Journal of Law and Policy Volume 13 Issue 2 SCIENCE FOR JUDGES IV: Article 4 Agent Orange Revisited and Human Behavior Research
2005 How Scientists View Causality and Assess Evidence: A Study of the Institute of Medicine's Evaluation of Health Effects in Vietnam Veterans and Agent Orange Irva Hertz-Picciotto
Follow this and additional works at: https://brooklynworks.brooklaw.edu/jlp
Recommended Citation Irva Hertz-Picciotto, How Scientists View Causality and Assess Evidence: A Study of the Institute of Medicine's Evaluation of Health Effects in Vietnam Veterans and Agent Orange, 13 J. L. & Pol'y (2005). Available at: https://brooklynworks.brooklaw.edu/jlp/vol13/iss2/4
This Article is brought to you for free and open access by the Law Journals at BrooklynWorks. It has been accepted for inclusion in Journal of Law and Policy by an authorized editor of BrooklynWorks. 20313_blp_13-2 Sheet No. 31 Side A 06/23/2005 10:19:08 Other Herbicides. Other rature on a topic or in rature on a topic or in rtment of Public Health Sciences, Health Sciences, rtment of Public 553 Agent Orange and Orange Agent 5/23/2005 7:48 PM Irva Hertz-Picciotto, Ph.D., M.P.H. Irva Hertz-Picciotto, DOC 051905. VETERANS AND AGENT ORANGE AND AGENT ORANGE VETERANS OF HEALTH EFFECTS IN VIETNAM EFFECTS IN VIETNAM OF HEALTH Professor of Epidemiology, Depa of Epidemiology, Professor ACROED ASSESS EVIDENCE: A STUDY OF THE OF A STUDY EVIDENCE: ASSESS M The courts are often called upon to settle disputes in which often called upon to settle disputes The courts are agencies or regulatory by which governmental One mechanism HOW SCIENTISTS VIEW CAUSALITY AND VIEW CAUSALITY SCIENTISTS HOW INSTITUTE OF MEDICINE’S EVALUATION EVALUATION OF MEDICINE’S INSTITUTE ERTZ NTRODUCTION M K University of California, Davis; Chair, 2000 and 2002 Institute of of Institute 2002 2000 and Chair, Davis; California, of University Committee on the Health Effects in of Sciences Medicine/National Academy to of Exposure Veterans Vietnam
response to specific needs. For example, panels may be assembled be assembled panels may response to specific needs. For example, in drinking for a chemical to help formulate a regulatory standard Thus, the environment. air, or the workplace water, ambient I been caused by environmental are alleged to have health damages or biologic agents. Similarly, physical, exposures to chemical, to assess evidence regarding are often called upon health scientists as be regarded that might injuries diseases or developmental purpose of this overarching specific exposures. The resulting from scientists readers with the way in which paper is to familiarize the example about causality, using assess data and view evidence by U.S. military incurred and related exposures of herbicide personnel during service in Vietnam. regional levels seek advice from or national, at the international, panels. These panels or advisory scientists is by convening expert as part of an ongoing program that be assembled boards may lite reviews the state of the scientific H C Y 20313_blp_13-2 Sheet No. 31 Side A 06/23/2005 10:19:08 A 06/23/2005 31 Side Sheet No. 20313_blp_13-2 20313_blp_13-2 Sheet No. 31 Side B 06/23/2005 10:19:08 M K C Y 05 Stat. 11 (codified as tion of the scientific tion to provide reports on a biannual basis to to provide reports 1 991, Pub. L. No. 102-4, 1 991, Pub. L. No. 5/23/2005 7:48 PM JOURNAL OF LAW AND POLICY POLICY AND LAW OF JOURNAL DOC 051905. ACROED Agent Orange Act of 1 Act of Agent Orange M 1 The Institute of Medicine Committee to Review the Health the Health to Review Committee of Medicine The Institute the Committee, the to the charge article introduces Part I of this In contrast to the preceding sections, which focus on individual In contrast to the preceding sections, ERTZ
554 the become may committees expert by produced documents policies. of health-related for the development foundation Veterans (“IOM to Herbicides of Exposure in Vietnam Effects This Committee one such panel. is or “Committee”) Committee” 102-4 (better known under the mandate of Public Law was formed Orange Act) as the Agent of Veterans beginning in 1994. Affairs (VA), the Department the potential adverse effects with concerned These reports were served in Vietnam those who by been experienced have that might the mixture to herbicides, particularly exposures because of in this mixture, Orange, or contaminants found dubbed Agent commonlyreferred compound chemical including the well-known to as “dioxin.” followed in order to reach conclusions process the Committee of studies it considered, and the about the evidence, the types specific health for classifying it established categories evidentiary IOM for the decisions of the Part II provides context outcomes. of the principles that guided the through a discussion Committee process and a presenta evaluative Committee’s H foundation for inferences about concepts that constitute the III explains the approach research. Part causation in biomedical conducting for epidemiologists, used by scientists, specifically, causal effects, and examining studies in populations, estimating to concretely on the obstacles hypotheses. It also focuses more which is the imprecision, inferences about causation, specifically, bias, samples, and small studying uncertainty that arises from imperfections in study from that derives which is the uncertainty a description of Part IV narrows this discussion to methodology. selection, and types of bias—confounding, information, the major statistical bias. process by which studies, Part V delineates the epidemiologic commonly the framework and presents reach consensus scientists amended at 38 U.S.C. § 1116) [hereinafter § 1116) Agent Orange Act]. at 38 U.S.C. [hereinafter amended 20313_blp_13-2 Sheet No. 31 Side B 06/23/2005 10:19:08 B 06/23/2005 31 Side Sheet No. 20313_blp_13-2 20313_blp_13-2 Sheet No. 32 Side A 06/23/2005 10:19:08 This FFECTS 3 E FFECTS IN EDICINE OF EDICINE E M EDICINE EDICINE 555 555 EALTH M EALTH :H H The Institute of The Institute 4 RANGE NSTITUTE OF O ,I NSTITUTE OF EVIEW THE I GENT R A HE ERBICIDES :T H work of the IOM Committee and and Committee the IOM work of three questions regarding specific three questions regarding 221 (1994) [hereinafter VAO 221 (1994) [hereinafter 1994]. RANGE OMMITTEE TO ETERANS AND O C ,V XPOSURE TO iring that a report be submitted to the Secretary of Secretary to the a report be submitted iring that IETNAM E V GENT A 5/23/2005 7:48 PM See also See also DOC CADEMIES SED IN Through this Act, Congress directed the Secretary of Congress directed the Secretary Through this Act, A U 2 The first was “whether a statistical association with association with The first was “whether a statistical 051905. ETERANS OF 5 V §§ 2-3. . § 3(g)(1) (requ . § .3(d)(1). § ACROED Id. Id. Id Id ATIONAL M ERBICIDES N ETERANS AND 2 3 4 5 A. Charge to the Committee A. Charge to the the health of Vietnam about growing concern In light of H OMMITTEE IETNAM ERTZ M K V legislation also called for reviews of newly available information of newly available information for reviews legislation also called of ten years. on a biannual basis for a period to carry out a Committee Medicine (IOM) of the NAS convened “to the was to determine the Committee this work. The charge to meaningful data permit extent that available scientific to the answers determinations” to Agent Orange and their relationships health outcomes exposure. account the strength of the into herbicide exposure exists, taking of the statistical and and the appropriateness evidence scientific veterans, Congress enacted Public Law 102-4, the Agent Orange enacted Public Law 102-4, veterans, Congress Act of 1991. of to request from the National Academy Veterans Affairs of the potential health evaluation comprehensive a Sciences (NAS) used compound a chemical exposure to Agent Orange, effects from War. during the Vietnam as a defoliant by the U.S. military dozens sometimes involving evidence body of a in weighing used VI returns to the Part of studies. ORANGE OF AGENT HEALTH EFFECTS the Committee evidence of the a detailed discussion provides four regarding the reviewed above, taking mentioned outcomes V. III through in Parts presented the concepts into consideration I. V C H OF THE Veteran Affairs “at least once every two years”). two years”). every Affairs “at least once Veteran C Y 20313_blp_13-2 Sheet No. 32 Side A 06/23/2005 10:19:08 A 06/23/2005 32 Side Sheet No. 20313_blp_13-2 20313_blp_13-2 Sheet No. 32 Side B 06/23/2005 10:19:08 M K , C Y The The 6 XPOSURE Finally, E CADEMIES 8 A note 5, at 221 note 5, at 221. note 5, at 221. 5, note Further, the Further, 7 account “strength” supra supra supra supra supra at several stages: ATIONAL ETERANS OF N V ce for causation. These required thoughtful required thoughtful ce within and between ce within and between Notably, any determination any Notably, the Committee evaluate the VAO 1994, VAO 1994, VAO 1994, IETNAM that takes into onsideration of virtually all of the of onsideration ndividual reports; deciding on ndividual V 2002 28 VAO (2003) [hereinafter nding, which are defined in detail in in defined are which nding, e association and the methods used) used) the methods association and e ating the conclusions themselves. themselves. conclusions ating the to a possible “statistical association.” “statistical association.” to a possible see also see also also see see also the combination of responses to questions questions to of responses the combination a conclusion were required. As stated in a in a As stated required. were a conclusion ration of eviden PDATE oaches at several points and could not not and could points several oaches at the first charge does not mandate the the first charge does not mandate EDICINE OF THE FFECTS IN IN FFECTS M :U E quantitative procedures n indeed requests that RANGE rating the overall eviden EALTH O H ce of a causal relationship.” relationship.” of a causal ce 5/23/2005 7:48 PM NSTITUTE OF GENT JOURNAL OF LAW AND POLICY POLICY AND LAW OF JOURNAL DOC A ,I EVIEW THE 051905. R 2002]. TO . ACROED Agent Orange Act § Orange 3(d)(1)(A); Agent 3(d)(1)(B); Act § Orange Agent Act § 3(d)(1)(C); Orange Agent ERBICIDES M 6 7 8 the possible influence of error, bias, confounding, or chance on the the on or chance confounding, bias, of error, the possible influence reported results; integ The evaluation of evidence to reach conclusions about statistical about conclusions to reach of evidence The evaluation associations goes beyond validity of i assessing the relevance and be accomplished by adherence to a narrowly prescribed formula. formula. prescribed narrowly to a by adherence be accomplished diverse fields of research; and formul and research; of fields diverse Those aspects of the committee’s review consideration of alternative appr H ETERANS AND PDATE OMM ERTZ V
556 association.” the to detect used methods epidemiologic risk “the increased determining with was charged also Committee service in to herbicides during those exposed among of the disease era.” the Vietnam and during of Vietnam the Republic a plausible there exists to assess “whether was asked Committee evidence of a causal relationship or other biologic mechanism question. exposure and the disease” in between herbicide recommendations with making the Committee Congress charged H U issues that would be discussed if such if such discussed would be issues that by 2002 the recent update Committee: issued concerns (for example, the strength of th the strength example, (for concerns and confou bias as such rise to issues give Parts II through IV. Thus, although the Committeenot was charged with about causation, a conclusion drawing oneeffectively and results three in a lengthy c of the evidence and “appropriateness” of the methods examines the same examines of the methods and “appropriateness” evidence of the conside a enter into that concerns (stating “the increased risk of each disease in question among those exposed to exposed those question among in of each disease risk (stating “the increased service”). Vietnam during herbicides about the existence of “statistical association” However, the third questio existence of “eviden Some authors have argued that Some instead but “causal association,” or of “cause” Committee’s examination look in Committee only that the requires TO C 20313_blp_13-2 Sheet No. 32 Side B 06/23/2005 10:19:08 B 06/23/2005 32 Side Sheet No. 20313_blp_13-2 20313_blp_13-2 Sheet No. 33 Side A 06/23/2005 10:19:08 ee ee 505 Y ’ OL 557 557 at 17-18. This Agent Orange in 13 J.L. & P Id. Jeanne Mager Stellman Stellman Mager Jeanne See ng to herbicide exposure”); s e National Academy of Sciences to to of Sciences Academy National e Agent Orange exposure in Vietnam in Vietnam exposure Agent Orange r additional scientific studies to resolve r additional scientific studies to for Epidemiological Studies, Studies, for Epidemiological Stellman in this issue. Stellman ensation in its deliberations. ensation in its deliberations. Characterization of Exposure to Characterization of note 5, at 15. One of these recommendations was to these recommendations of 5, at 15. One note 5/23/2005 7:48 PM supra supra DOC 051905. 9 ACROED Agent Orange Act § 3(e) (directing th Orange Agent VAO 1994, M 9 Faced with the above mandates, the Committee first clarified the Committee the above mandates, Faced with In the course of examiningAgent Orange the effects of Committee of the the members Before beginning its work, ERTZ M K & Steven D. Stellman, D. Stellman, & Steven (2005).
of the questions answer help study might further which in for areas concern. ORANGE OF AGENT HEALTH EFFECTS focused specifically The Committee to be evaluated. the exposures the other Orange and Orange. Agent to Agent on exposure Vietnam were compriseddefoliants used in of one of combinations acid), of four herbicides: 2,4-D (dichlorophenoxyacetic or more 4-amino-3,5,6- acid), 2,4,5-T (trichlorophenoxyacetic acid and dimethylarsenic (picloram), acid trichloropiclorinic 2,4-D or 2,4,5-T acid). Mixtures containing (DMA or cacodylic during the production by chemicals formed were contaminated 2,3,7,8-trichlorodibenzodioxinprocess, including (2,3,7,8-TCDD). also formed, dioxins and dibenzofurans were Although other the toxic and, as such, was considered the most 2,3,7,8-TCDD is reviewed extensively by the Committee. compound most of any evaluated the claim never exposure, the Committee Agent not its charge. Indeed, the individual veteran, as this was by the decisions would be made Orange Act specified that such was instructed not to consider the VA. Moreover, the Committee issue of potential comp or biases, or of interest conflicts were required to disclose potential of interest. create the appearance of a conflict anything that might consulting activities, holdings, These included financial service, areas of research, and professional affiliations government to relevant positions or intellectual public statements as well as any served without members Committee the topic of the Committee. H Vietnam Veterans As a Basis As Vietnam Veterans recommendation led to the studies of studies to the led recommendation described by Dr. Jean Mager by described “make any recommendations it has fo any recommendations “make scientific uncertainty relati areas of continuing reconstruction. commission an historical exposure also C Y 20313_blp_13-2 Sheet No. 33 Side A 06/23/2005 10:19:08 A 06/23/2005 33 Side Sheet No. 20313_blp_13-2 20313_blp_13-2 Sheet No. 33 Side B 06/23/2005 10:19:08 M K C Y Pier See or alternatively, or alternatively, 11 first and third questions third questions first and (b) populations with 10 1031 (2001). (2001). 1031 representing expertise in a wide range of a wide range of expertise in representing Health Effects of Dioxin Exposure: A 20-year Mortality Health 5/23/2005 7:48 PM PIDEMIOLOGY JOURNAL OF LAW AND POLICY POLICY AND LAW OF JOURNAL DOC .J.E M 051905. 2,3,7,8-TCDD is produced as a by-product of the bleaching process process bleaching of the a by-product as is produced 2,3,7,8-TCDD at a chemical Italy, when an explosion in Seveso, occurred an event Such ACROED ,153 A ,153 M 10 11 The three main sources of epidemiologic data used to address The three main sources of epidemiologic Because the scope of the review is broad, the Committee Committee the is broad, of the review scope the Because Reviewed B. Types of Evidence any that it was obvious Committee, on the For the scientists ERTZ Alberto Bertazzi et al., Bertazzi Alberto Study plant caused 2,3,7,8-TCDD to contaminate a wide residential area. a wide residential to contaminate 2,3,7,8-TCDD plant caused
environmental exposures, which typically result from accidents from result which typically exposures, environmental recreational areas, or residential that contaminate are in which herbicides regions in agricultural residence from posed to it by the Act. conducted in: (a) occupational the first question were studies such as chemical workplace, groups with exposures in the herbicides, or paper and of application farming, manufacturing, is produced as a by- 2,3,7,8-TCDD (where pulp manufacturing the bleaching process); product of 558 of expenses. reimbursement for except compensation, health scientists includes reproductive neurology, oncology, epidemiology, fields covering review, assists with the The IOM staff toxicology. health, and if not a few searches that begin with hundreds, conducting library articles, and worksthousand, of to with the Committee down to those articles that are pertinent them progressively narrow at hand. to the questions exposures could serve as same these effects from findings of health if the veterans, even effects in the Vietnam evidence for potential Scientists consider populations. results were obtained in other similar to be sufficiently beings in human biological systems proportion of research findings, throughout the world that a high been replicated in several studies, can be that have especially those beyond those that were larger“generalized” to much populations were conducted on Vietnamstudied. Because few studies actually frequently used as the basis for veterans, other data sources were the regarding decisions the Committee’s H 20313_blp_13-2 Sheet No. 33 Side B 06/23/2005 10:19:08 B 06/23/2005 33 Side Sheet No. 20313_blp_13-2 20313_blp_13-2 Sheet No. 34 Side A 06/23/2005 10:19:08 N ,A . 212, . 212, ANCER C ED ERSONNEL L TUDY ’ P S XAMINATION XAMINATION the cohort AT E 13 559 559 .J.M ORCE NG UP F - E anded and Updated EALTH Workers Exposed to Workers Exposed to IR H 91 J. N A EW 1061, 1061(1997). 1061(1997). 1061, OLLOW ORCE F Cancer Mortality in Workers Mortality Cancer , 324 N FFECTS IN IR E (1997), F ., A PIDEMIOLOGY ORP Cancer, Heart Disease, and Diabetes in Diabetes and Disease, Heart Cancer, EALTH Cancer Mortality in C .J.E H M a similar multinational cohort from multinational a similar L nols, and Dioxins:nols, and An Exp ’ 12 ERBICIDES 15 trachlorodibenzo-p-dioxin. H NT I and the Air Force Health Study (AFHS), and the Air Force Health Study note 11. , 145 A , 145 14 chlorodibenzo-p-dioxin 5/23/2005 7:48 PM supra supra DOC NVESTIGATION OF I , Marilyn A. Fingerhut et al., Fingerhut , Marilyn A. XPOSURE TO PPLICATIONS E 051905. Bertazzi, .A (2000). CI Manolis Kogevinas et al., et al., Kogevinas Manolis See S See, e.g. ACROED M . 779 (1999). 13 14 15 Each of these cohorts was characterized by higher than usual Each of these cohorts was characterized 12 Although hundreds of studies have been reviewed each time reviewed each have been hundreds of studies Although ESULTS PIDEMIOLOGIC OLLOWING ERTZ NST M K International Cohort Study Exposed to 2,3,7,8-tetra Exposed to Phenoxy Herbicides, Chlorophe I E F R exposed to the explosion of a chemical plant in Seveso, Italy, in plant in Seveso, Italy, exposed to the explosion of a chemical over an area populated by more1976 that released 2,3,7,8-TCDD than 200,000 persons; study, of U.S. Air Force also known as the “Ranch Hand” to defoliate spraying missions personnel responsible for flying were termed missions (these using Agent Orange North Vietnam “Operation Ranch Hand”). exposures. For instance, in the two occupational cohorts, a subset reaction of skin an acute chloracne, of the workers had experienced including in Vietnam, served who veterans and (c) used; widely the U.S. armednot only from Australia. but also those forces, ORANGE OF AGENT HEALTH EFFECTS there are (every two years), been convened has the Committee role prominent have played a persons that cohorts of exposed some and were These cohorts had high exposures in the deliberations. outcomes often for different health times, evaluated numerous disorders, heart disease, diabetes, neurologic (such as cancer, etc.), each and allergies, reproductive events, immune function Some to our knowledge base. information contributing more time the National Institute of of these were important of the most cohort of workers (NIOSH) and Health Occupational Safety chemicals at twelve plants that manufactured after 1942 employed containing 2,3,7,8-TCDD; H by the assembled countries, a dozen European more than half Cancer (IARC); for Research on Agency International 212 (1991); Kyle Steenland et al., 212 (1991); Kyle Steenland Workers Exposed to 2,3,7,8-te to Exposed Workers C Y 20313_blp_13-2 Sheet No. 34 Side A 06/23/2005 10:19:08 A 06/23/2005 34 Side Sheet No. 20313_blp_13-2 20313_blp_13-2 Sheet No. 34 Side B 06/23/2005 10:19:08 M K C Y of an of an sufficient evidence sufficient outcomes for which the available which the available for outcomes note 5, at 246. note 5, limited or suggestive evidence supra supra 5/23/2005 7:48 PM JOURNAL OF LAW AND POLICY POLICY AND LAW OF JOURNAL DOC This category may apply when multiple studies apply when multiple may This category This category applies when multiple studies are studies applies when multiple This category 17 18 The first category consists of those health outcomes for for outcomes those health first category consists of The 051905. VAO 1994, 16 at 247. See Id. Id. ACROED M 16 17 18 The Ranch Hand study was the most extensive study of extensive study was the most The Ranch Hand hearings and invited written held public also The Committee C. The Process committee, decisions, the initial for its To provide a framework ERTZ observe an association, but the magnitude is sufficiently small that is sufficiently small observe an association, but the magnitude variation cannot be ruled out. bias, confounding, or random which the available data provide which the available data provide and bias, confounding, or consistent in showing an association, to explain the findings. The second variation are not likely random health of those consists category research provides association. 560 In addition to 2,3,7,8-TCDD. high exposures follows that eruptions subsets numerous endpoints, health of multiple to the examination Furthermore, more extensively. examined also were of the cohorts point, was, at some cohorts exposure of these four in each subset of participants. a blood drawn from in measured study, which this cohort Force initiated Air veterans. The who were identified as to recruit about 1,200 servicemen attempted were Force personnel who and 1,700 Air Ranch Hand personnel not exposed in Southeast Asia, but were assigned to duty was examination herbicides. In 1982, a baseline occupationally to took place every and follow-up both groups of men, conducted of five years thereafter. with an members Committee These provided the submissions. with the conditions familiar those most opportunity to hear from of as the authors in Vietnam, as well and sequelae of service yet not but press, were in that relevant papers, including some published. of in 1992, defined four categories which began meeting evidence. association. H 20313_blp_13-2 Sheet No. 34 Side B 06/23/2005 10:19:08 B 06/23/2005 34 Side Sheet No. 20313_blp_13-2 20313_blp_13-2 Sheet No. 35 Side A 06/23/2005 10:19:08 This This 20 19 . 561 561 evidence of no association evidence of no inadequate or insufficient evidence or insufficient inadequate 5/23/2005 7:48 PM DOC 051905. Id. Id. ACROED M 19 20 The third category is used to identify those health outcomes for outcomes health to identify those category is used The third with to the first question were applied The above categories ERTZ M K
high quality reasonably one or more be may there Alternatively, do not confirm. that other studies an association studies showing ORANGE OF AGENT HEALTH EFFECTS literature provides which the studies of reasonably there are numerous is used when category between they consistently show no association high quality, and the outcome. the exposure and regard to the second With which Congress charged the Committee. those who served in Vietnam question, the paucity of data on about the a determination part, making precluded, for the most exposures assign to inability the of increased risk. First, magnitude of those who vast majority the to individual veterans, including conducted, was seen that were participated in the research studies it is an agent induces a response, as an enormous obstacle. When response, or the likelihood of of the recognized that the magnitude developing a disease, tends to increase as the exposure gets larger. as “dose-response.” The is referred to This phenomenon concluded that, without knowledge of the exposure Committee not be quantified. Even if an level, the size of the risk could it would still be difficult to average exposure level were known, because the existing research, whether in an average risk estimate accidentally-exposed populations, veterans, exposed workers, or is, did not quantify, the dose- usually could not establish, that how the lack of information about response relationship. Given evaluated would be health outcomes the risk for each of the steeply to it was unable concluded that rise, the Committee expected to answer the second question regarding the “increased risk of each H exists. an association whether which to determine from category is used when there are very few studies, none of which is when there are very few studies, category is used quality is the studies, but are many where there or definitive, failed to control confounding) have studies might inadequate (the is used to category the last Finally, are inconsistent. or the findings research extant the for which health outcomes designate those or suggestive provides limited C Y 20313_blp_13-2 Sheet No. 35 Side A 06/23/2005 10:19:08 A 06/23/2005 35 Side Sheet No. 20313_blp_13-2 20313_blp_13-2 Sheet No. 35 Side B 06/23/2005 10:19:08 M K C Y 21 this question is that any any is that this question d later in this article but, for now, it 5/23/2005 7:48 PM JOURNAL OF LAW AND POLICY POLICY AND LAW OF JOURNAL DOC 051905. The term “risk” will be further define The term “risk” will be further ACROED M 21 The responses to the third question—whether a biologically a biologically question—whether to the third The responses In evaluating the evidence pertaining to its congressional In evaluating the evidence pertaining ERTZ shall suffice to say that, in the judgment of the Committee, the number of cases number the the Committee, of judgment say that, in the shall suffice to be not could exposure herbicide to due veterans Vietnam among of each disease accuracy. any reasonable with estimated
562 any specificity. with exposed” those among disease a causal supporting evidence or other mechanism plausible beyond of the Committee the work existed—expanded association review of a broad in the Committee engaged the and epidemiology of premise The of studies. spectrum H when the is strengthened relationship about a causal determination researchers For example, of action is understood. mechanism have taken a certain blood pressure in persons who find that might not. If in addition lower than in those who have drug is generally in muscles smooth the relaxes drug this that researchers determine to blood pressure known to be inversely related the arterial walls it), but relaxation reduces contraction increases pressure, (muscle (in this case having a causal effect of the drug then the plausibility biologic is enhanced. The data used in evaluating a protective one) a wide of scientific fields, range derive from plausibility may what rate how and at examines which including toxicokinetics, the body, distributed to different are absorbed into compounds animal whole excreted; and metabolized, organs, chemically the pathologic and homeostatic toxicology, which addresses in rodents but also in other often responses of the organism, molecularspecies, including humans; and and cellular biology, alterations that result biochemical which seeks to understand the cell an exposure consequences for and the subsequent from studies in experimental from functioning. Thus, biologic evidence is such as cell cultures and test systems animals, other humans, Such exists. mechanism whether a plausible used to determine support for inferring causation evidence is considered to provide studies. been observed in human when statistical associations have the relationship decisions regarding made the Committee mandate, and dozens of health outcomes. between Agent Orange exposure in detail: (a) non-Hodgkin’s Four of these will be reviewed (b) Type II diabetes, (c) prostate cancer, and (d) the lymphoma, 20313_blp_13-2 Sheet No. 35 Side B 06/23/2005 10:19:08 B 06/23/2005 35 Side Sheet No. 20313_blp_13-2 20313_blp_13-2 Sheet No. 36 Side A 06/23/2005 10:19:08 563 563 with regard to the to the with regard only 5/23/2005 7:48 PM DOC FFECTS E 051905. ACROED AUSAL M The concept of causation is fundamental to scientific inquiry, two identical an exposure, To study the causal effects of ERTZ M K exposure. Each unit is evaluated for some response, unit is evaluated for some such as exposure. Each or electrical activity, or structural or functional growth, chemical change. The difference in response between the exposed unit and the unexposed unit represents the “causal effect.” which seeks to understand cause and effect relationships of and effect relationships of which seeks to understand cause biomedical Within or biological phenomena. physical, chemical, disorders and developmental sciences, potential causes of disease and including epidemiology are studied using a variety of tools, the concept of “cause” differs toxicology. In these fields, however, or even class settling individual that which courts use in from action cases. and one unexposed. A unit one exposed be compared, “units” must a cell, be, among a laboratory animal, other things, a person, might results about to produce tissue. In order for the study or a piece of two studied units be absolutely the that causal effects, it is essential differ is to say that they which identical, health three are first The cancer. for respiratory period presumptive and causation. of timing one is an issue final the while outcomes, ORANGE OF AGENT HEALTH EFFECTS with an association for the evidence that concluded The Committee that biologic sufficient and was lymphoma non-Hodgkin’s and for prostate II diabetes Type For was established. plausibility but was limited that there concluded cancer, the Committee had ruled that for an association. The VA suggestive evidence only if it service-related be considered cancer could respiratory service in years after the end of of thirty within a period manifested with Charged period.” the “presumptive termed Vietnam, period had a scientific basis, whether this presumptive determining To provide the reader that it did not. concluded the Committee reached how the Committee for understanding with a background to an exposition of this article now turns each of these conclusions, research. scientific and epidemiologic key concepts in II. C H C Y 20313_blp_13-2 Sheet No. 36 Side A 06/23/2005 10:19:08 A 06/23/2005 36 Side Sheet No. 20313_blp_13-2 20313_blp_13-2 Sheet No. 36 Side B 06/23/2005 10:19:08 M K C Y Outcome is measured: is measured: Outcome the with vary reliability will and the nature of the outcome quality of the protocol for its measurement Units not identical Units not identical beyond the Exposure occurs of the scientist control exposure Scientist measures be subject may (measurements to greater error than in experiment) Table 1 5/23/2005 7:48 PM JOURNAL OF LAW AND POLICY POLICY AND LAW OF JOURNAL DOC 051905. Experiment Observational Study Observational Experiment ACROED M Notably, it is easier to ensure the use of identical “units” in an use of identical “units” in an Notably, it is easier to ensure the Studies can be classified in many ways, but one significant significant but one ways, in many classified be can Studies ERTZ Outcome is measured: is measured: Outcome the with vary reliability will and the nature of the outcome quality of the protocol for its measurement study than in an observational study. However, the experimental study, the differencemore fundamental is that, in an experimental exposure is controlled by the investigator; that is, the investigator the exposure and which will not. decides which unit will receive and either of the units randomly Typically, this decision is made investigator also exposure. The could be the chance recipient of the assign each unit receives and may the level of exposure determines an the units to different amounts or intensities of exposure. In observational study, by contrast, exposure is not assigned, but rather, occurs for reasons that have nothing to do with any Scientist manipulates exposure Scientist manipulates units are which and determines or are not exposed (measures) Scientist determines exposure levels 564 studies. and observational experimental is between distinction types of studies: two compares these Table 1 as a single such Identical units, mice strain of laboratory H 20313_blp_13-2 Sheet No. 36 Side B 06/23/2005 10:19:08 B 06/23/2005 36 Side Sheet No. 20313_blp_13-2 20313_blp_13-2 Sheet No. 37 Side A 06/23/2005 10:19:08 The 23 the fact that 565 565 ts and Analytical compliant with the with compliant acebo-controlled trials, Causal Effects in Clinical and Causal s the likelihood of confounding s the likelihood of confounding 121 (2000). . Additionally, despite randomization, double-blind, pl problematic, due largely to EALTH H Part III. tential Outcomes: Concep Under scenario two, we suppose that Under scenario 24 these studies and who are these studies and UBLIC .P See infra See infra 6/6/2005 1:06 PM EV DOC . .R NN ORRECTED C , 21A Donald B. Rubin & Roderick J. Little, & Roderick B. Rubin Donald 22 See pressure, such as blood be a continuous measurement might A response It should be noted that even in be It should ACROED M 23 24 22 Recently however, a conceptual paradigm has been developed has a conceptual paradigm Recently however, Unfortunately, the individual causal effect can never be known Unfortunately, the individual causal ERTZ M K inferring general causation can be in participate persons who chance, by ways, differ in unmeasured may unexposed and the exposed reduce trials. Randomization particularly in small but does not eliminate it. treatment regimes are often a select group regimes are often treatment Epidemiological Studies Via Po Via Studies Epidemiological Approaches
physical and political, social, Historical, actions. researcher’s also may choices that well as individual forces, as shaped by be ORANGE OF AGENT HEALTH EFFECTS and where exposure when will determine above factors, any of the to the is rarely identical unit exposed As a result, the occurs. in concept of causation reason, the unit. For this unexposed elusive than in experimental has been more observational studies studies. causal which under of the conditions that aids in the understanding observational investigations. from made inferences can be that contrasts two is the “counterfactual” underlying concept unit (usually a the first scenario, the individual scenarios. Under exposed and is possibly a non-laboratory animal) person, but also its response is measured. H the can measure not exposed and, therefore, we the individual is had the individual, counter to response that would have occurred call this the counterfactual response. fact, not been exposed. We setting is the in an observational Thus, the individual causal effect the counterfactual response. difference between the actual and and the factual both never observe since researchers can however, strive to counterfactual experience. Epidemiologists, which represents a type of the group-level causal effect, measure that under the assumption effects, average of the individual-level unexposed) each represent the the two groups (exposed and of the other. In order to do counterfactual experience, on average, risk (R), first define must the following terms: so, epidemiologists or a binary outcome, such as the presence or absence of disease. of disease. or absence or such presence a binary outcome, as the C Y 20313_blp_13-2 Sheet No. 37 Side A 06/23/2005 10:19:08 A 06/23/2005 37 Side Sheet No. 20313_blp_13-2 20313_blp_13-2 Sheet No. 37 Side B 06/23/2005 10:19:08 M K C Y U T V S situation) P required (common required (common C: Multiple causes are R Figure 1 P B: Two causes are required and sufficient 5/23/2005 7:48 PM JOURNAL OF LAW AND POLICY POLICY AND LAW OF JOURNAL DOC 051905. Q ACROED situation) M The importance of the counterfactual assumption cannot be cannot the counterfactual assumption of The importance sufficient (rare ERTZ A: Single cause is 566 is (RR). Risk ratio and risk (RD), difference risk factor (RF), risk refers to an factor risk of disease, while as the probability defined a or serves as risk that increases or characteristic exposure difference is risk. Risk that increases for a factor surrogate “risk the from exposed” value the “risk if by subtracting calculated known as relative Finally, the risk ratio, also if unexposed” value. by “risk if unexposed.” exposed” divided “risk if risk, is defined as is possible to make In any study, it overemphasized. ratio can the risk difference or risk studies, In many measurements. them or measuring defining these terms However, be measured. of causation. in terms meaningful them make does not in itself often say that, “association scientists and other Epidemiologists gain additional imply causation.” One can does not necessarily diseases through source of various conditions and insight into the model. Figure 1 provides an the use of the sufficient causes of the paradigm: application of this example H 20313_blp_13-2 Sheet No. 37 Side B 06/23/2005 10:19:08 B 06/23/2005 37 Side Sheet No. 20313_blp_13-2 20313_blp_13-2 Sheet No. 38 Side A 06/23/2005 10:19:08 In In 25 23, 28 28 23, EDIATRIC P 567 567 EMINAR PIDEMIOLOGY , 11 S , 3 E 27 ., Synergism Between Occupational Arsenic Arsenic Occupational Between Synergism ., 8-12 (Kenneth J. Rothman & Sander Greenland Greenland & Sander Rothman J. 8-12 (Kenneth Lung Cancer Induction The Genetics of Autism However, each child with autism probably does child with autism probably does However, each 5/23/2005 7:48 PM 26 PIDEMIOLOGY DOC E 196, 198 (2004). (2004). 198 196, 051905. ODERN M Spence, J. Sarah al et Irva Hertz-Picciotto ACROED M 25 26 27 The sufficient causes model is also instructive in terms of instructive in terms also The sufficient causes model is Each circle, or pie, represents a set of sufficient causes. of sufficient a set represents or pie, circle, Each EUROLOGY ERTZ M K eds., 1998). Exposure and Smoking in and Smoking Exposure N inferring individual causes. Knowledge about the presence orinferring individual causes. Knowledge changes the probability that a absence of other known risk factors case. If an an individual factor was causal for suspect risk whose parents never smoked, individual who has never smoked, develops lung cancer, the to a smoker and who is not married other known lung by some was caused probability that this cancer not require all such genes to develop this disorder, and there may and there may genes to develop this disorder, not require all such also involved. Note also that for factors be several environmental be several different sets of sufficient any given disease there may others will individuals will require one set and causes; some overlapping, set. For example, require a different, though possibly workers are who smoke and among exposed to arsenic at their the from cancer respiratory develop might workplace, some the from develop cancer while others might alone, cigarette smoke develop respiratory cancer might arsenic alone, and still others both exposures. only because they received This cause might in the disease. will result a single cause circle A, ORANGE OF AGENT HEALTH EFFECTS the alone causes virus. The virus example, the measles be, for factor is circle B, a second In measles. entity we call clinical to exposed not all individuals apply if might this example needed; the disease, of symptoms clinical the actually exhibited the virus Thus, virus. to the susceptibility lacked individuals if some that is, because neither P the virus, but R is also necessary in circle B, P is C, five factors are results in the disease. In circle alone nor R alone to of scenario corresponds disease. This type cause necessary to for which multiple diseases, or non-infectious, most chronic, case. By way of to play a role in any individual factors are likely than ten be more there may suggested that it has been example, genes for autism. H (1992). C Y 20313_blp_13-2 Sheet No. 38 Side A 06/23/2005 10:19:08 A 06/23/2005 38 Side Sheet No. 20313_blp_13-2 20313_blp_13-2 Sheet No. 38 Side B 06/23/2005 10:19:08 M K C Y RECISION P causal effects. In recognition of causal effects. In STIMATION AND :E 5/23/2005 7:48 PM ROUPS JOURNAL OF LAW AND POLICY POLICY AND LAW OF JOURNAL DOC G of the true proportion of high schoolof the true proportion of high with students 051905. ACROED TUDIES IN M Researchers prefer to enroll groups for their studies rather than rather than for their studies groups prefer to enroll Researchers with that adolescents concerned researchers For example, of those high school many If researchers also found out how estimate ERTZ 568 to is known that individual instance, If, for increased. is carcinogen caused that the radon the likelihood exposure to radon, have high with the another individual it would be for is higher than the cancer or was exposed smoked to radon who high exposure same to tobacco smoke. passively III. S never almost because individuals primarily rely on individuals, evidence about provide definitive an enrolled group with are made on measurements this limitation, population from results can be extrapolated to the the idea that the who were arose, and hence, to other individuals which the group a that is studied is termed in the study. The group not participants is considered an sample on the and any measure “sample,” for the ratio, for instance) (risk of the parameter “estimate” population. complete engage in binge drinking of alcohol of depression may symptoms sample students. In the sample, a group of high school might what proportion of tenth and eleventh determine researchers may all high from selected at random graders attending one high school district exhibit depressive school schools in a metropolitan (perhaps of a questionnaire). This result provides by use symptoms an in that in that school district and perhaps depressive symptoms countries. or all similar country, area, that state, the metropolitan the risk they could estimate students engaged in binge drinking, those with depressive ratio for binge drinking by comparing The resulting risk ratio symptoms. to those without such symptoms of the risk ratio in the population. If the risk would be an estimate that high school students in the study ratio were 1.5, it would mean more werewho had depressive one and one-half times symptoms likely to engage in binge drinking than those who did not. If the that each group of high school mean 1.0, it would risk ratio were risk of engaging in binge drinking. students had the same H 20313_blp_13-2 Sheet No. 38 Side B 06/23/2005 10:19:08 B 06/23/2005 38 Side Sheet No. 20313_blp_13-2 20313_blp_13-2 Sheet No. 39 Side A 06/23/2005 10:19:08 569 569 ecause large if it were true, then 5/23/2005 7:48 PM DOC 051905. ACROED M However, epidemiologists recognize that the sample studied studied the sample that recognize epidemiologists However, of effects. The the estimation The above exposition emphasizes The merits and misuses of p-values have been the subject of and misuses The merits ERTZ M K might be different from or unrepresentative of the complete of the complete or unrepresentative different from be might this a range around also construct and thus they population as range is known This and confidence interval a estimate. certain and under that, on average a range of values represents value. The to include the true population conditions, is expected study size, a good is roughly a function of the width of this interval as statistical power. known technical quantity indication of a more is exposed and of the population less than half In a study in which by the determined common, this power is mostly disease is not of exposed persons with disease. number As the number of confidence in increases, the who develop disease exposed persons the around tighter becomes increases and the interval the estimate have 1.5 might with an RR of study a small For example, estimate. case we would interval of 0.5 to 4.5, in which a 95% confidence an that also had study is low. A much larger say that the precision have a 95% confidence interval of 1.3 to 1.7, RR of 1.5 might indicating very high precision. in confidence intervals) is precision of these estimates (reflected invoked in recent scientists and concept used by related to another of scientific evidence, court decisions regarding admissibility testing.” A common practice in “statistical hypothesis namely which a “null hypothesis,” scientific fields is to construct many between the exposure and thestates that there is no association is Once the study has been conducted, the result outcome. If the study result is extremely with the null hypothesis. compared what is predicted by the “null hypothesis,” then, different from conclude that the null may the data are reliable, one assuming hypothesis is not supported b ORANGE OF AGENT HEALTH EFFECTS To quantify the the null would be improbable. deviations from of its probability calculates of the result, one improbability and of no association occurring under the dual assumptions The resulting absence of any other information. complete as an referred to It is sometimes probability is called a “p-value.” rate. “error” H C Y 20313_blp_13-2 Sheet No. 39 Side A 06/23/2005 10:19:08 A 06/23/2005 39 Side Sheet No. 20313_blp_13-2 20313_blp_13-2 Sheet No. 39 Side B 06/23/2005 10:19:08 M K C Y One One 28 http://www. See or for considering the 30 s Questioning the Indiscriminate Indiscriminate s Questioning the the scientific community. scientific the The result of a statistical hypothesis test The result of a statistical 29 Instead, they are calculated by either Instead, they are calculated 31 ratio), then will be greater than 0.05. the p-value 5/23/2005 7:48 PM JOURNAL OF LAW AND POLICY POLICY AND LAW OF JOURNAL DOC Part V. Part IV. 051905. One website lists “326 Articles/Book website lists “326 One for a (0 value null the includes interval 95% confidence if the Note that See infra See infra ACROED M 28 29 30 31 It has also been noted that although a p-value providesIt has also been noted that ERTZ Use of Statistical Hypothesis Tests in Observational Studies.” Tests in Observational Studies.” of Statistical Hypothesis Use cnr.colostate.edu/~anderson/thompson1.html. risk difference, 1 for a risk difference, 1 risk
possibility of biases. 570 within debate considerable using a convention of to the p-value relates of the criticism a finding is “significant” whether of 0.05 to determine cutpoint is, when than 0.05, that p-value is less when the (the designation if the null one in twenty is less than of the result the probability p-values above true), and declaring all results with hypothesis were 0.05 as “nonsignificant.” In practice, to “reject” the null hypothesis. is a decision of whether are with a p-value of 0.051 argue that results it is difficult to those with from qualitatively different a p-value of 0.049. Another of the two different aspects p-value combines is that the problem association and its precision. For of the magnitude study result: the of 0.04 when the RR is 8.0; a p-value have may instance, one study be will interval (the confidence less precise estimate a this will be an RR of 2.5. p-value of 0.04 and study with a wider) than another have preferred to epidemiologists many To address this concern, limits,” and “confidence with “estimates” express their results of the study findings clear and thereby keeping these two aspects separate. between the “null hypothesis” about the consistency information at all about any no information and the data collected, it provides to hypothesize that a risk is other hypothesis. If one wanted exposed, one would not calculate doubled for individuals who are suggested if previous studies have already a p-value. Similarly, be of greater not be true, then it may that the null hypothesis may the new data are consistent with interest to evaluate whether the rather are previously published findings than whether they In fact, p-values do not provide the a null effect. consistent with for placing findings in context, means H 20313_blp_13-2 Sheet No. 39 Side B 06/23/2005 10:19:08 B 06/23/2005 39 Side Sheet No. 20313_blp_13-2 20313_blp_13-2 Sheet No. 40 Side A 06/23/2005 10:19:08 7, 571 571 PIDEMIOLOGY , 9 E 286 (2001). (2001). 286 ility that the estimate estimate ility that the PIDEMIOLOGY probability would correspond to the correspond to the probability would and frequently asks authors to to authors asks and frequently 33 32 , 12 E That Confounded P-Value Confounded That The Value of P Value The 5/23/2005 7:48 PM d a reasonable doubt.” reasonable d a DOC 051905. Janet M. Lang et al., M. Lang Janet See what to guess I will not presume ACROED M 32 33 While epidemiologists strive to conduct studies that produce strive to conduct While epidemiologists Overall, it is unwise to make decisions on the basis of a single on the basis of decisions make to it is unwise Overall, of p<0.05 as a use point out that the common Further critiques ERTZ M K 8 (1998); The Editors, criterion of “beyon
precise estimates, there is always the possib there is always precise estimates, that of chance “sampling error” could be wrong, not because of but because samples, moderate-sized or even occurs with small it. ignoring or by explicitly information no other assuming ORANGE OF AGENT HEALTH EFFECTS of p-values. by the use is encouraged a practice that set of data, by implied in the manner proceed not actually does Science at on decisions than relying and, rather hypothesis testing statistical of review the body and study, scientists gather the end of each that the practice of It has been suggested evidence as a whole. thinking; indeed, one scientific detracts from hypothesis testing the use of strongly discourages of epidemiology journal in the field results summarize p-values to of accepting a paper. them as a condition remove is based on the the null hypothesis to reject criterion for deciding rejecting cost to mistakenly that there is a high assumption implicit other an association.” In and thereby “finding the null hypothesis that such a conclusion should be words, this convention presumes this only very cautiously (society cannot afford to make made this circumstances, In some than 5% of the time). more mistake an from harm If the prove problematic. may assumption implicit wish to err may body, for example, exposure is severe, a regulatory health. This, however, would on the side of protecting public a “more In the courtroom, require the use of different criteria. the bar as circumstances in some not” standard is used likely than In a single study (absent any against which to evaluate evidence. 50% probability is less than the other research), a p<0.50 means data) arose from a population in extreme that the data (or more not associated. Hence, a p<0.50 which exposure and disease are likely than not” for of “more would be much closer to the criterion in which a population from evaluating whether the data arose exposure does not cause disease. H C Y 20313_blp_13-2 Sheet No. 40 Side A 06/23/2005 10:19:08 A 06/23/2005 40 Side Sheet No. 20313_blp_13-2 20313_blp_13-2 Sheet No. 40 Side B 06/23/2005 10:19:08 M K C Y IAS :B or masking true effects: true masking or 5/23/2005 7:48 PM ROUPS JOURNAL OF LAW AND POLICY POLICY AND LAW OF JOURNAL G DOC Figure 2: Upward and Downward Bias and Downward Figure 2: Upward 051905. ACROED TUDIES IN M Bias is present when, on average, the estimates tend to be tend to be estimates the when, on average, Bias is present the true is of each arrow The base of the wedge at the start ERTZ 572 present, bias is When as bias. known problem systematic a more does the p-value but incorrect, association is the estimated not only is see, bias As we shall “error rate.” the purported not represent fluctuations due to random than errors concern a greater usually studies. rates in observational these error that produce IV. S parameter. too low relative to the true population either too high or risk by creating how bias can distort a relative Figure 2 displays either artificial effects arrowhead is at the biased the value of the risk ratio, and increased risk due to a harmful(observed) value. In case 1, an is. In case 2, than it truly to be smaller exposure will be presumed to reducean exposure with no effect be presumed risk. In case will will appear to be (reduces risk) 3, an exposure that is beneficial in case 4, a beneficial whereas more beneficial than it really is, In harmful effect. it has a small exposure will appear as though to be presumed has no effect will be case 5, an exposure that harmful exposure will be harmful and, in case 6, a slightly harmful than it is. to be more presumed H 20313_blp_13-2 Sheet No. 40 Side B 06/23/2005 10:19:08 B 06/23/2005 40 Side Sheet No. 20313_blp_13-2 20313_blp_13-2 Sheet No. 41 Side A 06/23/2005 10:19:08 6 5 573 573 34 12 5/23/2005 7:48 PM 2.0 1.5 1.0 0.5 DOC 051905. Cases 1-3 show “downward” bias, and Cases 1-3 show “downward” cases 4-6 show “upward” bias. ACROED M The main types of epidemiologic bias are selection bias, types of epidemiologic The main ERTZ M K No effect information bias, confounding bias, and statistical bias. Selection bias, confounding bias, information not represent do the study sample bias occurs when the subjects in to the exposure and the disease. the targeted population with regard in which two-by-two table Consider Figure 3, the epidemiologic with disease, four cells: exposed one of falls into each individual with disease, or unexposed exposed without disease, unexposed will take representative sample A completely without disease. each out of the population proportion from the same approximately if 90% of the population is in the of the four cells. (This means that then 90% of the samplecell for unexposed without disease, also that cell.) It is also possible to intentionally sample would be from still obtain an or one row and one column at a different rate from investigator ensures that both but only if the unbiased estimate, proportion. in the same cells in that row or column are sampled ORANGE OF AGENT HEALTH EFFECTS H C Y 20313_blp_13-2 Sheet No. 41 Side A 06/23/2005 10:19:08 A 06/23/2005 41 Side Sheet No. 20313_blp_13-2 20313_blp_13-2 Sheet No. 41 Side B 06/23/2005 10:19:08 M K C Y .J. M This 34 , 158 A 931 (2003)). 931 Total without disease Total diseased Hot Tub Use during Hot Tub Use PIDEMIOLOGY .J.E tary by Irva Hertz-Picciotto & Hertz-Picciotto by Irva tary M Unexposed without disease Unexposed with disease ,158A Unexposed: Invited Commentary: Hot Tubs and Miscarriage: Hot Tubs and Miscarriage: Invited Commentary: Total exposed Total unexposed Grand Total disease disease Figure 3: The Two-by-Two Table Two-by-Two The Figure 3: 5/23/2005 7:48 PM JOURNAL OF LAW AND POLICY POLICY AND LAW OF JOURNAL DOC If the true risk ratio were 1.0, we might, for example, might, If the true risk ratio were 1.0, we 938 (2003) (critiquing Li De-Kun et al., Li 938 (2003) (critiquing 35 Exposed without Exposed 051905. case 6 in Figure 2. Figure 6 in case Exposed with Exposed Exposed: This point was made in a commen was made This point See ACROED M 34 35 More concretely, suppose that a study is conducted to examine to examine study is conducted More concretely, suppose that a Not diseased: Diseased: PIDEMIOLOGY ERTZ Penelope P. Howards, Howards, Penelope P. Is Weak Case the Why Reasons Substantive Methodological & Pregnancy and the Risk of Miscarriage and the Risk Pregnancy would lead to an upward bias in the estimated RR. Thus, if, for the the estimated would lead to an upward bias in from the true risk ratio for spontaneous abortion sake of argument, risk see an estimated we might hot tub use were 1.2, in this study ratio of 1.5.
the hypothesis that the use of hot tubs by pregnant women hot tubs by pregnant women the hypothesis that the use of abortion. Suppose further that increases the risk of spontaneous the study participate in likely to are more tubs who use hot women who have and that women leisure time because they have more likely to participate because more spontaneous abortions are also pregnancies. In why they lost their about they are concerned population in the upper left cell essence, a larger percentage of the two-by-two table participated in the study of the epidemiologic other words, In in the other cells. than the population percentage or who did who did not use a hot tub proportionately fewer women participate in the study. not spontaneously abort would E 574 H 20313_blp_13-2 Sheet No. 41 Side B 06/23/2005 10:19:08 B 06/23/2005 41 Side Sheet No. 20313_blp_13-2 20313_blp_13-2 Sheet No. 42 Side A 06/23/2005 10:19:08 In the 38 575 575 recall every insecticide or or insecticide recall every 36 alternately, if the true RR were if alternately, the high fat diet when it is quite high fat diet when it is quite the 37 5/23/2005 7:48 PM DOC 051905. case 2 in Figure 2. Figure 2 in case case 5 in Figure 2. Figure 5 in case 2. Figure 1 in case See See See ACROED M 36 37 38 In other examples, the bias might occur in the opposite the opposite occur in might the bias examples, In other Information bias, by comparison, occurs when information when information occurs bias, by comparison, Information ERTZ M K
greater. 1.2 or ratio of a risk observe ORANGE OF AGENT HEALTH EFFECTS and high fat diets who studied researchers instance, For direction. and diabetics high fat diets persons eating find that might diabetes left cell case, the upper participate. In this less likely to would be to the compared be underrepresented as in Figure 3 would 1.8, then one the true RR were Therefore, if population at large. 1.2; observe an RR of, say, might a lower RR of, for instance, 0.7. observe 1.0, one might H former case, researchers might incorrectly conclude that there is there incorrectly conclude that might case, researchers former effect of detrimental only a small suggests a the latter case, the study incorrectly harmful, and, in those who among that is, a lower risk of diabetes protective effect, one to draw the In short, selection bias can lead eat high fat diets. wrong conclusion. between those who are exposed about the disease diagnosis differs result bias might For example, and those who are unexposed. status who do participate where individuals of low socioeconomic socioeconomic than those at higher exposed to be likely are more they lack health because levels, but less likely to be diagnosed Thus, persons with theinsurance and rarely see a physician. yet as healthy because they are not be misclassified disease may occur when data on bias also might diagnosed. Information those who have the disease and exposure differs with regard to in a study of the possible those who do not. For example, and incidence around the home connection between pesticide use what parents may be asked to recall of childhood leukemia, when. The parents of affected pesticide products they used and likely to be more might children fungicide used in or around their house than the parents of healthy house than the fungicide used in or around their bias information type of in a specific This would result children. usually results in or recall bias, which reporting bias termed upward bias. C Y 20313_blp_13-2 Sheet No. 42 Side A 06/23/2005 10:19:08 A 06/23/2005 42 Side Sheet No. 20313_blp_13-2 20313_blp_13-2 Sheet No. 42 Side B 06/23/2005 10:19:08 M K C Y ase (one that is not the exposure is not the exposure that ase (one 5/23/2005 7:48 PM JOURNAL OF LAW AND POLICY POLICY AND LAW OF JOURNAL DOC 051905. ACROED M Another type of bias, confounding bias, occurs when an when occurs bias, confounding of bias, type Another as Statistical bias occurs bias. A fourth type of bias is statistical types of bias that all of these keep in mind to It is important ERTZ 576 the dise risk factor for alternative less frequently or occur more to happens the study) for of interest for unexposed. Consider, with the as compared in the exposed to that exposure the hypothesis study to examine a example, biphenyls (PCBs) duringpolychlorinated adversely affects infancy source Suppose that a major of children. the cognitive development who mothers Then suppose that is breast milk. of PCBs to infants to likely and are more educated are more their infants breastfeed Notice or offer other intellectual stimulation. read to their children affect hypothesis that PCBs adversely to test the that an experiment to mothers assign some would randomly cognitive development in the real world, However, give formula. to breastfeed and others do those who to breastfeed are not the same as who choose women serve as the breastfeed and hence cannot not elect to those who do not breastfeed. The “counterfactual” experience for with a higher exposure to result is confounding bias: children example, this In stimulation. PCBs were given greater intellectual other in that but it is possible the RR would be biased downward, the RR could be biased upward. examples in data. analysis or limitations in statistical errors of a result the used for analysis do not match the methods Sometimes the variables as collected or conditions in which the data were In other instances, bias results. defined by the investigator; hence, is done incorrectly, and bias is the adjustment for confounders to avoid statistical bias, introduced inadvertently. Thus, understanding of in addition to having an intimate epidemiologists, be knowledgeable about both the subject they are studying, must selection strategies. statistical methods and proper confounder or negative (downward) (upward) positive could be in either the the results of a study one cannot dismiss direction. However, of bias or confounding. is a possibility because there simply that bears on the direction Frequently, one can glean information if the factors tending toward downward bias of bias. For example, are stronger than those that would magnify the association between the true relationship to be exposure and disease, one would expect H 20313_blp_13-2 Sheet No. 42 Side B 06/23/2005 10:19:08 B 06/23/2005 42 Side Sheet No. 20313_blp_13-2 20313_blp_13-2 Sheet No. 43 Side A 06/23/2005 10:19:08 577 577 (c) confounder data are (c) confounder effect of exposure. Of 40 causal (b) exposures and disease have (b) exposures and 39 ability of selection bias. ability of selection 5/23/2005 7:48 PM ONSENSUS DOC C 051905. This ensures a low prob low This ensures a bias. reduce information This acts to ACROED EACHING M In practice, epidemiologic studies are never perfect, and even are never perfect, studies In practice, epidemiologic 39 40 In other words, as long as the quality of data is reliable and the In other words, as long as the quality This discussion about bias and precision can now be used to can now be used and precision about bias This discussion ERTZ M K course, this measured causal effect may or may not be a precise or may may causal effect course, this measured the study has an adequate- as that will depend on whether estimate, quality of an individual study, therefore, The sized sample. bias, which is achieved depends on there being (1) minimum and of data collection methods through careful design, sound disease, and appropriate statistical of exposures and measurement study sample. an adequate-sized of the data; and (2) treatment V. R the necessary conditions meet the best studies only approximately as causal effects. to be interpreted or risk differences for risk ratios be For this reason, it is nearly always true that causation cannot complete and adequately measured; and (d) the appropriate and adequately measured; and complete the to analyze have been used techniques multivariable statistical have been conditions, once all confounders data. Under these provides a good representation unexposed group accounted for, the group and the of the exposed experience of the counterfactual the group responses. analysis properly compares of takes account correct and appropriately is statistically analysis can be groups (exposed and unexposed) confounders, then the two RD that the study can infer scenario, one In this compared. validly of the or RR will be a measure study. in the observed the one than stronger ORANGE OF AGENT HEALTH EFFECTS effects in groups. causal of how to measure the problem answer are met, or requirements conditions is that when certain The key be interpreted may exposure and disease between the association conclude that such an inference at least one can as a causal one or and the truth. These conditions far from not stray does probably have been be satisfied when (a) study subjects may requirements and recruited; properly sampled accurately; or diagnosed been measured H C Y 20313_blp_13-2 Sheet No. 43 Side A 06/23/2005 10:19:08 A 06/23/2005 43 Side Sheet No. 20313_blp_13-2 20313_blp_13-2 Sheet No. 43 Side B 06/23/2005 10:19:08 M K C Y evidence is more straightforward straightforward is more evidence 5/23/2005 7:48 PM JOURNAL OF LAW AND POLICY POLICY AND LAW OF JOURNAL DOC 051905. ACROED M As the body of evidence grows and new hypotheses are As the body of evidence grows with is not synonymous Consensus does not require and ERTZ 578 a in be examined must but rather, study, a single from inferred experimental less acute when is problem studies. The of multitude evaluation of such as for the are possible, studies (randomized) In them. taking those to benefit a impart are believed to drugs that of the evaluation this situation, be unethical to for exposures for which it would than it would be or asbestos (such as cigarette smoking conduct such research that have exposures these latter, allegedly harmful exposure). It is This discussion about how to infer causation. generated discussion should evaluate a body of how epidemiologists has focused on epidemiologic human including multiple studies, evidence from and whole animals, data from experimental investigations, to tissues are manipulated which cells or in research mechanistic to be processes believed or biochemical understand physiologic body. in the human related to pathogenesis the process of reaching begins proposed, the research community and ideas it finds convincing. consensus regarding which studies For months, years, or decades. Arriving at a consensus can take consensus regarding the role of the human example, immunodeficiency in AIDS took a relatively short virus (HIV) breast cancer still to contribution whereas the environmental time, contentious. remains who are possible to find some Even today it is unanimity. unconvinced about the relationship HIV and AIDS or between being said, the reaching of and lung cancer. That between smoking pattern, in which evidence consensus often follows a typical consider a study example, shifts. For opinion accrues and scientific association in which exposure E that finds a previously unstudied receive attention, disease D. To an increased risk of is related to observed a strong association. the study often would have size. sample a small are based on Frequently, these first findings reject these findings because they object to scientists may Some Other researchers will then attempt to the study’s methodology. and maybe methodology replicate the finding using improved the studies of that only some it is possible but larger study samples, the weight of the Over time, will confirm the original result. H 20313_blp_13-2 Sheet No. 43 Side B 06/23/2005 10:19:08 B 06/23/2005 43 Side Sheet No. 20313_blp_13-2 20313_blp_13-2 Sheet No. 44 Side A 06/23/2005 10:19:08 579 579 . 295 (1965). . 295 (1965). ED : A high RR or RD provides M Y : Known biologic facts should ’ The Environment and Disease: Association or Association The Environment and Disease: OC S OYAL : A cause must precede an effect. : A cause must precede an effect. 5/23/2005 7:48 PM .R : Evidence from other fields should support, other : Evidence from DOC and include the following primary considerations: considerations: and include the following primary ROC 41 58 P 051905. Biologic Plausibility Strength of Association Coherence Temporality Austin Bradford Hill, Austin ACROED M 41 1. 2. greater weight than a low one. 3. not contradict, the causal hypothesis. 4. support, not contradict, the proposed causal effect. Although ideally scientists will evaluate evidence in a value- in a will evaluate evidence scientists Although ideally for inferences about microbial Although criteria have existed ERTZ M K Causation?,
a point, At some other. or the one side fall on tend to will evidence is a combined which review,” “quantitative or meta-analysis ORANGE OF AGENT HEALTH EFFECTS this, it is conducted. For studies, will be of multiple analysis analysis is this type of quality studies as to use high preferable results than the precision of addressing the in more effective studies may toxicologic or other basic science biases. Meanwhile, the Thus, mechanism. a plausible not demonstrate or may of a in contradiction or in support build either consensus will causal effect. for that it is impossible it is increasingly recognized free context, individuals are totally “objective” because scientists to be and personal by their particular cultures unavoidably influenced these experiences documented how Studies have experiences. scientific studies and assess in which individuals influence the way or lines of evidence as certain studies place greater weight on in with others. It should be noted that the IOM, compared only achieve not seeks to consciously its committees, assembling possible also “balance” among diversity of fields of expertise, but biases on its committees. a century, the discussion about causes of infections for more than In the 1960s, recent. is more causal inference for chronic diseases causes lung cancer smoking the debate as to whether cigarette of a specific set of for the development provided the impetus by Sir were summarized These guidelines for inferring causality. Bradford Hill H C Y 20313_blp_13-2 Sheet No. 44 Side A 06/23/2005 10:19:08 A 06/23/2005 44 Side Sheet No. 20313_blp_13-2 20313_blp_13-2 Sheet No. 44 Side B 06/23/2005 10:19:08 M K , , C Y 3 See See 43 NNOVATIONS PECIFIC &I t/pdf/1742-5573-1- S The Missed Lessons of Lessons The Missed n, and Causal Inference in n, and Causal The Case Against Differential Against The Case ERSPECTIVES Moreover, it can be shown Moreover, it can P usion of causality. In fact, it usion of causality. 42 t of Sir Karl Popper’s Philosophy t of Sir Karl Popper’s VALUATION OF ectives.com/conten E e evidence and reasoning behind behind reasoning e evidence and man ed., 1988). ed., man spilled over into the courts as well. the into over spilled TS I ETERANS V PIDEMIOLOGIC note 5. : The greater the exposure, the greater the greater the exposure, : The greater , 1 E Falsification, Verificatio supra supra : Multiple studies using different designs designs using different studies : Multiple (Kenneth J. Roth IETNAM IETNAM http://www.epi-persp 5/23/2005 7:48 PM : The outcome should be less frequent in the frequent in the should be less : The outcome , Medical Causation Testimony, and the Scientific Method , Medical Causation Testimony, and the V A sizable number of studies in occupational A sizable number JOURNAL OF LAW AND POLICY POLICY AND LAW OF JOURNAL OMMITTEE AND DOC 44 ,Goodman, Karen J. V. Phillips & Carl L. 85 (2004). 051905. NFERENCE Daubert VAO 1994, Bradford Hill I IOM C Consistency Dose-response available at Specificity Mervyn Susser, Mervyn Susser, See See, e.g. EALTH ACROED HE M 43 44 42 Applying the epidemiological principles discussed earlier in Applying the epidemiological the first Committee, case of non-Hodgkin’s lymphoma, In the 5. finding. the should confirm populations and/or different 6. of a response. the likelihood should be 7. of the exposure. or after removal absence of exposure Hill himself and criteria are not formal These considerations AUSAL C UTCOMES FOR ERTZ 37 J. H Sir Austin Epidemiology: Reconsiderations in the Ligh Reconsiderations Epidemiology: in cohorts had been conducted, and although many showed either no showed either although many cohorts had been conducted, and slight associations, quite a few association (RR=1.0) or very VI. T O th this article, this section reviews regard to non- with Committee the decisions reached by the Type II diabetes, prostate cancer, and the Hodgkin’s lymphoma, period for respiratory cancer. presumptive its review in 1994, concluded that the evidence which completed with herbicides or their an association was sufficient regarding contaminants. 580 as such, is although such misuse using them cautioned against scientific literature. often found in the these facets of an association does several of that failure to observe the concl from not necessarily detract truly required. is that only temporality has been argued H 3.pdf. These considerations have now 3.pdf. These considerations & Eric Joe G. Hollingsworth G. Lasker, Diagnosis: (2004), 20313_blp_13-2 Sheet No. 44 Side B 06/23/2005 10:19:08 B 06/23/2005 44 Side Sheet No. 20313_blp_13-2 20313_blp_13-2 Sheet No. 45 Side A 06/23/2005 10:19:08 46 , 18 , 256 ,83J. Also, 52 Malignant Malignant and in a erratum 208 (1980). 208 (1980). 581 581 51 167, 171 Tbl.5 e Use and Risk of Use and Risk e herbicide appliers appliers herbicide EALTH Canadian farmers Canadian farmers rophenol Exposure in a rophenol Canadian Male Farm 47 to these addition In .H 50 203 (1989). 203 (1989). NVTL AKARTIDNINGEN E 94 (1989). 94 EALTH Non-Hodgkin’s Lymphoma among Mortality Among Forest and Soil and Among Forest Mortality , 77 L , 77 &H Substances, in Particular Organic Organic in Particular Substances, EALTH and Italian farmers licensed to licensed to and Italian farmers T . 575, 579 Tbl.7 (1990). ements of Phenoxy Herbicides of Phenoxy ements ’ 256 1141 (1986), JAMA 49 RCHIVES .H Mortality Study of Study Mortality NV NST Malignant Lymphomasand Occupational I Agricultural Herbicid . 516 (1989); Lennart Hardell, Lennart (1989); . 516 ,E NVTL , 47 A ED E Cancer Risk in a Cohort of Licensed Pesticide Pesticide of Licensed a Cohort Risk in Cancer ORK Incidence Rates of and Soft-Tissue Incidence Lymphomas ANCER .M forest conservationists who worked for the worked for who forest conservationists C J. W L ND ’ 45 Cancer Incidence Following Chlo Following Cancer Incidence RCHIVES and Phenoxyacetates AT Tissue Sarcoma, Washington State forestry Washington 6/12/2005 2:54 PM . 362 (1991). 48 .J.I DOC R , 44 A , 44 NST I 401 (1987). , 82 J. N Shelia Hoar et al., et Shelia Hoar 051905. Michael C. Alavanja et Michael C. al., Alavanja Bodil Persson et al., Bodil Persson G. Corrao et al., G. Corrao Donald T. Wigle et al., James S. Woods & Polissar, James L. CANDINAVIAN CANDINAVIAN , 46 B ANCER See et al., Paolo Vineis et al., P. Lampi See See See See See 15 S C ACROED L M 50 51 52 46 47 48 49 45 ’ AT HEMOSPHERE ERTZ M K JAMA 3351 (1986). (1992). Lymphoma and Exposure to Chemical to Exposure and Lymphoma Chlorphenol Solvents, Sarcomas and Environmental Measur and Environmental Sarcomas Finland Southern in Community Conservationists State in Western Washington Farmworkers Herbicide-Exposed Phenoxy Users, Exposures studies of occupational exposures, non-Hodgkin’s lymphoma was lymphoma exposures, non-Hodgkin’s studies of occupational of Italian provinces in residents male increased among (RR=2.2, 95% CI=1.4 to 3.5), areas contaminated lymphoma. non-Hodgkin’s risk of elevated an showed studies to were exposed workers who of Swedish studies These included ORANGE OF AGENT HEALTH EFFECTS herbicides; phenoxy to 6.3); 95% CI=1.0 (RR=2.5, of Agriculture U.S. Department than twenty for more used herbicides Kansas who had in farmers 95% CI=1.9 to 19.5); days per year (RR=6.0, to 19.4); (RR=4.8, 95% CI=1.2 was contaminated in which the water supply Finnish community to 5.6). (RR=2.8, with a 95% CI=1.4 with chlorophenols non- examined, of the other health outcomes unlike many rate in Vietnam a higher was observed at Hodgkin’s lymphoma H 250 acres (RR=2.2, 95% than to more who applied pesticides CI=1.0 to 4.6); CI=1.2 to 2.5). 95% use pesticides (RR=1.8, C N Operators: Non-Hodgkin’s Lymphoma Mortality and Agricultural Practices in Practices and Agricultural Mortality Lymphoma Non-Hodgkin’s Operators: Saskatchewan Lymphoma and Soft- Lymphoma and C Y 20313_blp_13-2 Sheet No. 45 Side A 06/23/2005 10:19:08 A 06/23/2005 45 Side Sheet No. 20313_blp_13-2 20313_blp_13-2 Sheet No. 45 Side B 06/23/2005 10:19:08 M K . - C Y ED ON M ,N or Marine or Marine Thirty-Four- PIDEMIOLOGY 53 .J.E CCUPATIONAL M . 2495(1990). DMINISTRATION ED A (1987). M osed to 2,3,7,8-TCDD after osed to 2,3,7,8-TCDD , 129A S , 30 J. O ’ and RR=3.2 95% CI =1.4 95% CI =1.4 and RR=3.2 54 Ten-Year Mortality Study of Ten-Year Mortality the ETERANS NTERNAL V I ETERAN Cancer Morbidity in the Seveso Area, in the Seveso Cancer Morbidity nor the chemical production nor the chemical 56 ative Study Group, The Association of ative Study Group, The Association ., V IETNAM RCHIVES V note 12, at 216; Andreas Zober et al., Zober et al., note 12, at 216; Andreas 209 (1992). Proportionate Mortality Study of U.S. Army and Army Proportionate Mortality Study of U.S. of BASF Employees Exp ns of the Vietnam War , 150 A MONG A supra supra 5/23/2005 7:48 PM RESLIN ET AL B JOURNAL OF LAW AND POLICY POLICY AND LAW OF JOURNAL DOC Hodgkin’s Disease, Hodgkin’s Cancer, Cancer, Nasopharyngeal Nasal HEMOSPHERE YMPHOMA YMPHOMA 051905. Pier Alberto Bertazzi et al., Alberto Bertazzi Pier L experienced increased risks for non-Hodgkin’s experienced increased risks , 25C S ’ 57 ). ATRICIA P See et al., Fingerhut The Selected Cancers Cooper Patricia Breslin et al., 55 ACROED M 55 56 57 53 54 In total, more than two dozen studies showed some indication showed some than two dozen studies In total, more Neither the Seveso cohort ODGKIN ERTZ 412, 416 Tbl.6(1988). Year Mortality Follow-Up Selected Cancers with Service in the U.S. Military in Vietnam III, Centers for III, Centers Military in Vietnam the U.S. in with Service Selected Cancers Disease Control, 1976 in Incident Seveso in the Involved Population U.S. Marine Corps Vetera H workers 1187 (1989); Angela C. Pesatori et al., 1976-1986 582 review the As of population. general in the than veterans of non- an excess IOM Committee, by the first conducted several studies observed in cases had been lymphoma Hodgkin’s to 3.9), (RR =2.2, 95% CI=1.2 personnel of U.S. Navy CI=1.2 to 3.8 (RR=2.1, 95% personnel to 7.4 lymphoma. non-Hodgkin’s from incidence or of excess mortality there were were of the highest quality and studies Not all of these no excess risk, that is, no significant studies that showed some of the many expected level of risk. Although the departures from such adjusted for potential confounders, studies cited above association created the appearance of an have could variables have obscured an RR) or could estimated (increased the of the studies, the RR). In some (reduced the estimated association broad and probably included extremely exposure was definition of who were not exposed to any of a high proportion of individuals resulting in “information that were used in Vietnam, the herbicides the be easy to underestimate it would bias.” In such circumstances, be an expected of what might effect of an exposure. In light of across quite a number “downward” bias, the replication size was impressive. sample investigations that had an adequate H and Primary Liver Cancer and Primary Liver 20313_blp_13-2 Sheet No. 45 Side B 06/23/2005 10:19:08 B 06/23/2005 45 Side Sheet No. 20313_blp_13-2 20313_blp_13-2 Sheet No. 46 Side A 06/23/2005 10:19:08 : ELL ELL 1998 EALTH 2002, 2002, FFECTS RANGE IETNAM IETNAM EDICINE H E O V M 139 (1990); (1990); 139 PDATE 1996 (1996) (1996) 1996 7 C NSTITUTE OF PDATE 583 583 :U ,I EALTH GENT EDICINE OF THEEDICINE OF H A EALTH M PDATE EVIEW THE H FFECTS IN IN FFECTS R RANGE E L :U ’ NSTITUTE OF O ERBICIDES ,I NVT H EVIEW THE E RANGE Workers in Chemical Plant EALTH GENT 2000]; VAO 2000]; U R O H A ETERANS AND NSTITUTE OF ERBICIDES OMMITTEE TO TO OMMITTEE PDATE ,I ,V GENT H 59 A 959 (1991). 959 XPOSURE TO E Hexachlorodibenzo-p-dioxins, CCUPATIONAL EVIEWTHE OMMITTEE TO R 1998]; C 1998]; ETERANS AND .O CADEMIES ERBICIDES ANCET Long-Term Carcinogenesis Studies on 2,3,7,8- on Studies Carcinogenesis Long-Term A H ,V RCH XPOSURE TO 67 (1991). PDATE E .A ETERANS AND 1996]; C , 338 L ETERANS OF NST ,V V Cancer Mortality among ATIONAL 5/23/2005 7:48 PM CADEMIES PDATE However, the Committee noted that the the noted that Committee However, the N OMMITTEE TO A DOC , 62 I 58 XPOSURE TO , C OXICOLOGY E ETERANS OF T IETNAM CADEMIES V V 051905. James Huff et al., James A ATIONAL 2000 (2001) [hereinafterVAO U N See See, e.g. ACROED note 8. M IETNAM Type II diabetes and prostate cancer are both characterized as are both characterized Type II diabetes and prostate cancer 58 59 The conclusion of sufficient evidence drew on a set of studies drew on a set of studies of sufficient evidence The conclusion Biologic plausibility that Agent Orange was capable of that Agent Orange was Biologic plausibility V EDICINE OF THE ATIONAL PDATE ETERANS OF IOLOGY AND FFECTS IN ERTZ M K [hereinafter VAO U [hereinafter supra (1999) [hereinafter VAO U (1999) [hereinafter VAO N E M B V herbicides contained in Agent Orange, including 2,4-D, 2,4,5-T, in Agent Orange, including herbicides contained and been inadequately tested in cacodylic acid, had picloram, animals. could While not all studies consistency. that showed fair it was unlikely that all of exclude bias or confounding, definitively Moreover, in several direction. the studies were biased in the same or highest best-documented with the investigations, the groups Later greatest increase in risk. of exposure showed the probability risk for non-Hodgkin’s the findings of excess studies confirmed in yet other populations. lymphoma to 2,3,7,8- exposed heavily most were these groups As lymphoma. in Agent the herbicides no exposure to with little or TCDD, ORANGE OF AGENT HEALTH EFFECTS that the tended to suggest data the epidemiologic Orange, 2,4,5-T. However, to 2,4-D and likely due were more associations these the case that to make attempt did not the Committee causal agents. were the compounds a study that cancer was supported by type of producing this of after the administration mice in female produced lymphoma 2,3,7,8-TCDD. H U IN OF THE the 1953 Accident Contaminated with Dioxin Contaminated Alfred Manz et al., Manz Alfred tetrachlorodibenzo-p-dioxin and tetrachlorodibenzo-p-dioxin C Y 20313_blp_13-2 Sheet No. 46 Side A 06/23/2005 10:19:08 A 06/23/2005 46 Side Sheet No. 20313_blp_13-2 20313_blp_13-2 Sheet No. 46 Side B 06/23/2005 10:19:08 M K C Y . 270 IETNAM ED ]; Morris V OMMUNITY .M C OXICOLOGICAL -653vena/vena. NVTL IETNAM VETERAN e Expanded IARC e Expanded IARC Effects: A Mortality V 645 (Supp. 2 1998), 1998), 2 (Supp. 645 , 56 T &E S ORBIDITY OF ’ 252 Angela (1997); C. URVEY AND ,M S 98/Suppl-2/645 FFAIRS OMMONWEALTH STUDY USTRALIA ERSPECTIVE Evaluation of Diabetes Mellitus, Evaluation P A . 126 (1998); John Vena et al., Vena (1998); John . 126 lignant Health lignant Health ’A ETERANS CCUPATIONAL A flurry of papers appeared A flurry of papers ED V rbicide and Chlorophenol Production and Chlorophenol rbicide PIDEMIOLOGY 60 Insulin Resistance tic Mortality in th among United States Workers Exposed to Workers Exposed among United States EALTH .M Serum Dioxin and Diabetes Mellitus in and Serum Dioxin , 8 E Excess mortality from diabetes was Excess mortality from ETERANS , 56 O , 56 .H The Seveso Studies on Early and Long-Term Seveso Studies The IETNAM EALTH OF V 62 NVTL V H NVTL note 59, at 11. T OF &E ’ ALE EP (1998) [hereinafter C (1998) [hereinafter sulinemia and As a result, the As a result, which Committee, fourth D 1: M supra supra 61 , 106 , 106 E Study of Phenoxy He 5/23/2005 7:48 PM Exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is (TCDD) to 2,3,7,8-tetrachlorodibenzo-p-dioxin Exposure JOURNAL OF LAW AND POLICY POLICY AND LAW OF JOURNAL DOC TUDY OF THE 1998, , Geoffrey M. Calvert et al., M. Calvert , Geoffrey UTCOMES OLUME Dioxin Exposure and Non-Ma O CCUPATIONAL http://ehp.niehs.nih.gov/members/19 ,V 051905. Pier A. Bertazzi et al., Pier A. Bertazzi :AS 431, 433 (2000). 433 431, PDATE OMMONWEALTH See See, e.g. ACROED , 55 O M 62 61 VAO U ETERANS OMMUNITY OMPARISON CIENCES ERTZ Serum Glucose, and Thyroid Function and Thyroid Glucose, Serum 2,3,7,8-tetrachlorodibenzo-p-dioxin Pesatori et al., available at html; C V C C S 60 published its result in 2000, determined that the evidence was that the evidence in 2000, determined published its result with exposures incurred in suggestive of an association but limited, the because of to dioxin exposed Among residents Vietnam. diabetes occurred at a from industrial accident in Seveso, deaths population that was not exposed, higher rate than in the reference females. particularly among 584 Type For association. of an evidence “limited/suggestive” having the first the time at inadequate were considered data II diabetes, two (The first the evidence. evaluated three Committees of metabolic grouping the broader considered Committees largely as a whole, disorders been research had because little or in Vietnam used diabetes to the herbicides published relating the Nevertheless, their contaminants.) which third Committee, that a number of in Update 1998, noted published its findings showed one on the Ranch Hand personnel, reports, including The “Further Update reported, metabolism. altered glucose justify a may publication of existing studies analyses and full this conclusion.” reevaluation of with 2,3,7,8- association 2000 suggesting some between 1996 and TCDD (“dioxin”). H Workers and Sprayers Exposure to Dioxin and Nonneoplas and Exposure to Dioxin F. Cranmer et al., F. Cranmer Hyperin with Associated Study International Cohort (1999); Gary L. Henriksen et al., Henriksen L. (1999); Gary Veterans of Operation Ranch Hand Ranch Veterans of Operation 20313_blp_13-2 Sheet No. 46 Side B 06/23/2005 10:19:08 B 06/23/2005 46 Side Sheet No. 20313_blp_13-2 20313_blp_13-2 Sheet No. 47 Side A 06/23/2005 10:19:08 625 625 ANCER C L ’ AT 585 585 ERSPECTIVE P , 91 J. N Among Air Force Among Air Force EALTH 65 .H ns with Background Levels of NVTL Serum Dioxin Level in Relation to to in Relation Level Serum Dioxin note 60. its complications is the cause of is the cause of its complications , 106 E supra supra Cancer, Heart Disease, and Diabetes in Diabetes in and Heart Disease, Cancer, , note 60. http://ehp.niehs.nih.gov/members/1998/Suppl-2/ trachlorodibenzo-p-dioxin note 60. 44 (2000). supra supra although the excess was not statistically not statistically the excess was although 63 supra supra 5/23/2005 7:48 PM available at DOC Table 2 shows the risk ratios for men whose blood Table 2 shows the risk ratios for PIDEMIOLOGY 67 OMMONWEALTH STUDY Additionally, higher blood serum concentrations of concentrations serum higher blood Additionally, 051905. Kyle Steenland et al., Kyle Steenland Matthew P. Longnecker et al., P. Longnecker Matthew C Vena et al., Vena et al., Henriksen 66 64 , 11 E See See See See See ACROED M . 779, 785 (1999). 64 65 66 67 63 Typically, Type II diabetes is not fatal and is often not listed on fatal II diabetes is not Typically, Type ERTZ NST M K Exposure Diabetes Mellitus among Air Force Vetera I
death. For this reason, studies of mortality from diabetes would be diabetes from studies of mortality death. For this reason, By with exposures. to detect associations their ability in limited provide a more the living might diagnoses among comparison, on morbidity hence, studies cases, and of ascertainment complete such study, self- more definitive. In one would be considered than expected in were substantially higher reports of diabetes Vietnam. in served who Australian veterans an elevated incidence of Type 2,3,7,8-TCDD were associated with II diabetes. with quartiles as compared TCDD was in the three upper serum was in the lowest quartile. Thethose whose blood serum TCDD of increasing risk, but the upper data do not show a perfect trend two. to be at higher risk than the lower two quartiles seem of chemical cohort European a multinational in observed workers, production ORANGE OF AGENT HEALTH EFFECTS al., who by Steenland et was observed No excess significant. by assembled workers of chemical the U.S. cohort studied NIOSH. even if one of a death certificate, study, glucose participated in the “Ranch Hand” personnel who diabetes were for and use of oral medications abnormalities elevated. H 625-633bertazzi/bertazzi.html. 625-633bertazzi/bertazzi.html. (Supp. 2 1998), Effects of Dioxin Exposure: A Review Effects of Dioxin Exposure: Workers Exposed to 2,3,7,8-te to Exposed Workers C Y 20313_blp_13-2 Sheet No. 47 Side A 06/23/2005 10:19:08 A 06/23/2005 47 Side Sheet No. 20313_blp_13-2 20313_blp_13-2 Sheet No. 47 Side B 06/23/2005 10:19:08 M K C Y quartile th (highest) quartile 4 rd quartile 3 nd 2 note 60,431-33. at supra -- (0.5, 1.6) (1.1, 3.2) (1.0, 2.9) quartile st 5/23/2005 7:48 PM 1 (lowest ) JOURNAL OF LAW AND POLICY POLICY AND LAW OF JOURNAL DOC concentration of dioxin, in quartiles. in of dioxin, concentration In general, the conclusion that the data showed In general, the conclusion 051905. Cranmer et al., Cranmer 68 Ranch Hand personnel according to blood serum according to blood personnel Ranch Hand See Table 2: Incidence of Type II diabetes among Air Force among II diabetes Incidence of Type Table 2: ACROED M 68 A large number of studies have addressed the risk for prostate The confidence intervals (CIs) indicate that the data are (CIs) The confidence intervals ERTZ
limited/suggestive evidence of association was based on both the evidence of association was based limited/suggestive on the latter. The studies, with emphasis mortality and morbidity veterans occurred in Vietnam of these associations fact that some deliberations. Nevertheless, the Committee’s into also weighed illness, of the studies relied on self-reported because many fell far short of bias, the evidence therefore raising the possibility of being sufficient. Risk ratio* 95% confidence 1interval occupation history, age, race, and military *adjusted for family 0.9 increased risk rather small a between consistent with anywhere a fairly substantial one (a nearly (RR just slightly above 1.0) and study is notable in that the designation three-fold higher risk). This 1.9 not self-reporting. examination, of diabetes was based on a clinical hazardous residents near a among Additionally, a study conducted showed elevated risks for waste site with dioxin contamination 1.7 was TCDD concentration serum “high” fasting insulin if their elevated. 586 dioxin Serum concentration: H 20313_blp_13-2 Sheet No. 47 Side B 06/23/2005 10:19:08 B 06/23/2005 47 Side Sheet No. 20313_blp_13-2 20313_blp_13-2 Sheet No. 48 Side A 06/23/2005 10:19:08 , , 2 72 YPE T EDICINE M 587 587 In subsequent 71 XPOSURE AND E and a number of and a number NSTITUTE OF 70 IOXIN /D ce versus mortality. Mortality Mortality ce versus mortality. note 8. note 59; I Farmingand Prostate Cancer Mortality ERBICIDE supra supra supra supra :H 2002, 2000, 2000, note 56. RANGE 270 (1993). 270 O PDATE supra 5/23/2005 7:48 PM PDATE GENT DOC A , VAO U PIDEMIOLOGY 051905. VAO U Howard Morrison et al., et al., Morrison Howard Evaluation of this health outcome is difficult for several for several difficult is outcome of this health Evaluation (2000). 69 .J.E See, e.g. See Bertazzi et al., See ACROED M M 69 70 71 72 The Committee has, during updates of the reports, changed the has, during updates The Committee ETERANS AND IABETES ERTZ M K 137 A 137 V D
occupational cohort studies in which risk was increased, but not occupational cohort studies in which exposed population in Seveso significantly so. Additionally, the prostate cancer. showed an increased risk of studies trend continued as many reviews of the evidence, the while a few studies suggested produced slightly elevated risk ratios a stronger association. as For example, outcomes. of some of the health classification as having inadequate classified above, diabetes was first mentioned or suggestive as having limited evidence and then categorized by a separate an association at the 2000 Update and evidence of this question on its own. convened to address committee the Committee is possible that yet, it Although it has not happened outcome to be inadequate some could find the evidence regarding cancer. and second, among elderly men, common First, it is very reasons. ORANGE OF AGENT HEALTH EFFECTS is likely 1.2). This (approximately small the risk ratios are most of no single causes because multiple has when an outcome to occur factor of cases. Another a high proportion responsible for cause is of inciden question to consider is the by several but also tumor, of a the aggressiveness is influenced by and the treatment, of care, the the quality other factors, including these factors are In turn, disease was diagnosed. stage at which the and a patient’s variables as access to care affected by such increases the status. Thus, even if an exposure socioeconomic with not show an association prostate cancer, it may incidence of can intervene to prostate cancer because so much mortality from of the early disease. Some of occurrence after the alter survival a well- from came decision the Committee’s evidence used in or herbicide applicators, where conducted investigation of farmers risk, greater exposures conferred higher H C Y 20313_blp_13-2 Sheet No. 48 Side A 06/23/2005 10:19:08 A 06/23/2005 48 Side Sheet No. 20313_blp_13-2 20313_blp_13-2 Sheet No. 48 Side B 06/23/2005 10:19:08 M K C Y 75 This 74 , 47 J. This thirty-year This thirty-year orinated Dibenzo-p- orinated 73 scientific basis for this this scientific basis for Certain Herbicide Agents Herbicide Certain Fed. Reg. 29723-01 Fed. Reg. 9, (June ns of Operation Ranch Hand: 15- Hand: Ranch ns of Operation Thus, given the lack of pertinent pertinent of lack given the Thus, Elimination of Polychl Elimination of Occupationally Exposed Persons Occupationally Exposed 363, 377 (1996); Joel E. Michalek & Ram C. Michalek & Ram 377 (1996); Joel E. 363, e’s service in Vietnam. e’s service will risk continue to be increased? Most to be increased? will risk continue EALTH ends at 38 C.F.R. pt. 3). pt. at 38 C.F.R. .H 5/23/2005 7:48 PM JOURNAL OF LAW AND POLICY POLICY AND LAW OF JOURNAL DOC NVTL E 051905. Disease Associated with Exposure to with Associated Disease Dieter Flesch-Janys et al., Flesch-Janys Dieter Pharmacokinetics of TCDD in Vetera Pharmacokinetics See half to decrease to concentration it takes for the half-life is the time The See ACROED M 74 75 73 The fourth and final example of how the Committee has Committee of how the and final example The fourth OXICOLOGY ERTZ Tripathi, of what it was. 1994) (to be codified codified 1994) (to be (Multiple and Myeloma 59 Respiratory Cancers), TCDD half-life is estimated at between seven and nine years, but at between TCDD half-life is estimated individual of fat in the studied this period depends on the amount 588 if newer category or suggestive limited in the was that disease after that tendedwere conducted studies and no association to show ones. the earlier higher quality than were of the and cancer respiratory evidence concerns reviewed that respiratory cancer period.” The VA had ruled “presumptive within only if it manifested related service could be considered on thirty years following The Committee period.” to as the “presumptive period was referred there was a whether was asked to determine based on all of the empirical period. However, presumptive populations, veterans and other exposed Vietnam evidence from time of could not be answered. The analysis the question simply jobs suggested that in exposed of employment since the beginning continue for at least cancer might respiratory risk for the elevated begs the question, how long the third decade. But this analysis exposure after an cohorts among the mortality occupational studies had not analyzed cancer risk of respiratory whether excess of workers to determine For the Seveso cohort, an since exposure ended. changed with time the thirty-year evaluate to has elapsed insufficient period of time 1976, fewer than in occurred accident period (the presumptive thirty years prior to this writing). relied on toxicokinetic data data, the Committee epidemiologic are stored in the body and on of interest about how the chemicals cancer. Dioxin is of human the biology of understanding current tissues. half-life in human known to have a relatively long H T dioxins and Dibenzofurans in Dibenzofurans dioxins and 20313_blp_13-2 Sheet No. 48 Side B 06/23/2005 10:19:08 B 06/23/2005 48 Side Sheet No. 20313_blp_13-2 20313_blp_13-2 Sheet No. 49 Side A 06/23/2005 10:19:08 589 589 369, 376 (1999). (1999). 376 369, EALTH tumor, age of the person, and age of the person, tumor, .H NVTL E OXICOLOGY 5/23/2005 7:48 PM 76 DOC , 57 J. T 051905. The period between the start of a disease process and the time it isthe time process and disease the start of a between period The ACROED M 76 Cancer progresses through multiple stages, beginning with with beginning stages, multiple through Cancer progresses by biologic, diagnosis occurs is determined The point at which Given the above considerations, the Committee concluded that the Committee Given the above considerations, ERTZ M K diagnosed is termed the “latent period.” the “latent period.” diagnosed is termed
after external Hence, women. and men between differ may and circulates in in fatty tissue, remains ends, the compound exposure ORANGE OF AGENT HEALTH EFFECTS during organs. At any time in various and deposits itself the blood, external even though can occur disease induction this period, occur long detection may addition, disease has ceased. In exposure after induction. The at which a cell’s DNA is damaged. initiation, the time body’s repair the cell escapes the surveillance of then damaged hunts out damaged which usually system, immune and the system occur until the cell known as promotion, may cells. Other changes, Further unchecked, resulting in proliferation. begins to divide blood supply. to develop its own tumor stages enable the determinants psychologic factors. Biologic social, and individual of the the aggressiveness will include H influence conditions that might presence of other medical factors will include access to The social immunologic competence. and the skill and program, quality of any screening care, the that Individual characteristics the health provider. vigilance of process a diagnosis is made influence how early in the disease include the propensity to seek is highly medical care, which trust is related to the degree of variable in the population and of and the fear of a diagnosis profession, medical the in placed cancer. of period for a presumptive scientific justification there was no that circulating possibility The cancer. thirty years for respiratory of cancer decades after a the initiation result in TCDD might had ended could not be excluded. A veteran’s service in Vietnam length of the latency period further consideration was the uncertain process and the diagnosis. between the initiation of the disease Year Follow-Up C Y 20313_blp_13-2 Sheet No. 49 Side A 06/23/2005 10:19:08 A 06/23/2005 49 Side Sheet No. 20313_blp_13-2 20313_blp_13-2 Sheet No. 49 Side B 06/23/2005 10:19:08 M K C Y 6/6/2005 1:05 PM DOC . JOURNAL OF LAW AND POLICY POLICY AND LAW OF JOURNAL ORRECTED C ACROED M The IOM Committees were charged with determining whether whether determining charged with were Committees The IOM to it is important findings, the Committees’ In reviewing UMMARY ERTZ 590 S herbicides and between associations there were health outcomes IOM Committees The or their contaminants. Vietnam used in was a statistical questions: whether there addressed three what the exposures association between any health outcomes, and be expected risk Vietnam veterans would of increased magnitude herbicide due to of the health outcomes for each to experience and whether evidence while in Vietnam, exposures incurred association. To plausibility of a causal supported the biologic the outcomes the Committees classified question, answer the first or suggestive, of evidence (sufficient, limited into four categories and adopted an evidence of no association) inadequate, or limited and took into weighed the body of evidence approach that regard to With rigor of the studies. consideration the methodologic the risk to Vietnam quantifying the second question, that of could risk increased that the concluded Committee veterans, the the lack of adequate data quantifying the to due not be identified To address the third in Vietnam. exposures of those who served exists biologic mechanism question, that is, whether a plausible could cause their contaminants through which the herbicides and of wide range a evaluated the Committee specific health outcomes, and studies in humans data types, including toxicologic that use tissues and research on mechanisms animals, experimental and cell cultures. non-infectious by multiple diseases are caused most that remember causality is the effects of exposure, factors and that to determine only be measured in groups. defined in an individual, but can and, for ethical reasons, study groups therefore Epidemiologists methods. experimental than rather frequently rely on observational the depends on minimizing The quality of observational studies precision by using large sample four types of bias and maximizing cases of of exposed regard to the number sizes (particularly with part of evidence, and the disease). Statistical significance is a small use of p-values for causal inference can result in faulty evidence for conclusions. Single studies can add to or detract from H 20313_blp_13-2 Sheet No. 49 Side B 06/23/2005 10:19:08 B 06/23/2005 49 Side Sheet No. 20313_blp_13-2 20313_blp_13-2 Sheet No. 50 Side A 06/23/2005 10:19:08 591 591 5/23/2005 7:48 PM DOC 051905. ACROED M ERTZ M K on depends of causality an inference ultimately but causality, of effects estimates that provide precise across studies replication ORANGE OF AGENT HEALTH EFFECTS Accrual of epidemiologicfree of bias. are relatively and that and in animals studies experimental along with over time, evidence generally leads mechanisms, that establish cultures cell or tissue causes a health as to whether an exposure towards a consensus years or longer. The takes often although this process outcome, used in Vietnam andeffects of herbicides health evidence about partially because a accumulate, to was slow their contaminants beginning to study the veterans longitudinally, concerted effort was not States, the United to of their return the time from technologically difficult to was because it partially and undertaken, quantities. it is present in such small study dioxin, as H C Y 20313_blp_13-2 Sheet No. 50 Side A 06/23/2005 10:19:08 A 06/23/2005 50 Side Sheet No. 20313_blp_13-2