Exposure to Chemical Substances

Among the 10 million known chemical compounds, there are some 50 000 which are in common use. Workers are usually exposed to several agents si­multaneously (their interactions are considered in section In addi­tion, many impurities in workplace air are inherently complex mixtures, which may consist of hundreds of different compounds. Mineral oils and wood dusts are examples of common complex mixtures. Characterization of Exposures

Indoor and Outdoor Exposure to Pollutants

Occupational and environmental exposure to chemicals can take place both indoors and outdoors. Occupational exposure is caused by the chemicals that are used and produced indoors in industrial plants, whereas nonoccupa — tional (and occupational nonindustrial) indoor exposure is mainly caused by products. Toluene in printing plants and styrene in the reinforced plastic indus­try are typical examples of the two types of industrial occupational exposures. Products containing styrene polymers may release the styrene monomer into indoor air in the nonindustrial environment for a long time. Formaldehyde is another typical indoor pollutant. The source of formaldehyde is the resins used in the production process. During accidents, occupational and environmental exposures may occur simultaneously. Years ago, dioxin was formed as a by­product of production of phenoxy acid herbicides. An explosion in a factory in

Seveso, Italy, caused wide-spread pollution of the industrial site as well as its surroundings. Serious effects of dioxin were detected both in domestic animals, such as cows and sheep, and in humans, the most serious early effects being a serious skin disease, chloracne, and alterations in the function of the immune system. Follow-up studies have demonstrated that this accident also increased the cancer risk in exposed individuals.51

Outdoor inhalation exposure is mainly due to traffic, energy production, heating, and natural factors such as pollen and mineral dusts. These outdoor sources of pollution also affect indoor air quality. The indoor concentration is typically 20-70% of the corresponding outdoor concentration. Occasionally the indoor concentrations of an external pollutant (especially radon) may even exceed the concentrations outdoors.41

In densely populated areas, traffic is responsible for massive exhausts of ni­trous oxides, soot, polyaromatic hydrocarbons, and carbon monoxide. Traffic emissions also markedly contribute to the formation of ozone in the lower parts of the atmosphere. In large cities, fine particle exposure causes excess mortality which varies between one and five percent in the general population.45 Con­tamination of the ground water reservoirs with organic solvents has caused con­cern in many countries due to the persistent nature of the pollution. A total exposure assessment that takes into consideration all exposures via all routes is a relatively new concept, the significance of which is rapidly increasing.52’53

Characteristics of Industrial Processes

The in-plant emissions can be divided into process and manual emissions. In the process industry, the emission sources can usually be enclosed and the workers do not need to stay for long periods close to the emissions. The emis­sions are minor, and even if they do occur, they are generally released far from the areas where workers have their accommodation. Often, workers can spend most of their time in clean control rooms. In certain process industries, such as the petrochemical industry, the processes are located largely outdoors, and the emissions are mainly fugitive emissions from leaking seals of flanges, valves, and pump shafts. Manual emissions occur in the immediate vicinity of the worker due to the task he or she is performing. Typical examples include welding, painting, gluing, sawing, and grinding. It is natural that the exposure control is much easier for process emissions than for manual ones. Even very toxic substances can be used safely in the process industry whereas even mod­erately noxious chemicals may cause major problems in manual tasks. Thus, avoidance of those manual tasks with chemicals known to cause adverse health effects is important. If the automation of these tasks becomes very ex­pensive, it may be possible to use subcontractors who specialize in this kind of work and have adequate control arrangements in their production facilities.

The best way to control exposure is to replace dangerous agents with safer ones. Today, highly toxic solvents, such as benzene, bromobenzene, car­bon tetrachloride, and chloroform are no longer extensively used. Benzene re­mains, however, an important chemical in the petrochemical industry, but the processes where it is used are closed.

The use of other highly toxic substances, such as lead and carbon disul­fide, which have in the past caused many occupational diseases, is also rare in

Manual tasks nowadays. Thus, relatively tew possibilities for substitution are left in individual workplaces. One rather common exception does exist; very fine powders can often be replaced with granular or liquid products. All possi­bilities to replace solvent-based products with water-based alternatives have not yet been utilized. However, one must be aware of the possible novel risks involved with the use of the new products; for example, when acid-cured fur­niture paints and lacquers, which released formaldehyde, have been replaced with acrylic resins, skin sensitization has become more common among furni­ture painters.

Since process disturbances do take place, and accidental releases are possible, even from processes closed under normal conditions, the plants where highly toxic or sensitizing substances are in use or may be generated should be provided with continuous monitoring and alarm systems in the critical areas. Exposure Routes

The exposure routes include the lungs, i. e., inhalational exposure, the skin, i. e., dermal exposure, and the mouth, i. e., oral exposure.52’54 Inhalation is usually considered to be the most important route for occupational expo­sure. Some chemicals are also absorbed via the skin or damage (irritation or sensitization) to the skin, and thereby amplify their own absorptions. Poor personal hygiene may result in oral exposure from eating or smoking with dirty hands. Toxic effects also often depend on the exposure route. The effects of irritating agents occur at the contact site. On the other hand, many com­pounds are distributed widely in the body and the target organ may be situ­ated far from the entry site. Compounds may become concentrated in certain organs. The organ with the highest concentration is, however, not necessarily the target organ; for example, lead is accumulated in the bones but its most se­vere effects appear in the central nervous system. Many lipophilic carcinogens are accumulated in the adipose tissue but the cancer does not usually develop there but rather in the target organs, such as the liver, the kidneys, or the lungs.5-57

Inhalational Exposure

Gases, vapors, mists, and dusts are mainly absorbed into the body through the lungs. Lipid-soluble vapors, especially those of solvents, and gases reach the alveolar space without any difficulty from where they pass through the respiratory tract, and diffuse readily across alveolar lining to reach the systemic circulation. Passive diffusion is based on a concentration gradient between alveolar air and the blood. The rapidity of the saturation of the blood with gaseous compounds largely depends on the blood and lipid solubility of the gas. Highly blood — and lipid-soluble compounds reach saturation slowly whereas vapors and gases with low blood — and lipid-solu — bilitv rapidly become saturated in the blood.58-60 Also, water-solubility and reactivity greatly affect penetration through the lung. Very water-soluble and reactive compounds tend to dissolve in the mucus in the upper respira­tory airways, or react with proteins in the mucus, and only a small portion of the dose of such compounds ever reaches the alveolar region of the lungs. Examples include sulfur dioxide and formaldehyde. Especially, the latter reaches the alveolar region only at high concentrations because it reacts with proteins in the mucus and in the cells of the epithelial lining of the up­per respiratory tract. On the other hand, as a consequence of its reactivity, high concentrations of formaldehyde cause serious lung injury and lung edema upon reaching the alveolar region.58’59

Aerosols reach the alveolar space depending on their particle size and physico-chemical characteristics. Small particles that reach the alveolar region (see Sections 2.3.7 and 3.1.1) may reach the circulation through the lymphatic drainage of the alveolar region.

Dermal Exposure

Skin is also important as an occupational exposure route. Lipid-soluble solvents often penetrate the skin, especially as a liquid. Not only solvents, but also many pesticides are, in fact, preferentially absorbed into the body through the skin. The ease of penetration depends on the molecular size of the compound, and the characteristics of the skin, in addition to the lipid solubil­ity and polarity of the compounds. Absorption of chemicals is especially effec­tive in such areas of the skin as the face and scrotum. Even though solid materials do not usually readily penetrate the skin, there are exceptions (e. g., benzo(<z)pyrene and chlorophenols) to this rule.57’60’61

Oral Exposure

In the occupational setting, oral exposure is of minor significance, being mainly due to poor personal hygiene. In addition, gases that dis­solve or are otherwise trapped in the upper respiratory tract, usually are swallowed and enter the gastrointestinal tract. Particles that are removed as such or are captured by macrophages by the mucociliary escalator from the respiratory tract are also ultimately swallowed and enter the gastrointestinal tract. Physico-Chemical Determinants of Exposure

Physico-chemical characteristics greatly determine the entry of chemicals into the body, and also their behavior in the body (distribution, biotransfor­mation, and excretion). Therefore, the physico-chemical characteristics of a compound affect its dose and its subsequent effects by determining how quickly and extensively a chemical reaches the target organs. In the following section, some of these important physical-chemical characteristics of chemi­cals will be discussed.

Water Solubility

The site and the severity of the effect of respiratory irritant gases depend largely on their water solubility. Very water-soluble gases and vapors, such as ammonia, hydrogen chloride, sulfur dioxide, and formaldehyde dissolve in the mucus of the nose and upper airway and cause inflammation. Poorly water — soluble gases, such as nitrogen dioxide and ozone, are able to reach the deep lung area. Inflammation results from damage to cellular membranes of bron — chiolar and alveolar cells, and subsequent accumulation of liquid in the lungs (edema). Because the alveoli have no receptors for irritation, the effects are generally noticed only several hours after the exposure when the amount of liquid accumulating has become so large that it impairs gas exchange. In addi­tion to water-solubility, the reactivity of the gas with airway proteins is impor­tant. Thus, sulfur dioxide is removed effectively by the nose while ethanol is partially absorbed. If a soluble gas is adsorbed on fine particles, it can be transported deep to the lungs.58’59

The solubility coefficient S is used as a measure of water solubility. It is the ratio between the concentrations in water and air phases at equilibrium. Ethanol, a very soluble gas, has a solubility coefficient of 1 100 at 37 °C while the coefficient for nitrous oxide, a poorly soluble gas, is 0.15.

The Importance of pH and pKa

Under physiological conditions, pKa (negative common logarithm of the acid constant) of a compound largely determines its behavior at varying pH. This is important because the dissolution of polar molecules in lipid bi­layers is a difficult and slow process, and from a practical toxicokinetic point of view, most polar compounds fail to penetrate biological mem­branes to any significant extent. Ionization of most weak acids and bases depends on their dissociation constant and pH according to the Henderson- Hasselbach equation:62

Log[ A~/HA] — pH — pKa (for weak acids) log[B/BH+] = pH — pKa (for weak bases)

The proportion of ionized and unionized forms of a chemical compound can be readily calculated according to the above equation. It can be easily

Seen that pKa is also a pH value at which 50% of the compound exists in

Ionized form. The ionization of weak acids increases as the pH increases, whereas the ionization of weak bases increases when the pH decreases. As the proportion of an ionized chemical increases, the diffusion of the chem­ical through the biological membranes is greatly impaired, and this attenu­ates toxicokinetic processes. For example, the common drug acetosalicylic acid (aspirin), a weak acid, is readily absorbed from the stomach because most of its dose is in an unionized form at the acidic pH of the stom­ach.62’63

Lipid Solubility

Cell membranes are composed of lipid bilayers which contain large pro­tein molecules and glycoproteins. To be able to penetrate through the cell membrane, a compound has to dissolve in the lipid bilayer, where it diffuses according to the concentration gradient across both sides of the membrane, and after passing through the membrane, dissolve once more in the water phase within the cell. Lipid-soluble compounds can reach high concentra­tions in lipid-rich organs, such as the adipose tissue, brain, bone marrow, and spleen. Lipid-solubility is often characterized by an octanol/water coef­ficient which indicates the concentration ratio of the compound between these two phases. For example, xylene, a non-polar lipid-soluble organic solvent, has an octanol/water coefficient of 3200. In addition to polar or­ganic compounds, many inorganic gases have low octanol/water coeffi­cients.62

Blood Solubility

Absorption of a gaseous compound from the lungs depends on its blood solubility. For most compounds, blood solubility is similar to water solubility. Flowever, the blood solubility coefficient may hccomc much higher than the water solubility coefficient if the blood proteins have a high affinity for the compound. Carbon monoxide, for which hemoglobin has a high affinity, is a good example (see Section 4.3.3). Blood solubility is deci­sive for the rapidity of the action of the compound, especially on the ctntral nervous system, but also on other organs. Often lipid-soluble vapors such as diethyl ether or organic solvents such as xylenes also have a high blood solubility.62,63

The toxic effect depends both on lipid and blood solubility, [‘his will be il­lustrated with an example of anesthetic gases. The solubility of dinitrous ox­ide (N20) in blood is very small; therefore, it very quickly saturates in the blood, and its effect on the central nervous system is quick, but because N20 is not highly lipid soluble, it does not cause deep anesthesia. Halothane and diethyl ether, in contrast, are very lipid soluble, and their solubility in the blood is also high. Thus, their saturation in the blood takes place slowly, For the same reason, the increase of tissue concentration is a slow process. On the other hand, the depression of the central nervous system may become deep, and may even cause death. During the elimination phase, the same processes occur in reverse order. N20 is rapidly eliminated whereas the elimination of halothane and diethyl ether is slow. In addition, only a small part of halothane and diethyl ether are eliminated via the lungs. They require first biotransfor­mation and then elimination of the metabolites through the kidneys into the llrine.62’63

Partition Coefficients

Other important determinants of the effects of compounds, especially sol­vents, are their partition coefficients, e. g., blood-tissue partition coefficients, which determine the distribution of the compound in the body. The air-blood partition coefficient is also important for the absorption of a compound be­cause it determines how quickly the compound can be absorbed from the air­space of the lungs into the circulation. An example of a compound that has a high air-blood partition coefficient is trichloroethane (low blood solubility) whereas most organic solvents (e. g., benzene analogues) have low air-blood partition coefficients (high blood solubility).62,63

Vapor Pressure

Vapor pressure is important simply because a compound that is easily va­porized can also readily cause a marked exposure through the lungs. Organic solvents are good examples of volatile compounds, and known to cause marked exposure via the lungs, in addition to exposure via the skin.64

Particle Size

The size of inhaled particles varies markedly. The size distribution ap­proximates a log-normal distribution that can be described by the median or the geometric mean, and by the geometric standard deviation. For fibers, both fiber diameter and length are important determinants of their behavior in the airways. The effect of particle size on the fate of particles is discussed in more detail in sections 3.1 and 5.2.M) Physiological Determinants of Exposure

Anthropologic features of humans, their physical activities, ventilation ca­pacities, and the state of their circulation all affect exposure to chemical com­pounds. Some of the physiological determinants of exposure will be dealt with below. Exercise typically increases cardiac output, facilitates circulation, in­creases the minute volume of ventilation, is associated with vasodilation of the skin circulation, and increases perspiration and secretory activity of the sweat glands. All of these changes tend to facilitate the absorption of chemicals through multiple routes.

Inhalational Exposure

During exercise, both minute ventilation and cardiac output increase dra­matically. Whereas minute ventilation averages 7-10 L/min at rest for an aver­age person of about 70 kg, it can increase to 160 L or more/min during intense exercise, and be 25-^40 L/min with moderate exercise. This has a considerable direct effect on exposure through the lungs. For example, when young persons were exposed to m-xylene at a concentration of 100 ppm, the concentration of m-xylene in their venous blood reached a level of 19 (xmol/L whereas after a moderate exercise at 100 W, a concentration of 100 (imol/L w’as reached in their blood. Thus, the exercise caused about a five-fold increase in the concen­tration of m-xylene in the blood compared to values in sedentary subjects even though the ambient air xylene concentration was the same.65 The increase was approximately equivalent to the change in minute ventilation (which was four to six fold). Increased cardiac output and thereby increased circulation helped in maintaining the concentration gradient between the alveolar space and the blood and thereby facilitated pulmonary absorption of m-xylene.66’67

Dermal Exposure

Exercise also increases skin circulation and perspiration, which both en­hance dermal penetration of compounds into the body. Furthermore, skin le­sions, such as wounds and dermatitis, can increase the permeability of the skin to chemicals. Also, exposure of the skin to solvents and removal of skin fat in­crease dermal penetration of a number of compounds. Compounds penetrate the skin more readily in places where the skin is thin, like the face, hands and scrotum. Increased dermal blood flow due to exercise facilitates the penetra­tion of the skin by chemicals.65-67

Considerable protection against dermal exposure can be achieved by using the appropriate protective clothing, such as overalls, rubber gloves, and boots. For example, protective clothing provided 80-95% protection when workers manually handled ethylenebisdithiocarbamate fungicides in agriculture.52-‘-4—7 It would seem that a similar protection against dermal exposure can be achieved in agriculture and industry in general. Figure 5.33 shows that urinary excretion of ethylenethiourea mainly depends on dermal absorption of the parent com­pound, maneb (a dithiocarbamate) because a delay can be seen before the start

Exposure to Chemical Substances

Time after the end of the exposure (h)

(b i 1000

Exposure to Chemical Substances

10 ———— ‘——— ‘———— 1—————— -■———- ‘———- ‘

0 10 20 30 40 .50 60 70

Time after the end of the exposure (h)

FIGURE 5.33 (a) Excretion rate (means and standard deviations of the means) of ethyle —

Nethiourea (ETU) in the urine (ng/h) of potato field applicators (circles) (groups I and II) and pine nursery weeders (squares) (group IV) after exposure to ethylene bisdithiocarbamates during pesticide application (groups I and II) and the weeding of the sprayed vegetation (group IV). The ETU concentrations were at the detection limit in group IV after two weeks of follow-up (two last time points), (b) Excretion rate of ethylenethiourea (ETU) (means and standard deviations of the means) in the urine (ng/h) of potato field applicators (group I) during 60 h after the cessation of exposure to ethylene bisdithiocarbamate fungicides. The first time point at 10 h after the ces­sation of the application was omitted from the analysis because of possible continuous exposure for a few hours after the application and because of the effect of dermal absorption. The regres­sion equation is y = -6x + 455, where y is the excretion rate of ETU (ng/h), x is the time (h), and the correlation coefficient squared (r2) is 0.86. [With permission from Kurttio, P., and Savol — ainen, K., (1990). Ethylenethiourea in air and in urine: Implications to exposure to ethylenebis — dithiocarbamate fungicides. Scand. J. Work Environ. Health 16, 203-207.]

Of urinary elimination of ethylenethiourea (Fig. 533b). Figure 5.33a shows that the urinary elimination of ethylenethiourea has several elimination phases due to the distribution of the compound in different body compartments.