photo 49).

Lead and mercury poisoning can cause a dark blue-black line along the gum-tooth margin, and in organophosphate poisoning the lungs may appear markedly oedematous and frothy fluid may exude from the mouth and nostrils (photo 47). Potassium dichromate can stain the tissues an orange colour. It has also been observed that flies which feed from the body of a person who died from insecticide poisoning also die. If there is a smell of bitter almonds when the skull is opened, one should suspect cyanide poisoning. Microscopic examination of the tissues could also indicate poisoning. Certain changes in liver cells could indicate paracetamol poisoning, and in kidney cells, glycol poisoning.

Remnants of capsule coverings, insects, and leaves in the stomach contents could suggest the analytical procedure to be followed during toxicological examination.

In general the post-mortem examination provides little evidence to indicate a particular form of poisoning. The various organs and systems affected by a poison however do display specific signs and symptoms. Whatever the poison affecting the intestinal tract, the clinical features are usually nausea, retching, vomiting, diarrhoea, constipation and cramp (colic). In the same way, the effects of any poison acting on the respiratory system are manifested in interference with the breathing, for example the victim has difficulty in breathing in or breathing out; he breathes rapidly or slowly; the breathing is deep or shallow; there may be a cough, et cetera.

Arsenic acts on almost every system of the body. Hence, in chronic arsenic poisoning, where arsenic has been ingested over a period of many weeks or months, the victim may show evidence of vomiting and diarrhoea, thickening of the skin, especially of the palms and the soles, uniform or spotty pigmentation of the skin, rashes of one kind or another, inflammation of nerves in different parts of the body, producing, for example, hoarseness of the voice or weakness of the limbs, sometimes amounting to paralysis.

Arsenic poisoning has so many different faces that it can be mistaken for many diseases. It could simulate laryngitis, scarlet fever (because of the type of rash it produces), alcoholic neuritis, and attacks of diarrhoea and vomiting, which could be (and often have been) mistaken for bacterial food poisoning. The pigmentation of the skin could resemble certain natural diseases associated with weakness of the limbs, vomiting, et cetera.

The problem is, therefore, to decide whether the different clinical signs as a group could have been caused by a natural disease or by a poison. Otherwise one has to decide how much each contributes to the total picture. The post-mortem examination thus becomes important in excluding certain diseases, and the chemical analysis can provide confirmation of the nature and amount of the poison, which will indicate what condition the victim suffered from and what caused his death.

It is often the virtually negative findings at a post-mortem examination which arouse suspicion about poison as a possible explanation of the cause of death. A negative post-mortem finding thus becomes a very important factor in the investigation of a case of suspected poisoning.

The clinical history, the post-mortem findings and the results of any special investigations (such as the chemical analysis for the presence of a poison) must all be evaluated in order to arrive at a conclusion. The answer is not to be found in one isolated part of the inquiry, but in a combination of all the steps involved in making a medical diagnosis.

Since the final cause of death in a case of poisoning is often a condition such as pneumonia, liver failure or kidney disease, it is understandable why, even despite an autopsy, the true cause of death could easily be missed if circumstantial evidence does not suggest a non-natural death. The value placed on toxicological analysis adds to the problems relating to diagnosis. The fact that a poisonous substance is found in the tissue does not necessarily indicate that this was the cause of death. Such a finding could indicate that the deceased was exposed to that poison, either in the environment or in his workplace. Conversely, the opposite finding does not mean that poison was not the cause of death, since death could be caused by some extremely poisonous substances in such minute quantities as to defy routine chemical analytical detection. In experimental animals the botulism toxin (a bacterial toxin) can cause death in doses as small as 0,0001 mg/kg of body mass. Some poisons are broken down so rapidly in the body that the metabolites cannot be identified; others are present in the tissues as normal elements and only relatively small additional quantities may cause death, particularly if given intravenously. Potassium chloride used as a resuscitative drug to replenish tissue potassium after certain forms of cardiac collapse could have disastrous consequences if administered incorrectly. Yet, on analysis the blood potassium levels may have returned to normal at the time of death a little while later. Various remedies are used by herbalists and medicine men for a variety of ailments. The pharmacologically active substances in these preparations are not always chemically identifiable.

Certain preparations are made from the wing cases of the Cantharides beetle (Spanish fly), and concoctions are also made from the bulb of the candelabra flower (Buphanedisticha). The use of Cantharides as an abortifacient and an aphrodisiac has led to fatal poisoning, as have concoctions made from the bulb of Buphanedisticha, given to adults for a variety of complications.

Understandably a death suspected to have been the result of poisoning may only be brought to the notice of the appropriate authorities a considerable time later. This could necessitate an exhumation, in which case special precautions (in addition to the standard precautions) have to be taken when sampling for poisons. While care must be taken to avoid contamination of samples by extraneous chemical substances, steps must also be taken to identify possible contamination after burial by sampling the soil above and below the body, as well as the shrouds and the coffin.

Case studies

1.           During a six-week period in 1969 seven young children died. Their illness was heralded by fever, vomiting and diarrhoea, followed by severe liver and kidney failure. Despite intensive medical supportive therapy, death ensued within four days of admission to hospital. Initially the illness was thought to be a ``natural disease'', probably viral in origin. An autopsy (not medico-legal) was undertaken to confirm the clinical diagnosis. However, the findings of a microscopic examination of tissues sampled at the autopsy were suggestive of diethylene glycol poisoning. Epidemio-logical studies revealed a single common factor in all the cases, namely a proprietary brand of paediatric sedative mixture with a pharmaceutical formulation which included propylene glycol as a solvent for the active ingredients. An analysis of this medicine taken from the homes of the victims established that these medicines did not contain propylene glycol, but diethylene glycol  -   a related highly toxic anti-freeze agent used in engine-cooling systems. The source of the diethylene glycol was a drum (incorrectly) labelled propylene glycol, which contained diethylene glycol. This had been supplied to the manufacturing pharmaceutical company by the importers as propylene glycol.

2.           In contrast with (1) above the death of a young male in 1977 following on vomiting, delirium, jaundice, kidney failure and widespread tissue haemorrhages was initially considered to have probably been the result of poisoning. A medico-legal autopsy was therefore performed by Professor N Scheepers. Microscopic examination of the tissues sampled at the autopsy suggested that the condition was probably viral in origin. Further virological studies subsequently confirmed this diagnosis; it was a case of haemorrhagic fever caused by the Marburg virus. This was the first case reported in South Africa, and the second series of cases in the world.

3.           A party of forty-five adult males was given an ointment containing mercury, then commonly known as ``blue-butter'' and formerly used for treating pubic lice infestation. The week's supply of ointment was (contrary to instructions) enthusiastically rubbed into the pubic area that same evening by forty of the ``patients'', who all became acutely ill within 12 hours with signs of mercury poisoning, including nausea, burning sensation in the chest, salivation, followed by a loosening of teeth in the jaw, and kidney disturbances. Mercury was isolated in their urine samples. All of them later developed the typical blue-line-on-the gum margins. Specific antidote treatment was instituted, and after a ``stormy passage'' all the patients recovered. A variety of toxic substances (and medica-ments) can be readily absorbed through the skin; amongst these are mercury and various nitrites, such as TNT. Five patients who were not poisoned had either not used the ointment, or had used it according to instructions.

4.           A middle-aged company director was admitted to hospital, acutely shocked and with severe abdominal pain and vomiting. A year earlier he had been treated for a peptic ulcer. An emergency operation was considered necessary for a suspected perforation of the ulcer. The patient died while still under general anaesthetic and before the abdomen could be opened. In terms of the provisions of the Health Professions Act relating to death while under, or in consequence of a general or local anaesthetic, a medico-legal autopsy was performed. At the autopsy the stomach lining had a velvety appearance, and a large subendocardial haemorrhage was observed in the left ventricle of the heart. No other significant signs which could account for death were found. The sub-endocardial bleeding necessitated chemical analysis of the organs. Large quantities of arsenic were discovered, enough to cause acute poisoning. The source of the poison was never found, but in the light of circumstantial evidence, suicide was suspected.

5.           An asthmatic patient also suffering from high blood pressure was issued with a prescription for an anti-hypertensive medicine, containing an adrenalin-blocking agent, in small therapeutic quantities. Within minutes of taking the first dose the patient suffered an acute attack of asthma which did not respond to the adrenalin-like anti-asthmatic medicine she had been accustomed to use, since the former blocked the cellular receptor sites for the latter. The patient died in status asthmaticus despite having been rushed to hospital, and despite the expeditious application of resuscitative measures.

6.           The deceased, a political defector form Eastern Europe, felt something sting him on the back of his thigh whilst waiting for a bus in London. On reaching home his suspicion that a wasp had stung him was ``confirmed'' by the discovery of a small puncture wound in the centre of a large inflamed area of his thigh. He mentioned that he had noticed a man with a furled umbrella hurrying away from the scene shortly after he had been stung. At the subsequent autopsy a few days later a very small object which resembled a ball-bearing through which a minute hole had been bored was found in the depths of the affected tissues. It was later established that another defector in Paris had had a similar experience but had not succumbed despite a stormy passage in hospital. He was traced, his leg X-rayed and a similar object was revealed to be embedded in the leg. This was removed, and both objects were identified as being of the same composition and dimensions, and peculiar to an alloy used in the country from which the two victims hailed. Subsequently it was established that the hole in the object contained ricin in a concentrated form. The substance had been the subject of research by a scientist in the aforementioned country. Available evidence suggested that the furled umbrella was a cover for an airgun-type weapon. The volume of ricin in the hole constituted a possible lethal dose.

Post-mortem examination

In addition to the above signs of poisoning, it is also important to submit the relevant specimens for toxicological analysis during the post mortem. Blood, kidneys and urine, the liver and the stomach and stomach contents will be routinely analysed. In some cases eye fluid or vitreous humour (for alcohol) and other organs such as the brain, will also be analysed. Hair and nails will also be examined especially in heavy metal poisoning.