Fundamental Toxicology for Chemistsby Douglas B McGregor
This book is a core introductory text to the subject of toxicology and the use of toxicological information for risk assessment by chemists. Increasingly, chemists are being required by law to advise on the safe handling of chemicals. Few chemists, however, have been trained in toxicology, and the subject is often not covered in a chemistry degree curriculum. It is
This book is a core introductory text to the subject of toxicology and the use of toxicological information for risk assessment by chemists. Increasingly, chemists are being required by law to advise on the safe handling of chemicals. Few chemists, however, have been trained in toxicology, and the subject is often not covered in a chemistry degree curriculum. It is to address this problem that this book has been written. Fundamental Toxicology for Chemists contains a proposed curriculum for teaching toxicology to chemists, which gives a firm grounding in the basics. With this book as a guide, lecturers will be able to design courses that cover all their students needs. In addition, students in all areas of chemistry will find it invaluable. Fundamental Toxicology for Chemists offers a unique assessment of the subject specifically for chemists. It is both comprehensible and fully comprehensive, covering developing areas such as reproduction, behavioural and ecological toxicology. The book has been approved by the IUPAC (International Union of Pure and Applied Chemists) committees on toxicology and the teaching of chemistry. It has a comprehensive index and an extensive glossary of terms, and will have lasting value to all chemists as a reference, and a text book.
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Fundamental Toxicology for Chemists
By John H. Duffus, Howard G.J. Worth
The Royal Society of ChemistryCopyright © 1996 The Royal Society of Chemistry
All rights reserved.
Introduction to Toxicology
JOHN H. DUFFUS
Toxicology is the fundamental science of poisons. A poison is generally considered to be any substance that can cause severe injury or death as a result of a physicochemical interaction with living tissue. All substances are potential poisons since all of them can cause injury or death following excessive exposure. However, all chemicals can be used safely if exposure of people or susceptible organisms is kept below defined tolerable limits, i.e. if handled with appropriate precautions. If no tolerable limit can be defined, zero exposure methods must be used.
Exposure is a function of the amount (or concentration) of the chemical involved and the time of its interaction with people or organisms at risk. For very highly toxic substances, the tolerable exposure may be close to zero. In deciding what constitutes a tolerable exposure, the chief problem is often in deciding what constitutes an injury or adverse effect.
An adverse effect is defined as an abnormal, undesirable, or harmful change following exposure to the potentially toxic substance. The ultimate adverse effect is death but less severe adverse effects may include altered food consumption, altered body and organ weights, visible pathological changes, or simply altered enzyme levels. A statistically significant change from the normal state of the person at risk is not necessarily an adverse effect. The extent of the difference from normal, the consistency of the altered property, and the relation of the altered property to the total well-being of the person affected have to be considered.
An effect may be considered harmful if it causes functional or anatomical damage, irreversible change in homeostasis, or increased susceptibility to other chemical or biological stress, including infectious disease. The degree of harm of the effect can be influenced by the state of health of the organism. Reversible changes may also be harmful, but often they are essentially harmless. An effect which is not harmful is usually reversed when exposure to the potentially toxic chemical ceases. Adaptation of the exposed organism may occur so that it can live normally in spite of an irreversible effect.
In immune reactions leading to hypersensitivity or allergic responses, the first exposure to the causative agent may produce no adverse response, though it sensitizes the organism to respond adversely to future exposures.
The amount of exposure to a chemical required to produce injury varies over a very wide range depending on the chemical and the form in which it occurs. The extent of possible variation in harmful exposure levels is indicated in Table 1.1, which compares LD50 values for a number of potentially toxic chemicals. The LD50 value is more descriptively called the median lethal dose as defined below.
Median lethal dose (LD50) is the statistically derived single dose of a chemical that can be expected to cause death in 50% of a given population of organisms under a defined set of experimental conditions. Where LD50 values are quoted for human beings, they are derived by extrapolation from studies with mammals or from observations following accidental or suicidal exposures.
The LD50 has often been used to classify and compare toxicity among chemicals but its value for this purpose is limited. A commonly used classification of this kind is shown in Table 1.2. Such a classification is arbitrary and not entirely satisfactory. For example, it is difficult to see why a substance with an LD50 of 200 mg kg-1 body weight should be regarded only as harmful while one with an LD50 of 199 mg kg-1 body weight is said to be toxic, when the difference in values cannot be statistically significant.
In decisions relating to chemical safety, the toxicity of a substance is less important than the risk associated with its use. Risk is the predicted or actual frequency (probability) of a chemical causing unacceptable harm or effects as a result of exposure of susceptible organisms or ecosystems. Assessment of risk is often assessment of the probability of exposure.
Conversely, safety is the practical certainty that injury will not result from exposure to a hazard under defined conditions; in other words, the high probability that injury will not result. Practical certainty is the numerically specified low risk or socially acceptable risk applied to decision making. For example, a chance of one in a million of suffering harm would generally be regarded as negligible and therefore safe.
In assessing permissible exposure conditions for chemicals, uncertainty factors are applied. An uncertainty factor is the mathematical expression of uncertainty that is used to protect populations from hazards which cannot be assessed with high precision. For example, the 1977 report of the US National Academy of Sciences Safe Drinking Water Committee proposed the following guidelines for selecting uncertainty (safety) factors to be used in conjunction with no observed effect level (NOEL) data. The NOEL should be divided by the following uncertainty factors:
1 An uncertainty factor of 10 should be used when valid human data based on chronic exposure are available.
2 An uncertainty factor of 100 should be used when human data are inconclusive, e.g. limited to acute exposure histories, or absent, but when reliable animal data are available for one or more species.
3 An uncertainty factor of 1000 should be used when no long-term, or acute human data are available and experimental animal data are scanty.
This approach is subjective and is being continually updated.
Safety control often involves the assessment of acceptable risk since total elimination of risk is often impossible. 'Acceptable' risk is the probability of suffering disease or injury that will be tolerated by an individual, group, or society. Assessment of risk depends on scientific data but its 'acceptability' is influenced by social, economic, and political factors, and by the perceived benefits arising from a chemical or process.
1.2 EXPOSURE TO POTENTIALLY TOXIC SUBSTANCES
Injury can be caused by chemicals only if they reach sensitive parts of a person or other living organism at a sufficiently high concentration and for a sufficient length of time. Thus, injury depends upon the physicochemical properties of the potentially toxic substances, the exact nature of the exposure circumstances, and the health and developmental state of the person or organism at risk.
Major routes of exposure are through the skin (topical), through the lungs (inhalation), or through the gastrointestinal tract (ingestion). In general, for exposure to any given concentration of a substance for a given time, inhalation is likely to cause more harm than ingestion which, in turn, will be more harmful than topical exposure.
1.2.1 Skin (Dermal or Percutaneous) Absorption
Many people do not realize that chemicals can penetrate healthy intact skin and so this fact should be emphasized. Among the chemicals that are absorbed through the skin are aniline, hydrogen cyanide, some steroid hormones, organic mercury compounds, nitrobenzene, organophosphate compounds, and phenol. Some chemicals, such as phenol, can be lethal if absorbed for a sufficient time from a fairly small area (a few square centimetres) of skin. If protective clothing is being worn, it must be remembered that absorption through the skin of any chemical which gets inside the clothing will be even faster.
Gases and vapours are easily inhaled but inhalation of particles depends upon their size and shape. The smaller the particle, the further into the respiratory tract it can go. Dusts with an effective aerodynamic diameter of between 0.5 and 7 µm (the respirable fraction) can persist in the alveoli and respiratory bronchioles after deposition there. Peak retention depends upon aerodynamic shape but seems to be mainly of those particles with an effective aerodynamic diameter of between 1 and 2 µm. Particles of effective aerodynamic diameter less than 1 µm tend to be breathed out again and do not persist in the alveoli or enter the gut (see below).
The effective aerodynamic diameter is defined as the diameter in micrometres of a spherical particle of unit density which falls at the same speed as the particle under consideration. Dusts of larger diameter either do not penetrate the lungs or lodge further up in the bronchioles and bronchi where cilia (the mucociliary clearance mechanism) can return them to the pharynx and from there to the oesophagus.
From the oesophagus, dusts are excreted through the gut in the normal way: it is possible that particles entering the gut in this way may cause poisoning as though they had been ingested in the food. A large proportion of dust breathed in will enter the gut directly and may affect the gut directly by reacting with it chemically or indirectly from contamination with micro-organisms. As already mentioned, some constituents of dust may be absorbed from the gut and cause systemic effects.
Physical irritation by dust particles or fibres can cause very serious adverse health effects but most effects depend upon the solids being dissolved. Special consideration should be given to asbestos fibres which may lodge in the lung and cause fibrosis and cancer even though they are insoluble and therefore not classical toxicants; similar care should also be taken with manmade mineral fibres. Insoluble particles may be taken in by the macrophage cells in the lung which normally remove invading bacteria. This is the process called phagocytosis. Phagocytosis is the process whereby certain body cells, notably macrophages and neutrophils engulf and destroy invading foreign particles. The cell membrane of the phagocytosing cell (phagocyte) invaginates to capture and engulf the particle. Hydrolytic enzymes are secreted round the particle to digest it and may leak from the phagocyte and cause local tissue destruction if the particle damages the phagocyte. If phagocytic cells are adversely affected by ingestion of insoluble particles, their ability to protect against infectious organisms may be reduced and infectious diseases may follow.
Some insoluble particles such as coal dust and silica dust will readily cause fibrosis of the lung. Others, such as asbestos, may also cause fibrosis depending on the exposure conditions.
Remember that tidal volume (the volume of air inspired and expired with each normal breath) increases with physical exertion; thus absorption of a chemical as a result of inhalation is directly related to the rate of physical work.
Airborne particles breathed through the mouth or cleared by the cilia of the lungs will be ingested. Otherwise, ingestion of potentially toxic substances in the work, domestic, or natural environment is likely to be accidental and common-sense precautions should minimize this. The nature of the absorption processes following ingestion is discussed elsewhere.
The importance of concentration and time of exposure has already been pointed out. It should be remembered that exposure may be continuous or repeated at intervals over a period of time; the consequences of different patterns of exposure to the same amount of a potentially toxic substance may vary considerably in their seriousness. In most cases, the consequences of continuous exposure to a given concentration of a chemical will be worse than those of intermittent exposures to the same concentration of the chemical at intervals separated by sufficient time to permit a degree of recovery. Repeated or continuous exposure to very small amounts of potentially toxic chemicals may be a matter for serious concern if either the chemical or its effects have a tendency to accumulate in the person or organism at risk.
A chemical may accumulate if absorption exceeds excretion; this may happen with substances that combine a fairly high degree of lipid solubility with stability.
1.3 ADVERSE EFFECTS
Adverse effects may be local or systemic. Local effects occur at the site of exposure of the organism to the potentially toxic substance. Corrosives and irritants always act locally.
Systemic effects occur at some distance from the site of exposure. Most substances which are not highly reactive are absorbed and distributed around the affected organism causing systemic injury at a target organ or tissue distinct from the absorption site. The target organ is not necessarily the organ of greatest accumulation. Adipose (fatty) tissue accumulates organochlorine pesticides to very high levels but does not appear to be harmed by them.
Some substances produce both local and systemic effects. For example, tetraethyl lead damages the skin on contact and is then absorbed and transported to the central nervous system where it causes further damage.
Effects of a chemical can accumulate even if the chemical itself does not. There is evidence that this may be true of the effects of organophosphate pesticides on the nervous system.
A particularly harmful effect that may accumulate is death of nerve cells, since nerve cells cannot be replaced, though damaged nerve fibres can be regenerated.
It will be clear that the balances between absorption and excretion of a potentially toxic substance and between injury produced and repair are the key factors in determining whether any injury follows exposure. All of the possible adverse effects cannot be discussed here but some aspects should be mentioned specifically.
Production of mutations, tumours and cancer, and defects of embryonic and fetal development are of particular concern.
Adverse effects related to allergies appear to be increasing. Allergy (hypersensitivity) is the name given to disease symptoms following exposure to a previously encountered substance (allergen) which would otherwise be classified as harmless. Essentially, an allergy is an adverse reaction of the altered immune system. The process, which leads to the disease response on subsequent exposure to the allergen, is called sensitization. Allergic reactions may be very severe and even fatal.
To produce an allergic reaction, most chemicals must act as haptens, i.e. combine with proteins to form antigens. Antigens entering the human body or produced within it cause the production of antibodies. Usually at least a week is needed before appreciable amounts of antibodies can be detected and further exposure to the allergen can produce disease symptoms. The most common symptoms are skin ailments such as dermatitis and urticaria, or eye problems such as conjunctivitis. The worst may be death resulting from anaphylactic shock.
Of particular importance in considering the safety of individuals is the possibility of idiosyncratic reactions. An idiosyncratic reaction is an excessive reactivity of an individual to a chemical, for example an extreme sensitivity to low doses as compared with an average member of the population. There is also the possibility of an abnormally low reactivity to high doses. An example of a group of people with an idiosyncrasy is the group that has a deficiency in the enzyme required to convert methaemoglobin (which cannot carry oxygen) back to haemoglobin; this group is exceptionally sensitive to chemicals like nitrites which produce methaemoglobin.
Another factor to be considered is whether the adverse effects produced by a potentially toxic chemical are likely to be immediate or delayed. Immediate effects appear rapidly after exposure to a chemical while delayed effects appear only after a considerable lapse of time.
Among the most serious delayed effects are cancers; carcinogenesis may take 20 or more years before tumours are seen in humans.
Perhaps the most difficult adverse effects to detect are those that follow years after exposure in the womb; a well established example of such an effect is the vaginal cancer produced in young women whose mothers have been exposed to diethylstilbestrol during pregnancy.
Another important aspect of adverse effects to be considered is whether they are reversible or irreversible. For the liver, which has a great capacity for regeneration, many adverse effects are reversible, and complete recovery can occur. For the central nervous system, in which regeneration of tissue is severely limited, most adverse effects leading to morphological changes are irreversible and recovery is, at best, limited. Carcinogenic and teratogenic effects may also be irreversible, but suitable treatment may reduce the severity of effects.
1.4 CHEMICAL INTERACTIONS
A major problem in assessing the likely effect of exposure to a chemical is that of assessing possible interactions. The simplest interaction is an additive effect: this is an effect which is the result of two or more chemicals acting together and which is the simple sum of their effects when acting independently.
In mathematical terms: 1 + 1 = 2, 1 + 5 = 6 etc.
The effects of organophosphate pesticides are usually additive.
More complex is a synergistic (multiplicative) effect: this is an effect of two chemicals acting together which is greater than the simple sum of their effects when acting alone; it may be called synergism.
In mathematical terms: 1 + 1=4,1+5 = 10 etc.
Asbestos fibres and cigarette smoking act together to increase the risk of lung cancer by a factor of 40, taking it well beyond the risk associated with independent exposure to either of these agents.
Excerpted from Fundamental Toxicology for Chemists by John H. Duffus, Howard G.J. Worth. Copyright © 1996 The Royal Society of Chemistry. Excerpted by permission of The Royal Society of Chemistry.
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