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Effect of Age, Sex and Other Factors

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There are often large differences among humans in the intensity of response to toxic chemicals, and variations in susceptibility of an individual over a lifetime. These can be attributed to a variety of factors capable of influencing absorption rate, distribution in the body, biotransformation and/or excretion rate of a particular chemical. Apart from the known hereditary factors which have been clearly demonstrated to be linked with increased susceptibility to chemical toxicity in humans (see “Genetic determinants of toxic response”), other factors include: constitutional characteristics related to age and sex; pre-existing disease states or a reduction in organ function (non-hereditary, i.e., acquired); dietary habits, smoking, alcohol consumption and use of medications; concomitant exposure to biotoxins (various micro- organisms) and physical factors (radiation, humidity, extremely low or high temperatures or barometric pressures particularly relevant to the partial pressure of a gas), as well as concomitant physical exercise or psychological stress situations; previous occupational and/or environmental exposure to a particular chemical, and in particular concomitant exposure to other chemicals, not necessarily toxic (e.g., essential metals). The possible contributions of the aforementioned factors in either increasing or decreasing susceptibility to adverse health effects, as well as the mechanisms of their action, are specific for a particular chemical. Therefore only the most common factors, basic mechanisms and a few characteristic examples will be presented here, whereas specific information concerning each particular chemical can be found in elsewhere in this Encyclopaedia.

According to the stage at which these factors act (absorption, distribution, biotransformation or excretion of a particular chemical), the mechanisms can be roughly categorized according to two basic consequences of interaction: (1) a change in the quantity of the chemical in a target organ, that is, at the site(s) of its effect in the organism (toxicokinetic interactions), or (2) a change in the intensity of a specific response to the quantity of the chemical in a target organ (toxicodynamic interactions). The most common mechanisms of either type of interaction are related to competition with other chemical(s) for binding to the same compounds involved in their transport in the organism (e.g., specific serum proteins) and/or for the same biotransformation pathway (e.g., specific enzymes) resulting in a change in the speed or sequence between initial reaction and final adverse health effect. However, both toxicokinetic and toxicodynamic interactions may influence individual susceptibility to a particular chemical. The influence of several concomitant factors can result in either: (a) additive effects—the intensity of the combined effect is equal to the sum of the effects produced by each factor separately, (b) synergistic effects—the intensity of the combined effect is greater than the sum of the effects produced by each factor separately, or (c) antagonistic effects—the intensity of the combined effect is smaller than the sum of the effects produced by each factor separately.

The quantity of a particular toxic chemical or characteristic metabolite at the site(s) of its effect in the human body can be more or less assessed by biological monitoring, that is, by choosing the correct biological specimen and optimal timing of specimen sampling, taking into account biological half-lives for a particular chemical in both the critical organ and in the measured biological compartment. However, reliable information concerning other possible factors that might influence individual susceptibility in humans is generally lacking, and consequently the majority of knowledge regarding the influence of various factors is based on experimental animal data.

It should be stressed that in some cases relatively large differences exist between humans and other mammals in the intensity of response to an equivalent level and/or duration of exposure to many toxic chemicals; for example, humans appear to be considerably more sensitive to the adverse health effects of several toxic metals than are rats (commonly used in experimental animal studies). Some of these differences can be attributed to the fact that the transportation, distribution and biotransformation pathways of various chemicals are greatly dependent on subtle changes in the tissue pH and the redox equilibrium in the organism (as are the activities of various enzymes), and that the redox system of the human differs considerably from that of the rat.

This is obviously the case regarding important antioxidants such as vitamin C and glutathione (GSH), which are essential for maintaining redox equilibrium and which have a protective role against the adverse effects of the oxygen- or xenobiotic-derived free radicals which are involved in a variety of pathological conditions (Kehrer 1993). Humans cannot auto-synthesize vitamin C, contrary to the rat, and levels as well as the turnover rate of erythrocyte GSH in humans are considerably lower than that in the rat. Humans also lack some of the protective antioxidant enzymes, compared to the rat or other mammals (e.g., GSH- peroxidase is considered to be poorly active in human sperm). These examples illustrate the potentially greater vulnerability to oxidative stress in humans (particularly in sensitive cells, e.g., apparently greater vulnerability of the human sperm to toxic influences than that of the rat), which can result in different response or greater susceptibility to the influence of various factors in humans compared to other mammals (Telišman 1995).

Influence of Age

Compared to adults, very young children are often more susceptible to chemical toxicity because of their relatively greater inhalation volumes and gastrointestinal absorption rate due to greater permeability of the intestinal epithelium, and because of immature detoxification enzyme systems and a relatively smaller excretion rate of toxic chemicals. The central nervous system appears to be particularly susceptible at the early stage of development with regard to neurotoxicity of various chemicals, for example, lead and methylmercury. On the other hand, the elderly may be susceptible because of chemical exposure history and increased body stores of some xenobiotics, or pre-existing compromised function of target organs and/or relevant enzymes resulting in lowered detoxification and excretion rate. Each of these factors can contribute to weakening of the body’s defences—a decrease in reserve capacity, causing increased susceptibility to subsequent exposure to other hazards. For example, the cytochrome P450 enzymes (involved in the biotransformation pathways of almost all toxic chemicals) can be either induced or have lowered activity because of the influence of various factors over a lifetime (including dietary habits, smoking, alcohol, use of medications and exposure to environmental xenobiotics).

Influence of Sex

Gender-related differences in susceptibility have been described for a large number of toxic chemicals (approximately 200), and such differences are found in many mammalian species. It appears that males are generally more susceptible to renal toxins and females to liver toxins. The causes of the different response between males and females have been related to differences in a variety of physiological processes (e.g., females are capable of additional excretion of some toxic chemicals through menstrual blood loss, breast milk and/or transfer to the foetus, but they experience additional stress during pregnancy, delivery and lactation), enzyme activities, genetic repair mechanisms, hormonal factors, or the presence of relatively larger fat depots in females, resulting in greater accumulation of some lipophilic toxic chemicals, such as organic solvents and some medications.

Influence of Dietary Habits

Dietary habits have an important influence on susceptibility to chemical toxicity, mostly because adequate nutrition is essential for the functioning of the body’s chemical defence system in maintaining good health. Adequate intake of essential metals (including metalloids) and proteins, especially the sulphur-containing amino acids, is necessary for the biosynthesis of various detoxificating enzymes and the provision of glycine and glutathione for conjugation reactions with endogenous and exogenous compounds. Lipids, especially phospholipids, and lipotropes (methyl group donors) are necessary for the synthesis of biological membranes. Carbohydrates provide the energy required for various detoxification processes and provide glucuronic acid for conjugation of toxic chemicals and their metabolites. Selenium (an essential metalloid), glutathione, and vitamins such as vitamin C (water soluble), vitamin E and vitamin A (lipid soluble), have an important role as antioxidants (e.g., in controlling lipid peroxidation and maintaining integrity of cellular membranes) and free-radical scavengers for protection against toxic chemicals. In addition, various dietary constituents (protein and fibre content, minerals, phosphates, citric acid, etc.) as well as the amount of food consumed can greatly influence the gastrointestinal absorption rate of many toxic chemicals (e.g., the average absorption rate of soluble lead salts taken with meals is approximately eight per cent, as opposed to approximately 60% in fasting subjects). However, diet itself can be an additional source of individual exposure to various toxic chemicals (e.g., considerably increased daily intakes and accumulation of arsenic, mercury, cadmium and/or lead in subjects who consume contaminated seafood).

Influence of Smoking

The habit of smoking can influence individual susceptibility to many toxic chemicals because of the variety of possible interactions involving the great number of compounds present in cigarette smoke (especially polycyclic aromatic hydrocarbons, carbon monoxide, benzene, nicotine, acrolein, some pesticides, cadmium, and, to a lesser extent, lead and other toxic metals, etc.), some of which are capable of accumulating in the human body over a lifetime, including pre-natal life (e.g., lead and cadmium). The interactions occur mainly because various toxic chemicals compete for the same binding site(s) for transport and distribution in the organism and/or for the same biotransformation pathway involving particular enzymes. For example, several cigarette smoke constituents can induce cytochrome P450 enzymes, whereas others can depress their activity, and thus influence the common biotransformation pathways of many other toxic chemicals, such as organic solvents and some medications. Heavy cigarette smoking over a long period can considerably reduce the body’s defence mechanisms by decreasing reserve capacity to cope with the adverse influence of other life-style factors.

Influence of Alcohol

Consumption of alcohol (ethanol) can influence susceptibility to many toxic chemicals in several ways. It can influence the absorption rate and distribution of certain chemicals in the body—for example, increase the gastrointestinal absorption rate of lead, or decrease the pulmonary absorption rate of mercury vapour by inhibiting oxidation which is necessary for retention of inhaled mercury vapour. Ethanol can also influence susceptibility to various chemicals through short-term changes in tissue pH and increase in the redox potential resulting from ethanol metabolism, as both ethanol oxidizing to acetaldehyde and acetaldehyde oxidizing to acetate produce an equivalent of reduced nicotinamide adenine dinucleotide (NADH) and hydrogen (H+). Because the affinity of both essential and toxic metals and metalloids for binding to various compounds and tissues is influenced by pH and changes in the redox potential (Telišman 1995), even a moderate intake of ethanol may result in a series of consequences such as: (1) redistribution of long-term accumulated lead in the human organism in favour of a biologically active lead fraction, (2) replacement of essential zinc by lead in zinc-containing enzyme(s), thus affecting enzyme activity, or influence of mobil- ized lead on the distribution of other essential metals and metalloids in the organism such as calcium, iron, copper and selenium, (3) increased urinary excretion of zinc and so on. The effect of possible aforementioned events can be augmented due to the fact that alcoholic beverages can contain an appreciable amount of lead from vessels or processing (Prpic-Majic et al. 1984; Telišman et al. 1984; 1993).

Another common reason for ethanol-related changes in susceptibility is that many toxic chemicals, for example, various organic solvents, share the same biotransformation pathway involving the cytochrome P450 enzymes. Depending on the intensity of exposure to organic solvents as well as the quantity and frequency of ethanol ingestion (i.e., acute or chronic alcohol consumption), ethanol can either decrease or increase biotransformation rates of various organic solvents and thus influence their toxicity (Sato 1991).

Influence of Medications

The common use of various medications can influence susceptibility to toxic chemicals mainly because many drugs bind to serum proteins and thus influence the transport, distribution or excretion rate of various toxic chemicals, or because many drugs are capable of inducing relevant detoxifying enzymes or depressing their activity (e.g., the cytochrome P450 enzymes), thus affecting the toxicity of chemicals with the same biotransformation pathway. Characteristic for either of the mechanisms is increased urinary excretion of trichloroacetic acid (the metabolite of several chlorinated hydrocarbons) when using salicylate, sulphonamide or phenylbutazone, and an increased hepato-nephrotoxicity of carbon tetrachloride when using phenobarbital. In addition, some medications contain a considerable amount of a potentially toxic chemical, for example, the aluminium-containing antacids or preparations used for therapeutic management of the hyperphosphataemia arising in chronic renal failure.

Influence of Concomitant Exposure to Other Chemicals

The changes in susceptibility to adverse health effects due to interaction of various chemicals (i.e., possible additive, synergistic or antagonistic effects) have been studied almost exclusively in experimental animals, mostly in the rat. Relevant epidemiological and clinical studies are lacking. This is of concern particularly considering the relatively greater intensity of response or the variety of adverse health effects of several toxic chemicals in humans compared to the rat and other mammals. Apart from published data in the field of pharmacology, most data are related only to combinations of two different chemicals within specific groups, such as various pesticides, organic solvents, or essential and/or toxic metals and metalloids.

Combined exposure to various organic solvents can result in various additive, synergistic or antagonistic effects (depending on the combination of certain organic solvents, their intensity and duration of exposure), mainly due to the capability of influencing each other’s biotransformation (Sato 1991).

Another characteristic example are the interactions of both essential and/or toxic metals and metalloids, as these are involved in the possible influence of age (e.g., a lifetime body accumulation of environmental lead and cadmium), sex (e.g., common iron deficiency in women), dietary habits (e.g., increased dietary intake of toxic metals and metalloids and/or deficient dietary intake of essential metals and metalloids), smoking habit and alcohol consumption (e.g., additional exposure to cadmium, lead and other toxic metals), and use of medications (e.g., a single dose of antacid can result in a 50-fold increase in the average daily intake of aluminium through food). The possibility of various additive, synergistic or antagonistic effects of exposure to various metals and metalloids in humans can be illustrated by basic examples related to the main toxic elements (see table 1), apart from which further interactions may occur because essential elements can also influence one another (e.g., the well-known antagonistic effect of copper on the gastrointestinal absorption rate as well as the metabolism of zinc, and vice versa). The main cause of all these interactions is the competition of various metals and metalloids for the same binding site (especially the sulphhydryl group, -SH) in various enzymes, metalloproteins (especially metallothionein) and tissues (e.g., cell membranes and organ barriers). These interactions may have a relevant role in the development of several chronic diseases which are mediated through the action of free radicals and oxidative stress (Telišman 1995).

Table 1. Basic effects of possible multiple interactions concerning the main toxic and/or essential metals and matalloids in mammals

Toxic metal or metalloid Basic effects of the interaction with other metal or metalloid
Aluminium (Al) Decreases the absorption rate of Ca and impairs the metabolism of Ca; deficient dietary Ca increases the absorption rate of Al. Impairs phosphate metabolism. Data on interactions with Fe, Zn and Cu are equivocal (i.e., the possible role of another metal as a mediator).
Arsenic (As) Affects the distribution of Cu (an increase of Cu in the kidney, and a decrease of Cu in the liver, serum and urine). Impairs the metabolism of Fe (an increase of Fe in the liver with concomitant decrease in haematocrit). Zn decreases the absorption rate of inorganic As and decreases the toxicity of As. Se decreases the toxicity of As and vice versa.
Cadmium (Cd) Decreases the absorption rate of Ca and impairs the metabolism of Ca; deficient dietary Ca increases the absorption rate of Cd. Impairs the phosphate metabolism, i.e., increases urinary excretion of phosphates. Impairs the metabolism of Fe; deficient dietary Fe increases the absorption rate of Cd. Affects the distribution of Zn; Zn decreases the toxicity of Cd, whereas its influence on the absorption rate of Cd is equivocal. Se decreases the toxicity of Cd. Mn decreases the toxicity of Cd at low-level exposure to Cd. Data on the interaction with Cu are equivocal (i.e., the possible role of Zn, or another metal, as a mediator). High dietary levels of Pb, Ni, Sr, Mg or Cr(III) can decrease the absorption rate of Cd.
Mercury (Hg) Affects the distribution of Cu (an increase of Cu in the liver). Zn decreases the absorption rate of inorganic Hg and decreases the toxicity of Hg. Se decreases the toxicity of Hg. Cd increases the concentration of Hg in the kidney, but at the same time decreases the toxicity of Hg in the kidney (the influence ofthe Cd-induced metallothionein synthesis).
Lead (Pb) Impairs the metabolism of Ca; deficient dietary Ca increases the absorption rate of inorganic Pb and increases the toxicity of Pb. Impairs the metabolism of Fe; deficient dietary Fe increases the toxicity of Pb, whereas its influence on the absorption rate of Pb is equivocal. Impairs the metabolism of Zn and increases urinary excretion of Zn; deficient dietary Zn increases the absorption rate of inorganic Pb andincreases the toxicity of Pb. Se decreases the toxicity of Pb. Data on interactions with Cu and Mg are equivocal (i.e., the possible role of Zn, or another metal, as a mediator).

Note: Data are mostly related to experimental studies in the rat, whereas relevant clinical and epidemiological data (particularly regarding quantitative dose-response relationships) are generally lacking (Elsenhans et al. 1991; Fergusson 1990; Telišman et al. 1993).



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