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Michael H. Don g MPH, DrPA, PhD readin gs Epidemiology and Risk Assessment (4th of 10 Lectures on Toxicologic Epidemiology)

Michael H. Dong MPH, DrPA, PhD readings Epidemiology and Risk Assessment (4th of 10 Lectures on Toxicologic Epidemiology)

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  • Michael H. DongMPH, DrPA, PhDreadingsEpidemiology andRisk Assessment(4th of 10 Lectures on Toxicologic Epidemiology)

  • Taken in the early 90s, when desktop computers were still a luxury.

  • Learning ObjectivesAppreciate the recent advances in epidemiology pertinent to health risk assessment (RA).Study the epidemiologic approaches to human exposure assessment.Learn about the biomarkers used in epidemiology as well as in RA.

  • Performance ObjectivesAble to list and describe the recent advances in epidemiology pertinent to health risk assessment (RA).To describe the epidemiologic approaches to exposure assessment.To discuss the strengths and limitations of the use of biomarkers in epidemiology and in RA.

  • Health Statutes & RegulationsToxicity Studies/DataResearch Developments

  • Recent Advances in EpidemiologyBranching out from general epidemiology.Specialty disciplines now including: psychosocial; pharmaco-; occupational; environmental; nutritional; genetic; molecular; cancer epidemiology; and more.

  • Psychosocial EpidemiologyDeterminants of disease: social; psychological; behavioral factors.Not directly of regulatory concern.But offering valuable information for health risk assessment.

  • PharmacoepidemiologyStudying the use, efficacy, and safety of pharmaceuticals.Beginning to flourish in 1980s.Adding a new twist to the regular course of health risk assessment.

  • Nutritional EpidemiologyStudying the role of nutrition/ diet in the etiology of disease.Nutritional epidemiologists conducted the first clinical trials.Human and social factors affect dietary intake.

  • Genetic and Molecular EpidemiologyActually two separate branches.Molecular: studying with known genes.Genetic: studying with unknown genes.Useful in flagging preclinical effects of exposure.

  • Cancer EpidemiologyRelated closely to molecular and genetic epidemiology.Now more into identifying and quantifying nutritional and other environmental carcinogens.Epidemiology on cancer effects becoming more available for health risk assessment.

  • Environmental & Occu- pational EpidemiologyActually two separate branches.But both are linked together due to studying exposures to common toxic agents which are relatively more preventable.Occupational epidemiology tends to use biomarkers more.

  • Clinical TrialsWere conducted as early as 1537.Sometimes referred to as human intervention trials.Used to test not only treatment but also adverse (side) effects.A simplified or special version of health risk assessment.

  • Phases of Regulatory Clinical TrialsPreclinical: a series of laboratory or animal studies.Trial Phases: (I) testing for human safety; (II) testing for efficacy; (III) overall trial assessment.Postlicensing surveillance.Ideally should follow a double-blind randomization design.

  • Meta-Analysis of Clinical Trial DataFirst used around 1976.Uses routine statistical methods on data pooled from various trials typically not following the same study protocol.A controversial technique unacceptable to some statisticians.

  • Basic Epidemiologic Study DesignsUsing primarily observational data.Descriptive studies.Cohort studies.Case-control studies.Cross-sectional studies.Ecological studies.

  • Guidance for Epidemiology StudiesEpidemiologic study designs can be used to assess human exposures.Good epidemiology practices by: International Society for Pharmaco-epidemiology; International Epidemiological Association; and World Health Organization.

  • Human Exposure: Basic DefinitionHuman exposure to a toxic agent is defined as the (level of) contact of a person with the toxicant.Human exposures can be categorized by route of entry; exposure source; and exposure duration.

  • Human Exposure: Methods and AdvancesMethods: direct monitoring of individuals; and from measurement of environmental levels.Advances: Social Readjustment Rating Scale; Stress Process Model; geographic information system; biomarkers, etc.

  • Use of BiomarkersLimitations: low detection levels; compliance with sample collection.Related to biological monitoring.Types of biomarkers: for exposure; adverse response; susceptibility.Best estimate for aggregate dose.

  • Criteria of Selection of BiomarkersCriteria: availability; specificity; invasiveness; persistence; time-to-appearance; intra- and interperson variability.Multiple factors causing biological variation in dose-response.

  • Biomarkers: Legal and Ethical ConsiderationsLegal authority as barrier; privacy act.Ethical implications concerning the subjects right-to-know.These considerations making biomarkers useful at a slow pace.

  • Overview of Next Lecture Toxicologic Side of EpidemiologyIllustrating this side through use of historical cases.Epidemiologic activities might have initiated/dominated in these cases.But the toxicologic side was also there and critical.

    This is the fourth of 10 lectures on toxicologic epidemiology. It has been prepared to expand on the brief discussion of the linkage between health risk assessment (RA) and epidemiology that was presented in Lecture 1. As mentioned in Lecture 3 on toxicology and RA, the close relationship between RA and epidemiology likewise cannot be fully disclosed in one or two lectures of this type. The documentation and literature on such a relationship is simply too much to appreciate. Accordingly, this lecture is necessarily compact, with the materials organized primarily for easy access by the novice.The relationship between epidemiology and RA is essentially the same as discussed in the last lecture between toxicology and RA, at least in scope. As a matter of fact, if epidemiologic studies on health effects were ethical and as readily available as animal studies and in vitro assays are, there would be no need to provide the last lecture on toxicology and RA. Nor would there be a need to separate toxicologic experiment from human testing or clinical trials. The discussion in this lecture hence will be more focused and specific, at the expense of a broader, more general presentation already given in Lecture 3. The titles of the 10 lectures are: (1) Toxicology and Epidemiology; (2) Public Health and Risk Assessment; (3) Toxicology and Risk Assessment; (4) Epidemiology and Risk Assessment; (5) Toxicologic Side of Epidemiology; (6) Epidemiologic Side of Toxicology; (7) Human Exposure Assessment I; (8) Human Exposure Assessment II; (9) Characterization of Health Risk; and (10) Toxicologic Epidemiology.Dr. Michael H. Dong, born in Hong Kong, holds a DrPA (Doctor of Public Administration) in health policy from the University of Southern California, and a PhD in Environmental Epidemiology from the University of Pittsburgh. He has also earned a BSc in biochemistry from the University of California at Davis/Riverside, a second BSc in forensic science from the California State University at Sacramento, and a MPH in environmental and nutritional sciences from UCLA. Dr. Dong currently is a Diplomate of the American Board of Toxicology (DABT) and a Certified Nutrition Specialist (CNS).Dr. Dong has been working for 11 years as a regulatory toxicologist at the State of California Department of Pesticide Regulation. Previously, he was on active duty for several years as a U.S. Public Health Service Commissioned Corps officer, working at the Center for Drug Research and Evaluation, U.S. Food and Drug Administration. He also served for several years as a U.S. Army Medical Service Corp officer with various assignments working as a nutritional, clinical, or research biochemist. Between the two military services, Michael worked for a year as an occupational toxicologist as well as an environmental epidemiologist at the Occupational Safety and Health Administration, U.S. Department of Labor.Michaels academic and professional trainings, his selected published work in such innovative concepts as physiologically-based pharmacokinetic (PB-PK) modeling and aggregate exposure assessment through Monte Carlo simulation, and the series of 10 lectures on toxicologic epidemiology, all point to his continuing interest in and commitment to promoting global health. In this lecture, students will learn about the recent advances in epidemiology relevant to health risk assessment (RA). As mentioned in Lecture 3, toxicity assessment, exposure assessment, and risk characterization are now the three subprocesses involved in the revised RA scheme. The newer scheme is different from the one first formulated (National Research Council, 1983) only in that hazard identification and dose-response assessment are now treated as one process. In either case, epidemiologic studies by far provide the most relevant evidence for hazard identification. This strength is offset to a great extent, however, by the difficulties associated with obtaining and interpreting epidemiologic information since such is derived from observational studies.Epidemiology involves the association of diseases to risk factors and human exposures. Accordingly, here the students are also expected to learn some of the recent developments in human exposure assessment, specifically those pertinent to the recent advances in epidemiology or RA. One recent advance in epidemiology especially noteworthy is the use of biomarkers, which are physiological, biochemical, or molecular alterations measurable in biologic media such as human cells, fluids, or tissues (Hulka, 1990).The use of biomarkers in epidemiologic studies has now become a popular assessment tool. In the last part of this lecture, students will learn how and why biomarkers can be used to extend our understanding of the steps between exposure and disease occurrence, and about the limitations of this use.At the end of this lecture, students should be able to characterize briefly the recent advances in epidemiology that are pertinent to health risk assessment (RA). Recent epidemiologic advances relevant to RA include the branching of epidemiology into several well-recognized specialty disciplines, such as pyschosocial epidemiology, occupational epidemiology, environmental epidemiology, nutritional epidemiology, pharmaco-epidemiology, genetic epidemiology, molecular epidemiology, and cancer epidemiology.These specialties involve special study designs and specific information for epidemiologic investigations. The human exposures and risk factors in these specific studies hence require some special tools for assessment or measurement. From this lecture, students should be able to identify the recent advances in these areas.Finally, students should also be able to outline the strengths and limitations of the use of biomarkers in epidemiologic investigations. The biomarkers available for exposure assessment or for risk factor measurement often vary from one epidemiologic specialty to another. However, it is important to note that their general use in epidemiologic investigations (and hence in RA as well) remains the same. Again, this lecture is on health risk assessment (RA) and epidemiology. Much of this linkage can be summarized in the flowchart presented here. This flowchart was presented in the last lecture on RA and toxicology, where the impacts and effects involved in some cases are necessarily different since toxicologic studies by design are different from epidemiologic investigations. For those students who would like to appreciate more about the linkages depicted in this flowchart, they are referred to Lecture 3.As mentioned earlier in the title slide of this lecture (and in the last overview slide of the last lecture), if epidemiologic studies on health effects were ethical and as readily available as animal studies and in vitro assays are, there would be no need to provide the last lecture relating RA specifically to toxicology. Nor would there be a need to separate toxicologic experiment from human testing. We already know from the start that epidemiologic data are most direct for RA, but for ethical and resource reasons such are often unattainable.In this lecture, the discussion will be more focused and specific, at the expense of a broader, more general presentation already given in Lecture 3. Topics to be discussed here include: (1) The recent epidemiologic advances that are pertinent to RA; (2) the epidemiologic approaches used to conduct exposure assessment and risk factor measurement that are specific to the epidemiologic specialties involved; and (3) the use of biomarkers, which is not only a recent advance but also a subject specifically related to human exposure assessment.Recent advances in epidemiology that are pertinent to health risk assessment include several specialty areas into which basic and intermediate-level general epidemiology have branched out. These specialty areas include, but are limited to: pharmacoepidemiology, pyschosocial epidemiology, occupational epidemiology, environmental epidemiology, nutritional epidemiology, genetic epidemiology, molecular epidemiology, and cancer epidemiology.A course in general epidemiology, whether at the basic or intermediate level, typically teaches students how to measure disease occurrence and how to measure associations between exposures and outcomes (see, e.g., Gordis, 1996; Lilienfeld and Stolley, 1994; Rothman and Sander, 1998; Szklo and Nieto, 2000). Students in those courses are thus trained to measure incidence, prevalence, and their interrelation. Incidence and prevalence involve the number of new and existing cases, respectively, at a time point or during a time period. These rates and other measures of morbidity and mortality are primarily the objectives of descriptive epidemiology, in which the attempt is to characterize the amount and distribution of disease within a population.General epidemiology students are also given basic training in analytic epidemiology, in which several study designs are available as options to measure associations between exposures and outcomes. These study designs include case-control studies, cohort studies, cross-sectional studies, clinical trials, quasi-experimental studies, and ecological studies (see Slide 16 and references cited above for definition and description of these study designs).As defined by Friis and Sellers (1999), psychosocial epidemiology can be more broadly conceptualized to include psychosocial, behavioral, and social factors. That is, the determinants of health or disease studied in psychosocial epidemiology are not single agents such as specific bacteria or chemicals, but a host of less tangible human factors.Psychosocial determinants such as stress, alcohol consumption, dietary practice, and smoking habit are almost of little or no direct concern to regulatory agencies. However, this type of epidemiologic studies usually offers invaluable information regarding the adverse health effects caused by toxic agents of regulatory concern. For example, there are interactive and synergistic effects of smoking and occupational exposures to asbestos, nickel, and chromium.Another example is the information gained on dietary practice in a population. The relationship between diet and cancer or coronary heart disease has long been the subject of investigation on nutrient toxicity. A food additive is a substance used to facilitate some part of the processing of a foodstuff, or deliberately added to a foodstuff to effect a particular characteristic such as taste, smell, or color. Both the toxicology of food additives and the pesticide residues in food are of regulatory concern to the U.S. Food and Drug Administration (Slide 17 of Lecture 2). Assessment of the intake of these food contaminants requires information on a populations dietary pattern, which to a great extent is culture-bound and economics-based.Another branch of epidemiology pertinent to health risk assessment (RA) is pharmacoepidemiology, which applies epidemiologic methods to study the use, efficacy, and safety of pharmaceuticals. An overview of this branch of epidemiology has been given by Dr. Boji Huang as one of the Supercourse lectures. Like pharmaceutical toxicology, although pharmacoepidemiology has not flourished until the 1980s, its history goes back to the 1920s when salvarsan was used to treat syphilis in soldiers returning from World War I.A timeline of notable drug disasters and important adverse drug effects has been given by DArcy (1993), who noted that the antimicrobial sulfa drugs (sulfanilamides) disaster in the 1930s shocked the people in the United States and prompted the passage of the Food, Drug, and Cosmetic Act of 1938. The thalidomide tragedy in the 1960s perhaps drew the greatest public attention. In the 1990s, there were disasters or important adverse effects related to the use of Terolidine, Propofol (not used in the United States), and varicella vaccines.The regulation of drugs and medicines, and hence the RA involved as well, is quite different from those of pesticides, food, and other environmental or industrial contaminants. This is because both the therapeutic and side effects from drugs and medicines are more tangible, direct, and individual, than those from industrial or environmental contaminants. It is primarily due to these differences that pharmacoepidemiology has added a new twist to the regular course of RA. That is, comparatively speaking, more human toxicity data are used in this type of RA than in those concerning environmental contaminants. Nutritional epidemiology is an area of epidemiology that studies the role of nutrition and diet in the etiology of disease such as cancer and heart disease, and monitors nutritional status of populations. It thus involves the assessment of food consumption and nutrient intake, an area referred to as assessment of dietary intake or of dietary exposure. In addition to the use of demographic and psychosocial variables, today nutritional epidemiology also attempts to study nutrition-related diseases by means of clinical trials and to monitor nutrient intake with biochemical markers (Margetts and Nelson, 1997).The field of nutritional epidemiology can often be traced back to 1747, when James Lind (1753) observed that fresh fruits and vegetables could be used to cure scurvy. His observation represents one of the earliest clinical trials. The cause of the scurvy disease was later found to be vitamin C deficiency (see, e.g., Sandstead, 1973). Then in 1884, Kanehiro Takaki (1887) linked Japanese sailors diet of polished rice to the disease beriberi (which is due to vitamin B1 deficiency). The disease was eliminated when he added milk and vegetables to the soldiers diet.The relationship between nutritional epidemiology and health risk assessment is quite unique in that the consumption of too much or too little nutrients of certain kind may lead to some chronic diseases. The measure of nutritional status is also unique since socioeconomics, education, and cultural habit can have a great influence on an individual as well as a populations nutrient or dietary intake.Molecular and genetic epidemiology actually represent two separate branches of epidemiology. The terms molecular and genetic epidemiology are sometimes used interchangeably, however, because one common application of molecular epidemiology is the use of inherited (vs. acquired) variation in DNA to classify study subjects. As Friis and Sellers (1999) put it well, the distinction between the two fields is that Molecular epidemiology evaluates the association of variation in known genes with risk of disease, whereas genetic epidemiology includes the identification of unknown genes that influences risk of disease. In addition, molecular epidemiology also uses molecular markers to link exposures to disease, especially to cancer. Advances in molecular (or genetic) markers have a great impact on health risk assessment (RA) in that they can be used to flag preclinical effects of exposure. The advantages of using molecular markers or genetic factors in RA may be illustrated with the examples provided by Friis and Sellers. For example, rather than treating all cases of breast cancer as the same disease, an epidemiologist can use tumor markers to identify potentially more heterogeneous subsets. Another example is that we can assess serum levels of micronutrients to obtain more accurate measurements, rather than to rely on the individuals recall of usual diet to estimate his or her intake of fruits, vegetables, and the likeIn addition to genetic epidemiology, cancer epidemiology is another branch of epidemiology that is related very closely to molecular epidemiology. In fact, the term molecular cancer epidemiology is brought to being in the early 1980s primarily because of this close interrelationship. Insofar as carcinogenesis often initiates with DNA damage, biomarkers that can be used to identify early responses to such damage are important to the assessment of cancer risk. Unscheduled DNA synthesis, chromosome aberrations, sister chromatid exchanges, and the micronucleus tests are some examples of these tumor markers. As Weinstein (1988) put it, These markers can be scored long in advance of preneoplastic lesions that are detected by histologic methods. Because these markers are genetic materials in nature, they are often referred to as genetic markers.Modern cancer epidemiologists are no long just preoccupied with the study of the effects of cigarette smoking and radiation, nowadays they are also interested in identifying and quantifying diets and other environmental contaminants as potential carcinogens. Because cytogenetic monitoring is more feasible than histologic examination for neoplastic lesions in human subjects, epidemiological data on carcinogenic effects are becoming more available for health as well as cancer risk assessment.

    Environmental and occupational epidemiology are the last two branches of epidemiology discussed in this lecture. Both branches are oriented primarily towards the study of causative exposures, rather than of the disease outcome. Occupational epidemiology is closely related to environmental epidemiology in that many of the environmental contaminants of concern are man-made products or by-products. Therefore, certain occupational groups are often subject to the same type of contaminant insults as the general public is, although the levels of exposure that they receive are likely different. Workers and users will receive the exposure during manufacturing or handling of the products. On the other hand, the general public will be exposed to the products or their by-products when these contaminants have been emitted, spread, or otherwise precipitated into the environment.The exposures to environmental and occupational health hazards are the domain of health risk assessment because they are not only of great concern to the public, but also thought to be highly preventable. It is under this notion that several health statutes have been passed in the United States (and in other industrial countries) to regulate the exposures to these types of health hazards. A brief description of these health statutes was presented in Lecture 3.Of all branches of epidemiology, occupational epidemiology tends to use biomarkers the most to monitor human exposures. This is because occupational groups are relatively easier to be identified, worked with, and followed up.Despite the popularity of biomarkers, their use as a tool for measuring human health effects or human exposures is not always necessary or applicable in other branches of epidemiology. One reason for this is that there are other epidemiologic methods or study designs that can serve as more appropriate alternatives. In pharmacoepidemiology, for example, clinical trials can be used not only to test the efficacy of a therapeutic measure, but also to monitor the adverse health effects from the dosing. It was mentioned in Slide 9 that in 1747, James Lind was credited with designing one of the first clinical trials. Clinical (sometimes referred to as human intervention) trials are planned experiments designed to assess the efficacy of a treatment in man by contrasting the outcomes of a group of patients or subjects treated with the test treatment with those observed in a comparable group of patients receiving a control treatment. In the case with James Lind, he used lemon juice as the treatment for scurvy, which can be caused by vitamin C deficiency.Linds clinical trial was not the very first of its kind. In 1537, French army surgeon Ambroise Par (a barber surgeon as well) applied an experimental treatment for battlefield wounds with a digestive made from rose oil, turpentine, and egg yolks (see e.g., Friis and Sellers, 1999; Sawyer, 2000). In addition to treatment efficacy, which actually reflects the effects of dosing or exposure, side effects are often included in a trial as outcomes of interest. Because side effects are linked to dosing, clinical trials are in fact a simplified, special version of health risk assessments.Today, several phases or stages are involved in a clinical trial conducted for marketing a new drug or vaccine in the United States. The suggestion that a new agent has a promising therapeutic action usually comes from a series of laboratory studies in vitro and in vivo among animals. This is referred to as the preclinical trial phase. Phase I trials consist of testing the agent among human volunteers, primarily for safety concern rather than for treatment efficacy. Phase II is concerned with testing treatment efficacy. At the conclusion of Phase III, much information would have been gathered about the agents overall protective efficacy. The evaluation of treatment or drug safety and efficacy continues through postlicensing surveillance.Clinical trials are more complicated than animal controlled experiments, in that ethical and treatment crossover issues are always barriers to achieving a successful randomization design, in which the test subjects would otherwise be randomly assigned to the treatment or control conditions. At times, a treatment crossover for a patient is necessary during the course of a clinical trial, because the patients health condition may have been deteriorated to the point to require the same test or a special treatment. Ideally, clinical trials should be conducted with a randomized, double blind-design in order to minimize experimental biases. Multiple independent clinical trials are typically conducted at various research or medical centers to test the efficacy of a particular treatment or drug. The results of these clinical trials are then pooled by a somewhat controversial procedure called meta-analysis. According to a series of debate on this statistical issue in the British Medical Journal (Egger et al., 1997), the term meta-analysis was coined in 1976 by the psychologist Gail Glass. Meta-analysis was later revisited by medical researchers for use primarily in randomized clinical trials. A useful definition was given by Huque (1988): A statistical analysis that combines or integrates the results of several independent clinical trails considered by the analyst to be combinable.In a meta-analysis, different statistical methods may be used to combine the data. However, a typical procedure will use a weighted average of the results, with the larger trials having more influence over the smaller ones. The more complicated problems with the use of this type of analysis are, however, the parts that deal with identifying the relevant studies and with expressing the individual results in a standardized format.Despite its widespread use, meta-analysis continues to be a controversial technique unacceptable to some statisticians. This is because the pooling of results from clinical trials that involved independent but varied study protocols is simply statistically unsound. Epidemiologists continue to take advantage of meta-analysis because a single study often cannot detect or exclude with certainty a modest, yet clinically relevant, difference in two treatment effects.Perhaps except clinical trials, other study designs used by epidemiologists are generally less experimental in nature. These include descriptive studies, case-control studies, cohort studies, cross-sectional studies, and ecological studies. Descriptive studies make use of available data to examine how mortality, morbidity, and other exposure- or risk-related rates vary according to certain demographic, geographic, and environmental variables.The other study designs listed here basically are for analytical epidemiology, in which the associations between exposures (including all relevant risk factors such as age and sex) and outcomes are tested or measured. Cohort studies involve the follow up of a group of healthy people (cohort) for a certain time period to ascertain the occurrence of health-related events in relation to the exposure or risk factor of interest. Case-control studies, on the other hand, compare the odds of usually past exposure to a suspected risk factor between diseased individuals (cases) and nondiseased individuals (controls). In a cross-sectional study, a reference population is examined at a given point in time to measure the prevalence of disease and the level of exposure of interest. Ecological studies are conducted to determine the number of exposed persons and the number of cases that may or may not be related, usually due to the lack of the ability to determine the number of exposed cases. Thus, in ecological studies, the unit of analysis is the group, not individuals.Descriptive studies, cohort studies, case-control studies, cross-sectional studies, and ecological studies were briefly discussed in the last slide. These study designs are investigation tools fundamental to all branches of epidemiology. They are not recent epidemiologic advances but are included here primarily for completeness only. Further elaboration on their use in epidemiology can be found in recent textbooks (Gordis, 1996; Lilienfeld and Stolley, 1994; Rothman and Sander, 1998; Szklo and Nieto, 2000).Both the International Society for Pharmacoepidemiology (ISPE, 1996) and the International Epidemiological Association (IEA, 2000) have provided sound guidance for good epidemiology practices. The guidance document provided by ISPE is more on practices for drug, device, and vaccine research, whereas the IEA guidance has a focus on competence criteria for use to qualify a well-trained epidemiologist. To date, World Health Organization (WHO, 1983) has provided the most comprehensive guidance document for use of epidemiologic studies within the context of health risk assessment (RA). This WHO document, entitled Guidelines on Studies in Environmental Epidemiology, was coincidentally published in the year the RA scheme was first formulated by the National Research Council (1983).The WHO document covered not only the various basic epidemiologic study designs mentioned above, but also such topics as assessment of exposure and adverse health effects. As discussed in Lecture 3, human exposure assessment and hazard identification are two of the four key components of RA.All study designs discussed in textbooks of epidemiology (and in the last two slides as well) can be used to assess or measure human exposures to some degree. Although it is one of the central components of health risk assessment, human exposure assessment is not covered in any great length in (many) textbooks of toxicology. This does not mean that toxicologists are not qualified to perform human exposure assessment. As a matter of fact, many forensic and clinical toxicologists are required by their occupation to determine the amount of toxic substance present in human bodies. However, their focus appears to be more on individuals, not on groups.Human exposure to a toxic agent is defined simply as the (level of) contact of a person with the toxicant. Dose on the other hand is the amount of that toxicant that is present in (or sometimes even on) a person at specific time intervals. As to be discussed more extensively in Lectures 7 and 8, there are several types of human exposures that epidemiologists have to deal with.In terms of route of entry, human exposures to toxic agents can be subdivided into primarily the following three categories: oral, inhalation, and dermal. Human exposures can also be categorized according to their sources: outdoor, indoor, occupational, residential, postapplication (reentry), passer-by, ambient air, dietary, drinking water, etc. These different types of human exposures can be further qualified according to their duration: acute, short-term, intermediate, long-term, chronic, and lifetime.In some cases (especially when direct measurements are not available), human exposures to a certain toxic agent can be measured indirectly through use of environmental concentrations and some physiological intake or uptake parameters. For instance, multiplying the air level of a toxic agent by an individuals hourly inhalation rate would give an estimate of the amount of an air pollutant taken into his or her respiratory tract in one hour. Multiplying the food residue levels by an individuals daily consumption rate would also provide an estimate for his or her daily dietary intake of those residues.In psychosocial epidemiology, example advances that are relevant to human exposure assessment include the Social Readjustment Rating Scale (Holmes and Rahe, 1967) used to measure the amount of stress from life events, and the more recent revised stress process model (Pearlin, 2000) designed to associate the individuals health with exposure to stress and other factors.For the other branches of epidemiology, in addition to having better designed studies or surveys and hence higher quality data nowadays, perhaps the most widely-mentioned, if not widely-accepted, tool for human exposure assessment is biological markers. Recent advances in analytical chemistry and geographic information system (GIS) too contribute a great deal to environmental monitoring. For example, a chemical that could only be quantified at PPM (parts per million) before can now be detected at PPB. The use of a GIS will also improve the predicted environmental concentrations by its aiding in selection of appropriate meteorological data and source location.The use of biomarkers as an exposure assessment tool is not without limitations. Some of its limitations were discussed in Lecture 3, specifically those with respect to low levels of markers available for quantification and the impracticality of collecting 24-hour urine samples. Other aspects of the down-side are discussed here and in the two slides that follow, which shall conclude the presentation of this lecture on epidemiology and health risk assessment.In addition to the scientific, legal, and ethical concerns, the discussion on the use of biomarkers cannot be considered as complete without mentioning the techniques and purposes of biomonitoring.Biomonitoring is defined as the measurement and assessment of toxic agents or their metabolites in human tissues, secreta, excreta, expired air, or any combination of these for the purpose of evaluating exposure and health risk. However, biomonitoring may also be broadly defined to include medical surveillance or genetic monitoring (Ashford et al., 1990). The use of biomarkers is closely related to biomonitoring because the toxic agent or its metabolites to be monitored can be used as a marker of exposure. As discussed in Slide 11, certain biomarkers are used to detect an adverse or a biologic response, such as DNA damage that leading to the initiation of an oncogenic event. There are also markers of disease or susceptibility (Hulka, 1990; National Research Council, 1989; Perera and Weinstein, 1982; Vine, 1994). In the case of exposure markers, their use provides the best estimate of an aggregate dose intended to account for all exposure pathways and sources.Criteria or considerations for the selection of biomarkers in epidemiologic studies have been summarized by Vine (1994). These include: (a) Availability of markers; (b) specificity of the marker; (c) invasiveness of the sampling method; (d) time-to-appearance of the marker; (e) persistence and stability of the marker; (f) intra- and interperson variability; and (g) cost and reliability of the assay.Scientific and technical concerns with the use of biomarkers that are more basic to all types of epidemiologic studies appear to center around the assays sensitivity, specificity, and predictive value. These are standard issues concerning diagnostic tests. Another related problem is the baseline value used, which is the level of the marker dose occurring naturally as a result of other than the exposure(s) in question. These concerns often make it difficult for epidemiologists to use the biomarker data effectively in assessing human exposures.Ashford et al. (1990) provide a good discussion on the scientific and technical concerns related to medical surveillance, genetic monitoring, and biological monitoring. As pointed out by these authors, medical and genetic tests too are subject to similar concerns regarding the issues of sensitivity, specificity, and predictability. They also outline the multiple factors that can cause biological variations in response among subjects exposed to the same substance, such as the individuals diet, rate of metabolism, age, sex, and health condition.Legal authority to even passively monitoring human exposure is an additional concern or barrier in the use of biomarkers. For instance, under the Privacy Act, an employee could refuse to participate in most any worker monitoring program. For biomonitoring studies conducted under good laboratory practices, informed consent forms must be well designed and carefully executed. According to Ashford et al. (1990), the U.S. Supreme Court in 1989 ruled that certain exceptions such as for monitoring drinking and drug taking on the job are outside worker privacy.The use of biomonitoring results can have ethical implications. When a biomarker test shows a positive result or a high level of exposure, the study investigator may be morally obligated to inform the test individual this unpleasant finding. If not, the test subjects health may be in jeopardy or compromised. Yet the investigators first obligation is to use the study data in accord with the research intent. To alert subjects tested with high levels of exposure may require more than results from the study. The investigator might have to go beyond the normal course to ascertain the subjects exposure activity, his or her personal habit, and health condition. Students are referred to the papers by Lappe (1986) and by Last (1994) for more generic ethical issues/principles (e.g., paternalism, beneficence, autonomy, nonmaleficence).These legal and ethnical conditions, along with the scientific and technical concerns discussed in the last two slides, are barriers to the use of biomarkers in human exposure assessment, which is central to health risk assessment.The linkage between toxicology and epidemiology was conceptualized briefly in the first lecture, and further substantiated in this and the last two lectures. For some toxicologist and epidemiologist practitioners, perhaps the best approach to convincing them about the close relationship between toxicology and epidemiology is through use of historical cases.In the next two lectures, that on toxicologic side of epidemiology and on epidemiologic side of toxicology, a total of six (6) cases will be described in depth to illustrative this point. The point is that in many instances both toxicologists and epidemiologists have been working in one way or another to pursue or fulfill more or less the same study goals.It is important to note, however, that the distinction made in the next two lectures between the two sides is more a gimmick of drawing the students attention, than a representation of the reality. For each of these six cases and others not discussed, there is some truth that one side might have initiated or dominated the historical events or activities, but that would be pretty much the extent of the distinction.