ENCYCLOPEDIA OF ENVIRONMENTAL SCIENCE AND ENGINEERING - TOXICOLOGY ppsx

1152 TOXICOLOGY The terms toxicology, toxicity, or toxic substance ( toxicant ) are used daily in the scientific and general literature. Review of almost any daily newspaper will reveal one or more arti- cles on the toxic effects of a substance, most of which when released into the environment are called pollutants. Today there are scientific journals devoted to the subject of toxicity, illustrating the importance of this topic. However, many do not understand the term toxicology or have an understanding of its concepts. So what is a good definition of toxicity? It can be best defined as the science of poisons. Of course, this brings us to the question of what a poison is: any substance that can result in a detrimental effect when the concentration is increased. An increased response as compared to increasing concentration has been called a “dose-response curve,” which will be discussed later. When using the definition of toxicity provided above, most will consider poisoning of animals and humans; how- ever, this definition can be extended to all life forms, includ- ing microbes (Thomulka et al., 1996) and plants (Haarmann and Lange, 2000). In the broadest term, toxic insult can be evaluated from an ecological viewpoint and can encompass effects to an ecosystem. This is what is commonly consid- ered when looking at poisoning in an industrial environment. However, in today’s changing environment, the viewpoint from an industrial perspective is changing to include the entire environment. The scope of toxicology is ever-increasing, and from the point of view of an engineer, especially an envi- ronmental engineer, should not be limited. Depending on the focus, toxicity can also be viewed from global impact (e.g., mercury release from burning fossil fuels) to that which affects single-celled organisms in a local pond. Public awareness has raised the term toxicity to an every- day usage, although most do not understand how to properly apply this term. Most consider that when something is listed as toxic it means an effect from an exposure has occurred. Certainly in the most general sense this is true. Forgotten for the term toxicity is that every substance is toxic, at least in the right dose. So what can be added to the concept of a poison is that the dose makes the poison. For engineers, often the terms hazardous substance or waste are used as substitutes for toxicity. This in the strict definition is not correct, in that a hazardous waste may not act as a poison, but rather result in a physical effect (e.g., a burn). However, even a substance capable of causing a burn will do so in proportion to the concentration applied. Thus, even for these types of substances, there is a dose-response effect. If any effect from a substance is considered a toxic response, then hazardous waste is another name for toxicity. In most cases a hazardous waste is a mixture of substances andրor chemicals at a site, and its release was uncontrolled or unregulated. Regardless, this mixture will have its own dose- response, while the individual chemicals or substances will exhibit separate responses (a differing dose-response curve). What is of importance to many engineers when examining toxicity is the use of standard references. Table 1 lists number of textbooks and governmental sources that contain various numerical values for toxicity and basic information on chemi- cals. These sources are a very good staring point to obtain basic information about a chemical, its regulatory limits, and general information on the hazards associated with the substance. AREAS OF TOXICOLOGY Toxicology can be divided into a variety of subareas. These areas can be categorized by organ systems, chemicals (substances), or discipline. Examples of categorization are shown in Table 2, along with a brief description. For the most part, engineers will work in the general areas of environmental and occupational toxicology, although some will venture into others as well. In special cases, engineers will venture into areas such as forensic toxicology. What needs to be kept in mind is that toxicology is an area that borrows from other basic fields of science, such as chemistry, physics, biology, and mathematics. ENDPOINTS OF TOXICITY Historically, toxicology was associated with the response of animals when exposed to an agent or agents. Mostly this has been performed using small rodents such as mice and rats. However, for engineers, animal toxicity data are only one part, especially for work that relates to the environmental areas. For example, evaluation of a hazardous-waste site can involve the toxic effects to plants, invertebrates, microbes, and aquatic organisms. Commonly, toxicity of a substance or toxicant is often referred to a single organism. In the environmental area, as well as in others, there may be many different types of organisms affected, along with different effects among these organisms. Use of a single value will not likely represent toxicity to entire groups or a system. Thus, representation of toxicity as a single value may be misleading. Toxicity end- points for a chemical can vary by logarithmic orders, even for C020_003_r03.indd 1152C020_003_r03.indd 1152 11/18/2005 11:09:27 AM11/18/2005 11:09:27 AM © 2006 by Taylor & Francis Group, LLC TOXICOLOGY 1153 TABLE 1 Some common references on environmental and occupational toxicology Klaassen CD (1996), Casarett and Doulls Toxicology: the basic science of poisons An excellent reference on toxicology, although generally written at the graduate level. ACGIH ® (2004), TLV’s and BEI’s Threshold limit values (TLVs) and biological exposure indices (BEIs) values, which provide the upper exposure limit for many chemicals. Hathaway et al. (1991), Proctor and Hughes’ chemical hazards of the workplace Provides information on many chemicals—including regulatory exposure limits and basic information on the chemical. OSHA (29 CFR 1910. 1000) Permissible exposure limits (PELs), which are the maximum exposure limit set by the U.S. government. NIOSH Criteria Documents Information on a specific chemical as provided by NIOSH. However, these reports are not updates and some that are older will not have the most up-to-date information. Niesink et al. (1995), Toxicology: principles and applications General toxicology reference that focuses on the occupational environment. Lippmann (1992), Environmental toxicants: human exposures and their health effects Provides information through chapters on specific topics that relate to both environmental and occupational toxicology. Rand and Petrocelli (1985), Fundamentals of aquatic toxicology: methods and applications A good basic textbook on aquatic toxicology. NIOSH (1994), NIOSH pocket guide to hazardous chemicals Provides exposure values, physical properties, and keywords on health hazards for many chemicals of industrial interest. ACGIH ® —American Conference of Governmental Industrial Hygienists OSHA—U.S. Occupational Safety and Health Administration NIOSH—National Institute for Occupational Safety and Health (an example of these documents is NIOSH, Criteria for recommended standard occupational exposure to hydrogen fluoride, Department of Health and Human Services (DHHS) (NIOSH) Pub Nos. 76–141) the same organism. This is illustrated by the chemical copper for Strongylocentrotus purpuratus using the endpoint EC 50 , which is the median effective concentration (where 50% of the organisms are affected at a given period of time). ED 50 is the median exposure dose, which is the concentration in air or water. The other commonly used endpoint of measure for industrial (occupational) toxicology is the median lethal dose (LD 50 ; again, this is a value where 50% of the organisms die at the given concentration, assuming that the mean and median values are equal, as in a normal curve, although used in more studies to refer to the median concentration). Obviously the LD 50 is not useful in setting occupational-exposure limits, but provides a relative comparison for different chemicals. Similar in nature to the LD 50 is the EC 50 . Here the concentration has to be in some unit of air or liquid (water) for the endpoint to be measured. The variability for a chemical as related to effective endpoints (dose) can be illustrated using copper in aquatic organisms (Table 3). The LD 50 of copper for the vari- ous organisms listed have a large variation (log order). This variation is commonly observed when evaluating a chemi- cal among different organisms and even the same organism between laboratories. A toxic response can be reported as any endpoint mea- surement that is reproducible. This can include death, as rep- resented by an LD 50 or another, such as a behavior endpoint measurement, which could be an EC 50 . When evaluating TABLE 2 Some areas of toxicology Environmental Concerned with effects on the environment, which can be considered pollution. This can be further divided into air, soil, and water systems. There can also be a measurement on a species as well. Forensic The occurrence of toxic effects on people and possibly other organisms, such as livestock, that is in relation to a crime. Occupational Effects of chemicals or substances on those in the working environment and industry. Regulatory Effects of chemicals (may also be drugs) in regard to the risk associated with the purposes or in some cases prevention of that chemical’s use. This is often associated with some regulation or law, like the U.S. Clean Air Act (CAA). Mechanistic Evaluates a chemical’s mechanism of action and how this action causes a toxic effect on the organism. TABLE 3 Aquatic toxicology values of various organisms for copper Organism LD 50 Reference Mesocyclops peheiensis 75 ␮g/l Wong and Pak, 2004 Tilapia zillii 6.1 mg/l Zyadah and Abdel- Baky, 2000 Mysis sp. (from Nile River) 2.89 mg/1 Zyadah and Abdel- Baky, 2000 Mugil cephalus 5.3 mg/1 Zyadah and Abdel- Baky, 2000 Photobacterium phosphoreum Ͼ100 mg/1 Thomulka et al., 1993 Strongylocentrotus purpuratus 15.3 ␮g/1 ϩ Phillips et al., 2003 Penaes merguiensis 0.38 mg/1 Ahsanullah and Ying, 1995 ϩ An EC 50 . C020_003_r03.indd 1153C020_003_r03.indd 1153 11/18/2005 11:09:27 AM11/18/2005 11:09:27 AM © 2006 by Taylor & Francis Group, LLC 1154 TOXICOLOGY data, the endpoint must be identified, especially when look- ing at nonlethal measurements such as EC 50 ’s. There are three general routes of exposure: inhalation, dermal (skin), and ingestion (oral). A fourth route, which is more related to medical situations, is injection. Depending on the chemical and the activity employed, one or more of these will have a great deal of importance in the toxic outcome. Occupationally, the most important route is inhalation, since it generally results in the most severe health consequences. Dermal effects are the most numerous, but in most cases are of minor importance. Most dermal effects are related to irri- tation of the skin and related allergic reactions. As a general rule in occupational toxicology, skin problems are the most common, although effects such as cancer of various organs can also be of concern (Lange, 2003). Using cement as an example, epidemiological studies have reported this agent to cause cancer in a variety of organs. The organs or systems of carcinogenic concern include the skin, bladder, stomach, and lungs (Smailyte et al., 2004), although the most common problem reported in occupations using this building material is dermatological (skin) (Winder and Carmondy, 2002; Lange, 2003), which is a noncarcinogenic occupational hazard. This illustrates that a chemical can have multiple toxic endpoints for different organs. Most toxicologists divide the exposure to humans and organisms into four categories: acute, subacute, subchronic, and chronic. Acute is commonly defined as a single or repeated exposure that occurs over a 24-hour period that results in a measurable effect. Although this definition is not perfect, it tells us that acute cases are generally of short duration and high concentration. Subacute, on the other hand, is exposure that occurs over about a 1-month time period and in this case is generally lower in concentration, and the effect requires a longer period of time to occur in comparison to a true acute exposure. It is not uncommon to report acute effects as case studies. In the case report by Dote et al. (2003), an industrial worker accidentally exposed (sprayed) himself with the agent hydrogen fluoride (HF), or hydrofluoric acid. HF is a highly corrosive agent that can result in serous chemical burns, and in this case the burns occurred on the face of the industrial worker. As a result of this exposure, the worker died within a half hour as a result of acute respiratory failure. In the case of HF, this substance would be considered a hazard to both the respiratory and dermal systems, in this case inhalation being the main route of exposure that resulted in death. To put HF exposure in perspective, Hathaway et al. (1991) reported that the LD 50 for a 5-minute exposure is between 500 and 800 parts per million (ppm). Chronic toxicology is defined as an effect resulting from an exposure that occurs over a long period of time, like years. Certainly the time period of measurement also depends on the length of an organism’s life history as well. Subchronic, as compared to chronic, is of shorter duration with a higher con- centration and can be considered to occur within a time period of 1 to 3 months for people. Although these terms are dis- cussed for an occupational setting, the terms are also applied to environmental toxicology. Historically, acute exposure was a key factor in exposure prevention. As industrial exposures are becoming better controlled, there has been a change in focus to chronic conditions, at least in the developed countries. Since inhalation is the most important route of exposure in the occupational (industrial) environment, most reported limits of acceptable exposure are for this route. However, in other systems, such as aquatic or terrestrial, dermal contact or ingestion may be the most important routes of exposure. OCCUPATIONAL EXPOSURE LIMIT VALUES For occupational exposure, established upper limits have been published by governmental and private agencies or groups. These values are: permissible exposure limit (PEL), thresh- old limit value (TLV), and recommended exposure limit (REL). PELs are established by the U.S. Occupational Safety and Health Administration (OSHA) and are the legal stan- dard for the maximum exposure level. OSHA PELs are pub- lished in the Code of Federal Regulations (CFR) at 29 CFR 1910.1000. It should be noted that these exposure concentra- tions are mostly for inhalation, as previously mentioned, and the levels represented are somewhat out of date, since they have to go through a regulatory process for updating. TLVs are established by the American Conference of Governmental Industrial Hygienists (ACGIH), which is considered a consen- sus organization. Many consider these values to be the most up-to-date, although they are, like most decision-making pro- cesses, subject to industry pressure and other political factors when being established. Generally, TLVs are lower in concen- tration than PELs, although there are exceptions to this state- ment. It can be considered that the PELs, as they change, are also subject to industry and political considerations as well. Both the PELs and TLVs are established for an 8-hour time- weighted average (TWA). This average is an arithmetic mean of all the exposures collected in that workday. The formula for making a TWA is shown below. TWA ϭ ( C 1 ϫ T 1 ) ϩ ( C 2 ϫ T 2 ) ϩ ϩ ( C n ϫ T n )ր ( T 1 ) ϩ ( T 2 ) ϩ ϩ ( T n ) C —concentration T —time The maximum and ideal time of sample (exposure) col- lection is 8 hours, although this is not usually feasible. Most consider that to obtain a TWA the sample should be collected for at least 6.5 hours of the 8-hour work shift. The remaining 1.5 hours would be included as a 0 exposure level. The REL is a 10-hour TWA exposure limit and is set by the National Institute of Occupational Safety and Health (NIOSH) as a value to be considered by OSHA in the rule-making process. For all the values (PEL, TLV, and REL), they are established for a 40-hour workweek. When evaluating exposure limits, exceedance can be considered for a single measurement or summation of mea- surements (Letters to the Editor, 1998). There has been considerable discussion of the correct evaluation for expo- sure. For those chemicals that are considered to be chronic in nature, disease appears to follow the arithmetic mean of C020_003_r03.indd 1154C020_003_r03.indd 1154 11/18/2005 11:09:27 AM11/18/2005 11:09:27 AM © 2006 by Taylor & Francis Group, LLC TOXICOLOGY 1155 exposure, suggesting that summation exposure values best represent potential health effects (Lange, 2002). A short-term exposure limit (STEL) has also been estab- lished for many chemicals. STELs are for 15-minute periods with at least 2 hours of exposure below the PEL, as an exam- ple, with no more than four exposure periods (STELs) occur- ring per day. When applying STELs, the PEL should not be exceeded when these values are included in the TWA. If there is an exceedance of the PEL, appropriate personal protective equipment is then required. Exposure limit values (TLV-TWA) are established using three general criteria. First, in order of importance, are epi- demiological data. Occupational and in some cases environ- mental epidemiology studies provide the most important information on the hazards from a chemical. Since there are different types of epidemiological studies, those of the greatest strength, in order, are: cohort, case-control, cross- sectional, and ecological. Next is animal experimentation in identifying hazards, and last are case studies or reports. The ACGIH publishes documentation summarizing the basis for establishing and setting TLVs and is often useful as a general reference. Another good reference that provides summary information on chemicals is Hathaway et al. (1991). Exposure levels are given in units of mgրm 3 , ppm, and fibers per cubic centimeter (fրcc). In most cases these values are for inhalation, but there are some listed for skin (e.g., decaborane). Another value that is of importance to toxicologists in the industrial environment is IDLH (immediately dangerous to life and health). The problem with IDLH is that it has two differ- ent definitions (NIOSHրOSHAրUSCGրEPA, 1985). The Mine Safety and Health Administration (MSHA) (30 CFR 11.3[t]) defines IDLH as the concentration that will cause immediate death of permanent injury. However, NIOSH, in the Pocket Guide (1994; see Table 1), defines this as the maximum con- centration where one can escape within 30 minutes without irreversible health effects. So care must be taken when using IDLH values, as each source has completely different criteria. DOSE-RESPONSE In toxicity there exists an increased response to a chemical with the chemical’s increasing concentration. This is known as the “dose-response effect” and is fundamental to toxicol- ogy. In general, it can be said that every chemical has a dose- response effect. The response is any repeatable indicator or measurement that is used to evaluate the response of an organ- ism to the chemical. At some point the concentration becomes high enough that the response is 100%. Figure 1 shows time of exposure to various concentrations of the chemical sodium bisulfate (Haarmann and Lange, 2000). As the concentration of each chemical varies there is a reduction in root length after a given period of time. In many cases the curve would appear reversed, where there would be no inhibition at the lower con- centrations and inhibition at the higher levels. However, here, for the root length, which was for radish-seed elongation, the highest length is at the lower concentration of chemical. The shape of the dose-response curve can provide informa- tion on the effect of a chemical, and data extracted from this relationship is often used in risk-assessment analysis. LD 50 and related values are extracted from dose-response curves. Different formulas can be used to obtain this information as well (Thomulka et al., 1996). 0.1 1 10 100 1000 10000 Sodium Bisulfate (ppm) 0 20 40 60 80 100 120 140 Root Length (mm) FIGURE 1 Dose-response curve for sodium bisulfate in Lake Erie water (from Haarmann and Lange, 2000; with permission from Parlar Scientific Publications). C020_003_r03.indd 1155C020_003_r03.indd 1155 11/18/2005 11:09:28 AM11/18/2005 11:09:28 AM © 2006 by Taylor & Francis Group, LLC 1156 TOXICOLOGY Dose-response curves are often used to provide informa- tion on a chemical as well as comparison to other chemicals. Potency is one factor that can be derived from the dose- response. This term refers to the concentrations that result in an increasing response to the chemical. Two chemicals can have the same slope on a dose-response curve, but have dif- ferent potencies. Thus, various information can be extracted from dose-response curves. EXPOSURE Exposure can be considered to be at the heart of toxicology. Just because you are exposed does not mean that there will be an effect or even that the chemical will be taken up by the organism. There are a number of factors that influence the cause and effect, including absorption, distribution, excre- tion, and biotransformation. To understand exposure, a brief discussion of each will be presented. A toxicant is often called a xenobiotic, which means a foreign substance, and these terms are often used interchange- ably in texts. In some cases, a xenobiotic may not be foreign to the organism (e.g., selenium), but exist in a higher or lower concentration that results in a disease state. Of importance to environmental and occupational toxicology is that a lower concentration may also result in disease or an undesired event, which for the purposes of this chapter will be considered a toxic action. In some unusual cases increased occupational exposure has been reported to result in beneficial effects. This has been illustrated by the exposure of organic dust that appears to reduce lung cancer (Lange, 2000; Lange et al., 2003). However, it needs to be noted that exposure to organic dust (like cotton dust, in the textile industry) also results in severe respiratory diseases (e.g., bysinosis), which outweigh any benefits of reduced lung cancer, as in this case. Absorption Absorption is the process where a xenobiotic crosses a mem- brane or barrier (skin) and enters the organism, most com- monly into the blood. As previously mentioned, the major routes of absorption are ingestion (the gastrointestinal [GI] system), inhalation (lungs), and dermal (skin). Oral intake is not a common route of occupational exposure, but one of major importance environmentally. Transport across barriers occur as passive transport, active transport, facilitated dif- fusion, or specialized transport. Transport can occur in the uptake and excretion of chemicals. Passive transport, which is simple diffusion, follows Frick’s Law and does not require energy. Here a concentration gradient exists, and molecules move from the higher to the lower concentration. As a rule, for biological systems, the more nonionized the form of a molecule, the better it is transported across lipid membranes. The membranes of cells are composed of a lipid bilayer, thus favoring nonionized compounds. Active transport involves the movement of a chemical against a gradient and requires the use of energy. This requires a transporter molecule to facilitate the movement and would be subject to saturation of the system. Facilitated transport is similar to active trans- port, except it does not work against a gradient and does not require energy. There are other specialized forms of transport, such as phagocytosis by macrophages. These various transport mechanisms are also used to bring essential substances and xenobiotics into the organisms. Absorption in the GI tract can occur anywhere from the mouth to the rectum, although there are some generalizations that can be made. If the chemical is an organic acid or base, it will most likely be absorbed in locations where it exists in its most lipid-soluble form. The Henderson-Hasselbalch equation can be used to determine at what pH a chemical exists as lipid-soluble (nonionized) as compared to ionized. As a general rule, ionized forms of a chemical are not easily absorbed across biological membranes. For the lungs, gases, vapors, and particles can be absorbed. In the lungs, ionization of a chemical is not as important as it is for the GI tract. This is due to the rapid absorption of chemicals and the thinness of the separation of alveolar cells (air in the lungs and blood system) with the body fluids (blood). Ionized molecules are also generally nonvolatile and are therefore usually not in high concentra- tion in the air. Particles are separated as they travel the pul- monary system. The larger ones (say, greater than 10 ␮ m in size) are removed early in the pulmonary system, like in the nasal area, whereas the smaller ones (say, 1 ␮ m) enter the alveolar region. As a general rule, it can be said that particles around 5 to 10 ␮ m are deposited in the nasopharyngeal area, those 2 to 5 ␮ m in the tracheobronchial area, and those less than 1 to 2 ␮ m in the alveolar region. The alveolar region is where air is exchanged with the blood system, oxygen is taken up, and waste gases (carbon dioxide) are returned to the atmosphere. Particles that are deposited into the alveolar region have been termed “respirable dust” (Reist, 1993). Distribution of particles described is not exact, but provides a generalization of particle distribution for lungs. Some chemicals, like those that are highly water-soluble (e.g., formaldehyde), can be scrubbed out at various locations of the respiratory tract. Here, formaldehyde is removed by the nose, and in general this is a site of its toxic action, irritation, and nasal cancer (Hansen and Olsen, 1995). Skin is generally not highly penetrable and is a good overall protective barrier. This protection is a result of the multiple layers of tissue associated with the skin. However, the primary layer of protection is the stratum corneum. This is the top layer of cells on the skin; it is dead and can vary in thickness. On the hands and feet this cell layer can be 400 to 600 ␮ m thick, while on the legs it can be 8 to 15 ␮ m. Some chemicals can disrupt the skin’s protection and allow chemi- cals to pass more easily. An example of this is dimethyl sulf- oxide (DMSO), which can de-fat the skin and allow better penetration of chemicals. Distribution After a chemical enters the organism, it is usually distributed rapidly. This distribution is commonly achieved by the blood system. Many chemicals have locations in the organism where C020_003_r03.indd 1156C020_003_r03.indd 1156 11/18/2005 11:09:29 AM11/18/2005 11:09:29 AM © 2006 by Taylor & Francis Group, LLC TOXICOLOGY 1157 they concentrate (e.g., lead in bone). It is often important to know where a chemical is concentrated or its organ of toxic- ity. Some generalities, although not complete, can be made for different classes of compounds (Table 4). However, when evaluating toxicity it is necessary to obtain specific informa- tion on the compound because there are many exceptions to general rules of site of toxic action. It is not uncommon that one chemical will have multiple organs or locations of toxic- ity. A good example of this is the metal arsenic. Arsenic can be both an environmental and occupational poison. Ingestion of arsenic in drinking water, at elevated concentrations, has been shown to result in skin cancer (which has been referred to as Blackfoot disease) as well as other forms of cancer (e.g., lung; Bhamra and Costa, 1992) and noncancer diseases (e.g., der- matological; Lange, 2004a). Environmental problems associ- ated with arsenic exposure (via water) can be most acute and are well illustrated in a well-water problem for Bangladesh (Murshed et al., 2004). Here water wells were established to provide safe drinking-water sources (free of microbial con- taminates). However, at the time these wells were placed it was not known that the soil contained high levels of arsenic. This resulted in drinking-water sources being contaminated with this metal. Subsequently, there has been a high rate of arsenic-related diseases (e.g., bladder, liver, and lung cancer; Chen and Ahsan, 2004) as a direct result of using these water sources. Arsenic does not only result in cancer, it also causes many environmentally related noncancer diseases (Milton et al., 2003). As mentioned, there are also occupational diseases from this metal (Bhamra and Costa, 1992; Lange, 2004a). For example, workers in smelting plants that use arsenic have been shown to exhibit elevated levels of lung cancer, and from these types of studies arsenic has been identified as a lung carcinogen. Although arsenic has been reported to cause detrimental effects, it should be noted that it is also an essential trace element. Deficiency in arsenic has been reported to result in various health problems as well as increased mortality (Bhamra and Costa, 1992). Thus, many chemicals can have a dual role in causing and preventing disease. It has even been suggested that some chemicals and substances can have a protective effect in the occupational environmental (Lange, 2000; Lange et al., 2003). Chemicals can also be identified individually with a site or organ system being affected. Examples of chemicals and their general site of action are shown in Table 5. Certainly this list is not comprehensive, but provides the range of organ systems a single chemical can influence in the disease process. Effects can be both acute and chronic along with many having both carcinogenic and noncarcinogenic proper- ties (e.g., benzene). Excretion Toxicants that are taken up by an organism must be eliminated in some way. There are three major routes of excretion (urine, feces, and air [exhalation]) and several minor routes (hair, nails, saliva, skin, milk, and sweat). Many compounds are biotrans- formed before being excreted. This biotransformation results in xenobiotics being more water-soluble. As will be mentioned later, biotransformation involves a two-step process known as Phase I and Phase II biotransformation. Generally, substances with the greatest toxicity are those that do not completely undergo the biotransformation process. Urinary excretion involves elimination through the kidney and is commonly considered the most important route of excretion. The kidney receives about 25% of the cardiac output. Toxic agents are generally excreted by being filtered out through the glomeruli or tubules in the kidney. Fecal excretion can involve both the GI tract and liverր gallbladder. Some toxicants pass through the alimentary system (GI tract) unabsorbed or modified by bacteria or other processes in this system. Biliary excretion involves removal of toxicants from the blood by the liver and their subse- quent elimination through a fecal route. Here a xenobiotic is TABLE 4 Locations or organs of toxic action by classes of chemical compound Class of Chemical/Substance Location or Organ (Example) Metals Kidney, bone, immune Solvents Liver Pesticides Nervous Radiation Blood TABLE 5 Specific chemicals and some of their general organs or sites of action Chemical Location or Organ (Example) Aluminum Endrocrine, kidney, lung Arsenic Bladder, skin, heart, liver, lung, nervous Benzene Blood, liver Cadmium Kidney, reproductive Carbon monoxide Blood Coke oven gases Lung Cotton dust Lung Ethanol Liver Formaldehyde Lung (respiratory) Fungus (Fusarium moniliforme) Liver Lead Bone, blood, heart, kidney, nervous Mercury Kidney, nervous, heart Methyl ethyl ketone Heart Paraquat G1, heart, lung Phenol Liver, skin Polyaromatic hydrocarbons Immune, liver, reproductive Polychlorinated biphenys Immune Rotenone Endrocrine, eye, lung, skin Tetrachloroethylene Kidney Thallium Eye “Heart” includes the vascular system as a general group. C020_003_r03.indd 1157C020_003_r03.indd 1157 11/18/2005 11:09:29 AM11/18/2005 11:09:29 AM © 2006 by Taylor & Francis Group, LLC 1158 TOXICOLOGY biotransformed by the lever and transported to the gallblad- der, which then excretes the chemical into the GI tract for elimination. There are some cases where a chemical elimi- nated by this route is then reabsorbed by the intestine into the body, resulting in a long half-life for this substance. This process is known as the “enterohepatic cycle.” Ideally chemi- cals are metabolized into a polar form, making these poorly reabsorbable. However, microbes in the intestine can trans- form these compounds into a more lipid-soluble compound, which favors reabsorption. Exhalation Substances that exists in a gas phase are mostly eliminated through the lungs. These chemicals are mostly eliminated through simple diffusion, with elimination generally related to the inverse proportion of their rate of absorption. Thus, chemicals with low blood-solubility are rapidly eliminated, while others with high solubility are eliminated slowly. Other Routes Several other routes of excretion have been mentioned. Overall, these other routes are of minor importance in elim- ination of toxicants. However, they can be used to test the existence and concentration of various toxicants in the organ- ism. This is commonly known as “biological monitoring.” For example, hair can be used to test where a person has suffered from previous exposure to and possible toxicity of heavy metals, like arsenic. Thus, these minor excretion routes can be important for specific areas of toxicology (e.g., forensic). It should be noted that the major routes can also be used for biological monitoring, with urine and blood being the most important, particularly clinically and occupationally. Biological Monitoring Biological monitoring has become a common method for evaluating absorption of chemicals and drugs. It has been used for such activities as drug and alcohol testing. Methods have been established to determine the absorbed dose of a chemi- cal, which are therefore important in many areas of toxicol- ogy, including clinical, forensic, and occupational toxicology. The ACGIH has established BEI values for some chemicals as one measure of monitoring risk to industrial populations. This allows evaluation of exposure from all routes, including occupational and nonoccupational. In many cases, only one route of exposure is evaluated, airborne levels, while exposure from other routes (e.g., dermal) contributes to the absorbed and toxic dose. Biological monitoring can be used for both major and minor routes of excretion. As noted, hair and nails can be used to evaluate exposure to heavy metals. An exam- ple of biological monitoring in the occupational environment is for methyl ketone (MEK), which has been suggested to be measured at the end of a work shift using urine as the biologi- cal fluid. The ACGIH BEI for MEK is 2 mgրl. Biological monitoring is also used as part of medi- cal evaluations and in environmental toxicology as well. A good example of its use in medical evaluations is for lead- abatement workers. Blood lead levels (BLL) for workers in this industry or exposure category have been established by OSHA. Here workers having a BLL over 40 ␮ gրdl (deciliter of whole blood—100 ml of blood) are required to undergo an annual medical examination. Workers over 50 ␮ gրdl are required to be removed from the work area (removal from exposure) until the BLL (two connective readings) is below 40 ␮ gրdl. This illustrates the use of biological monitoring in prevention of occupational disease and its incorporation in regulatory toxicology. Environmentally, lead is often monitored in children since it can cause harm in a number of organ systems and with effects that are characterized with a developing organ- ism. The Centers for Disease Control and Prevention (CDC) suggest that children below the age of 6 not have a BLL that exceeds 10 ␮ gրdl. This is the lowest level that has been suggested to have biological effects for humans. Biological concentrations of chemicals have also been used to evaluate exposure and toxic effects in organisms other than man. Monitoring of biological fluids and tissue in environmen- tal toxicology is a common practice (Pip and Mesa, 2002). Both plants (Pip and Mesa, 2002) and animals (Madenjian and O’Connor, 2004) are used for evaluating the distribu- tion and uptake of toxicants from polluted environments. Monitoring can also be extended to abiotic conditions that influence toxicity to organisms (Mendez et al., 2004). The use of biological systems for monitoring can include effects on metabolism and other systems as well (Lange and Thomulka, 1996). Thus, biological monitoring is commonly used in both environmental and occupational settings as well as other areas of toxicology. Monitoring of this nature has even been extended to ecosystems as a methodology for evaluating health. Biotransformation Xenobiotic substances that are taken up by an organism must eventually be eliminated. To eliminate many of these chemicals, they must be transformed into a water-soluble product. This transformation is called “biotransformation.” In many vertebrates, this transformation occurs in the liver, although other tissues and organs (e.g., the kidney) are also involved. Generally, chemicals are absorbed as lipid com- pounds and excreted as water-soluble (hydrophilic) com- pounds. Hydrophilic compounds can be easily passed along with the urine and feces. In the lungs, volatile compounds are favored for excretion in the exhaled gas, while those that are nonvolatile are generally retained. If chemicals were not biotransformed, their rate of excretion as lipid-soluble com- pounds would be very long, and this would result in buildup of xenobiotics. The rate at which a chemical is metabolized or excreted is called its half-life ( t 1 ր2 ). Half-lives can be very short (as in minutes) or long (as in years). Biotransformation and metabolism are often used as synonymous terms. In general they can be used interchange- ably, although here biotransformation is used in describing the metabolism of xenobiotics that are not part of normal C020_003_r03.indd 1158C020_003_r03.indd 1158 11/18/2005 11:09:29 AM11/18/2005 11:09:29 AM © 2006 by Taylor & Francis Group, LLC TOXICOLOGY 1159 metabolism or at concentrations related to pollutant or toxi- cant exposure. Some chemicals are able to actually increase or stimulate the biotransformation of other compounds. This is known as “induction.” Induction can occur for a variety of compounds. As previously mentioned, biotransformation is generally divided into two categories, Phase I and Phase II. Phase I reactions involve oxidation, reduction, and hydrolysis, which prepare the compound to undergo a Phase II reaction. Phase II involves conjugation. Commonly the most toxic products of a chemical are those from Phase I. If the system becomes saturated, Phase I compounds will seek alternative routes of metabolism, and this may result in more toxic intermediates. If this occurs, it is said that the metabolic system has become saturated. MIXTURE TOXICITY Most toxicology studies involve the use of a single com- pound; however, rarely in the real world does exposure occur to only a single substance. Although single-exposure events do occur, they generally result in acute toxicity, while mul- tiple exposures are more frequently associated with chronic events. Certainly there are numerous exceptions to this rule, like asbestos and mesothelioma, but even with asbestos there are mixtures associated with this substance. One of the best illustrations for a mixture is asbestos and smoking in the case of lung cancer. Here smoking magnifies the potential effect of inhaled asbestos, resulting in a higher-than-expected rate of lung cancer than would occur for either alone. Most exposures in the industrial environmental focus on a single predominant toxicant associated with that activity, or at the most the top two or three chemicals, and generally concerns are identified with acute events. Both PEL and TLV are established with nonexposure time periods between exposures and often have an emphasis on acute occurrences. In environmental toxicol- ogy this is not always the case, since most regulatory stan- dards have been established to protect against chronic events, considering most organisms spend their entire life in a single media. This is also true for humans as related to air and water pollution. Mixture toxicity or interaction studies can be generally categorized by several terms (Table 6). Additivity is when two chemicals together exhibit equal toxicity with each having the same additive response. So if chemicals A and B were mixed and have an effect of ten, by adding five units of each, than adding ten units of A alone or B alone would have the effect of ten as well. Synergism is where the combination of the two chemicals magnify the outcome, as in asbestos and smoking. Asbestos may cause 1 cancer in 1000 and smoking 200 cases in 1000, but when together this may rise to 700 cases out of 1000. Antagonism is when one chemical reduces the effect caused when combined with another. Potentiation is when one chemical allows another to have its full toxic potential. This can be illustrated when the barrier of the skin is disrupted, as with DMSO, and a chemical that would not previously pass through the skin now enters easily. Generally, most chemical combinations exhibit additivity. Unfortunately, little information exists on chemical com- binations (Lange and Thomulka, 1997). The lack of informa- tion is often due to the complexity and costs associated with these studies. However, recent advances in using bacterial systems (Lange and Thomulka, 1997) for evaluating mix- tures does provide a more cost-effective and convenient way of testing more than one chemical. There have been a number of methods published, exclud- ing statistical comparisons, for evaluating two chemicals in combination. One of the early methods was a graphic repre- sentation of the two chemicals together, called an “isobole plot” (Lange and Thomulka, 1997). Here chemical combina- tions at some set value (like each chemical’s LD 50 ) are plot- ted. Usually combinations of 100% of A, 80(A)ր20(B)%, 60ր40%, 20ր80%, and 100% of B are used in making the plot. When this graph is represented in proportions, it is called an isobologram (Lange et al., 1997). Another method that employs a formula is called the additive index (AI) (Lange and Thomulka, 1997). Here two chemicals using the same endpoint value (like LD 50 ) are evaluated, and these results are incorporated into the formula to obtain the AI. The AI is shown below: S ϭ A m րA i ϩ B m րB i S is sum of activity A and B are chemicals i is individual chemical and m is mixture of toxicities (LD 50 ) for S 1.0, the AI ϭ 1ր S Ϫ 1.0 for S 1.0, the AI ϭ S (Ϫ1) ϩ 1 For the AI, a negative number (sum of activity, S ) suggests that the chemicals are less than additive (antagonistic), with zero being additive and a positive value synergistic. Certainly in these calculations the numbers are not exact, so confidence intervals (CIs) are often incorporated to reflect the range of these mixture interactions. In using CI values, at 95%, the upper and lower CIs are used to determine the range. If the CI range includes zero, then this mixture is considered to be additive. Mixture toxicity is a commonly discussed topic, but as mentioned, it is not well understood. One basis for syner- gism is related to inhibition of detoxification pathways; however, as noted, most chemical mixtures are additive, TABLE 6 Terms used for identifying mixture interactions Term Example by Numerical Value Additivity 5 ϩ 5 ϭ 10 Synergism 5 ϩ 5 ϭ 40 Antagonism 5 ϩ 5 ϭ 7 Potentiation 1 ϩ 5 ϭ 12 C020_003_r03.indd 1159C020_003_r03.indd 1159 11/18/2005 11:09:30 AM11/18/2005 11:09:30 AM © 2006 by Taylor & Francis Group, LLC 1160 TOXICOLOGY which is probably due to few chemicals, at least in mixtures, using exactly the same metabolic pathways. Other meth- ods exist for evaluating mixtures (e.g., the mixture-toxicity index; Lange et al., 1997). Determination of interactions for more than one chemical can in many ways be identified as an art (Marking, 1985). However, as science develops, better methods are being developed to evaluate combinations. CARCINOGENICITY The existence of cancer-causing chemicals has been known for thousands of years. However, it was not until recently that a direct relationship between environment or occupa- tion and cancer was established. One of the early examples of an occupational relationship was provided by the English physician Percival Pott around 1775. Pott observed a high number of cases of scrotum cancer in chimney sweeps. He concluded that this cancer was a result of soot exposure in this occupational group. Later Japanese investigators (Yamagawa and Ichikawa, 1915) determined that coal tar (a common component of which is polyaromatic hydrocar- bons), a component in soot, exhibited carcinogenic effects on animals, providing a basic animal model to support the occupational observations of Pott. Cancer in its simplest term is the unregulated or uncon- trolled growth of cells in an organism. Cancer, or neoplasm, can be either benign or malignant. Those that are benign generally occupy a given space and do not spread to other parts of the body. If the cancer is said to be malignant, it is then metastatic and can spread and form secondary sites at various other locations within the body. Probably the best-known cancer-causing agent is ciga- rette smoke. Studies have shown that direct and indirect use of this product can result in cancer. Doll and Hill (1954) demonstrated that cigarette smoking was a major cause of lung cancer. Although this was an epidemiological study, these types of investigations opened up a new era of investi- gation into cancer-causing agents. A cancer-causing agent generally has two processes in the causation of a tumor: initiation and promotion. This has resulted in chemicals being identified as either initiators or promoters, although there are some, known as “complete carcinogens,” that exhibit both properties. This concept was developed by painting chemicals on the skin of mice at dif- ferent time periods and observing whether tumor formation occurred. It was discovered that for some chemical combi- nations, the initiator had to be applied before the promoter. When the promoter was applied first, a time period waited, and then the initiator applied, no tumor formation occurred. Cancer can also be caused by other nonchemical factors such as heredity and viruses. There has been considerable debate as to the amount of cancer caused by environmental pollutants and exposures in the occupational environment. However, it is known that there are a large number of agents capable of causing cancer in both the environmental and occupational settings. A list of a few occupationally associated carcinogens is shown in Table 7. This list is not complete but demonstrates the large variety and locations of cancers. Most environmental engineers look at the agents capable of or identified as causing cancer when evaluating a situation; however, this is usually done for sim- plicity, in that cancer is an endpoint of clarity—it exists or it does not exist. It must be kept in mind that there are other endpoints of interest as well that are noncarcinogenic (e.g., kidney toxicity). To classify carcinogens, several agencies list chemi- cals or substances according to their degree of carcino- genicity. One of the most frequently cited agencies is the International Agency for Research on Cancer (IARC). The IARC is located in Lyon, France, and is part of the World Health Organization. As part of this agency’s charter, it pub- lishes monographs for various substances and is considered by many an excellent reference on information on carcino- gens. This agency classifies cancer-causing agents into five different groups (Table 8). These grouping are based on data from epidemiological and animal studies. Many consider the IARC to be the best source of information and classification for carcinogens. Group 1 indicates that there is sufficient epidemiological data that the substance is a human carcinogen. This is the highest level of classification, and as noted in Table 8, an example is arsenic. Group 2 has two classifications, A and B. Group 2A represents limited epidemiological evidence but sufficient animal evidence that the substance is a carcino- gen, while with group 2B there is sufficient animal evidence, but epidemiological data are lacking or of poor quality. With Group 3 there is inadequate evidence for classifying a chem- ical or substance as a carcinogen. Group 4 evidence supports that it is not a carcinogen. The IARC is not the only agency that classifies carcinogens. The National Toxicity Program (NTP) provides a classification scheme. Here carcinogens are listed as known human carcino- gens or as reasonably anticipated to be a human carcinogen. TABLE 7 Some carcinogenic chemicals (substances) and the cancers they cause Substance Cancer Caused Aniline Bladder Arsenic Skin, lung Benzene Leukemia Cadmium oxide Prostate, lung Carbon tetrachloride Liver Cement dust (Portland cement) Lung, stomach Coke oven gases Lung, kidney Ethylene oxide Leukemia Lead arsenate Lung, skin Mustard gas Larynx, lung Nickel Lung, nasal Styrene oxide Stomach Toxaphene Liver C020_003_r03.indd 1160C020_003_r03.indd 1160 11/18/2005 11:09:30 AM11/18/2005 11:09:30 AM © 2006 by Taylor & Francis Group, LLC TOXICOLOGY 1161 For a chemical to be classified as a known human carcinogen there must be sufficient evidence to support a causal relation- ship between its exposure and the occurrence of human cancer. For substances to be listed as an anticipated human carcinogen there must exist sufficient evidence that it is a carcinogen, but alternative explanations exist or there is insufficient evidence supporting classification, experimentally and epidemiologi- cally, as a carcinogen. Regardless of the classification used, evidence of car- cinogenicity for a substance requires epidemiological and experimental evidence. Epidemiological information is con- sidered to be the strongest in establishing a substance as a carcinogen. REGULATORY TOXICOLOGY Regulatory toxicology is the area that interrelates toxicol- ogy with regulatory standards. The purpose of this area is to establish standards to provide protection against a specific chemical or group of chemicals. In many cases, standards are established before the full knowledge of a chemical is com- plete. Some identify this type of decision making to be part of risk assessment. In the United States, regulations related to toxicology can be generally divided into the major agencies that promulgate criteria for chemicals. These are the Food and Drug Administration (FDA), the Environmental Protection Agency (EPA), OSHA, MSHA, and the Consumer Product Safety Commission (CPSC). There are other agencies (e.g., the Department of Transportation), but for the purposes of this section they are considered minor. The agencies that are important for environmental engineers are the EPA and OSHA. However, those with the mining industry will also consider MSHA of great importance. The EPA, in general, establishes standards for environmental protection, and OSHA for protec- tion related to those in the occupational environment. For con- sumer substances and products, the CPSC regulates toxicity. OSHA came into existence with the passage of the Occupational Safety and Health Act on December 29, 1970 (effective April 28, 1971). OSHA as well as MSHA are part of the U.S. Department of Labor. OSHA has five major parts, with each regulating different industrial groups (Table 9). The OSHA act sets out two primary duties for employers, which are for them to maintain a workplace free of recognized hazards and to comply with OSHA regulations. The act also requires that employees comply with the act, although clari- fication of this requirement is often lacking. Requirements of the employer are called the General Duty Clause. States can have their own OSHA plan and enforce OSHA as a state pro- vision if they meet certain requirements. Currently, there are 23 state plans. Commonly, environmental engineers will be required to interact with OSHA inspectors. OSHA often conducts inspections as a random process, or more frequently does so as a result of complaint. When an inspection occurs, the inspector will present identification to the management of the facility. If a labor union exists, the inspector must also notify the labor-union representative. Usually there is then an examination of the OSHA records, usually materials safety data sheets (MSDS) and the OSHA 200 form. Lack of MSDS, which is part of the Hazard Communication Plan, is one of the most frequently cited violations. A walkthrough is then conducted, which may include the collection of samples. At the end of this process there is a closing conference. At this time alleged violations are discussed. If citations are issued they can consist of one of three types: imminent danger, serious violations, and will- ful violations. Employers can contest citations. This is usually initiated through an informal hearing. If the employer then decides to contest the citation, there is a specific process that must be undertaken. OSHA has an independent review commis- sion as part of the Department of Labor to hear contested citations. To contest the citation, the employer must file notice within 15 working days by certified mail. There is TABLE 8 IARC classification groups for carcinogenic substances Group 1: Carcinogenic to humans (common called “known”) carcinogen (examples: asbestos, arsenic) (evidence supports the chemical or substance as a human carcinogen) Group 2A: Probably carcinogenic to humans (examples: diethyl sulfate, vinyl bromide) (limited evidence in humans and sufficient evidence in experimental animals) Group 2B: Possibly carcinogenic to humans (examples: bracken fern, chlordane) (limited evidence in humans and less than sufficient evidence in experimental animals) Group 3: Unclassified or not classified as carcinogenic to humans (examples: aldrin, aniline) (inadequate evidence in humans and inadequate or limited evidence in animals) Group 4: Probably not carcinogenic to humans (example: caprolactam) (evidence suggesting lack of carcinogenicity in humans and animals) TABLE 9 Sections of the CFR related to OSHA standards 29 CFR 1910—General industry 29 CFR 1915—Shipyards 29 CFR 1917—Marine terminals 29 CFR 1918—Longshoring 29 CFR 126—Construction TABLE 10 Some environmental acts of importance Clear Air Act Clean Water Act Toxic Substance Control Act Resource Conservation and Recovery Act National Environmental Policy Act Comprehensive Environmental Response, Compensation, and Liability Act Emergency Planning and Right to Know Act C020_003_r03.indd 1161C020_003_r03.indd 1161 11/18/2005 11:09:31 AM11/18/2005 11:09:31 AM © 2006 by Taylor & Francis Group, LLC [...]... 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