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Reference Guide on Exposure Science JOSEPH V. RODRICKS Joseph V. Rodricks, Ph.D., is Principal at Environ, Arlington, Virginia. C onTenTs I. Introduction, 505 II. Exposure Science, 506 A. What Do Exposure Scientists Do? 507 B. Who Qualifies as an Expert in Exposure Assessment? 508 C. Organization of the Reference Guide, 508 III. Contexts for the Application of Exposure Science, 509 A. Consumer Products, 509 B. Environmental and Product Contaminants, 510 C. Chemicals in Workplace Environments, 511 D. Claims of Disease Causation, 511 IV. Chemicals, 513 A. Organic and Inorganic Chemicals, 513 B. Industrial Chemistry, 514 V. Human Exposures to Chemicals, 516 A. Exposure Sources—An Overview, 516 B. The Goal of Exposure Assessment, 518 C. Pathways, 519 D. Exposure Routes, 522 E. Summary of the Descriptive Process, 524 VI. Quantification of Exposure, 525 A. Dose, 525 B. Doses from Indirect Exposure Pathways, 527 C. Direct Measurement: Analytical Science, 528 D. Environmental Models, 530 E. Integrated Exposure/Dose Assessment, 533 VII. Into the Body, 534 A. Body Burdens, 534 B. Monitoring the Body (Biomonitoring), 535 VIII. Evaluating the Scientific Quality of an Exposure Assessment, 537 IX. Qualifications of Exposure Scientists, 539 503

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Reference Manual on Scientific Evidence Appendix A: Presentation of Data—Concentration Units, 541 Appendix B: Hazardous Waste Site Exposure Assessment, 543 Glossary of Terms, 545 References on Exposure, 548 504

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Reference Guide on Exposure Science I. Introduction The sciences of epidemiology1 and toxicology2 are devoted to understanding the hazardous properties (the toxicity) of chemical substances. Moreover, epidemio- logical and toxicological studies provide information on how the seriousness and rate of occurrence of the hazard in a population (its risk) change as exposure to a particular chemical changes. To evaluate whether individuals or populations exposed to a chemical are at risk of harm,3 or have actually been harmed, the information that arises from epidemiological and toxicological studies is needed, as is the information on the exposures incurred by those individuals or populations. Epidemiologists and toxicologists can tell us, for example, how the magnitude of risk of benzene-induced leukemia changes as exposure to benzene changes. Thus, if there is a need to understand the magnitude of the leukemia risk in populations residing near a petroleum refinery, it becomes necessary to understand the magnitude of the exposure of those populations to benzene. Likewise, if an individual with leukemia claims that benzene exposure was the cause, it becomes necessary to evaluate the history of that individual’s exposure to benzene.4 Understanding exposure is essential to understanding whether the toxic prop- erties of chemicals have been or will be expressed. Thus, claims of toxic tort or product liability generally require expert testimony not only in medicine and in the sciences of epidemiology and toxicology, but also testimony concerning the nature and magnitude of the exposures incurred by those alleging harm. Similarly, litigation involving the regulation of chemicals said to pose excessive risks to health also requires litigants to present evidence regarding exposure. The need to understand exposure is a central topic in the reference guides in this publication on epidemiology and toxicology. This reference guide provides a view of how the magnitude of exposure comes to be understood.5 1. See Michael D. Green et al., Reference Guide on Epidemiology, in this manual. 2. See Bernard D. Goldstein & Mary Sue Henifin, Reference Guide on Toxicology, in this manual. 3. See, e.g., Rhodes v. E.I. du Pont de Nemours & Co., 253 F.R.D. 365 (S.D. W. Va. 2008) (suit for medical monitoring costs because exposure to perfluoroctanoic acid in drinking water alleg- edly caused an increased risk of developing certain diseases in the future); In re Welding Fume Prods. Liab. Litig., 245 F.R.D. 279 (N.D. Ohio 2007) (exposure to manganese fumes allegedly increased the risk of later developing brain damage). 4. See, e.g., Lambert v. B.P. Products North America, Inc., 2006 WL 924988 (S.D. Ill. 2006), 2006 U.S. Dist. LEXIS 16756 (plaintiff diagnosed with chronic lymphocytic leukemia was exposed to jet fuel allegedly containing excessive levels of benzene). 5. This chapter focuses on measuring exposure to toxic substances as a specific developing area of scientific investigation. This topic is distinct from the legal concept of “exposure,” which is an ele- ment of a claim in toxic tort litigation. The legal concept of exposure relies on the evolving scientific understanding of the manner and extent to which individuals come into contact with toxic substances. However, the legal concept also reflects substantive legal principles and interpretations that vary across jurisdictions. Compare Parker v. Mobil Oil Corp., 793 N.Y.S.2d 434 (2005) (requiring findings of specific levels of exposure to benzene by plaintiff who claimed that his leukemia was the result of his 505

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Reference Manual on Scientific Evidence Not all questions concerning human exposures to potentially harmful sub- stances require expert testimony. In those circumstances in which the magni- tude of exposure is not relevant, or is clearly evident (e.g., because a plaintiff was observed to take the prescribed amount of a prescription medicine), expert testimony is not indicated. But if the magnitude of exposure is an important com- ponent of the needed evidence, and if that magnitude is not a simple question of fact, then expert testimony will be important. II. Exposure Science Exposure science is not yet a distinct academic discipline. Although some schools of public health may offer courses in exposure assessment, there are no academic degrees offered in exposure science. When regulatory and public health agencies began in the 1970s to examine toxicological risks in a quantitative way, it became apparent that quantitative exposure assessments would become necessary. Initially, exposure assessment was typically practiced by toxicologists and epidemiologists. As the breadth and complexity of the subject began to be recognized, it became apparent that scientists and engineers with a better grasp of the properties of chemicals (which affect how they behave and undergo change in different envi- ronments), and of the methods available to identify and measure chemicals in products and in the environment, would be necessary to provide scientifically defensible assessments. As the importance of exposure assessment grew and began to present significant scientific challenges, its practice drew increasing numbers of scientists and engineers, and some began to refer to their work as exposure science. Not surprisingly, most of the early expositions of exposure assessment came from government agencies that recognized the need to develop and refine the practice to meet their risk assessment needs. Indeed, various documents and reports used by the U.S. Environmental Protection Agency (EPA) remain essen- tial sources for the practice of exposure assessment.6 Academics and practitioners have written chapters on exposure science for major multiauthor reference works 17-year occupational exposure to gasoline containing benzene) with Westberry v. Gislaved Gummi AB, 178 F.3d 257 (4th Cir. 1999) (evidence of specific exposure level not required where evidence of talc in the workplace indicated that the worker was covered in talc and left footprints on the floor) and Allen v. Martin Surfacing, 263 F.R.D. 47 (D. Mass. 2009) (admissible expert testimony may be based on symptom accounts by those exposed rather than direct measurements of solvent concentrations). This chapter takes no position regarding exposure as a substantive legal concept. 6. U.S. Environmental Protection Agency, Exposure Assessment Tools and Models (2009), avail- able at http://www.epa.gov/oppt/exposure/ (last visited June 6, 2011); National Exposure Research Laboratory, U.S. Environmental Protection Agency, Scientific and Ethical Approaches for Obser- vational Exposure Studies, Doc. No. EPA 600/R-08/062 (2008), available at http://www.epa.gov/ nerl/sots/index.html (last visited July 14, 2010); U.S. Environmental Protection Agency. Exposure Factors Handbook (1997). 506

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Reference Guide on Exposure Science on toxicology,7 but most of the work in this area is still found in the primary reference works. Although exposure science is not yet a distinct academic discipline, in this reference guide the phrase is retained and used to refer to the work of scientists and engineers (“exposure scientists”) working in one or more aspects of exposure assessment. A. What Do Exposure Scientists Do? Human beings are exposed to natural and industrial chemicals from conception to death, and because almost all chemicals can become harmful if exposures exceed certain levels, understanding the magnitude and duration of exposures to chemi- cals is critical to understanding their health impacts. Exposure science is the study of how people can come into contact with (are exposed to)8 chemicals that may be present in various environmental media (air, water, food, soil, consumer products of all types) and of the amounts of those chemicals that enter the body as a result of these contacts.9 Exposure scientists also study whether and how those amounts change over time. The goal of exposure science is to quantify those amounts and time periods. The quantitative expression of those amounts is referred to as dose. Ultimately the dose incurred by populations or individuals is the measure needed by health experts to quantify risk of toxicity. Exposure science does not typically deal with the health consequences of those exposures. The dose entering the body (through inhalation or ingestion, through the skin, and through other routes) is often referred to as the “exposure dose,” to distinguish it from the dose that enters the bloodstream and reaches various organs of the body. The latter is typically only a fraction of the exposure dose and is iden- tified through studies that can trace the fate of a chemical after it enters the body. The term “dose” as used in this reference guide is synonymous with “exposure dose,” and doses reaching blood or various organs within the body are referred to as “target site doses” or “systemic doses,” Exposure assessments can be directed at past, present, or even future expo- sures and can be narrowly focused (one chemical, one environmental medium, one population group) or very broad in scope (many chemicals, several environ- 7. P.J. Lioy, Exposure Analysis and Its Assessment, in Comprehensive Toxicology (I.G. Sipes et al. eds., 1997); D.J. Paustenbach & A. Madl, The Practice of Exposure Assessment, in Principles and Methods of Toxicology (Wallace Hayes ed., 5th ed. 2008). 8. See, e.g., Kitzmiller v. Jefferson, 2006 WL 2473399, 2006 U.S. Dist. LEXIS 61109 (N.D. W. Va. 2006) (defendants offered expert’s testimony that plaintiff’s use of liquid cleaning agents con- taining benzalkonium chloride failed to show that she was exposed to benzalkonium chloride in the air); Hawkins v. Nicholson, 2006 WL 954654, 2006 U.S. App. Vet. Claims LEXIS 197, 21 Vet. App. 64 (Vet. App. 2006) (noting that “a veteran who served on active duty in Vietnam between January 9, 1962, and May 7, 1975, is entitled to a rebuttable presumption of exposure to Agent Orange”). 9. The term “enter the body” also includes entering the external surface of the body. 507

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Reference Manual on Scientific Evidence mental media, several different population groups). This reference guide explores the various contexts in which exposure assessments are conducted and how their scope is determined. B. Who Qualifies as an Expert in Exposure Assessment? As noted, it is unlikely that any expert can present evidence of having an academic degree in exposure science. An expert’s qualifications thus have to be tested by examining the expert’s experience,10 including his or her knowledge of and reli- ance on authoritative reference works.11 Experts generally will have strong aca- demic credentials in environmental science and engineering, chemistry, chemical engineering, statistics and mathematical model building, industrial hygiene, or other hard sciences related to the behavior of chemicals in the environment. To the extent exposure assessments deal with the amounts and behaviors of chemicals in the body, individuals can qualify as experts if they can offer academic credentials or substantial experience in toxicology and in the measurement of chemicals in blood or in biological tissues. Certainly, toxicology, epidemiology, or medical credentials are needed if experts are to offer testimony on the health consequences associated with particular exposures. Not all exposure assessments are complex; indeed, some, as will be seen, are relatively simple. Most toxicologists and epidemiologists have considerable training and experience assessing dose from medicines and other consumer products—and even from food. But if exposures result from chemicals moving from sources through one or more environmental media, it is unlikely that toxicologists or epide- miologists will be able to offer appropriate qualifications, because modeling or other forms of indirect measurement are needed to assess exposures. Further details on the qualifications of experts are offered in the closing sections of the reference guide. C. Organization of the Reference Guide The reference guide begins with a discussion of the various contexts in which exposure science is applied (Section III). Following that discussion is a section on chemicals and their various sources. Three broad categories of chemicals are dis- cussed: (1) those that are produced for specific uses; (2) those that are byproducts of chemical production, use, and disposal and that enter the environment as contaminants; and (3) those that are created and released by the combustion of all types of organic substances (including tobacco) and of fuels used for energy 10. See, e.g., Best v. Lowe’s Home Ctrs, 2009 WL 3488367, 2009 U.S. Dist. LEXIS 97700 (E.D. Tenn. 2009) (a medical doctor with extensive industrial toxicology and product safety experience opined that the plaintiff could not have been exposed to the chemical at issue as alleged). 11. Most of the EPA’s guidance documents on exposure assessment have been issued after extensive peer review and thus are considered authoritative. 508

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Reference Guide on Exposure Science production. Each of these categories can be thought of as a source for chemical exposure. Next, there is a discussion of the pathways chemicals follow from their sources to the environmental media to which humans are or could be in contact. Such contact is said to create an exposure. Chemicals can then move from these media of human contact and enter the body by different routes of exposure—by ingestion (in food or water, for example), by inhalation, or by direct skin contact (the dermal route). The section on exposure routes includes a discussion of how chemicals contact and enter the body and of how they behave within it. This last topic comprises the interface between exposure science and the sciences of epi- demiology and toxicology. Traditionally, exposure scientists have described their work as ending with the description of dose to the body (exposure dose). As will be seen, some practitioners are focusing on the amounts of chemicals present in blood or various tissues of the body as a result of exposure. Unlike the toxicolo- gist, the exposure scientist is not qualified to evaluate the health consequences of these so-called biomarkers of exposure. This reference guide first presents all of the above material in nonquantitative terms—to describe and illustrate the various processes through which human exposures to chemicals are created (Sections III–V). The guide then focuses on the quantitative aspects (Sections VI and VII). Without some quantitative under- standing of the magnitude of exposure, and of the duration of time over which exposure occurs, it becomes difficult to reach meaningful conclusions about health risks. Thus, the remaining sections are devoted to a critical quantitative concept in exposure science—that of dose—and are intended to integrate all of the earlier descriptive material. The reference guide ends with a review of the qualifications of exposure science experts and how they can be assessed. III. Contexts for the Application of Exposure Science There are perhaps four major contexts in which exposure science is applied: (1) consumer products, (2) contaminants in the environment and in consumer products, (3) chemicals in the workplace, and (4) disease causation. A. Consumer Products Many intentional uses of chemical substances lead to human exposures, and the health risks that are associated with those exposures need to be understood.12 In some cases, laws and regulations require that health risks be understood in 12. See, e.g., In re Stand ’n Seal, 623 F. Supp. 2d 1355 (N.D. Ga. 2009) (consumer use of spray- on product allegedly resulted in inhalation exposure to toxic substances, causing respiratory injuries). 509

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Reference Manual on Scientific Evidence advance of the marketing of such chemicals or products containing them. Thus, intentionally introduced food additives, pesticides, and certain industrial chemicals must have regulatory approvals before they are marketed, and manufacturers of such substances are required to demonstrate the absence of significant health risks (i.e., their safety) based on toxicology studies and careful assessments of expected exposures. Pharmaceuticals and other medical products must undergo similar pre- market evaluations. The safety and efficacy of such products must be demonstrated through clinical studies (which are undertaken after animal toxicology studies have been done and have demonstrated the safety of such products for individuals who are involved in clinical trials). Human exposure assessments are central to the regulatory approval of these products.13 Many other consumer products require risk assessments, but premarket approvals are not generally required under our current laws. The list of such products is very long, and not all substances included in these products have been subjected to exposure and risk assessments, but regulatory initiatives in the United States and abroad are creating new requirements for more complete assessments of consumer safety. B. Environmental and Product Contaminants Byproducts of many industrial processes, including those created by combustion, have led to much environmental contamination (see Section IV for a discussion of the sources of such contamination).14 Technically speaking, contamination refers to the presence of chemical substances in environmental media (including consumer products) in which such substances would not ordinarily be found. The term also may be used to refer to their presence in greater amounts than is usual.15 The assessment of health risks from such contaminants depends upon an understanding of the magnitude and duration of exposure to them. Exposures may occur through the presence of contaminants in air, drinking water, foods, consumer products, or soils and dusts; in many cases, exposures may occur simul- taneously through more than one of these media. The results from exposure and risk assessments (which incorporate informa- tion regarding the toxic properties of the contaminants) are typically used by regulators and public health officials to determine whether exposed populations are at significant risk of harm. If regulators decide that the risks are excessive, they 13. B.D. Beck et al., The Use of Toxicology in the Regulatory Process, in Principles and Methods of Toxicology (A. Wallace Hayes ed., 5th ed. 2008). 14. See, e.g., Orchard View Farms, Inc. v. Martin Marietta Aluminum, Inc., 500 F. Supp. 984, 1008 (D. Or. 1980) (failure to monitor fluoride emissions that harmed nearby orchards supported award of punitive damages). 15. For example, lead is naturally present in soils. It could be said that a sample of soil is con- taminated with lead only if it were clear that the amounts present exceeded natural levels. The issue is complicated by the fact that natural levels are highly variable. 510

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Reference Guide on Exposure Science will take steps to reduce them, typically by using interventions that will reduce exposures (because the inherent toxic properties of the chemicals involved cannot be altered). Exposure scientists are called upon to assess the magnitude of exposure reduction (and therefore risk reduction) achieved through a given intervention.16 C. Chemicals in Workplace Environments Workers in almost all industrial sectors are exposed to chemicals.17 Exposures are created in industries involved in the extraction of the many raw materials used to manufacture chemical products (the mining, agricultural,18 and petroleum indus- tries). Raw materials are refined and otherwise processed in thousands of different ways and are eventually turned into manufactured chemical products that number in the tens of thousands. These products enter many channels of distribution and are incorporated into many other products (so-called downstream uses). Occupa- tional exposures can occur at all of these various steps of manufacturing and use. Exposure also can occur from disposal of wastes. Exposure assessments in all of these various occupational settings are important to understand whether health risks are excessive and therefore require reduction.19 D. Claims of Disease Causation In the above three situations, the exposures of interest are those that are currently occurring or that are likely to occur in the future. In those situations the expo- sure assessments are used to ascertain whether risks of harm are excessive (and thus require reduction) or to document safety (when risks are negligible). There are, however, many circumstances in which individuals claim they actually have been harmed by chemicals. Specifically, they allege that some existing medical condition has been caused by exposures occurring in the past, whether in the workplace, the environment, or through the use of various consumer products.20 16. National Research Council, Air Quality Management in the United States (2004). 17. See, e.g., Kennecott Greens Creek Min. Co. v. Mine Safety & Health Admin., 476 F.3d 946 (D.C. Cir. 2007) (suit over regulations addressing miners’ exposure to diesel particulate matter). 18. The term “agriculture” is applied here very broadly and includes the production of a wide variety of raw materials that have industrial and consumer product uses (including flavors, fragrances, fibers of many types, and some medicinal products). See, e.g., Association of Irritated Residents v. Fred Schakel Dairy, 634 F. Supp. 2d 1081, 1083 (E.D. Cal. 2008) (methanol emissions from dairy allegedly resulted in exposure sufficient to create human health risks). 19. Office of Pesticide Programs, U.S. Environmental Protection Agency, General Principles for Performing Aggregate Exposure and Risk Assessments, available at http://www.epa.gov/pesticides/ trac/science/aggregate.pdf (last visited July 14, 2010). 20. See Michael D. Green et al., supra note 1, in this manual, for a discussion on disease causa- tion. Regulations and public health actions are usually driven by findings of excessive risk of harm (although sometimes evidence of actual harm). 511

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Reference Manual on Scientific Evidence Exposure science comes into play in these cases because the likelihood that any given disease or injury was induced because of exposure to one or more chemicals depends in large part on the size of that exposure.21 Thus, with the advent of large numbers of so-called toxic tort claims has come the need to assess past expo- sures. Exposure scientists have responded to this need by adapting the methods of exposure assessment to reconstruct the past—that is, to produce a profile of individuals’ past exposures.22 A plaintiff with a medical condition known from epidemiological studies to be caused by a specific chemical may not be able to substantiate his or her claim without evidence of exposure to that chemical of a sufficient magnitude.23 Exposure experts are needed to quantify the exposures incurred; causation experts are then called upon to offer testimony on whether those exposures are of a magnitude sufficient to cause the plaintiff’s condition. Chemicals known to cause diseases under certain exposure conditions will not do so under all exposure conditions. Exposure reconstruction has a history of use by epidemiologists who are studying disease rates in populations that may be associated with past exposures.24 Epidemiologists have paved the way for the use of exposure assessment methods to reconstruct the past. Although the methods for evaluating current and past expo- sures are essentially identical, the data needed to quantify past exposures are often more limited and yield less certain results than the data needed to evaluate current exposures. Assessment of past exposures is especially difficult when considering diseases with very long latency periods.25 By the time disease occurs, documentary proof of exposure and magnitude may have disappeared. But courts regularly deal with evidence reconstructing the past, and assessment of toxic exposure is another application of this common practice.26 21. See supra notes 1 & 2. Causation may sometimes be established even if quantification of the exposure is not possible. See, e.g., Best v. Lowe’s Home Ctrs, Inc., 563 F.3d 171 (6th Cir. 2009) (doctor permitted to testify as to causation based on differential diagnosis). 22. Confounding factors must be carefully addressed. See, e.g., Allgood v. General Motors Corp., 2006 WL 2669337, at *11 (S.D. Ind. 2006) (selection bias rendered expert testimony inadmissible); American Farm Bureau Fed’n v. EPA, 559 F.3d 512 (2009) (in setting particulate matter standards addressing visibility, the data relied on should avoid the confounding effects of humidity); Avila v. Willits Envtl. Remediation Trust, 2009 WL 1813125, 2009 U.S. Dist. LEXIS 67981 (N.D. Cal. 2009) (failure to rule out confounding factors of other sources of exposure or other causes of disease rendered expert’s opinion inadmissible); Adams v. Cooper Indus. Inc., 2007 WL 2219212, 2007 U.S. Dist. LEXIS 55131 (E.D. Ky. 2007) (differential diagnosis includes ruling out confounding causes of plaintiffs’ disease). 23. See Michael D. Green et al., Reference Guide on Epidemiology, in this manual. 24. Id. 25. W.T. Sanderson et al., Estimating Historical Exposures of Workers in a Beryllium Manufacturing Plant, 39 Am. J. Indus. Med. 145–57 (2001). 26. Courts have accepted indirect evidence of exposure. For example, differential diagnosis may support an expert’s opinion that the exposure caused the harm. Best v. Lowe’s Home Ctrs., Inc., 563 F.3d 171 (6th Cir. 2009). On occasion, qualitative evidence of exposure is admitted as evidence 512

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Reference Guide on Exposure Science IV. Chemicals Before embarking on a description of the elements of exposure science, it is useful to provide a brief primer on some of the characteristics of chemicals that influence their behavior and that therefore affect the ways in which humans can be exposed to them. The primer also introduces some technical terms that frequently arise in exposure science. A. Organic and Inorganic Chemicals For both historical and scientific reasons, chemists divide the universe of chemi- cals into organic and inorganic compounds. The original basis for classifying chemicals as organic was the hypothesis, known since the mid-nineteenth century to be false, that organic chemicals could be produced only by living organ- isms. Modern scientists classify chemicals as organic if they contain the element carbon.27 Carbon has the remarkable and nearly unique property that its atoms can combine with each other in many different ways, and, together with a few other elements—including hydrogen, oxygen, nitrogen, sulfur, chlorine, bromine—can create a huge number of different molecular arrangements. Each such arrange- ment is a unique chemical. Several million distinct organic chemicals are already known to chemists, and there are many more that will no doubt be found to occur naturally or that will be created by laboratory synthesis. All of life—at least on Earth—depends on carbon compounds and probably could not have evolved if carbon did not have its unique and extraordinary bonding properties. All other chemicals are called inorganic. There are 90 elements in addition to carbon in nature (and several more that have been created in laboratories), and because these elements do not have the special properties of carbon, the number of different possible combinations of them is smaller than can occur with carbon. Living organisms contain or produce organic chemicals by the millions. One of the most abundant organic chemicals on Earth is cellulose—a giant molecule containing thousands of atoms of carbon, hydrogen, and oxygen. Cellulose is produced by all plants and is their essential structural component. Chemically, cel- that the magnitude was great enough to cause harm. See, e.g., Westberry v. Gislaved Gummi AB, 178 F.3d 257 (4th Cir. 1999) (no quantitative measurement required where evidence showed plaintiff was covered in talc and left footprints); Allen v. Martin Surfacing, 263 F.R.D. 47 (D. Mass. 2009) (symptom accounts at the time of exposure formed the basis for expert’s opinion that exposure was high enough to cause harm). And courts have accepted the government’s reconstruction of exposure to radiation. Hayward v. U.S. Dep’t of Labor, 536 F.3d 376 (5th Cir. 2008); Hannis v. Shinseki, 2009 WL 3157546 (Vet. App. 2009) (no direct measure of veteran’s exposure to radiation was possible but VA’s dose estimate was not clearly erroneous). 27. There are a few compounds of carbon that chemists still consider inorganic: These are typi- cally simple molecules such as carbon monoxide (CO) and carbon dioxide (CO2) and the mineral limestone, which is calcium carbonate (CaCO3). 513

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Reference Manual on Scientific Evidence a description of how and when exposures have or could occur, the identities of the chemicals involved, the routes of exposure, the doses incurred, and the durations of exposure. In some cases, testimony will include a description and quantification of body burdens. If the exposure scientist is also an epidemiologist or toxicologist,84 he or she may offer additional testimony on the health risks associated with those exposures or even regarding the question of whether such exposures have actually caused disease. For purposes of this reference guide, it is assumed that questions regarding disease risk and causation are beyond the bounds of exposure science. Below is offered a set of questions that exposure scientists should be able to answer, with appropriate documentation and scientific reasoning, to support any given exposure assessment: • Is the purpose of the assessment clear? Is the exposed population specified? • What is the source(s) of exposure? • When did the exposures occur: past? present? If they are occurring now, will they continue to occur? • What is the assumed duration of exposure, and what is its basis? • What are the pathways from the source to the exposed individuals? How has it been established that those pathways exist (past? present? future?). • What is the concentration of the chemical in the media with which the exposed population comes into contact (past? present? future?). What is the basis for this answer: direct measurement? modeling? • If the concentration is based on direct measurement, what procedures were followed in obtaining that measurement? Was media sampling suf- ficient to ensure that it was representative? If not, why is representativeness not important? Were validated analytical methods used by an accredited laboratory? If not, how can one be assured that the analytical results are reliable? • If models were used, what is their reliability (see Section VI.D)? What is the variability over time in concentrations in the media of concern? How has the variability been determined? • What is the variability among members of the population in their exposure to the chemical of concern? How is this known? • What is known or assumed about the nature and extent of media contact by members of the exposed population? How has this been ascertained? • What dose, over what period of time, by which routes, has been incurred? What calculations support this determination? 84. See Section IX, which deals with the question of the qualifications of exposure scientists. In many cases, the work of exposure experts is turned over to the health experts to incorporate into their evaluation of risk and disease causation. In some cases, usually the less complex ones, exposure assessments may be undertaken by the health experts. 538

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Reference Guide on Exposure Science • What is the likely error in the exposure estimates? • What uncertainties are associated with the dose/duration findings? Is it a “most likely” estimate, or is it an “upper limit”? To what fraction of the population is the “upper limit” likely to apply? • What has been omitted from the exposure assessment, and why? These questions are perhaps the minimum that an expert should be able to address when offering testimony. Obviously, most such questions can be answered fully only if the expert can support the answers with documentation. As noted in Section III.D, the evaluation of whether a current medical con- dition is causally related to exposures occurring in the past (prior to the onset or diagnosis of the medical condition) requires a retrospective examination of the conditions that led to those exposures. Thus, for example, a plaintiff suffering from leukemia and who alleges that benzene exposure in his or her workplace caused the disease may easily demonstrate the fact of benzene exposure. But ordi- narily an estimation of the quantitative magnitude and duration of the incurred benzene exposure is necessary to evaluate the plausibility of the causation claim.85 The methodological tools necessary to “reconstruct” the plaintiff’s past exposure are identical to those used to estimate current exposures, but the availability of the data necessary to apply those methods may be limited or, in some cases, nonexistent. Reconstruction of occupational exposures has been a relatively successful pursuit, because often historical industrial hygiene data are available involving the measurement of workplace air levels of chemicals. If it is possible, through the examination of employment records, to reconstruct an individual’s job history, it may be possible to ascertain that individual’s exposure history.86 Guidelines for occupational exposure reconstruction have been published by the American Industrial Hygiene Association.87 Clearly, experts presenting testimony regarding exposure reconstruction must be queried heavily on the sources of data used in their applications of exposure methods. IX. Qualifications of Exposure Scientists Exposure science is not yet a true academic discipline. Rather, scientists and engineers from diverse backgrounds have, over the past several decades, come together to give shape and substance and scientific rigor to what is clearly a criti- 85. See Michael D. Green et al., Reference Guide on Epidemiology, Section VII, in this manual. 86. T.W. Armstrong, Exposure Reconstruction, in Mathematical Models for Estimating Occupa- tional Exposures to Chemicals (Charles B. Keil et al. eds., 2d ed. 2009). 87. American Industrial Hygiene Association, Guideline on Occupational Exposure Reconstruc- tion (S.M. Viet et al. eds., 2008). 539

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Reference Manual on Scientific Evidence cal element in understanding toxicity risks and disease causation. Typically, those who have contributed to this developing field have come from backgrounds in industrial hygiene, environmental and analytical chemistry, chemical engineering, hydrogeology, and even behavioral sciences (pertaining to those aspects of human behavior that affect exposures).88 Most toxicologists and epidemiologists have con- siderable experience in exposure science, as do pharmacologists who study drug kinetics and disposition. Many exposure assessments involve collaborative efforts among members of these various disciplines. There are currently no certification programs available for exposure scientists, but increasingly exposure science research appears in publications such as Envi- ronmental Health Perspectives, Risk Analysis, and the Journal of Exposure Science and Environmental Epidemiology. Certification programs do exist in occupational exposure science. Qualified industrial hygienists will almost always be certified (CIH). The American Indus- trial Hygiene Association Journal includes much scholarly work related to exposure science. 88. See, e.g., Allen v. Martin Surfacing, 2009 WL 3461145, 2008 U.S. Dist. LEXIS 111658, 263 F.R.D. 47 (D. Mass. 2008) (industrial hygienist qualified to testify regarding concentration and dura- tion of plaintiffs’ decedent’s exposure to toluene and other chemicals); Buzzerd v. Flagship Carwash of Port St. Lucie, Inc., 669 F. Supp. 2d 514 (M.D. Pa. 2009) (industrial hygienist qualified to opine on carbon monoxide exposure, but his conclusions were not based on reliable methodology). 540

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Reference Guide on Exposure Science Appendix A: Presentation of Data— Concentration Units Choosing the proper units to express concentrations of chemicals in environ- mental media is crucial for precisely defining exposure. Chemical concentrations in environmental media usually are reported in one of two forms: as numeric ratios, such as parts per million or billion (ppm and ppb, respectively), or as unit weight of the chemical per weight or volume of environmental media, such as milligrams per kilogram (mg/kg) or milligrams per cubic meter (mg/m3). Although concentrations expressed as parts per million or parts per billion are easier for some people to conceptualize, their use assumes that media are always sampled at standard temperature and pressure (25°C and 760 torr, respectively). Consequently, scientists prefer to express chemical concentrations as weight of chemical per unit weight or volume of media. This method also makes conver- sions to dose equivalents, usually expressed in terms of weight of chemical per unit body weight (mg/kg bw), more convenient. To permit the presentation of results without excessive zeroes before or after the decimal point, appropriate units are needed. The choice of units depends on both the medium in which the chemical resides and the amount of chemical measured. For example, if 50 nanograms of chemical were found in 1 L of water, the appropri- ate units would be ng/L, rather than 0.00005 mg/L. If 50 grams were found instead, the appropriate units would be 50,000 mg/L, because milligrams are generally the largest units used to express the mass of a chemical in media (Table 1). Table 1. Weight of Chemical per Unit Weight of Medium Preferred Unit Alternative Unit mg/kg ppm (parts per million) µg/kg ppb (parts per billion) ng/kg ppt (parts per trillion) pg/kg ppq (parts per quadrillion) In water or food, concentration expressed by the preferred unit equals con- centration expressed by alternative unit; thus, 2 mg/kg = 2 ppm. One mg (10−3 g) per kg (103 g) equals 1 part per million (10−3/103 = 10−6). Similarly, 1 µg (10−6 g) per kilogram (103 g) equals 1 part per billion (10−6/103 = 10−9), and so on (Table 2). Note that in air, parts per million and parts per billion have different mean- ings than they do in water or food; to avoid confusion, it is always preferrable to express air concentrations in weight of chemical per unit volume (rather than weight) of air (usually cubic meters, m3). 541

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Reference Manual on Scientific Evidence Table 2. Weight of Chemical per Unit Volume of Medium Water Air mg/m3 ≠ ppm mg/L = ppm mg/m3 ≠ ppb µg/L = ppb ng/m3 ≠ ppt ng/L = ppt 542

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Reference Guide on Exposure Science Appendix B: Hazardous Waste Site Exposure Assessment Several principles of exposure assessment can be illustrated by examining the steps taken to evaluate a hazardous waste disposal site. From 1964 to 1972, more than 300,000 55-gallon drums of solid and liquid pesticide production wastes were buried in shallow trenches at a hazardous waste disposal site in Hardeman County, Tennessee. As early as 1965, county engineers had raised concerns that these operations might have affected the aquifer supplying drinking water to the City of Memphis, Tennessee. The State of Tennessee ordered the landfill to stop accepting hazardous waste in 1972; all operations were reported to have ceased by 1975. Testing in 1978 confirmed the presence of toxic chemicals in domestic wells, and by January 1979 all uses of the contaminated well water had been discontinued. Among the chemicals of concern detected in the ground water were benzene, carbon tetrachloride, chlordane, chlorobenzene, chloroform, and several other pesticides or chemicals associated with pesticide production. As is often the case for ground water polluted by landfills, the observed concentrations fluctuated over a relatively wide range. For example, in a domestic well approximately 1500 feet north of the landfill, carbon tetrachloride concentrations ranged from 10 ppm to 20 ppm between November 1978 and November 1979; from May 1981 to June 1982, carbon tetrachloride levels varied from 18 ppm to 164 ppm. The chemicals of greatest concern detected during ground-water monitoring near the Hardeman site included carbon tetrachloride, chloroform, and tetra- chloroethylene. For each of these three chemicals, the concentrations detected in well water were significantly elevated over levels typically found in potable water. Health surveys conducted in 1978 and 1982 suggested that these chemicals might be causing a variety of health problems in nearby residents. To confirm the cause-and-effect relationship suggested by the health sur- veys, an exposure assessment was conducted so that the findings of the health surveys could be compared to adverse health impacts predicted from exposure estimates and toxicological data from laboratory experiments. The exposure assess- ment for the Hardeman site focused on carbon tetrachloride, because of the high concentrations of this chemical found in the ground water and the severity of the potential health effects associated with exposure to it. To estimate the range of possible exposures, the Hardeman site assessment considered exposures of both an adult and an infant. The exposure assessor then needed to identify the pathways of exposure that might be important. For the infant, the following exposure pathways were examined: • Consumption of formula made using well water, • Dermal absorption during bathing in contaminated water, and 543

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Reference Manual on Scientific Evidence • In-utero exposure of the fetus through exposure of the mother during pregnancy. Adult exposures were evaluated for two pathways: • Consumption of contaminated drinking water and • Inhalation of carbon tetrachloride emanating from water during showers. Because measurements of concentrations of carbon tetrachloride in the ground water were scant before 1978, estimates were modeled for these years; measured concentrations were used for 1978, the last year residents utilized ground water for drinking. Standard assumptions regarding the ingestion of water by adults (2 L/ day) were used; water consumption by a child was assumed to be 0.5 L/day for 3 months following birth. Dermal absorption by infants was estimated by assuming that the child bathed in 30 L/day of well water, that 50% of this volume contacted the skin, and that 10% of the contaminant was absorbed through the skin. Three baths per week were assumed for the first 3 months after birth. In-utero exposure was estimated assuming equal concentrations of carbon tetrachloride in fetal and maternal blood. The concentration of carbon tetrachloride in air during shower- ing was calculated assuming that it would quickly reach equilibrium with carbon tetrachloride in the shower water. In Table 3, carbon tetrachloride exposure estimates for the infant and adult are compared with the minimum daily exposure producing liver damage in guinea pigs and the lifetime cumulative exposure producing liver cancer in mice. Daily exposure rates were based on a predicted yearly average exposure during the highest year of exposure. Monitoring data indicate that the concentration of carbon tetrachloride in the ground water may have varied by a factor of 10 around the mean. The maximum daily exposure rate may have been considerably higher than the estimates presented in the table, whereas the long-term averages may have been lower. Table 3. Carbon Tetrachloride Exposure Estimates for Infants and Adults Compared with Minimum Daily Exposure Producing Liver Damage in Guinea Pigs and Lifetime Cumulative Exposure Producing Liver Cancer in Mice Daily Dose Rate (mg/kg/day) Liver damage in guinea pigs 1.5 Estimated infant exposure 1.8 Estimated adult exposure 0.3 Cumulative Dose (mg/kg) 40% Liver tumors in mice 1200 Estimated adult exposure 284 544

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Reference Guide on Exposure Science Glossary of Terms absorbed dose. The amount of a substance that actually enters the body follow- ing absorption. absorption. The penetration of a substance through a barrier (e.g., the skin, the gut, or the lungs). acute exposure. An exposure of short duration and/or rapid onset. An acute toxic effect is one that develops during or shortly after an acute exposure to a toxic substance. average daily dose (ADD). The average dose received on any given day during a period of exposure, expressed in mg/kg body weight per day. Ordinarily used in assessing noncancer risks. bioavailability. The rate and extent to which a chemical or chemical breakdown product enters the general circulation, thereby permitting access to the site of toxic action. body burden. The total amount of a chemical present or stored in the body. In humans, body burden is an important measure of exposure to chemicals that tend to accumulate in fat cells, such as DDT, PCBs, or dioxins. chronic exposure. A persistent, recurring, or long-term exposure, as distin- guished from an acute exposure. Chronic exposure may result in health effects (such as cancer) that are delayed in onset, occurring long after exposure has ceased. direct exposure. Exposure of a subject who comes into contact with a chemi- cal via the medium in which it was initially released to the environment. Examples include exposures mediated by cosmetics, other consumer products, some food and beverage additives, medical devices, over-the-counter drugs, and single-medium environmental exposures. dose. The amount of a substance entering a person, usually expressed for chemi- cals in the form of weight of the substance (generally in milligrams (mg) or micrograms (µg)) per unit of body weight (generally in kilograms (kg)). It is necessary to specify whether the dose referred to is applied or absorbed. The time over which it is received must also be specified. The time of interest is typically 1 day. If the duration of exposure is specified, dose is actually a dose rate and is expressed as mg or µg/kg per day. dose–response assessment. An analysis of the relationship between the dose administered to a group and the frequency or magnitude of the biological effect (response). duration of exposure. Toxicologically, there are three categories describing duration of exposure: acute (one time), subchronic (repeated, for a fraction of a lifetime), and chronic (repeated, for nearly a lifetime). 545

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Reference Manual on Scientific Evidence environmental media. Air, water, soils, and food; consumer products may also be considered media. Chemicals may be directly and intentionally introduced into certain media. Others may move from their sources through one or more media before they reach the media with which people have contact. exposure. The opportunity to receive a dose through direct contact with a chemical or medium containing a chemical. See also direct esposure; indirect exposure. exposure assessment. The process of describing, for a population at risk, the amounts of chemicals to which individuals are exposed, or the distribution of exposures within a population, or the average exposure over an entire population. frequency of exposure. The number of times an exposure occurs in a given period; exposure may be continuous, discontinuous but regular (e.g., once daily), or intermittent (e.g., less than daily, with no standard quantitative definition). indirect exposure. Often defined as an exposure involving multimedia transport of chemicals from source to exposed individual. Examples include exposures to chemicals deposited onto soils from the air, chemicals released into the ground water beneath a hazardous waste site, or consumption of fruits or vegetables with pesticide residues. intake. The amount of contact with a medium containing a chemical; used for estimating the dose received from a particular medium. levels. An alternative term for expressing chemical concentration in environmen- tal media. Usually expressed as mass per unit volume or unit weight in the medium of interest. lifetime average daily dose (LADD). Total dose received over a lifetime mul- tiplied by the fraction of lifetime during which exposure occurs, expressed in mg/kg body weight per day. Ordinarily used for assessing cancer risk. models. Idealized mathematical expressions of the relationship between two or more factors (variables). pathway. The connected media that transport a chemical from source to populations. point-of-contact exposures. Exposure expressed as the product of the con- centration of the chemical in the medium of exposure and the duration and surface area of contact with the body surface, for example, mg/cm2-hours. Some chemicals do not need to be absorbed into the body but rather produce toxicity directly at the point of contact, for example, the skin, mouth, GI tract, nose, bronchial tubes, or lungs. In such cases, the absorbed dose is not the relevant measure of exposure; rather, it is the amount of toxic chemical coming directly into contact with the body surface. 546

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Reference Guide on Exposure Science population at risk. A group of subjects with the opportunity to be exposed to a chemical. risk. The nature and probability of occurrence of an unwanted, adverse effect on human life or health or on the environment. risk assessment. Characterization of the potential adverse effects on human life or health or on the environment. According to the National Research Coun- cil’s Committee on the Institutional Means for Assessment of Health Risk, human health risk assessment includes the following: description of the poten- tial adverse health effects based on an evaluation of results of epidemiologic, clinical, toxicological, and environmental research (hazard identification); extrapolation from those results to predict the type and estimate the extent of health effects in humans under given conditions of exposure (dose–response assessment); judgments regarding the number and characteristics of persons exposed at various intensities and durations (exposure assessment); sum- mary judgments on the existence and overall magnitude of the public-health problem; and characterization of the uncertainties inherent in the process of inferring risk (risk characterization). route of exposure. The way a chemical enters the body after exposure, that is, by ingestion, inhalation, or dermal absorption. setting. The place or situation in which a person is exposed to the chemical. Setting is often modified by the activity a person is undertaking, for example, occupational or in-home exposures. source. The activity or entity from which the chemical is released for potential human exposure. subchronic exposure. An exposure of intermediate duration between acute and chronic. subject. An exposed individual, whether a human or an exposed animal or organism in the environment. An exposed individual is sometimes also called a receptor. systemic dose. A dose of a chemical within the body—that is, not localized at the point of contact. Thus, skin irritation caused by contact with a chemical is not a systemic effect, but liver damage due to absorption of the chemical through the skin is. Often referred to as target site dose. total dose. The doses received by more than one route of exposure are added to yield the total dose. 547

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Reference Manual on Scientific Evidence References on Exposure D.B. Barr, Expanding the Role of Exposure Science in Environmental Health, 16 J. Exposure Sci. Envtl. Epidemiol. 473 (2006). Exposure Assessment in Occupational and Environmental Epidemiology (M.J. Nieuwenhuiysen ed., 2003). S. Gad, Regulatory Toxicology (2d ed. 2001). Includes much discussion of phar- maceuticals, food ingredients, and other consumer products. P. Lioy, Exposure Science: A View of the Past and Milestones for the Future, 118 Envtl. Health Persp. 1081–90 (2010). U.S. Environmental Protection Agency, Guidelines for Exposure Assessment, Doc. No. EPA/600/Z-92/001 (1992), available at http://cfpub.epa.gov/ ncea/cfm/recordisplay.cfm?deid=15263. 548