Toxicology

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Chapter 40 Toxicology

Chapter contents

The occurrence of poisons 318
Drug absorption 318
Distribution and transport 319
Tolerance 322
Detoxification 322
Genetic factors 323
Factors that alter toxicity 323
Drug interactions 324
Plants absorbing chemicals 325

In the study of toxicology, a solid appreciation of pharmacokinetics and pharmacodynamics (see Chapters 14 to 19) is very important, as the mechanics of the two areas are very much a part of what makes a chemical harmful to a patient. Poisons or toxicants are chemicals that have harmful or adverse effects on living organisms. A chemical can be poisonous under one set of conditions and not under another. For example, potassium is a vital part of body metabolism, but too much will cause atrial fibrillation.

There are two different types of toxic reaction:

1. Irreversible: e.g. mutagenicity (mutation), carcinogenicity (cancer promoting), teratogenicity (congenital malformations) and death.
2. Reversible: providing the initial damage is not overwhelming, such as:

• organ damage, e.g. liver, kidney or skin
• functional damage, e.g. respiratory depression, loss of consciousness or convulsive effect.

When dealing with chemicals, the following must be kept in mind:

• The chemical must get to the effector site (such as a synapse or enzyme receptor site) in a biological system to produce a biological effect.
• Not all chemically induced biological effects are harmful, e.g. the therapeutic effects of herbs.
• The occurrence and intensity of chemical-induced biological effects are dose related.
• Interactions with other chemicals might potentiate the effect of one or more of the active compounds in the drugs, creating a toxic effect in the body.
• The chemical might be altered in the body and the metabolites might cause problems (see Chapter 7 ‘Free radicals’, p. 41).

The Occurrence of Poisons

Virtually all chemicals can be considered toxic under certain conditions, e.g. pure water when inhaled is rapidly absorbed across the lung alveoli to cause lysis of red blood cells. Poisoning is either:

• Acute: this usually manifests as anaphylactic shock e.g. to nuts. Remember that some Chinese herbs are nuts, e.g. Semen/Prunus persicae (peach kernels, Tao Ren) so it might be worth asking patients if they have any known allergies to nuts; they will usually know.
• Chronic: the more usual type of poisoning encountered by herbalists. The chemical builds up over a period of time in the body, particularly anything fat soluble. The symptoms can be far less obvious than for acute poisoning, and in the long term might be lethal or sublethal (e.g. the patient might be ill and tired all the time).

Drug Absorption

The tissues that are most susceptible are those directly in contact with the environment, e.g. skin, mucous membranes of the lungs and gut.

Gut

This is a common route of entry. Different parts of the gut allow different rates of absorption:

• Mouth: rapid absorption. Chemicals in the mouth are in a fairly pure form, not having been diluted or transformed by enzymes or stomach acid. Chemicals entering the body via the mouth will not immediately enter the liver (which is the main detoxifying organ). If you are not sure whether a patient is likely to react to a decoction, ask him or her to take a small amount into their mouth, swill it around, then spit it out.
• Stomach: the change in pH alters the absorption of chemicals (see Chapter 8 ‘Acids and bases’, p. 55). Decreasing pH leads to increased gastric clearance. Gastric movements mix the food material bringing it in close contact with gastric juices:

• Gastric retention increases with decreased motility: the gastric retention will increase if the toxin favours gastric absorption.
• Gastric retention decreases with increased motility: the toxin might be more of a problem in this case if it is better absorbed in the duodenum.
• A fatty diet increases gastric retention time: this is why good movement around the gastrointestinal tract is important so that the normal toxins ingested do not hang around.
• Small intestine: the major site for absorption. The absorption area is large – approximately 250 m2, which is the size of a tennis court.
• Large intestine and rectum: rectal absorption bypasses the liver and enters the bloodstream quickly. Thus suppositories can be used in cases where a drug is needed to act fast. However, because they initially bypass the liver, any reaction to the drug will be difficult to counteract.

Respiratory Tract

As much blood passes through the lungs as all the remaining parts of the body together. The lungs are therefore one of the most vascular and effective sites of absorption of the body. This is why it is possible for a patient to have an anaphylactic reaction from inhalation.

Skin

The total skin area of an average human is 2 m2; the skin is a relatively effective barrier to toxins. This is because the toxin has to reach the inner layer – the dermis – before it can diffuse into the bloodstream. The outer layer – the epidermis, through which the toxin must pass – is made up of dead, cornified cells and no active transport takes place. Only lipid-soluble substances will pass through the epidermis. This tends to occur at the sweat glands, sebaceous glands and hair follicles; however, these comprise only 1% of total skin’s surface area.

• Factors Affecting Toxin Absorption through the Skin

• If a toxin is lipid soluble and is contained in a lipid then its absorption is enhanced. Ointments tend to keep the chemical in one area for absorption, so a local as well as a systemic reaction might occur.
• Strong detergents and lipid solvents can remove the surface lipid layer from the skin and make it more susceptible to toxins.
• Damage or injury to the skin, e.g. cut or graze, will cause problems, as the underlying tissue will come into direct contact with toxins present in the environment. This is why Arnica cream must only be applied to unbroken skin.

Distribution and Transport

The Role of Blood

• Only high-molecular-weight materials, e.g. proteins, will be prevented from passing through the blood vessel wall.
• Toxins can travel free in plasma (where they are more of a problem) or bound to plasma proteins or within red and white blood cells (Chapter 16 ‘How do drugs get into cells?’, p. 123).
• The brain, cerebrospinal fluid and developing fetus are separated by a protective layer of cells from the blood (Chapter 16 ‘How do drugs get into cells?’, p. 126). However, the placenta is not a very effective barrier to the entry of toxic chemicals. Many toxins enter the fetus by diffusion, e.g. thalidomide. Herbs containing volatile oils are thought not to be advisable for use during pregnancy as they can easily pass through to the fetus.

Enzymes

Chemicals can interfere with the enzymes that are vital as catalysts of metabolic processes in the body (see Chapter 19 ‘Pharmacodynamics: how drugs elicit a physiological effect’, p. 137):

• Reversible and irreversible reactions: a toxin can attach itself to an enzyme, either reversibly or irreversibly. If the process is reversible then it might be a case of waiting until the toxin has been processed out of the body. If the process is irreversible then more enzymes have to be produced, which might take too long and result in the person’s death.
• Competitive inhibition: if there is more toxin than normal substrate then the toxin, by sheer weight of numbers, attaches to the active site of the enzyme.
• Non-competitive inhibition: the toxin binds to another site on the enzyme, creating inhibition.
• Structural change: when a toxin has hooked up to an enzyme then it might force a change in the shape of the protein. This will mean that the normal substrate is not able to lock into the enzyme because it no longer fits.

The Importance of Correct Cell Structure

An intact cell membrane is crucial. Sometimes, however, the cell membrane might not be functioning properly:

• The membrane might break down and release the contents of the cell.
• The membrane structure might be altered more subtly, e.g. pore size or structures such as ion channels or the sodium pump might be affected, reducing movement or absorption of vital chemicals into cells.
• Organelles might be affected, e.g. mitochondria, endoplasmic reticulum, lysozymes. This can affect function, e.g. mitochondria are no longer able to produce energy, or lysozymes break down to release destructive enzymes.

Silicosis is well documented in miners and stonemasons, who work in conditions in which silica is converted to silicic acid. This ruptures the lung macrophages by destabilizing the lysozymes in the lung cells. Enzymes are released, which eventually break down the macrophages.

RNA and DNA synthesis can be affected and as a result growth, cell division and general metabolism are affected. This is most likely the metabolic system that is affected by carcinogens and teratogens.

Terminology

• Carcinogen: a toxin that induces the formation of tumours.
• Teratogen: a toxin that can cross the placenta during pregnancy and damage the developing fetus. The important stage of pregnancy is the critical period from the end of the first week up to the 9th or 10th week after conception.
• Dose: the quantity of a chemical involved or introduced into a biologic system in a unit period of time (g/kg single dose, repeated dose g/kg/day dose).

Route of administration or exposure is usually indicated.

Dose–Response Relationships

The LD50 is widely used: It is the best estimation of the dose of a compound that will produce death in 50% of the test animals (i.e. the lethal dose for 50%). But there are flaws with LD50:

• It measures only mortality, and not toxicity that is non-lethal.
• There is a wide variation of LD50 between species so experimentation on animals cannot necessarily be extrapolated to humans. Rates also vary greatly with the age, health and sex of the patient.
• It measures only acute toxicity produced by a single dose, and not long-term toxicity.
• It cannot measure idiosyncratic reactions (abnormal sensitivity to toxins), which occur at low dosages in a small proportion of subjects.
• A great many animals are needed, which fuels the arguments against this type of experimentation.

Toxicity testing can be also dubious:

• The toxin is injected as a pure extract of an isolated chemical reputed to be an active ingredient (either as a toxin or with therapeutic qualities). Very high doses are administered to animals, whose size or metabolism might not necessarily match that of a human.
• It is important to remember that the usual way a herb or supplement is taken into the body is by ingestion as a whole product. The method of processing this chemical is likely to be very different, due to its exposure to the digestive system and processing in the liver.

Herbs can be tested on humans as standardized extracts, using a marker chemical, which is not necessarily the active ingredient. When reading research, it is necessary to discern the method that has been used in the study.

Degrees of Toxicity

• Extremely toxic: 1 mg/kg or less.
• Highly toxic: 1–50 mg/kg.
• Moderately toxic: 50–500 mg/kg.
• Slightly toxic: 0.5–5 g/kg.
• Practically non-toxic: 5–15 g/kg.
• Relatively harmless: more than 15 g/kg.

From this it is possible to see that the more toxic chemicals require a very low dosage.

Safety Versus Toxicity

All drugs, because of their ability to interfere with biological processes, are potentially harmful agents. This is particularly true if the action of the drug can also affect a normal life-preserving process, e.g. respiration. Once the therapeutic effect is exceeded then the vital process could be significantly affected to create harm to the patient, e.g. morphine produces analgesia but produces respiratory depression.

Potency

This is the relative dose of the drug required to produce an effect equal to that produced by a similarly acting drug. The margin of safety between the lethal effect and the desired effect is the therapeutic index. This must be large to be safe.

How is the Concentration of Chemicals in the Body Determined?

Blood is a handy sample material because it is the main method by which chemicals are carried to all parts of the body: movement of chemicals is largely via the blood and lymph systems. This is why blood tests are so commonly used for a range of diagnostic tests (see Chapter 41 ‘Scientific tests’, p. 331).

Accumulation and Storage of Chemicals in the Body

• The shorter the half-life of a toxin, the more rapidly it is metabolized and removed from the body.
• Toxins deposited and metabolized in fat can diffuse back into the blood. The lipid-soluble pesticide DDT (dichlorodiphenyltrichloroethane) is easily stored in the fat and remains in the body for months, only to be released when the lipids are mobilized, for example if the person loses weight.
• Toxins can become incorporated into the body, for example into bone, and remain in the body for years.

Tolerance

Tolerance is the ability of an organism to have less of a reaction to a specific dose of a chemical than it did on a previous occasion with the same dose. For example, tolerance to a drug such as morphine can be acquired over a period of time, which means that patients on morphine for pain relief over a period of time will need gradually higher dosages to get an effect.

Tolerance to many of the drugs that affect the human brain is accompanied by a desperate desire to take the drug. If this is sufficiently strong, so that the drug is taken repeatedly, there is a progressive increase in tolerance. Sudden withdrawal of the drug can lead to serious illness or even death.

Detoxification

This term covers the range of biochemical processes in the body that help to maintain its health by converting toxic substances to non-toxic ones and excreting them through the liver, skin, lungs and intestinal mucosa. The liver is the main site of detoxification in the body (see Chapter 17 ‘Metabolism’, p. 129).

Elimination of Toxins

• Skin

Many complementary practitioners believe that elimination of toxins thorough the skin is the reason for many skin reactions.

• Hair and Nails

The hair and nails are often used for detecting toxins. Historical note: it is possible that the emperor Napoleon was poisoned because arsenic was detected in his hair.

• Breast

The breast is an enlarged gland, and care should be taken when formulating herbs for a patient who is breast-feeding, as plant chemicals can come out in the breast milk.

• Lungs

Irritant substances can be removed from the respiratory tract by coughing and sneezing.

• Digestive Tract

Toxins are removed from the stomach by vomiting and from the gut by diarrhoea.

• The Liver

The liver is richly supplied by blood from the hepatic portal vein, which comes from the stomach and intestines. If the phase I and II pathways function properly then chemicals are rendered water soluble and pass out of the body via the kidneys.

An inefficient or impaired detoxification system can result in the accumulation and deposition of metabolic toxins and in increased free radical production and its ensuing pathology. Initially, the patient is usually unwell and lacks energy, but if this continues the effects may be lethal. It is also worth remembering the enterohepatic cycle (see Chapter 17 ‘Metabolism’, p. 131).

• Kidneys

The kidneys are a very important route for getting rid of water-soluble toxins. Good health of the kidneys is important, as is a reasonable amount of fluid consumption during the course of the day.

Genetic Factors

Some patients are more susceptible to allergens or toxins than others, for example hay fever and eczema run in families. As metabolic components such as enzymes are proteins, and as the information for producing proteins resides in the structure of the DNA, genetic input is now thought to be very relevant in this area as the whole of a patient’s metabolism is likely to be affected.

The phase I and II pathways of the liver are thought to be influenced by genetic factors.

Factors that Alter Toxicity

Age

• The Young

• The body is most susceptible to toxins before birth and when the growth rate is at a maximum and tissue and organ differentiation occurs.
• The toxins can cause teratogenic effects: e.g. thalidomide affects the limb buds.
• The predifferentiation period (the period before the cells differentiate into body tissues) occurs after 17 days; up to this point toxins can easily kill the fetus.
• From 17 to 55 days organogenesis occurs where the differentiation of the major body tissues occurs and organs are laid down. After this, limb-reduction deformities cannot occur because the limbs are fully formed.
• After birth, the enzyme system is not fully developed until 3 months of age.

• The Elderly

• Altered pH in the stomach can affect the ability to handle toxins.
• Renal clearance is reduced: drugs excreted through the kidneys take longer to remove from the body.
• Liver function might be reduced: metabolism of the elderly is often impaired
• Polypharmacy: elderly people are usually on more than one drug, quite often for cardiovascular conditions.

Size

• The smaller a person is, the lower the dosage they will need for a drug to be toxic.

Pregnancy

• Very few drugs are safe during pregnancy.

Organ Damage

• Damage to the liver and kidneys has a dramatic effect on how efficiently a patient can clear toxins. Careful consideration has to be given when treating a patient with liver disease such as cirrhosis and hepatitis.
• Metabolic illnesses, e.g. Wilson’s disease, can affect the function of the liver by damaging its cell structure; other inherited diseases might affect the function of the detoxification enzymes.

Stress

• Disease and nutritional deficiency lead to physiological stress.

Drug Interactions

This is a constantly changing field and a formulary will need to be consulted. Professional bodies should make practitioners aware of any particular changes in practice, but monitoring Medicines and Healthcare Products Regulatory Agency (MHRA) and Food and Drug Administration (FDA) sites should keep the practitioner aware of any developments. Reporting systems are in place throughout the world but as new drugs are developed the information will change.

Generally, care should be taken when treating a patient with herbs or supplements such as the following:

• Plants with alkaloid constituents: as alkaloids have the capability to interfere with metabolism at the genetic level (see Chapter 39 ‘Chemotherapy’, p. 310) and at the receptor level (see Chapter 31 ‘The nervous system’, p. 240), careful consideration has to be given to the potency of the alkaloid.
• Plants with constituents that are likely to upregulate cytochrome P450, e.g. Hypericum spp. (St John’s wort).
• Drugs that are prone to interactions are those suppressing the immune system:

• antiplatelet or anticoagulation
• nervous or psychiatric disorders

Professional bodies send out regular newsletters commenting on possible interactions. The websites of national agencies for drug safety (see Chapter 41 ‘Scientific tests’, p. 346) also have postings on the toxicology reports.

Plant Toxins

Correct preparation of herbs to prevent toxic reactions is vital. The use of an approved supplier should ensure that all herbs have been properly prepared. For example:

• Pulsatilla spp. have to be dried before a tincture is made.
• Pinellia ternate (Ban Xia) is treated with sulphur.
• Da Huang is a purgative if boiled for a short time; this quality is diminished if boiled for longer than 10 minutes.

Care must also be taken when using non-traditional preparations, e.g. a herb that has been extracted with alcohol when it is normally extracted using water.

Glycosides

Until the sugar is cleaved there is little risk of toxicity; as soon as the bacteria in the gastrointestinal tract remove the sugar the agent will work.

Oxalates

Generally, it is difficult to consume enough plant material for oxalates to cause problems. For example, it is found in high concentrations in rhubarb leaves, which are not normally eaten. Other examples include Polygonaceae: Rheum spp., which are varieties of rhubarb, including Rheum palmatum (Turkey rhubarb, Da Huang).

Lectins

Lectins are glycoproteins. They were discovered in the 1880s and found to be able to clump erythrocytes in vitro. They are now known to take part in several biological activities, including cell adhesion, the control of protein levels in the blood, glycoprotein synthesis (see Chapter 9 ‘Carbohydrates’, p. 71) and cause mitosis in cells that are not actively dividing. Because of this, lectins have the potential to alter cell permeability and generally interfere with cell metabolism.

Of interest in toxicology is that lectins are found in the skins of uncooked beans (the red kidney bean is well known for being toxic if eaten uncooked). There have been problems with cooking raw beans in slow cookers or casseroles when the temperature of the mixture was not high enough to destroy the lectins (this usually requires 80°C). Soaking for at least 5 hours, followed by brisk boiling in fresh water for at least 10 minutes is required to break the lectin down.

Ricin, made from the castor oil bean, became a very well-known lectin following its use, in 1978, in the assassination of the Bulgarian dissident Georgi Markov, who was shot with a pellet coated with ricin from a modified umbrella on Waterloo Bridge in London.

Different lectins have different levels of toxicity and not all lectins are toxic.

Plants Absorbing Chemicals

Plants are very good at absorbing chemicals from the ground in which they are growing. It is therefore possible that, in an area where a high volume of fertilizer is used, excessive nitrate compounds will be incorporated into the plant. Selenium poisoning is well documented in areas where natural deposits are high. Heavy metals can also be absorbed by plants.

Reputable herbal companies will continually spot-check batches of herbs to assay for these compounds.

Arsenic

Arsenic is usually present in very small amounts in soil and water, but should not normally reach dangerous levels. It is found in:

• Fish: it is important to consider the quality of the source when giving fish oils.
• Cereal products.

• Toxicity

• Well known as a deadly poison.
• In low doses can be:

• carcinogenic
• teratogenic.

One of the best known signs of arsenic poisoning is Mee’s lines or transverse lines across the nails.

Aluminium

Not an essential metal but is found in:

• Some medicinal products, e.g. antacids.
• Some antiperspirants.
• Some food additives, baking powder, cake mixes, self-raising flour, frozen dough and processed cheese.
• Many teas, although it is not easily absorbed.

Its interaction with the metabolism of the body is unknown.

• Toxic Effects

• Osteomalacia.
• Microcytic anaemia: the average size of the erythrocytes is smaller than normal.
• Encephalopathy.

There is an ongoing debate as to whether aluminium might be a contributing factor to Alzheimer’s disease.

Poorly Stored Herbs

• Mycotoxins

These are a potential problem with any food or herbal product.

Aspergillus flavus

This fungus produces aflatoxins, which are carcinogenic substances that have even been found in milk, linking the problem directly to grain contamination in cattle feed. It occurs mainly in contaminated cereals such as maize and legumes (e.g. peanuts), and most tree-based nuts. It is invisible to the naked eye but heat treatment and killing the fungus still leaves the aflatoxin behind. In the case of roasted peanuts, the fungus is not killed by roasting, so the longer they are left in storage, the worse the problem becomes.

Symptoms

There are is wide range, depending on the amount consumed:

• Abdominal pain.
• Vomiting.
• Pulmonary oedema.
• Liver cell damage: including fatty change.
• Haemorrhage.
• Loss of function of digestive tract.
• Convulsions.
• Cerebral oedema.
• Death.

• Claviceps purpurea (Ergot)

This is a parasite of cereal grains. Baking bread kills the mould but leaves the harmful alkaloids behind. These contract the arterioles and smooth muscles of the digestive tract.

Symptoms

• Gangrene in the extremities.
• Vomiting.
• Muscle twitching.
• Staggering gait.
• If consumption is continued, eventual death.

• Ginkgo biloba (Ginkgo, Maidenhair Tree, Bai Guo)

The ginkgo nut contains a neurotoxin that can result in convulsions and possibly death. This herb is traditionally prepared by boiling, which renders it safe.

Bibliograpy

Golan DE, Tashjian AH, Armstrong EJ. Principles of pharmacology. The pathophysiologic basis of drug therapy. Baltimore, MD: Lippincott Williams and Wilkins; 2004.

Hardman JG, Limbird LE. Goodman and Gilman’s the pharmacological basis of therapeutics, 11th edn. New York: McGraw-Hill; 2005.

Loomis TA, Wallace-Hayes. Loomis’s essentials of toxicology., 4th edn. London: Taylor and Francis; 2001.

Rang HP, Dale MM, Ritter JM. Pharmacology, 6th edn. Edinburgh: Churchill Livingstone; 2007; 2007.

Reid JL, Rubin PC, Whiting B. Clinical pharmacology., 7th rev. edn. Oxford: Blackwell; 2006; 2006.

Waller DG, Renwick AG, Hillier K. Medical pharmacology and therapeutics, 2nd rev. edn. Edinburgh: Elsevier Saunders; 2005.

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