~~~ Excellent. Thanks, Kathi! ~~~ http://www.bio.hw.ac.uk/edintox/Exposure.htm Exposure to potentially toxic substances and their adverse effects -------------------------------------------------------------------------------- OBJECTIVE You should know the routes of human exposure to potentially toxic chemicals and the ways in which resultant effects may depend upon these routes, exposure pattern and the properties of the chemicals. You should know about allergy and its possible consequences. You should know about idiosyncratic reactions, delayed effects and irreversible effects. You should know about the complexities of possible interactions between chemicals and their effects. Introduction 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. Skin (dermal or percutaneous) absorption Many people do not realise that chemicals can penetrate healthy intact skin and so this fact should be emphasized. Amongst 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. Inhalation 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 10 micrometres (the respirable fraction, the PM10 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 micrometers. Particles of effective aerodynamic diameter less than 1 micrometre tend to be breathed out again and do not persist either in the alveoli or enter the gut (see below). Remember: The effective aerodynamic diameter is defined as the diameter in micrometers 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 (phagocytosis). 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. Note: 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 and oxidative enzymes are released around the particle to cause its destruction: these enzymes may leak from the phagocyte and cause local tissue damage. Tissue damage may release biologically active substances which cause further adverse effects. Some insoluble particles such as coal dust and silica dust will readily cause fibrosis of the lung. Others, such as asbestos, may or may not 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. This is why jogging and other active exercise has been discouraged in certain cities during periods of severe air pollution. Ingestion 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 commonsense 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. 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 always act locally. Irritants frequently act locally. 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 is 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 have been referred to in Descriptive terms. Adverse effects related to allergies are a cause of increasing concern. 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, that is - 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. Most common symptoms are skin ailments such as dermatitis and urticaria, or eye problems such as conjunctivitis; the worst possibility is 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 the 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 which 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. Amongst 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 are also irreversible, but suitable treatment may reduce the severity of effects. A major problem in assessing the likely effect of exposure to a chemical is making allowance for 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 forty, taking it well beyond the risk associated with independent exposure to either of these agents. Another possible form of interaction is potentiation. In potentiation, a substance which on its own causes no harm makes the effects of another chemical much worse. This may be considered to be a form of synergism. In mathematical terms: 0 + 1 = 5, 0 + 5 = 20 etc. For example - isopropanol, at concentrations which are not harmful to the liver, increases (potentiates) liver damage caused by a given concentration of carbon tetrachloride. The opposite of synergism is antagonism: an antagonistic effect is the result of a chemical counteracting the adverse effect of another; in other words, the situation where exposure to 2 chemicals together has less effect than the simple sum of their independent effects; such chemicals are said to show antagonism. In mathematical terms: 1 + 1 = 0, 1 + 5 = 2 etc. Tolerance is a decrease in sensitivity to a chemical following exposure to it or a structurally related substance. For example - cadmium causes tolerance to itself in some tissues by inducing the synthesis of the metal-binding protein, metallothionein. However, it should be noted that cadmium-metallothionein sticks in the kidney causing nephrotoxicity. Resistance is almost complete insensitivity to a chemical. It usually reflects metabolic capacity to inactivate and eliminate the chemical and its metabolites rapidly. -------------------------------------------------------------------------------- SUMMARY You have now learnt about routes of human exposure to potentially toxic chemicals and how effects depend upon exposure pattern and the properties of the chemicals involved. You have also learned about allergy (hypersensitivity) and possible allergic reactions. You should know what an idiosyncratic reaction is, what a delayed toxic effect is and what may constitute an irreversible effect. Local and systemic injuries have been discussed. Definitions and examples have been given of possible interactions between potentially toxic chemicals. -------------------------------------------------------------------------------- SELF ASSESSMENT QUESTIONS What are the routes of human exposure to potentially toxic chemicals? Name 5 chemicals that are readily absorbed through the skin. What diameter of particle can reach the alveoli? What are phagocytosis and tidal volume and why are they important in human toxicology? How are inhalation and ingestion related? What combinations of exposure pattern and chemical properties are likely to be the most harmful? What are the key factors in determining whether injury follows exposure to a potentially toxic chemical? What is hypersensitivity (allergy)? What are the most common symptoms of allergy? Define "idiosyncratic reaction and give an example. Give an example of a delayed toxic effect and name the potentially toxic chemical that causes it. Name 3 adverse effects that are essentially irreversible. What is systemic injury and what is a target organ? What is the importance of body fat in relation to potentially toxic substances? What are the possibilities for interactions between potentially toxic substances in causing injury? Give examples.