© 2000 CRC Press LLC chapter twelve Human health effects 12.1Risk assessment Background For most of human history, concern about the toxic effects of chemicals has focused on poisons that act quickly and result in death. A well-known example is hemlock, which Socrates ingested to commit suicide. Until recently, exposure to these chemicals was not common and the risks were well known, so there was little public concern about these poisons. In this century, however, people have become increasingly concerned with poisons, including those that cause adverse effects only after long periods of exposure. There are two main reasons for this change. One is that the average human lifespan has increased tremendously due to cures and treatments for infectious diseases. This longer lifespan has made chronic, noninfectious illness more common. The second is that the Industrial Revolution has led to new and increased uses of known chemicals and the synthesis and widespread use of newly developed chemical compounds. This tremen- dous increase in both the quantity and variety of chemical uses has led to greater awareness of possible adverse health effects from industrial products. Risk assessment One result of this attention was the establishment of the Environmental Protec- tion Agency (EPA) in 1970 and the enactment of new legislation during the 1970s to regulate chemicals in the environment. With the passage of these laws, an important problem was how to evaluate the severity of the threat that each chemical posed under the conditions of use. This evaluation is known as risk assessment, and is based on the capacity of a chemical to cause harm (its toxicity), and the potential for humans to be exposed to that chemical in a particular situation, e.g., workplace or home. Risk assessment did not begin in the 1970s. The safety of our food supply has been investigated since early in the 20th century. In addition, scientists in industrial toxicology laboratories had been evaluating the toxic properties of potential products as early as the 1930s. Toxic side effects of drugs had long been of concern and received increased attention in the early 1960s after the discovery that severe birth defects resulted from ingestion of a seemingly safe drug, Thalidomide. During the 1970s, risk assessment procedures for all chemicals were reevaluated, improved, and more importantly, formalized. Standardized tests were developed so consistent evalua- tions could be performed and the scientific basis of regulations could be more easily applied. L1190 CH12 pgs Page 603 Friday, July 2, 1999 5:48 PM © 2000 CRC Press LLC During this time of change, the term “risk assessment” took on a variety of mean- ings. However, its definition is made up of two components: toxicity (dose-response) assessment and exposure assessment. The former is a measure of the extent and type of negative effects associated with a particular level of exposure, and the latter is a measure of the extent and duration of exposure to an individual or population. For example, characterizing the risk of a pesticide to applicators requires knowing exactly what dose (amount) of the pesticide causes which effects (dose-response assessment) and the dose to which workers are exposed (exposure assessment). Sometimes, the distinction between an exposure assessment and a dose-response assessment is forgotten and conclusions are drawn without measuring exposure levels. For example, dioxin is often referred to as the most toxic man-made chemical known based on dose-response data, and it is then concluded that it poses the greatest risk to society. However, this is not the case because the potential for dioxin exposure is usually very small. Exposure assessment How can exposure assessment be accomplished? There are two basic approaches: analysis of the source of exposure (e.g., levels in drinking water or workplace air), and laboratory tests (e.g., blood or urine analysis on the people thought to be exposed). Analyses of the air or water often provide the majority of usable informa- tion. These tests reveal the level of contamination in the air or water to which people are exposed. However, they only reflect the concentration at the time of testing and generally cannot be used to quantify either the type or amount of past contamination. Some estimates of past exposures may be gained from understanding how a chemical moves in the environment. Some other types of environmental measurements may be helpful in estimating past exposure levels. For example, analyses of fish or lake sediments can provide measures of the amounts of persistent chemicals that are and were present in the water. Past levels of a persistent chemical can be estimated using the age and size of the fish, and information about how quickly the chemical accumulates in the organism. Analyses of body fluid levels of possibly exposed people provide the best measurement of direct exposure. However, they do not provide good estimates of past exposure levels because the body usually reaches a balanced state so there is no longer any change in response to continued exposure. Many chemicals are excreted from the body after exposure ceases, and a basic understanding of what happens to chemicals in the human body is often lacking for those that do persist. Thus, direct examination of a population may provide information as to whether or not exposure has occurred but not the extent, duration, or source of the exposure. Overall, exposure assessments can be performed most reliably for recent events and much less reliably for past exposures. The difficulties in exposure assessment often make it the weak link in trying to determine the connection between an environmental contaminant and its adverse effects on human health. Although expo- sure assessment methods will undoubtedly improve, significant uncertainty will remain in the foreseeable future. Dose-response assessment Turning to the dose-response assessment, a distinction must be made between acute and chronic effects. Acute effects occur within minutes, hours, or days, while chronic effects appear only after weeks, months, or years. The quality and quantity L1190 CH12 pgs Page 604 Friday, July 2, 1999 5:48 PM © 2000 CRC Press LLC of scientific evidence gathered is different for each type of effect and, as a result, the conclusions from the test results are also different. Acute toxicity is easier to test or observe. Short-term animal studies provide evidence of which effects are linked with which chemicals and the levels at which these adverse effects occur. Often, some human exposure data are available as a result of accidental exposures. When these two types of evidence are available, it is usually possible to make a good estimate of the level at which a specific toxicant will cause a particular acute adverse effect in humans. This approach is the basis for the current regulation of toxic substances, especially in the occupational setting. Chronic toxicity is much more difficult to assess. There are a variety of specific tests to ascertain adverse effects such as reproductive damage, behavioral effects, cancer, etc. It is not possible to discuss all of these, but a look at cancer assessment will reveal some of the problems inherent in long-term toxicity assessments and also focus on the health effect that seems to be of utmost concern to the general public. In cancer assessment, it is not only the chronic nature of the disease but also the low incidence that causes difficulty. Society has decided that no more than one additional cancer in 100,000 or 1 million exposed people is acceptable, so assessment measures must be able to detect this small number. Two types of evidence are utilized to determine the chemical dose that will result in an adverse health effect. One is derived from animal experiments and the other is derived from human exposure experience. Ideally, to detect an increase of one cancer in a million animals, millions of animals would have to be exposed to environmentally relevant amounts of the chemical. However, there are neither scientific nor economic resources to carry out this type of study. Thus, investigations are performed on smaller numbers of animals (a few hundred) who have been exposed to very large amounts of a chemical. These large amounts are necessary to produce a high enough incidence of cancer to be detectable in this small population. Thus, the results of such studies indicate the levels of a chemical that will cause cancer in a high percentage of the population. How can this information be used to assess the chemical level that will cause one additional cancer in a million animals or, more importantly, in a million humans? Because our basic understanding is limited, mathematical models must be used to predict this level. There are a variety of possible models, and the one generally chosen is one that provides the greatest margin of safety, i.e., overestimating rather than underestimating the chemical’s ability to cause cancer. The other type of evidence utilized in chronic toxicity assessment is human exposure, better known as epidemiological evidence. With this type of study, human populations are carefully observed, and possible associations between specific chem- ical exposure and particular health effects are investigated. Considering the previous discussion about exposure assessment, it should be clear that this is not an easy task. It is even more difficult in cancer assessment because of the requirement of detecting very small changes in incidence, e.g., one extra cancer in a million people. As a result, epidemiological assessments have been useful in only certain situa- tions. One is exposure in the workplace, a place where exposure levels are usually much higher than in the environment and a place where the duration of exposure can be determined. However, even there, a sizable increase in cancer incidence is needed before a connection can be established. The conclusion that asbestos causes lung cancer is based on this type of situation. An exception to the need for a high cancer incidence is the situation where the effect is unique so that even a few cases are significant. An example of this was the observation that a small number of vinyl chloride workers developed a rare form of liver cancer. However, even with known L1190 CH12 pgs Page 605 Friday, July 2, 1999 5:48 PM © 2000 CRC Press LLC occupational carcinogens, the question of what happens at low exposures, such as common environmental exposures, has not been fully answered. Thus, the techniques available for assessment of chronic toxicity, especially car- cinogenicity, provide rather clear evidence as to whether or not a particular chemical causes a particular effect in animals. However, there is great uncertainty about the amounts needed to produce small changes in human cancer incidence. This uncer- tainty, together with the difficulties in exposure assessment, make it difficult to draw definitive conclusions about the relationship between most types of environmental exposure and observed chronic health effects. Summary Risk assessment is a complex process that depends on the quality of scientific information that is available. It is best for assessing acute risks where effects appear soon after exposure occurs. Uncertainty becomes greater the longer the period of time between exposure and appearance of symptoms. This is largely due to increased uncertainties in exposure assessment and also the problems involved in using epi- demiological or laboratory animal results in such cases. In many circumstances, these uncertainties make it impossible to come to any firm conclusions about risk. Thus, risk assessment is a process that is often useful but cannot always provide the answers that are needed. 12.2Epidemiology Introduction Epidemiology is the study of diseases within human or animal populations; specifically how, when, and where they occur. Epidemiologists attempt to determine which factors are associated with diseases (risk factors), and what factors may protect people or animals against disease (protective factors). The science of epidemiology was first developed to discover and understand possible causes of contagious human diseases like smallpox, typhoid fever, and polio. It has expanded to include the study of factors associated with nontransmissible diseases like cancer, and of poisonings caused by environmental agents. Epidemiological studies can never prove causation, which means that it cannot prove that a specific risk factor actually causes the disease being studied. Epidemi- ological evidence can only show that this risk factor is associated (correlated) with a higher incidence of disease in the population exposed to that risk factor. The higher the correlation, the more certain the association, but it does not prove causation. For example, the discovery of the link between cigarette smoking and lung cancer was based on comparisons of lung cancer rates in smokers and non-smokers. The rates of lung cancer are much higher in smokers than in non-smokers. Does this prove that cigarette smoking causes lung cancer? No. To prove that cigarette smoking causes lung cancer, it was necessary to expose animals to tobacco smoke and tobacco smoke extracts. This was done under highly controlled conditions where the only difference between the controls (animals not exposed to smoke) and treated animals was the exposure to smoke. These laboratory studies proved the causal association between smoking and increased risk of cancer. Two of the most common types of studies that epidemiologists perform are called case-control and cohort studies. A case-control study usually begins when a disease or adverse effect is noted and the causes of this disease or effect is not known. Epidemiologists then examine the histories of the cases (those showing the disease L1190 CH12 pgs Page 606 Friday, July 2, 1999 5:48 PM © 2000 CRC Press LLC or effect) and the controls (similar individuals who are not affected) to look for differences in their pasts that might plausibly be linked to the disease or effect. For example, the history of exposure to lead can be compared between people with neurological problems and those not affected to determine if lead is a risk factor. A cohort study is used to determine if populations with particular characteristics are more likely to develop a disease or show an effect. This is performed by following two groups of people — those with this characteristic and those without — for a period of time to see if there are any differences in the incidence of the disease or effect between the two groups. For example, a group of new workers in the lead industry without health problems and another group of workers not exposed to lead can both be followed over many years to determine if neurological problems are more common in one group than the other. The first step in an epidemiological study is to strictly define exactly what requirements must be met in order to classify someone as having a disease or showing an effect. This seems relatively easy, and often is when the outcome is clear (a person is either dead or alive). In other instances, it can be very difficult, partic- ularly if the experts disagree about the presence or absence of the effect. This happens often with the diagnosis of particular types of cancer. In addition, in case-control studies, it is necessary to verify that reported cases actually are cases, particularly when the study relies on personal reports and recollections about the disease made by a variety of individuals. The strength of an epidemiological study depends on the number of individuals in each group. The more individuals that are included in the study, the more likely that a significant association will be found between the disease or effect and a risk factor. And it is just as important to determine which behavioral, environmental, and health factors will be studied as possible risk or protective factors. If inappropriate factors are chosen, and the real factors are missed, the study will not provide any useful information. For instance, an association may be found between an inappro- priate factor and the disease because this inappropriate factor, which we will call Factor 1, is associated with another factor, Factor 2, which is actually related to the disease, but which was not studied. In such an instance, Factor 1 is called a confound- ing variable because it confounds the interpretation of the results of the study. Thus, it is very important that the epidemiologist choose the proper factors to study at the outset, and not study too many factors at once, since the possibility of finding confounding factors increases with the addition of more variables. Establishing the link Epidemiology relies heavily on statistics for establishing and quantifying the relationships between risk factors and disease, and for establishing whether or not there is an excessive amount of a particular disease occurring in a specific geographic area. Medical records can provide invaluable historical data for establishing trends in the incidence of diseases. There are vast collections of medical record information throughout the world, and sorting through the data can be a very expensive and time-consuming process. In addition, what can be gained from the records is only as good as the information they contain, and often the information is scanty or impossible to verify. One source of information commonly used is death certificate registries, which usually contain information about the cause of death. Using information from such a registry, a study was performed that showed an unusually high incidence of deaths from lung cancer in a large agricultural valley city. There was no question that the rates of deaths from lung cancer in this city were much higher than in other cities L1190 CH12 pgs Page 607 Friday, July 2, 1999 5:48 PM © 2000 CRC Press LLC of a similar size and location. Many possible causative agents were suggested, rang- ing from pesticide use to agricultural burning. Finally, it was realized that this particular city contained a renowned hospital treatment center for patients with lung cancer. As it turned out, the very high rate of cancer deaths there could be explained by the numbers of lung cancer patients who came there from all over the state for treatment and who died there. Epidemiologists are often called upon to investigate apparent “clusters” of dis- ease in specific geographical areas. For example, a woman in a community may have a miscarriage, and later learn that other people she knows in the neighborhood also have had miscarriages within the last couple of years. It may appear to her, her friends, and her family that a lot of miscarriages have occurred in their neighborhood. An epidemiologist may be called in to determine if the rate of miscarriages is higher than normal. The epidemiologist must interview all of the women in the community, and another similar community in a different geographical area, or select appropriate samples of women to be interviewed concerning their reproductive histories. This information will be validated through hospital records, and then analyzed and com- pared to other similar studies. Even in situations where the rate of disease is not higher than the normal rate, it may seem higher to the inhabitants because diseases are not evenly distributed throughout populations. Interpreting the results If the rate of occurrence of a disease in the general population of the U.S. is 10 per 1000, it does not mean that every group of 1000 people tested will provide ten cases of disease. Some groups may have 5 or less, others 15 or more; 10 is the mean rate. This uneven distribution is similar to the way chocolate chips cluster in cookies. Most of the time they are pretty well spread throughout; however, some cookies may have all the chips clumped together on one side. The only way to determine whether a cluster is a “real” cluster or just a “chance” cluster is to do a full-scale epidemio- logical study, which is an expensive and time-consuming process, and may still not able to resolve the question. Summary Case-control and cohort studies have been extremely valuable in discovering links between chemical exposure and disease. Perhaps the best example is the asso- ciation of cigarette smoking with lung cancer and emphysema. Epidemiological studies have also been especially useful in the occupational sector where workers are exposed to a small number of chemicals, at high dosage rates, for long time periods. Epidemiological studies are occasionally relatively easy, and especially sig- nificant when they uncover a very high incidence of an unusual disease in a popu- lation. For example, the finding of a very small number (about 10) of cases of a very rare liver tumor in workers heavily exposed to vinyl chloride, was a strong signal that vinyl chloride was the causative agent. Animal studies supported this conclu- sion. Epidemiological studies are least powerful in studying very common diseases that occur at high incidence rates in many different populations. In such instances, it is necessary to include huge numbers of subjects in the studies. Such large studies have been undertaken in regard to cardiovascular disease, and many factors that influence the development of cardiovascular disease have been found. Such large- scale efforts have provided information about diet and exercise habits that can be used to prevent the development of cardiovascular disease. L1190 CH12 pgs Page 608 Friday, July 2, 1999 5:48 PM © 2000 CRC Press LLC The same is true with respect to chemically induced diseases. We all reap the benefits of epidemiological studies of workers exposed to chemicals in occupational settings. We also reap the benefits of studies done on patients who must take certain medications daily, and who sometimes develop side effects. Epidemiological studies of disease related to chemical exposure are very difficult in the general population because of the multitude of chemicals to which we are daily exposed. This is, after all, a world made up of chemicals, just as we ourselves are. 12.3Entry and fate of chemicals in humans Routes of entry Chemicals, including pesticides, are widely distributed in the environment. Therefore, there are many possible sources of exposure to these chemicals for humans. Substances in ambient and indoor air may be inhaled into the lungs, while those in water may be ingested or inhaled through mist or steam (such as in the shower). Direct contact with the chemical is the most prevalent way environmental chemicals can penetrate the skin, but exposure through the skin may also occur as a result of contact with chemical contaminants in air and water (e.g., bathing or swimming). A single chemical can enter the body through all three routes of exposure — inhalation, ingestion, and skin penetration (dermal exposure). A compound, such as chloroform, which evaporates readily and which may be found in drinking water, illustrates this point. When someone drinks this water, ingestion is the route of exposure. When it is used for showering, exposure may occur from inhalation of the steam or mist and from direct contact through the skin. Similarly, pesticide use can involve more than one route of exposure if precautions are not taken. A pesticide that is sprayed can be inhaled during use, penetrate through the skin during mixing and application, and/or be ingested through food if hands are not washed. Absorption, distribution, and fate Once a chemical enters the body, it is often absorbed into the bloodstream and can move throughout the body. The amount absorbed and the rate of absorption depend on the chemical and the route of exposure. This movement of the substance through the bloodstream is called “distribution.” Through distribution, a chemical can come into contact with all parts of the body, not just the original site of entry. In some cases, such contact, distant from the site of entry, can lead to adverse health effects. For example, ingestion of the pesticide parathion into the stomach can lead to damage to the lungs. Once a chemical is absorbed into the bloodstream, it can have several different fates. In many cases, it is rapidly removed from the body through the urine or feces. In other situations, it may be stored in various parts of the body, such as fat or bone, and remain in the individual for many years. A compound may also lead to a toxic effect through interaction with certain organs or tissues in the individual or with other compounds in the body. Often, a substance that is absorbed into the body interacts with particular body chemicals and is changed into one or more other chemicals. This process is called “metabolism” and the products are called “metab- olites.” Metabolism may lead to products that are easier for the body to excrete and so can protect the body from possible adverse effects. In other cases, however, the metabolites may be more toxic than the original chemical that was absorbed. The L1190 CH12 pgs Page 609 Friday, July 2, 1999 5:48 PM © 2000 CRC Press LLC variety of products resulting from metabolism may have the same possible fates as the original chemical — storage, excretion, or toxicity. Chemical properties The particular properties of the absorbed chemical are quite critical to its fate in the body. Certain chemicals are very resistant to metabolism and readily dissolve in fat so that they tend to be stored. Dieldrin is a good example of this type of com- pound. Other chemicals are more rapidly metabolized and excreted, and so are gone before they can cause adverse effects. The organophosphate pesticides tend to behave this way at low doses. An individual’s characteristics The characteristics of the individual who is exposed are also very important in the fate of the chemical. The age, sex, genetic background, previous exposures, diet, and other factors play important roles in the way that the body interacts with a chemical and in turn the potential for adverse effects. Thus, the characteristics of both the chemical and the exposed individual are important factors in determining the fate of the chemical in the body. The time course for exposure In the case of a single-event exposure, it is the total amount of chemical to which a person is exposed that determines the severity of the toxic effect, if any. The greater the amount of exposure, the greater the potential for adverse health effects. In some cases, this is due solely to the inherent toxicity of the chemical and, in others, also to overwhelming the ability of the body to respond. In the latter case, the body may not be able to metabolize the chemical quickly enough to prevent an increase in concentration to toxic levels. In such a situation, there is a clear threshold above which toxic signs and symptoms appear. In the case of (repeated) multiple exposures to a chemical, it is not only the total amount of exposure, but also the rate or timing of exposure that is quite important. All processes in the body normally proceed at specific rates so that metabolism, excretion, and storage occur during a particular period of time after a chemical is absorbed. For a one-occurrence exposure, the time needed for the various processes to break down the compound completely will determine the length of the toxic response time, if any. However, if there are repeated exposures to the same chemical, the situation is more complicated. If there is enough time between exposures so that all of the chemical from the initial exposure is excreted, and no effects persist, then each exposure is essentially independent of the previous one and can be treated as a single exposure. However, if the time between exposures is so short that some of the chemical remains from the first exposure, then a build-up of the chemical can occur. Over time, the chemical can rise to toxic levels. The total amount of exposure can have different results, depending on whether the exposure occurred all at once or repeatedly over time (the time course of expo- sure). A high dose given once may have a toxic effect, while the same total dose given in small amounts over time will not. For example, drinking several ounces of alcohol at once may cause inebriation, while drinking 1 ounce every few hours may L1190 CH12 pgs Page 610 Friday, July 2, 1999 5:48 PM © 2000 CRC Press LLC not. Also, a particular dose given a few hours apart may have an adverse effect, while the same total dose given a few days apart will not. Summary The possible toxic effects of exposure to a particular chemical depend on many factors. These include the characteristics of the chemical and the individual exposed, the route of exposure, the total dose, and the time course of exposure. Unfortunately, scientists have not been able to determine exactly how each of these factors will affect any specific individual so that present understanding of chemical exposures provides only general guidance. Minimizing exposure will minimize the potential for adverse effects. In addition, a general knowledge of all the contributing factors will help reveal situations that have the most potential for adverse health effects and can aid in determining the best ways to manage chemicals. 12.4Manifestations of toxic effects Introduction The human body is a vastly complex biochemical organism, finely tuned, and adaptable. It contains many different regulatory systems to ensure the proper response to variations in external conditions. When it becomes too warm inside the body, the water cooling system is turned up, and more sweat is secreted by the skin. The sweat evaporates, cools the blood underneath the skin, which in turn cools the body core. The sensors in the brain detect that body temperature is within normal limits, and turn off the sweat glands. This type of regulation (known as homeostasis) occurs for all bodily processes, and usually without any awareness or thought on our part. When external circumstances (like extreme heat or cold) or internal conditions (disease or poisoning) cannot be adjusted by normal mechanisms, the signs of dis- comfort and disease appear. The types of physical effects seen or felt (signs and symptoms) depend on the type of stress to which the body has been exposed. Because there are so many complex interrelationships between the systems within the body, a single change in any one system may result in numerous effects on other systems. In addition, the types of response to disease are limited; thus, signs and symptoms of disease are often quite similar for different diseases. For example, headache, fever, nausea, vomiting, and diarrhea are very common nonspecific symptoms of disease, produced by many, many agents. Because of the generality of most physiological responses to disease, many other methods have been developed to help diagnose the actual causes of disease. These methods include physical, biochemical, and immunological techniques upon which modern clinical medicine is based. A body’s homeostasis can be upset by physical, chemical, and/or biological agents that put stress on the body. The body’s reaction to prolonged stress depends on the nature of the agent, the degree of stress, and the duration of stress. When the stress is too intense, and homeostasis cannot be maintained or restored, disease occurs. Poisoning by chemical agents is nothing more than chemically induced disease, and the symptoms of chemical poisoning are often the same as symptoms caused by biological agents such as bacteria or viruses. To better understand how disease is caused by exposure to toxic chemicals, we must first understand how poisons work within the body. L1190 CH12 pgs Page 611 Friday, July 2, 1999 5:48 PM © 2000 CRC Press LLC How poisons work Poisons work by changing the speed of different body functions, increasing them (e.g., increasing the heart rate or sweating) or decreasing them (e.g., decreasing the rate of breathing). For example, people poisoned by parathion (an insecticide) may experience increased sweating as a result of a series of changes in the body. The first step is the biochemical inactivation of an enzyme. This biochemical change leads to a cellular change (in this case, an increase in nerve activity). The cellular change is then responsible for physiological changes, which are the symptoms of poisoning that are seen or felt in particular organ systems (in this case, the sweat glands). The basic progression from biochemical to cellular to physiological effects occurs in almost all cases of poisoning. Depending on the specific biochemical mechanism of action, a poison may have very widespread effects throughout the body, or may cause a very limited change in physiological functioning in a particular region or organ. Parathion causes a very simple inactivation of an enzyme involved in communication between nerves. The enzyme that parathion inactivates, however, is very widespread in the body, and thus the varied effects on many body systems are easily detectable. Toxicity Toxicity is a general term used to indicate adverse effects produced by poisons. These adverse effects can range from slight symptoms like headaches or nausea, to severe symptoms like coma, convulsions, and death. Toxicity is normally divided into various types, based on the number of expo- sures to a poison and the time it takes for toxic symptoms to develop. The two types most often referred to are acute and chronic. Acute toxicity is due to short-term exposure and happens within a relatively short period of time, whereas chronic toxicity is due to long-term exposure and happens over a longer period. Most toxic effects are reversible and do not cause permanent damage, but com- plete recovery may take a long time. However, some poisons cause irreversible (permanent) damage. Poisons can affect just one particular organ system or they may produce generalized toxicity by affecting a number of systems. Usually, the type of toxicity is subdivided into categories based on the major organ systems affected. Some of these are listed in Table 12.1. Subsequent sections of this chapter more fully explain skin and nervous system effects. Another section covers the formation of tumors and cancer. Because the body only has a certain number of responses to chemical and bio- logical stressors, it is often difficult to sort out the signs and symptoms and determine the actual cause of human disease or illness. In many cases, it is impossible to determine whether an illness was caused by chemical exposure or by a biological agent (like a flu virus). A history of exposure to a chemical is one important clue in helping to establish the cause of illness, but such a history does not constitute conclusive evidence that the chemical was the cause. To establish this cause-effect relationship, it is important that the chemical be detected in the body (such as in the bloodstream) at levels known to cause illness. If the chemical produces a specific and easily detected biochemical effect (like the inhibition of the enzyme acetylcho- linesterase), the resulting biochemical change in the body may be used as conclusive evidence. People who handle chemicals frequently in the course of their jobs and become ill and need medical attention should tell their physicians about their occupational exposure to chemicals. L1190 CH12 pgs Page 612 Friday, July 2, 1999 5:48 PM [...]... chemical can be identified and measures taken to prevent or minimize future exposure The best way to prevent cutaneous toxicity is the appropriate and correct use of protective clothing, and the use of safe handling and application procedures 12. 6 Effects on the nervous system: cholinesterase inhibition Although a variety of nervous system effects may occur from excessive exposure to pesticides, the most... these symptoms during pesticide handling or through other sources of exposure, they should immediately remove themselves from possible further exposure Exposure to: Carbamates and organophosphates May result in: Build-up of acetylcholine cholinesterase inhibition and constant firing of electrical messages with potential symptoms of twitching, trembling, paralyzed breathing, convulsions, and in extreme cases,... harmful than they really are The types and severity of cholinesterase inhibition symptoms depend on: 1 2 3 4 Toxicity of the pesticide Amount of pesticide involved in the exposure Route of exposure Duration of exposure © 2000 CRC Press LLC L1190 CH12 pgs Page 618 Friday, July 2, 1999 5:4 8 PM Although the signs of cholinesterase inhibition are similar for both carbamate and organophosphate poisoning, blood... dermatitis, and vary from © 2000 CRC Press LLC L1190 CH12 pgs Page 615 Friday, July 2, 1999 5:4 8 PM redness, itching, and small blisters to widespread blisters that overlap, forming very large fluid-filled blisters Treatment involves thorough washing to remove the allergen (in the case of poison ivy and oak, it is the oils in the plants), followed by treatment to reduce the itching, pain, and swelling... include some of the most toxic pesticides They can enter the human body through skin absorption, inhalation, or ingestion They can affect cholinesterase activity in both red blood cells and in blood plasma, and can act directly, or in combination with other enzymes, on cholinesterase in the body The most commonly used OPs and carbamates are included in Tables 12. 6 and 12. 7 What happens as a result of... uncontrollably Signs and symptoms of cholinesterase inhibition from exposure to CMs or OPs include the following 1 In mild cases (within 4 to 24 hours of contact ): tiredness, weakness, dizziness, nausea, and blurred vision 2 In moderate cases (within 4 to 24 hours of contact ): headache, sweating, tearing, drooling, vomiting, tunnel vision, and twitching 3 In severe cases (after continued daily absorption ): abdominal... anesthetic creams (containing benzocaine) should be avoided since they also can act as contact sensitizers (may also cause allergic dermatitis) and also may delay healing (See Table 12. 3.) Table 12. 3 Plants and Pesticides That May Cause Allergic Contact Dermatitis (ACD) Pesticides Captan Triazines Malathion PCNB Maneb Some natural pyrethroids Plants Poison Ivy Poison Oak Poison Sumac Liverwort Onions Garlic... Rashes, itching, redness, swelling Infertility, miscarriage 12. 5 Toxic effects on the skin Introduction During mixing, loading, and application of pesticides, the skin is the most likely body surface to come into contact with the product Many pesticides can be absorbed through the skin into the blood and cause toxic effects The amount of pesticide absorbed through the skin (percutaneous absorption)... Page 617 Friday, July 2, 1999 5:4 8 PM Human exposure to cholinesterase-inhibiting chemicals can result from inhalation, ingestion, or eye or skin contact during the manufacture, mixing, or application of these pesticides Electrical switching centers, called “synapses,” are found throughout the nervous systems of humans, other vertebrates, and insects Muscles, glands, and nerve fibers called “neurons”... within an individual, between indi© 2000 CRC Press LLC L1190 CH12 pgs Page 619 Friday, July 2, 1999 5:4 8 PM Table 12. 6 Commonly Used Organophosphate (OP) Pesticides Acephate (Orthene) Azinphos-methyl (Guthion) Carbofuran (Furadan, F formulation) Carbophenothion (Trithion) Chlorfenvinphos (Birlane) Chlorpyrifos (Dursban, Lorsban) Coumaphos (Co-Ral) Crotoxyphos (Ciodrin, Ciovap) Crufomate (Ruelene) Demeton . cluster is to do a full-scale epidemio- logical study, which is an expensive and time-consuming process, and may still not able to resolve the question. Summary Case-control and cohort studies. mixing and application, and/ or be ingested through food if hands are not washed. Absorption, distribution, and fate Once a chemical enters the body, it is often absorbed into the bloodstream and can. chemicals. L1190 CH12 pgs Page 612 Friday, July 2, 1999 5:4 8 PM © 2000 CRC Press LLC 12. 5Toxic effects on the skin Introduction During mixing, loading, and application of pesticides, the