2 15 24 https://www.nal.usda.gov/exhibits/speccoll/files/original/e164bf97c6a64102fe32e9c7807bc2d0.pdf 1c4c5428b6284e286cea3ab8c325b281 PDF Text Text Item ID Number 01454 AUthOP Berger, Beverly Corporate Author Report/Article Title Typescript: Agent Orange Journal/Book Title °00° Year Month/Day Color 'J Number of Images 2 DBSCriptOD NotOS update on on-going Agent Orange studies Tuesday, May 15, 2001 Page 1454 of 1514 �C:\WRITE\WORDPERF\BERGER28,JUL AGENT ORANGE The AOWG was established in 1981 and is the overall coordinator, clearinghouse, and evaluator of the Federal research effort on health issues surrounding the use of Agent Orange (AO) during the Vietnam conflict. During FY'88 several important AO related events have taken place. The Science Panel of the AOWG issued a AO Status Report which was widely circulated and simultaneously implemented the Status Report as a "Living Document" residing on a VAX 780 DEC computer at the National Center for Toxicological Research. The status of any AO related project may be updated at any time via an electronic mail facility. The CDC's major effort on "The Vietnam Veterans Experience Study" was completed. One of the most revealing item from that study was that what was stated during the telephone interview was not always confirmed through the medical examination! {see item 1 and 4 below}. CDC summarized the study as follows: [1] Vietnam veterans were more likely to report health problems, yet few differences were detected on examination; [2] Vietnam veterans were found more likely to have hearing loss and certain deficiencies in semen quality; [3] Vietnam veterans were more likely to have psychological problems; and [4] Vietnam veterans reported more birth defects in their children, yet birth defect rates were not elevated based on objective evidence. The Air Force report on the second examination of the Ranch Hand personnel was released in November, 1987 (Air Force Health Study: An Epidemiologic Investigation of Health Effects in Air Force Personnel Following Exposure to Herbicides). This study was received with many accolades; it also negated many of the positive findings of the earlier 1984 examination. Unfortunately, a report of the 1984 findings by Dr. Richard A. Albanese entitled "United States Air Force Personnel and Exposure to Herbicide Orange" wasn't released until the Spring of 1988. Some individuals still do not understand that this is a much delayed release of the 1984 data and that the 1987 Ranch Hand reports negates most of the Albanese findings; several times it has been obvious that the 1988 Albanese report has been taken as the more current data base rather than the 1987 Ranch Hand report. This mistake is most unfortunate! The CDC's AO Exposure Study was cancelled after a great deal of time and effort had been expended in attempting to identify an exposed cohort. After rejecting all attempts at identifying a study population based on Vietnam military records alone due to valid scientific limitations, the CDC attempted to use a state-of-the-art GC/MS analytical technique that they had developed to measure the TCDD serum levels. The Validation Study found the following: (1) no association between TCDD serum levels and ANY indirect estimate of Agent Orange exposure in Vietnam; and [2] the median TCDD serum levels were 3.8 ppt in the Vietnam �veteran group (range of < 1 to 45 ppt) and 3.8 ppt in non-Vietnam veterans (range of < 1 to 15 ppt). However, the same CDC laboratory found the mean serum dioxin level in Ranch Hander's participating in the Air Force Health Study to be 49.4 ppt (range of 3.2 to 313 ppt) with a control group mean of 5.2 ppt (range of 2.0 to 21.3 ppt). Analyzing samples of stored serum from many Ranch Handers obtained over 5 years ago and comparing them with current serum samples from the same individual for TCDD levels, a serum TCDD half-life was able to be calculated of approximately 7 years. This half-life information coupled with the low TCDD serum levels found in the CDC Validation study provided the necessary information to conclude that an AO exposed Vietnam cohort could not be identified even using state-of-the-art techniques and that the AO Exposure Study could not be validly conducted. Prepared for: Dr. Beverly Berger Office of Science Technology Policy New Executive Office Building Room 5005 Washington, D.C. 20500 FTS 395-3902 � Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Alvin L. Young Collection on Agent Orange Description An account of the resource <p style="margin-top: -1em; line-height: 1.2em;">The Alvin L. Young Collection on Agent Orange comprises 120 linear feet and spans the late 1800s to 2005; however, the bulk of the coverage is from the 1960s to the 1980s and there are many undated items. The collection was donated to Special Collections of the National Agricultural Library in 1985 by Dr. Alvin L. Young (1942- ). Dr. Young developed the collection as he conducted extensive research on the military defoliant Agent Orange. The collection is in good condition and includes letters, memoranda, books, reports, press releases, journal and newspaper clippings, field logs and notebooks, newsletters, maps, booklets and pamphlets, photographs, memorabilia, and audiotapes of an interview with Dr. Young.</p> <p>For more about this collection, <a href="/exhibits/speccoll/exhibits/show/alvin-l--young-collection-on-a">view the Agent Orange Exhibit.</a></p> Text A resource consisting primarily of words for reading. Examples include books, letters, dissertations, poems, newspapers, articles, archives of mailing lists. Note that facsimiles or images of texts are still of the genre Text. Box The box containing the original item. 055 Folder The folder containing the original item. 1454 Series The series number of the original item. Series III Subseries II Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Creator An entity primarily responsible for making the resource Berger, Beverly Title A name given to the resource Typescript: Agent Orange Subject The topic of the resource AOWG CDC Air Force Health Study dioxin ao_seriesIII Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Alvin L. Young Collection on Agent Orange Description An account of the resource <p style="margin-top: -1em; line-height: 1.2em;">The Alvin L. Young Collection on Agent Orange comprises 120 linear feet and spans the late 1800s to 2005; however, the bulk of the coverage is from the 1960s to the 1980s and there are many undated items. The collection was donated to Special Collections of the National Agricultural Library in 1985 by Dr. Alvin L. Young (1942- ). Dr. Young developed the collection as he conducted extensive research on the military defoliant Agent Orange. The collection is in good condition and includes letters, memoranda, books, reports, press releases, journal and newspaper clippings, field logs and notebooks, newsletters, maps, booklets and pamphlets, photographs, memorabilia, and audiotapes of an interview with Dr. Young.</p> <p>For more about this collection, <a href="/exhibits/speccoll/exhibits/show/alvin-l--young-collection-on-a">view the Agent Orange Exhibit.</a></p> Text A resource consisting primarily of words for reading. Examples include books, letters, dissertations, poems, newspapers, articles, archives of mailing lists. Note that facsimiles or images of texts are still of the genre Text. Box The box containing the original item. 054 Folder The folder containing the original item. 1444 Series The series number of the original item. Series III Subseries II Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Creator An entity primarily responsible for making the resource Gough, Michael Source A related resource from which the described resource is derived Issues in Science and Technology Date A point or period of time associated with an event in the lifecycle of the resource 1987 Title A name given to the resource Environmental Epidemiology: Separating Politics and Science Subject The topic of the resource Agent Orange controversy AOWG CDC ao_seriesIII https://www.nal.usda.gov/exhibits/speccoll/files/original/8ce959abd4c29a8ef2aec37f5b90b5bb.pdf b8995078e6335274beb56006cba345d7 PDF Text Text Item ID Number 01430 Author Corporate Author RODOrt/ArtiClO Titlfl Typescript: Agent Orange Project Update Summary, December 4,1986 Journal/Book Title Year 000 ° Month/Day Color Number of ImaDos DOSCrlptOD Notes D 11 Lists ongoing health studies and projects from various agencies. Tuesday, May 15, 2001 Page 1430 of 1514 �AGENT ORANGE PROJECT UPDATE SUMMARY December 4, 1986 Information was taken from two sources: The Domestic Policy Council » Agent Orange Working Group* Status Report, October » 1985 Collection of Research Projects on Dioxins* Number 160, A report of the NATO/CCNS pilot study on International Information Exchange on Dioxins, Spring 1986. (obtained from Dr. Donald Barnes* EPA) Total number of projects identified = 245 Number listed as Complete = Number listed as Ongoing 87 = 158 Source Informations AO Status Report = NATO Report = 47 both reports = 4 Number of projects by Agency: Total Complete Ongoing CDC 11 a 9 DHHS 3 1 2. DoD 22 7 15 EPA 68 25 43 NCI 7 a 5 NIEHS 83 40 43 NIOSH 8 2 6 USDA 8 5 3 35 3 32 VA �Agent Orange Project List (AQ1) 11/27/86 ACC. NO. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 25 37 38 39 40 41 42 43 44 45 46 47 48 49 50 CDC CDC CDC CDC CDC CDC CDC CDC CDC CDC CDC DHHS DHH5 DHHS DoO DoD DoO DoD DoO DoD DoD DoD DoO DoD OoO DoD DoD DoD DoD DoD DoD DoD OoD DoD DoD DoD EPA EPA EPA EPA EPA EPA EPA EPA EPA EPA EPA EPA EPA EPA Conent Title Agency Agent Orange Study Birth defects and iilitary service in Vietnam study Published Aug 1984 Oevelopient of lab lethods for TCDD analysis of huian adipose tissues and bio Epideiiologic study of ground troops exposed lu <ujent orange during the Vietn Measurement of 2,3,7,8-TCDD in adipose tissue in populations in Hissouri National dioxin study Selected cancers study Study for body burden for dioxin in the general population Study of the distribution of 2,3,7,8-TCDD and related compounds in the huian Synthesis of polychlorinated dibenzo-p-dioxins and polychlorinated dibenzofur Vietnam Experience Study Detailed current literature reviews with published reports on the state of sc Measurement of TCOD levels in adipose tissue froi potentially exposed persons Reproductive outcomes in persons possibly exposed to 2,3,7,8 RDP 2,3,7,8-TCDD induced iuunosuppression ? Dioxin workers API Sarcota Study Air Force Ranch Hand Study Air Force soil tapping and groundwater survey at herbicide orange sites Anted Forces Institute of Pathology Agent Orange registry of Vietnai veteran CDC selected cancers Degradation of chlorinated xenobiotic compounds by anaerobes Dioxin plan for monitoring Johnston Atoll Environmental cheiistry of herbicide Orange AO 85 - NATO - Daniel HcGee, C NATO - Larry Needhai, CDC, Atl NATO - Larry Needhai, CDC, Atl NATO - Larry Needhai, CDC, Atl NATO - Larry L. Needhai, CDC Why both completed and ongoing _ ES8 ESG NATO - Ken Uade, EGtG Inc, Ida ES8 NATO - Lt Rhodes, Tyndall AFB, NATO - Linda Anderson, CDC, At NATO - Capt Stoddart, Tyndall Environmental cheiistry of herbicide orange and TCOD Epideiiologic investigation of health effects in Air Force personnel followin Fate of TCOD, 2,4-0 and 2,4,5-T at selected locations contaiinated with herbi Herbicide Orange -1U- treatment and environiental lonitoring Herbicide Orange soil tapping and groundwater survey Mechanism of cellular teibrane effects of TCDD Residual levels of 2,3,7,8-TCDD near herbicide Orange storage and loading are Services herbs tapes Site deionstration of full-scale rotary kiln incinerator (transportable) Site demonstrations: environmental restoration technologies VA chloracne VA Soft Tissue Sarcota Analysis of background levels of TCOD in the US environment Analysis of environmental samples for PCDDs and PCDFs Analytical lethods development of monoclonal antibodies Assess of PCS transformer /cap fires Assessment of exposure to TCDD from contaminated media Assessment of methods used for analysis of human adipose tissue Assessment of PCS transformer/capacitor fires Bacterial decomposition of TCDD Baseline in 1983 NATO - HQ AFESC/RDV, Tyndali A NATO - Haj Toi Doane, Brooks A NATO - Lt Rhodes, Tyndall AFB, NATO.- Capt Stoddart, Tyndall ESS NATO - Capt Terry Stoddart, Ty NATO - Capt Stoddart, Tyndall ESG Environiental Support Group NATO - Paul des Rosiers, EPA, Beef fat phase II Behavior of TCDD in blood Bioavailability of TCDD from contaiinated soils Unavailability to aniials Biodeg and carbon adsorption of TCDD Causal structure activity methods applied to the assessient of the toxicity o NATO - Huhae! Gallo, U New Jt NATO - P. Politzer, U New Orle �EPA EPA EPA EPA EPA EPA EPA EPA EPA EPA EPA EPA EPA EPA EPA EPA EPA EPA EPA EPA EPA EPa EPA EPA EFA EPA EPA EPA EPA EPA EPA EPA EPA EPA EPA EPA EPA EPA EPA EPA EPA EPA EPA EPA EPA EPA EPA EPA EPA EPA EPA EPA EPA EPA NCI NCI NCI NCI Clearance of TCDD from dose organists Development of lass spectrometric and fourier transform infrared spectroscopi Dioxin bioavailability - food chain Dioxin photolysis: Soil surfaces Embryotoxicity and pharmacokinetics fo dioxin in Harmosets and monkeys Evaluation municipal waste combustors NATO- Wayne Sovocool, EPA, La NATO - Phillip Cook, EPA, Dulu NATO - Glenn Miller, U Nevada, NATO - Diether Neubert, Berlin 1st table ongoing; 2nd table c Evaluation of combustion sources Evaluation of large scale combustion sources 1st table ongoing; 2nd table c Evaluation of TCOD destruction technologies Evaluation of the EPA mobile incineration system for dioxin-contaminated liqu NATO - Frank Freestone, EPA, E Evaluation of the white rot fungus, Phanerochaete chrososporium, for biodegra NATO - Pat Sferra, EPA, Cincin Exposure assessment methods for 2,3,7,8-TCDD and other dioxins NATO - John Schaum, EPA, Uashi Feasibility of utilizing mines as respositories for dioxin-contaminated soils NATO - Pat Esposito, PEI Assoc Field test of KOH/PE6 reagent to destroy 2,3,7,8-TCDD at a military site NATO - Charles Rogers, EPA, Ci Half-life of chemicals in soil NATO - Charles Nauman, EPA, Ua Health assessment of PCDFs Health assessment of PCOOs Herbicide Orange incinerator studies NATO - Capt Stoddart, Tyndall In-situ stabilization techniques for dioxiin-contaminated soils NATO.- Don Sanning, EPA, Cinci Invest, of in situ stabil. technology Investigation of bioavailability to fresh water fish of TCDDs in fly ash 2nd table indicated study to b LA crayfish/catfish study Methods analys. envir. of TCDD by (lass Spect. Methods for assessing exposure to dioxin related compounds other than 2,3,7,8 NATO - Les Ungers, PEI Assoc., Microb. dissia. of 2,3,7,8-TCDD Mississippi catfish study Movement of TCDD in the environment Annual reports ; Nebraska stud National pesticide monitoring project of human adipose tissue Northwest human milk study Oregon monkey study Performance of RCRA Method 8280 for the analysis of dibenzodioxins and dibenz Pharmacokinetics of 2,3,7,8-TCDD in monkeys Photochemistry Plant uptake and metabolism of polychlorinated dibenzodioxin isomers Plant uptake of dioxin Potential for 2,3,7,8-TCDD transport in soils using both static and dynamic s Preparation of dioxin analytical reference standards for lab analysis of huma Quality assur. support Region I deer and elk study Report of assessment of a field investigation of six-year spontaneous abortio Risk assessment approach for 2,3,7,8-TCDD and other dioxins Round robin survey-methods dioxin analysis in adipose Shallow mines as repositories for dioxin-contaminated soils Short-term bioassays for polychlorinated dibenzo-p-dioxins Sorption/desorption characteristics of 2,3,7,8-TCDD in contaminated soils TCDD vapor-phase photolysis Uptake of 2,3,7,8-tetrachlorodibenzo-p-dioxin by dairy cows Uptake of dioxins by plants and large animals Uptake of dioxins by fish UV photolysis/alkali polyethylene glycolates for the chemical detoxification UV photolysis/KPE6 chemical destruction of chlorinated dioxins and dibenzofur Vapor pressure and partitioning behavior of 2,3,7,8-substituted dioxins and f Wisconsin monkey study yorkshop report on bioavailability Case control study of lymphoaa and soft tissue sarcoma Case-control study of soft tissue sarcomas and lymphomas and their relationsh Control study of lymphoma and soft tissue sarcoma Lung cancer - structural pest control workers NATO - John Ballard, Lockheed NATO - Margaret Chu, EPA, Uash NATO NATO NATO NATO - Johne Coates, Midwest R Craig HcFarlane, EPA, C Richard Walters, U Mary Edward J. Kantor, EPA, Published NATO - Charles Ris, EPA, Uashi NATO NATO NATO NATO NATO - Janet Houthoofd, EPA, C - Richard Phillips, EPA, - Michael Roulier, EPA, C - John Schaum, EPA, Uashi - D.H. Jones, Texas AIM NATO - Charles Rogers, EPA, Ci NATO - R.L. Peterson, 6alson R NATO - Gregory Kew, EPA, Uashi �109 110 111 112 113 114 115 116 117 118 119 120 121 122 124 125 126 127 128 129 130 131 132 133 134 135 136 137 138 139 140 141 142 143 144 145 146 147 148 149 150 151 152 153 154 155 156 157 158 159 160 161 162 163 164 165 NCI NCI NCI NIEHS NIEHS NIEHS NIEHS NIEHS NIEHS NIEHS NIEHS NIEHS NIEHS NIEHS NIEHS NIEHS NIEHS NIEHS NIEHS NIEHS NIEHS NIEHS NIEHS NIEHS NIEHS NIEHS NIEHS NIEHS NIEHS NIEHS NIEHS NIEHS NIEHS NIEHS NIEHS NIEHS NIEHS NIEHS NIEHS NIEHS NIEHS NIEHS NIEHS NIEHS NIEHS NIEHS NIEHS NIEHS NIEHS NIEHS NIEHS NIEHS NIEHS NIEHS NIEHS NIEHS NIEHS NCI pesticide workers Study of lortality aiong pesticide applicators frot Florida Study of soft tissue sarcotas and non-Hodgkins lytphota in thirteen counties 1,2,4,6,8,9-Hexachlorodibenzofuran disposition 2,3,7,8-TCDD disposistion in rats, lice, and guinea pigs 2,3,7,8-tetrachlorodibenzofuran disposition in rats, tice, guinea pigs 2,4,5-T : Salionella 2,4,5-T cytogenetics 2,4,5-T Drosophilia 2,4,5-T N-butyl ester: salionella 2,4-0 : Salionella 2,4-0 cytogenetics 2,4-0 ditethylatine salt: Salionella 2,4-D Drosophilia 2,4-0 N-butyl esters salionella 2,7-Dichlorodibenzo-p-dioxin: salionella Alter, of cell-surface leibrane for DI Toxkity Arachidonate products in dioxin and PCB toxicity Atonic mission spectroscopy for dioxin trace analysis Bioassay of a lixture of 1,2,3,6,7,8- ? and a tixture of 1,2,3,6,7,8-hexachlo Bioassay of octachlorodibenzo-p-dioxin Bioassay of tetrachloro-dibenzo-p-dioxin Bioavailability of TCDD (rat) denial and oral Carcinogenesis bioassay of 2,3,7,8-tetrachlorodibenzo-p-dioxin in Sviss Uebst Carcinogenesis boassay of 2,3,7,8-tetrachlorodibenzo-p-dioxin in Qsborne-Hend Cotparative species evaluation of cheiical disposition and letabolisi of 2,3, Control of gene expression by dioxin DED-UEEO,LV-69: Salmonella Oi-Epith cell interaction, lechanisi and assay Dibenzofuran: cytogenetics Dibenzofuran: Salionella Dioxin - atoiic emission spectroietry for dioxin trace analysis (detection) Oioxin - toxic halogenated wastes: in vitro bioassay developient . Dioxin chlorinated dibenzo-p-dioxins; lechanisis of toxicity Dioxin environmental pollutants and toxicology of the liver Dioxin environnental health sciences center grant clinical studies Oioxin lechanisi(s) for toxicity of chlorinated dibenxodioxins (toxicology) Dioxin tolecular toxicology of TCDD Dioxin NHR study Dioxin xenobiotic induction of pleiotropic responses in liver Disposition of TCDD fetal distribution in nice Effects of Agent Orange components on lale fertility and reproduction Effects on intestinal cells Effects on intestinal cells UNC-CU grad student Effects on nutrient assiiilation Environiental health science center grant Establishient and laintenance of an international register of persons exposed Hexacholor dibenzo dioxin disposition laiunosuppression by in utero exposure Implications of low level exposure of dioxins Intl res/exposure to phenaxy acid herbicides Lipid assimilation NRSA Lipid assiiilation NRSA Matrix effect and sub parts-per-billion quantitative analysis of TCDD by lass Mechanist of iuunosuppression Mechanists of dioxin toxicity Mechanists of toxicity of the chlorinated-p-dioxins Publication in press Disposition studies cotpleted Disposition studies cotpleted Is the title wrong of what? Uhat is NRSA ? What is NRSA? 1st Table ongoing; 2nd table c �166 167 168 169 170 171 172 173 174 175 176 177 178 173 180 181 182 183 184 185 186 187 188 189 190 191 192 193 194 195 196 197 199 199 200 201 202 203 204 205 206 207 208 209 210 211 212 213 214 215 216 217 218 219 220 221 222 NIEHS NIEHS NIEHS NIEHS NIEHS NIEHS NIEHS NIEHS NIEHS NIEHS NIEHS NIEHS NIEHS NIEHS NIEHS NIEHS NIEHS NIEHS NIEHS NIEHS NIEHS NIEHS NIEHS NIEHS NIEHS NIEHS NIEHS NIEHS NIEHS NIOSH NIOSH NIOSH NIOSH NIOSH NIOSH NIOSH NIOSH USDA USDA USDA USDA USDA USDA USDA USDA VA VA VA VA VA VA VA VA VA VA VA VA ! Membrane / LP receptor NRSA ! Membrane / LP receptor NRSA . ! Methods for the measurement of dioxins and furans in human adipose tissue Uhat is NRSA? ! Molecular basis of dioxin toxicity Theoretical biochemical study 1st table ongoing; 2nd table c ! I ! I Molecular modeling of dioxin binding proteins Molecular, biochemical actions of chlorinated-p-dioxins Mutagenicity studies of TCDD, 2,4-0, 2,4,5-T and esters of 2,4-D and 2,4,5-T Neurotoxicity of 2,4-0 in rodents Occupational & environmental health center grant ! Occupational and environmental health center grant (toxicology) Pentachlor & Dioxin contam. in PCP Pest, i Trans, across bil. lip. mem. Pesticides and transport across bilayer lipid membranes (toxicology) Pre-dioxin in PCP biochemistry, effect, and toxicity Quantitative analysis of TCDD by mass spectroscopy Research toward understanding the molecular level mechanisms of toxicity of T Role of TCDD receptor in tumor promotion How can it be marked complete Structure-toxicity relationships Would like to see this report! Studies of the chemical disposition and metabolism of octachlorodibenzodioxin Synthesis of 6 chlorodibenzo-p-dioxins Synthesis of selected chlorinated dibenzo-p-dioxins and related compounds as TCDD effects on steroid hormone synthesis Teratogenicity of TCDD - Cleft palata induction (mice) Theoretical modeling of dioxin receptor Toxic actions of tetrachloroazobenzene dioxins Toxic and anorectic effects of TCDD Toxic his wst in vitro bioassay development Toxicant Ceres Endocrine Heme Biosynthesis Xenobiotic induction of pleiotropic responses in liver Health hazard evaluation and technical assistance involving PCBs, dioxins, et Investigation of leukemia cluster in Madison County, Kentucky allegedly assoc NIOSH dioxin registry and cohort mortality study NIOSH dioxin registry, morbidity and reproductive outcome study . NIOSH industrial morabidity study NJ/Missouri plant worker and worker's spouse reproductive outcom'e study Soft tissue sarcoma investigation Study of persistent health effects in chemical herbicide workers and in commu A case control study of the relationship between exposure to 2,4-D and sponta Biological and economic assessment of 2,4,5-T and Si hex Exposure measurements of mixers, loaders and applicators of 2.4-0 on wheat Exposure of forest workers to ground applications of 2,4-D Photolysis of 2,4,5-T Survey of phenoxy herbicide use by agricultural commodity Survey of phenoxy herbicide literature TCDD residue monitoring in deer A review of the soft tissue sarcoma cases in patient treatment file for Vietn AFIP case control study of soft tissue sarcoma Agent Orange register review Behavioral toxicity of an Agent Orange component 2,4-D Case control study of lymohoma Chronic effects of herbicide exposure on testicular function in Vietnam veter Cohort mortality study of Vietnam veterans Effect of TCDD on lipid metabolism Effects of 2,3,7,3-tetradiiorodibenzodioxins on hepatobiliary function in ani Effects of Agent Orange on sleep Effects of low dose TCDD on nammalian chromosomes and liver cells Fat tissue analysis for 2,3,7,8-TCDD (San Antonio) NATO - Jay Bainbridge, NIOSH, Published NTIS 1984 AQ 85 - 1st table completed it Published Scan J Uork Environ NATO - Marie Haring Sweeney, N 1st table has project ongoing; Annual bibliographies publish* Report in preparation AO 85 -> 1st table end date of Perhaps completed in 1984? Perhaps completed in 1993? End in 86 or 89? End in 86 or 89? End in 86 or 89? �223 224 225 226 227 228 229 230 231 232 233 234 235 236 237 238 239 240 241 242 243 244 245 VA VA VA VA VA VA VA VA VA VA VA VA VA VA VA VA VA VA VA VA VA VA VA Fat tissue analysis for 2,'3,7,8-TCDD (Dallas) Fetale veteran survey Mechanist of porphyria caused by TCDD and related cheiicals Mechanist of TCDD absorption and toxicity on lipid and lipoprotein tetabolist Mechanists of dioxin induced toxicity using the chloracne aodel - Phase II Mechanists of dioxin induced toxicity using the chloracne todel - Phase I End in 86 or 89? End in 86 or 89? End in 86 or 89 ? Publication in press End in 86 or 89? Hetabolist of the herbicides present in Agent Qrange and Agent White Monographs Neurotuscular toxicity of Agent Orange End in 86 or 89? PTF/Vietnat; service indicator Retrospective study of dioxins and furans in adipose tissue of Vietnat era ve AO 85 -> 1st table pending to Review of literature on herbicides, including phenoxy herbicides and associat Published in 1981; annual upda Review of soft tissue Sarcota study in patient treattent file, Agent Orange registry exatinations Survey of patient treattent file for Vietnat veteran in-patient care Initial 1983 survey TCDD exposed rhesus tonkeys: effects on behavior and stress hortones End in 86 or 89? TCDD in body fat of Vietnat veterans and other ten Published Uptake and tetabolist studies and phamacology and toxicology Urinary 6-hydroxy cortisol: physiological and phartacologk studies (includin Perhaps cotpleted in 1982? VA patient treatment file uview VA/EPA adipose tissue study Vietnat veteran identical twin studies Under review by OTA I AOUS - W Vietnat veteran tortality studies AO 85 -> 1st table end date of �CABINET COUNCIL ON DOMESTIC POLICY AGENT ORANGE WORKING GROUP FEDERALLY SPONSORED HUMAN STUDIES RELATED TO AGENT ORANGE TYPE OF STUDY AGENCY STUDY TITIE Mortality Morbidity Cancer Reproduct Jon Analytical STATUS Completed Estimated Ongoing Completion Date DEPARTMENT OF HEALTH AND HUMAN SERVICES Published NTIS 1984 NIOSli Investigation of Leukemia Cluster in Madison County, Kentucky Allegedly Associated with Pentachlorophenol Treated Aimun it ion Boxes NIOSli Dioxin Registry X NIOSli Soft Tissue Investigation X NIOSH NJ/Missouri plant worker and worker's spouse reproductive outcome study Reproductive outcomes in persons possibly exposed to 2,3,7,8 RDP Measurement of TCDD levels in udipoue tissue from potentially exposed persons in Missouri. Published Scan. J. Work EnvIron Health 1985 X (begins 1985) �TAIil.K I: The K I even M a j o r Kp idemi ol ogi ca 1 S t u d i e s of t l . S . V i e t n a m V e t e r a n s , Agent Orange'am) TCHIJ exposure, dii.l V i e t n a m K x p e i i eiu-'c- C u r r e n t l y Ongoing or Completed i it L i t e U n i t e d S t a l e s ( C o n t i n u e d ) . Responsible * Federal Aqency Ti t ic Tyj>e of Study Total Study E£?CiJi3 Complet ion Vietnam Experience E p i d e m i o l o g i c Study Centers for Disease Control, A t l a n t a Oeorgi a Matched Cohort Morbidity Study o f V i e t n a m and non-Vietnam Veterans 12,000 1987 VA/AFIP Soft Tissue Sarcoma Study Veterans A d m i n i s t r a t i o n Agent Orange Projects Office, W a s h i n g t o n , D.C. Case-Control Study of Soft Tissue Sarcoma 250 cases 750 controls Late Nlo:;il n i o x i n Kcrjiutry N a t i o n a l I n s t i t u t e for Occupational Safety and Health, C i n c i n n a t i . Ohio M o r t a l i t y Study of Workers at 12 Production Sites Where D i o x i n C o n t a i n i n g Products Were M a n u f a c t u r e d 6.0OO 1986 NIOSII I n d i i B t r i a l M o r b i d i ty Study N a t i o n a l I n s t i t u t e for Occupational Safety and Health, C i n c i n n a t i , Ohio M o r b i d i t y Study of Workers at 2 Production Sites Where D i o x i n Containing Products Were Manufactured and a Comparison Group 600 1988 NCI Kansas Soft Tissue Sarcoma Study N a t i o n a l Cancer I n s t i t u t e , IJethesda, M a r y l a n d Case-Control of Soft T i s s u e Sarcoma 1OO cases 3()O controls 1986 1986 �*ALTH MO rtUMN SBVICES/WEHS LAS/LITERATURE STUDIES TYPE OF STUDY STUDY EFFORT Aim smmneaH. ANALYTICAL LITERATURE • STATUS cwtira CUMINS STUDY TQTAc I 1991-97 rji?. 3F TCDO CLFT. PAL. Mfl!£?QSITOF TWO FTL. [J| OIST. IN DICE 10.000 "E-9IOX. IN PCP .. £F.. 4 TOI 1990-1992 I 4. OF 3 CHLflR OlSaZO-MHOl / I 199M89i "44,000 1992 4«C. EH. SPCT, FSR I'OISIIM TR. ANLYS. 172.000 61.000 !99!-!«SS i:0.000 l°90 l-JLs i? TOO *£•:•?• (I 0 I ijgj»i5S3 i'X'.'JOO I 1995-1-97 ««6.000 J 1993-1997 :00) :.'0 I «ORfl 1994-1"! lIO.OOO CTIC £?F--:TS OF TCCD9 / >* « 'SisAHlilS OF 2F riT-ACHLQRO-i)I8ENZOtoao aP-8I3l!.1 j . OF TC2D "iBtflASSjrt". r 4 <C HLS «ST IN TntCReTICAL iflLS OF REEPT3R OF T3HCITY 1983-1*34 ::.yoo 1 H I �- 131 - FORMAT FOR CCMS PILOT PROJECT ON INTERNATIONAL INFORMATION EXCHANGE ON OIOXINS AND RELATED COMPOUNDS WORKING GROUP: A COUNTRY OF ORIGIN: USA TITLE OF PROJECT OR ACTIVITY: VA/AFIP Soft Tissue Sarcoma Study NAME AND ADDRESS OF PRINCIPAL INVESTIGATOR: (INCLUDING TELEPHONE NUMBER) (202)-576-0366 NAME AND ADDRESS OF SUPPORTING AGENCY: (INCLUDING TELEPHONE NUMBER) Han K. Kang, Dr. P. H. Veterans Administration Office of Environmental Epidemiology AFIP Washington, D.C. 20306-6000 ^ Washington, D.C. 20420 (202)-389-3432 or 3886 Veterans Administration Agent Orange Projects Office (10X2) 810 Vermont Avenue, N.W. ? 8 83 STARTING DATE V / IDENTIFYING NUMBER: COMPLETION DATE: 6 30 8f / / GOAL/RATIONALE/SCOPE To determine the relationship of Vietnam service, probable Agent Orange exposure and other factors to the risk of developing soft tissue sarcoma. The study is being conducted in two phases. Phase I will'investigate whether service in Vietnam during 1965-71 increased the risk of developing STS. The histopathology and anatomic site of STS will be compared among Vietnam veterans. Phase II will investigate other host and environmental risk factors for the development of STS.. Information on environmental risk factors will be obtained by interviews and individual analysis. ESTIMATED RESOURCES (IN UNITED STATES DOLLARS TO NEAREST $1,000,) FUNDING * 182,000 1887 1966 1968 YEAR * 73,000 » MAJOR OUTPUTS: (e.g.. technical reports, other publications, patents) A technical report will be prepared and a manuscript will be submitted to a scientific journal for publication. tf other countries are interested, would it be possible to augment your present project? I I YES I X I NO Do you have access to a computer network? Network Name NIH DCRT r Host Name YES NO User Name �AGENT ORANGE PROJECT UPDATE AGENCY: VA DATE: Dec 4, 1986 TITLE: VA/AFIP Soft Tissue Sarcoma Study PRINCIPAL INVESTIGATOR: Han K. Kang, PhD DIVISION/DEPARTMENT: ADDRESS: Office of Environmental Epidemiology AFIP, Veterans Administration TELEPHONE NUMBER: Washington, D.C. 20306-6000 202/576-0366 PROJECT IDENTIFICATION NUMBER: TEST CHEMICAL: OBJECTIVE: To determine the relationship of Vietnam service, probable Agent Orange exposure and other factors to the risk of developing soft tissue sarcoma. EXECUTIVE SUMMARY: APPROACH: The study is being conducted in two phases. Phase I will investigate whether service in Vietnam during 1965-71 increased the risk of developing STS. The histopathology and anatomic site of STS w i l l be compared among Vietnam veterans. Phase II will investigate other host and environmental risk factors for the development of STS. Information on environmental risk factors will be obtained by interviews and individual analysis. FINDINGS/STATUS: SIGNIFICANCE: PUBLICATIONS: START DATE: July 1983 COMPLETION DATE: July 1986 LEVEL OF EFFORT (Total Project) TO DATE: PROJECTED TO COMPLETE PROJECT: FTEs: FUNDING: $ 255,000 $0 SOURCE OF FUNDING: Veterans Administration, Washington � Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Alvin L. Young Collection on Agent Orange Description An account of the resource <p style="margin-top: -1em; line-height: 1.2em;">The Alvin L. Young Collection on Agent Orange comprises 120 linear feet and spans the late 1800s to 2005; however, the bulk of the coverage is from the 1960s to the 1980s and there are many undated items. The collection was donated to Special Collections of the National Agricultural Library in 1985 by Dr. Alvin L. Young (1942- ). Dr. Young developed the collection as he conducted extensive research on the military defoliant Agent Orange. The collection is in good condition and includes letters, memoranda, books, reports, press releases, journal and newspaper clippings, field logs and notebooks, newsletters, maps, booklets and pamphlets, photographs, memorabilia, and audiotapes of an interview with Dr. Young.</p> <p>For more about this collection, <a href="/exhibits/speccoll/exhibits/show/alvin-l--young-collection-on-a">view the Agent Orange Exhibit.</a></p> Text A resource consisting primarily of words for reading. Examples include books, letters, dissertations, poems, newspapers, articles, archives of mailing lists. Note that facsimiles or images of texts are still of the genre Text. Box The box containing the original item. 054 Folder The folder containing the original item. 1430 Series The series number of the original item. Series III Subseries II Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Typescript: Agent Orange Project Update Summary, December 4, 1986 Subject The topic of the resource health studies veteran health and hygiene AOWG ao_seriesIII Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Alvin L. Young Collection on Agent Orange Description An account of the resource <p style="margin-top: -1em; line-height: 1.2em;">The Alvin L. Young Collection on Agent Orange comprises 120 linear feet and spans the late 1800s to 2005; however, the bulk of the coverage is from the 1960s to the 1980s and there are many undated items. The collection was donated to Special Collections of the National Agricultural Library in 1985 by Dr. Alvin L. Young (1942- ). Dr. Young developed the collection as he conducted extensive research on the military defoliant Agent Orange. The collection is in good condition and includes letters, memoranda, books, reports, press releases, journal and newspaper clippings, field logs and notebooks, newsletters, maps, booklets and pamphlets, photographs, memorabilia, and audiotapes of an interview with Dr. Young.</p> <p>For more about this collection, <a href="/exhibits/speccoll/exhibits/show/alvin-l--young-collection-on-a">view the Agent Orange Exhibit.</a></p> Text A resource consisting primarily of words for reading. Examples include books, letters, dissertations, poems, newspapers, articles, archives of mailing lists. Note that facsimiles or images of texts are still of the genre Text. Box The box containing the original item. 053 Folder The folder containing the original item. 1411 Series The series number of the original item. Series III Subseries II Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Creator An entity primarily responsible for making the resource Young, Alvin L. H. K. Kang B. M. Shepard Source A related resource from which the described resource is derived Chlorinated Dioxins and Dibenzofurans in the Total Environment II Date A point or period of time associated with an event in the lifecycle of the resource 1985 Title A name given to the resource Chapter 13: Rationale and Description of the Federally Sponsored Epidemiological Research in the United States on the Phenoxy Herbicides and Chlorinated Dioxin Contaminants Subject The topic of the resource herbicide toxicology AOWG ao_seriesIII https://www.nal.usda.gov/exhibits/speccoll/files/original/f9a43b5489fcaeec623ab493d8807bbd.pdf 41584cca05f4093c521e8da0cedfb4ff PDF Text Text Item ID Number 0136? Author Wilkins, John R. Corporate Author RepOrt/ArtlClO Title Epidemiologic Approaches to Chemical Hazard Assessment JOUmal/BOOk Title Hazard Assessment of Chemicals: Current Development Year 1983 Month/Day Color a Number of Images 29 Descrlpton Notes Thursday, May 03, 2001 Page 1367 of 1403 �Epidemiologic Approaches to Chemical Hazard Assessment John R. Wilkins III Department of Preventive Medicine The Ohio State University Columbus, Ohio Nancy A. Reiches Comprehensive Cancer Center The Ohio State University Columbus, Ohio I. Introduction II. Developing Clues to Chemically Related Disease: Descriptive Approaches A. Fundamental Epidemiologic Tools B. Variations of Disease Occurrence in Time C. Variations in Disease Occurrence from Place to Place . . III. Testing Etiologic Hypotheses: An Overview of Analytic Approaches A. Case-Control Studies B. Cohort Studies IV. Crucial Aspects of Environmental Study Design A. Measurement of Dose B. Measurement of Response V. Relating Measures of Dose to Measures of Response VI. Conclusion References I. 133 135 135 141 145 153 154 158 161 161 173 178 180 182 INTRODUCTION During this century, populations of industrialized nations have experienced dramatic changes in the pattern and relative importance of various life-threatening illnesses. At one time, diseases such as tuberculosis and 133 HAZARD ASSESSMENT OF CHEMICALS: Current Developments, Vol. 2 6dt- Copyright © 1983 by Academic Press, Inc. All rights of reproduction in any form reserved. ISBN 0-12-312402-6 �x-r-r junii iv. yniKins iu ana Nancy A. Ketches smallpox claimed large numbers of lives, especially in younger age groups. Now, these and many other conditions of infectious origin are rarely encountered. The resulting increase in average life expectancy, however, has resulted in a new set of public health problems. One of these problems, chemical contamination of the human environment and the assessment of health risks that may result, is the focus of this article. Perhaps one of the most difficult questions in contemporary epidemiology and public health stems from evidence suggesting that most malignant disease is of environmental, perhaps chemical, origin. This supposition is particularly significant in the context of public health since cancer is the second leading cause of death, accounting for approximately one in every five deaths. Furthermore, mortality from cancer has increased in recent years, leading to the hypothesis that the spread and diversity of chemical contamination of the environment may largely account for this trend. To the extent that carcinogenic agents are exogenous in nature, there is potential for intervening in the environmental network and thus preventing the occurrence of disease. It is this concept that forms the cornerstone of epidemiologic research. The primary purpose of epidemiologic inquiry is to estimate quantitatively the effects of those factors that determine whether disease does or does not occur in human populations. Classic epidemiologic models, in combination with evidence from laboratory research, are powerful tools for both generating and testing hypotheses about the etiologic significance of environmental contaminants. Epidemiologic investigations often result in the institution of preventive or control strategies—i.e., interventions in the process of disease causation— even in the absence of knowledge regarding the underlying biologic mechanisms. Consequently, epidemiologic research assumes a central role in the protection of the public health. In this article, the major features of the epidemiologic approach to chemical hazard assessment are discussed. At the outset the fundamental sources of epidemiologic data and the process of generating testable hypotheses are described. Next, the methods by which such hypotheses are tested are considered. In particular, the focus is on the ways in which measures of dose and measures of response are derived and evaluated in epidemiologic research. Finally, questions regarding the interpretation of dose and response measures are addressed. The epidemiologic approach to disease may be described as proceeding in two major phases. The first phase, discussed in the following section, involves the conduct of "descriptive" epidemiologic studies. It is important to emphasize that the primary purpose of these studies is to generate hypotheses of cause and effect, a goal achieved primarily by examining Epidemiologic Approaches to Chemical Hazard Assessment 135 patterns of disease occurrence with respect to time and place. The second phase, discussed in Section III, involves conducting more rigorous "analytic" studies, studies whose purpose is to test hypotheses previously set forth. II. A. DEVELOPING CLUES TO CHEMICALLY RELATED DISEASE: DESCRIPTIVE APPROACHES Fundamental Epidemiologic Tools 1. Measures of Disease Frequency In this subsection, measurements of disease occurrence that are fundamental to any epidemiologic investigation are discussed. Subsequently, the role of these measurements in typical epidemiologic models is considered. There are several measurements that reflect various aspects of the frequency of disease in a population. In general, these can be divided into two major categories. The first relates to measures of morbidity, or illness; the second concerns mortality. One of the most basic concepts with respect to the measurement of disease occurrence is that of a rate. Most simply, a rate may be defined as the frequency of a condition in a defined population over a specific period of time. Clearly, an absolute count of cases, without reference to a population of known size, precludes direct comparisons between groups. For example, if it is known only that /i, cases of Disease X occurred in Community A, and n2 cases in Community B, there is insufficient information to determine in which community the occurrence of the disease is greater. If, however, the size of the population in which the cases were detected is also known, the rate at which disease occurs can be computed, thereby yielding figures that are comparable. With respect to morbidity, the rate that is usually of most interest is the incidence rate. This is a direct measure of the probability or risk of illness. Ideally, incidence rates would be based on prospective surveillance of a well-defined population in which only those individuals who are at risk of developing the disease under consideration are included in the denominator. Although denominators are rarely this precise, they should not include persons who already have the disease or are not susceptible. Mortality rates, on the other hand, represent the probability or risk of death. The number of deaths in a defined group constitutes the numerator of a mortality rate, while the denominator represents the total number �136 Epidemiologic Approaches to Chemical Hazard Assessment John R. Wilkins III and Nancy A. Reiches of persons in the defined group, i.e., the number of persons at risk of dying. Morbidity and mortality rates may be expressed as either crude, specific, or adjusted rates. Crude rates can be constructed from a minimal amount of information; they require knowledge only of the total number of events (e.g., births, deaths) and the size of the population in which the events occurred. However, to the extent that the risk of illness or death is not uniform (equally probable) across all members of a population, specific rates can provide more useful information. Typically, specific rates are defined with respect to age, race, sex, or some combination of these demographic characteristics. The basic formula for a specific rate includes in the numerator the number of events of interest in a homogeneous population subgroup, and in the denominator, the number of persons at risk in that same subgroup. Therefore, an age-specific death rate could be computed for persons 50-54 years of age; the rate could further be confined to white male members of the population in this age group. The general advantage of specific rates, whether for morbidity or mortality, is that they do not obscure potentially significant differences among population subgroups. Since these rates provide a high degree of detail, they are very useful for both analytic and health planning activities. This is particularly true if the condition under consideration exhibits great variation in occurrence among different age groups. Most chronic diseases, such as cancer and cardiovascular disease, manifest such a pattern. When morbidity and mortality rates are, however, used to compare disease experience in two or more populations, specific rates can present problems. Age-specific rates are often computed for either 5- or 10-year intervals, thus yielding as many as 18 rates per population. For many types of comparisons the task becomes cumbersome and the results difficult to interpret. Therefore, it is often preferable to compute some type of summary figure, which usually implies an adjusted rate. Adjustment is a procedure by which differences in the composition of groups are removed, so that the difference does not bias the comparisons of interest. The need for adjustment is illustrated by the difficulties that can be introduced when only crude rates are used. For example, if interest centers on a disease such as cancer, an illness occurring more frequently in older persons, the rationale for adjusting for age is clear. If Population A has a higher proportion of older individuals than does Population B, but the risk of dying for persons in any specific age group is the same, the crude rate will be greater for Population A. This would lead to a misinterpretation of the risk of dying in each population. What Hs required is a method of comparing the two groups as if the age distributions were identical. This can be accomplished by the "direct method" 137 of adjustment. By this method, age-specific rates are weighted not by the proportion of the population under study in the given age group, but rather by the proportion of an external standard population in the same age group. This procedure answers the question: "What would the rate in the study population be if its age distribution were equivalent to that of the standard population?" By .adjusting several population rates to the same standard, direct, unbiased comparisons between groups can be made. Although adjustment for age is probably the most common form of adjustment (or standardization), the same technique can be applied to remove differences with respect to other characteristics, such as sex or race. While the procedure is both well accepted and useful in a variety of analytic settings, it is not without disadvantages. First, it must be remembered that an adjusted rate is, in one sense, "fictional." That is, its magnitude depends not only on the "real" death rate in the study population, but also on the choice of the standard population. Second, because the adjusted rate is a summary figure,, it may obscure different trends among subgroups. For example, if only temporal changes in ageadjusted rates are examined, differences across selected age groups with respect to the rate of change, or even the direction of change, may go unnoticed. 2. Sources of Morbidity and Mortality Data This subsection considers some of the major sources of morbidity and mortality data commonly employed in epidemiologic studies of environmental phenomena. Some of the advantages and disadvantages of these sources are also discussed. First, we consider mortality data, a source of information that appears to be quite straightforward, but in truth is rather complex. The fundamental resource for mortality data is the death certificate. A standard form for death certification has been developed by the National Center for Health Statistics, the agency responsible for the detailed tabulation of all vital records. The death certificate contains demographic information, such as the decedent's age, race, sex, place of birth, place of death, place of usual residence, marital status, and occupation. The medical portion of the certificate includes data on the immediate and underlying causes of death and on other significant conditions that may have contributed to the death. There is also an item indicating whether or not an autopsy was performed. There has been a great effort to ensure uniformity in the death certification process and in the subsequent reporting of death records. In this regard, the Physician's Handbook on Medical Certification specifies rules for �138 John R. Wilkins III and Nancy A. Reiches recording the cause of death, rules that distinguish between the immediate cause and the underlying cause (760). The immediate cause of death is the disease or injury that directly preceded death; the underlying cause, which is the most important item for epidemiologic studies, is "the condition that started the sequence of events between normal health and the immediate cause of death." Additionally, there are internationally accepted rules for coding the medical information contained in the death certificate. Numeric codes, as specified in the International Classification of Diseases (ICD) manuals, are assigned to each cause on the certificate. The most crucial part of the coding process is the choice of underlying cause of death, since this item becomes the officially reported cause. Rules for this section are outlined in a National Center for Health Statistics publication entitled "Instructions for Classifying the Underlying Cause of Death, 1979" (767). However, owing to differences in the way in which physicians complete the death certificate form, the process of choosing the underlying cause does involve judgment and is therefore subject to both random and systematic error. In addition to outright errors in death certification and coding, there are some questions inherent in the way mortality data are reported that bear on their epidemiologic usefulness. One central question involves the forced choice of a single, underlying cause of death. Published statistics might lead one to believe that each death is the consequence of just one disease. However, the majority of death certificates, particularly for older persons, contain two or more diagnoses. This raises the medical question of how exact cause of death can be determined in an individual with multiple, potentially life-threatening infirmities (93). Furthermore, there is the data-management and statistical problem of tabulating multiple causes of death, which in practice is seldom done. Although computerization of death records is relatively recent, the coding of cause-ofdeath data into machine-readable form opens up the possibility of routine tabulations of multiple-cause data (60, 91). The validity—i.e., the accuracy—of mortality data has been studied extensively. In this context, questions of validity relate to difficulties in ascertaining the exact cause of death. This issue is extremely important, since mortality data are perhaps the primary source of information on the consequences of illness experiences. For example, in several studies reported cause of death has been compared with autopsy findings (64, 149) and hospital diagnosis (2). Results of these studies indicate that complete concordance between clinical diagnosis and stated cause of death does not exist. Sources of discrepancies have been identified (84), 1 and their effect on subsequently computed mortality statistics estimated Epidemiologic Approaches to Chemical Hazard Assessment 139 (773). While significant problems with the reliability and validity of death certificate data have been identified, the utility of this source of information remains high, assuming that the proper interpretive safeguards are heeded. Some of these cautions were pointed out in a study that directly compared the epidemiologic inferences that could be drawn using mortality versus morbidity data. In this study it was demonstrated that both sources of data lead to essentially the same conclusions (182). For examining trends in the occurrence of disease over time or among selected populations, mortality data are the only resource that satisfies the criteria of continuity and coverage. As is discussed below, there is no single source of information on morbidity that is available for an entire country. In studies of cancer, for example, mortality data have been employed extensively because such data are assumed to be adequate surrogates for incidence data. This will be true for any condition for which the interval between onset of disease and death is reasonably short and for which the case fatality rate is high. Since mortality data are comprehensive, it is a reasonably straightforward task to compute death rates, assuming that appropriate population figures are available. These rates can then be applied in a variety of analytic models. Although it is clear that mortality data are not error-free, morbidity data introduce additional complexities. With the exception of certain infectious and communicable diseases, incident cases of disease such as cancer are not reportable to any public health agency. Therefore, only through specialized programs are incidence data collected. With regard specifically to cancer cases, there are several data systems that compile information about individuals with malignant disease. The first such category of data systems is not population based, i.e., not all cases in a defined or definable population are included. Under these circumstances it is not possible to compute incidence rates. Despite this limitation, these systems have provided a substantial portion of our knowledge about the determinants of cancer. Most of these systems are hospital-based tumor registries, the purpose of which is to collect a standardized set of demographic and medical information for each cancer patient treated at the particular institution (727). However, since patients are not admitted or referred to hospitals on a random basis, the sample of patients in a tumor registry is rarely representative of all cancer cases in the community. Although population-based analyses cannot be done with hospital registry data, these programs serve several useful research purposes. First, the health or vital status of patients is monitored over time, thus yielding data for the computation of survival rates. These are, of course, the most common endpoints for evaluating the effectiveness of cancer-directed therapy. Second, registry data allow for studies of specific variables �140 Epidemiologic Approaches to Chemical Hazard Assessment John R. Wilkins III and Nancy A. Reiches related to prognosis. Third, registries are extremely valuable for locating subjects for studies of factors related to the occurrence of disease. An ambitious multiinstitutional tumor registry program has recently been undertaken in this country. The Centralized Cancer Patient Data System (CCPDS) is a network of tumor registries at institutions designated as Comprehensive Cancer Centers by the National Cancer Institute. Data for all patients treated at these major centers are entered into a common data base, and follow-up information is obtained annually. Between July 1, 1977 and December 31, 1980, data for 142,079 tumors were registered. Although these data are not population-based (therefore reflecting the selection factors intrinsic to referral centers), the value of the CCPDS lies in the high reliability and validity of the data that are abstracted. The system has rigid coding categories, a well-defined program of quality control, frequent training sessions for nonphysician abstractors, and computerized editing of each data item. The data base provides unique opportunities for the study of cancer etiology, particularly with regard to rare tumors, only a few cases of which may be treated at a single institution (77). In addition to tumor registry data, there are some sources of populationbased cancer incidence data in the United States. The largest of these is the Statistics, Epidemiology, and End Results (SEER) program (234, 235). The purposes of the SEER program include estimating cancer incidence in the U.S., monitoring trends in survival, and identifying etiologic factors. Each of these can be studied with respect to a variety of demographic and social characteristics of the population. There are 11 geographically defined areas that participate in the program, representing about 10% of the U.S. population. Although fairly representative of the entire U.S. population with respect to age, blacks and rural residents are somewhat underrepresented. This program is an outgrowth of the End Results program and the National Cancer Surveys (49, 50). Data are collected for all new malignancies occurring in the study communities. Cases are identified from hospital charts, pathology reports, radiation therapy records, death certificates, autopsy reports, tumor registries, and private laboratories. Complete information about the patient's demographic characteristics is collected, along with data describing the anatomic site and histology of the tumor, extent of disease, and first course of therapy. Active follow-up is maintained for all cases. Although it has been established that cancer mortality rates are an acceptable surrogate for incidence rates, programs such as the Third National Cancer Survey (TNCS) and SEER provide certain information that cannot be obtained from death records. Most notable in this regard 141 are data on histologic type of the tumor and on stage or extent of disease at the time of diagnosis. The former is significant because cell type might be related to etiologic variables. The latter is important because of its relationship to survival. B. Variations of Disease Occurrence in Time The relation of disease occurrence to time is an important aspect of any epidemiologic evaluation of chemical hazards. While the occurrence of disease may be measured in terms of morbidity or mortality, time itself may be measured in terms of any appropriate dimension (hours, days, weeks, months, years, etc.). The relation between time and disease may therefore be viewed from a number of perspectives. In general, this involves examining fluctuations in disease occurrence that take place either over relatively short periods of time (e.g., over a number of hours, days, or weeks) or over relatively longer periods of time (e.g., over a .number of years or decades). Although the temporal focus of the two approaches differs, the intent of each view is to gain insight into the reason or reasons why disease occurrence has fluctuated during the time period. 7. Short-Term Fluctuations When a limited, well-defined, and homogeneous population is subjected to a single and intense chemical exposure, the effects of such exposure are likely to be manifested in a matter of minutes, hours, days, or weeks. Although the average amount of time that elapses before disease appears will depend on, at least, the mode and intensity of the exposure and on the toxicity of the agent involved, the pattern of disease occurrence in time over the short term may be expected to parallel (at least qualitatively) patterns demonstrated by common-vehicle, point-source epidemics of microbial origin. Following this type of exposure, such acute outbreaks may be described by the shape and location in time of their epidemic curves. Characteristically, onset of disease is explosive in nature; the epidemic curve is positively skewed (i.e., the distribution of onset times is log-normal); and the time interval between exposure to the agent and clincial manifestation of the illness is short. In this regard, Sartwell's method for estimating median incubation periods for infectious diseases is a traditional epidemiologic tool (796). Although originally developed to study temporal patterns of infectious diseases with relatively short incubation periods, this technique has been successfully applied to various neoplastic diseases resulting from certain chemical exposures, including �142 John R. Wilkins III and Nancy A. Reiches Epidemiologic Approaches to Chemical Hazard Assessment angiosarcoma of the liver following exposure to vinyl chloride (205, 275) and tumors of the urinary bladder following exposure to dyestuff intermediates (4). Thus, conventional epidemiologic methods pertaining to the investigation ,of common-vehicle, point-source epidemics of infectious diseases may be appropriately applied to the study of acute outbreaks of chemically related illness. When the conditions of exposure previously set forth prevail (i.e., single and intense exposure of a limited, well-defined, and ^homogeneous population), the epidemiologic interpretation is usually Straightforward, because cause and effect are close in time (192). However, when the introduction of the toxicant into the population is gradual or intermittent, and thus occurs over a long period of time, the incubation, or latent, period is likely to be measured in years or decades rather than in hours, days, or months. In this case, the epidemiologic interpretation, i.e., the linking of cause and effect, is much more difficult. human origin (i.e., an increase or a decrease in a death rate over time may be artifactual), or that changes in mortality over time may indeed reflect a true change in the incidence of the disease. Real changes in death rates, of course, may result when the genetic composition of a population changes (possibly the result of population migration or the dilution of genetic isolates), or when the environmental milieu changes. Real changes in mortality may also result when the age distribution of a population shifts or when the case fatality rate for a given disease changes. Before it can be concluded that changes in mortality rates are real, however, alternative explanations should be ruled out. In this context, at least two sources of error, both of which relate to the numerator of a death rate, must be considered. First, medical advances are likely to result in more accurate methods of diagnosis, which in turn might yield more precise determination of underlying cause of death. Consequently, a decline in the degree of misclassification of the underlying cause of death for a specific cause may result in an apparent, but spurious, decline in the cause-specific mortality rate. For example, improvement over time in the ability to identify correctly the primary site of malignant tumors in all likelihood explains the steady decline in mortality from primary cancer of the liver over the past 40 years. Misleading trends in death rates may also result from revisions in the ICD, which occur approximately every 10 years. These revisions may involve either changes in the way various disease entities are defined or changes in the actual numerical code, or both. For example, Percy et al. (772) demonstrated that the 10% increase in the number of lung cancer deaths reported in 1968 over the number reported in 1967 was the result of a procedural change in the classification of malignant neoplasms that emphasized coding to a specific site rather than, as had been practiced before 1968, coding to unspecified or unknown categories. In general, changes in mortality that result from ICD revisions are likely to be quite striking and readily identified as such. With respect to changes in mortality rates that result from improved diagnostic methods, however, the evaluation is much more difficult. Specific techniques have been suggested in this regard (128). The denominator of a death rate, i.e., the estimated population at risk, is also subject to error. This error is usually one of underestimation, the net effect of which is an artificial inflation of the rate. If the degree of error in population enumeration varies from census to census, a misleading trend in mortality may be observed. To complicate the picture further, inaccuracies in the census may not be of consistent magnitude across age, race, and sex groups (203). 2. Long-Term Variations The epidemiologic view of time and disease also involves the examination of changes in disease frequency over long periods of time. These "secular .trends" are usually investigated in terms of mortality rates because adequate morbidity data are rarely available. For example, examination of the temporal trends in sex- and site-specific cancer mortality rates for the years 1930-1978 reveals several patterns worthy of further investigation. Particularly notable are the decline in gastric cancer mortality for both males and females and the disproportionate increase in lung cancer mortality among females as compared to males (204). By contrast, other neoplasms such as pancreas, bladder, and esophagus show little change over the time period. The observed increases in cancer mortality have raised questions about the role of chemicals in the human environment. One such question focuses on toxic chemicals, the chemical industry, ' and their relation to recent temporal trends in cancer rates (57, 779, 206, 277). A related question focuses on quantifying the proportion of all cancers attributable to "environmental" factors (29, 98, 99, 101, 232). Although quite a debate has ensued and several articles addressing these issues have been published, there seems to be, at present, little chance of reaching definitive conclusions in the near future, given the overwhelming lack of relevant scientific knowledge. Part of the debate alluded to above involves the interpretation of observed time trends in mortality rates. Although specific guidelines and techniques have been proposed (123, 128), the importance of systematically -..evaluating such trends is not always appreciated. It must be recognized that apparent changes in mortality over time may result from errors of 143 �144 Finally, we introduce a note of caution with regard to the interpretation of time trends in mortality rates. If it is observed that an increase in some disease is paralleled by a concomitant increase in some measure of a putative risk factor (and if it can be shown that the increase in disease is not artifactual), then can such an observation be used to support an argument of causality for the hypothesized factor? The answer is no, although one can legitimately say that such a result is not inconsistent with the stated hypothesis. If, on the other hand, there is no coincident rise (or fall) in the disease and the "risk factor," can it then be legitimately concluded that no causal link exists? The answer to this particular question is an emphatic no. Even if artifact is considered and judged negligible or somehow appropriately adjusted for, the general approach is sufficiently insensitive to support the hypothesis of no effect. Furthermore, it must be kept in mind that the results of time-trend analyses are only a small part of the overall process of making judgments about the causal role of some putative risk factor. In essence, time-trend analyses are most appropriate when the purpose is to generate hypotheses of cause and effect, not to test them. 3. Epidemiologic Approaches to Chemical Hazard Assessment John R. Wilkins III and Nancy A. Reiches Other Perspectives of Disease and Time Although acute outbreaks of disease and secular trends in mortality dominate epidemiologic interest regarding disease versus time considerations, other perspectives may be taken. For example, many diseases (including infectious and noninfectious ones) show some sort of cyclic or repetitious pattern of occurrence in time. While the focus of study in this context has been primarily on infectious conditions and their seasonal periodicity in relation to insect vectors and certain human activities, studies of various noninfectious diseases of early life [e.g., congenital anomalies (62)] have revealed variations in risk by season of birth, suggesting the possible influence of environmental factors operating in utero or in the early postnatal period (112, 128, 140). Another view of disease and time involves the investigation of temporal "clustering," i.e., the detection of epidemics (transient excesses in the incidence or prevalence of a disease or condition). In this regard, simple epidemic curves may be constructed, or more sophisticated methods like the scan statistic (762, 222, 226) may be applied. A related and somewhat broader view involves the examination of clusters of disease in time and space. So-called space-time clusters have been of interest with respect to several diseases, including leukemia (113, 122, 216) and Hodgkin's disease (220). Several statistical methods are available to test the significance of space-time clusters (134, 167, 176), although an in-depth discussion of these is beyond the scope of this article. C. 145 Variations in Disease Occurrence from Place to Place The examination of geographic patterns of disease occurrence also plays an important role in the epidemiologic evaluation of chemical hazards. A number of strategies may be employed, each generally involving differing definitions of "place." In this regard, in order to determine if differences in disease occurrence exist among different geographic areas, basically two types of comparisons can be made: groups of countries may be compared with respect to available morbidity and/or mortality figures; or, comparisons of disease rates may be made on an intracountry basis. 1. Intercountry Comparisons Differences between countries with respect to the occurrence of many diseases can be quite striking. For example, when cancer incidence rates (for both sexes and all sites combined) are compared worldwide, a threefold difference is obtained when the highest risk countries are contrasted with the lowest risk countries (59, 759, 224). When comparisons of high-risk and low-risk nations are of a sex- and site-specific nature, extremes in cancer incidence may vary by as much as a factor of more than 500 (232). Significant differences between countries with respect to cancer mortality have also been documented (799, 252). While racial or genetic differences among the populations compared, plus other endogenous factors, account for some of the observed variation between countries in cancer incidence and mortality, the magnitude of many of the differences suggests the influence of environmental factors (57, 232). Disease rates in the lowest risk countries may be considered "baseline" (i.e., spontaneous or genetically determined) levels of cancer. Thus, the amount of cancer (or other disease) above such "natural" levels may be the result of the action of environmental forces (759, 232). This particular inference, as some have argued (29,30,69), implicates exposures of human populations to chemical carcinogens. Others involved in the debate over the proportion of all cancers due to "environmental" factors have, however, used the word environmental in a much broader context—as a synonym for any extrinsic or exogenous exposure (98-100, 232). Thus, references to environmental factors, it must be emphasized, relate not only to chemical pollutants but also to physical carcinogenic agents such as ionizing radiation, biological carcinogenic agents such as tumor viruses, and life-style influences such as diet and behavior (7). Although the results of international comparisons of disease rates have relatively limited epidemiologic utility, the exercise can serve the very useful purpose of generating hypotheses of cause and effect; it may even suggest preventive strategies (759). Moreover, once it can be established �146 John R. Wilkins III and Nancy A. Reiches that observed differences among countries are not spurious, studies of migrant populations may then be initiated to attempt a separation of the influence of genetic factors from that of environmental factors (95, 111, 116). 2. Intracountty Comparisons Many diseases, for example, most forms of cancer (25, 104, 138), cardiovascular disease (70), and multiple sclerosis (3), to name a few, show a marked geographic variation in frequency when comparisons are made on an intracduntry basis. Unlike intercountry comparisons, however, where the size of the geographic unit of analysis is fixed by national boundaries, intracountry comparisons may be performed at many levels; theoretically, any geographic unit, from the largest of subnational units (regions or states) to the smallest of subnational units (census tracts, block groups, or the like), may be used. In practical terms, though, it is usually necessary to select for study a geographic unit that best satisfies the need to compare populations that are as homogeneous as possible and, at the same time, large enough to yield stable disease rates. As Hoover el al. (103) and Blot and Fraumeni (27) indicate, the optimal geographic unit of study seems to be the county, at least when epidemiologic interest centers on environmental causes of cancer. The initial work of Mason and McKay (737, 738) illustrates the approach. a. Mapping Cancer Death Rates. For the period 1950-1969, age-, race-, sex-, and site-specific cancer mortality rates were computed from National Center for Health Statistics death certificate data and U.S. Census figures for each of the 3056 contiguous U.S. counties (737). To allow valid comparisons among the counties, the death rates were agestandardized to the 1960 U.S. population, yielding average annual race-, sex-, site-, and county-specific rates for the 20-year period. From these summary data, an atlas of cancer mortality, color-coded to five levels, was created by comparing statistically each subgroup-specific county rate to the appropriate national rate and by, at the same time, classifying the rates into deciles (738). For the rarer malignancies, state economic areas (defined as groups of similar, contiguous counties) were used as the geographic unit of analysis. Virtually all of the resultant maps demonstrated that cancer death rates vary in magnitude across U.S. counties (or across state economic areas) in a nonrandom fashion. Furthermore, the number of identifiable "clusters" of high (or low) rate counties, the size of a given cluster, and the location of clustering depends on both the site of disease and on the sex-race subgroup examined. Striking geographic Epidemiologic Approaches to Chemical Hazard Assessment 147 patterns emerged for several malignancies, including, notably, cancers of the bladder, esophagus, lung, stomach, and oral cavity. This mapping approach is quite useful for a number of reasons. First, from a technical point of view, a large amount of data can be analyzed by computer relatively quickly and inexpensively. Second, because the data are presented visually, high-risk populations can be identified rapidly, which in turn, provides a firm basis to form causal hypotheses that can then be pursued by other means. Furthermore, mapping studies, sometimes referred to as the geographic pathology approach (87), serve as an important first step in a logical sequence of epidemiologic studies based on countylevel cancer mortality data (24). b. Correlation Studies. Although the benefits of mapping disease rates are clear, the identification of high-disease areas by this technique creates somewhat of an interpretational dilemma. Can the disease clustering be explained by the demographic and/or genetic characteristics of the people that inhabit the area, or are the chemical, physical, and biological (i.e., environmental) characteristics of the place responsible for the elevated disease rates in the resident population, or is the explanation some combination of these two factors? These questions give rise to a class of investigations often referred to loosely as "correlation" studies. The purpose of this type of study, simply stated, is to identify those demographic and environmental characteristics of the populations in question that covary with the disease rates, thereby providing etiologic clues. Such studies rely primarily on routinely collected data, such as U.S. Census figures and death certificate data. Quantitatively, although numerous statistical methods may be employed, correlation studies fall basically into one of two general categories: studies that employ standard univariate methods of analysis, i.e., studies that use the bivariate correlation coefficient to measure association between a single factor and a disease; and studies that employ multivariate methods of analysis. This typically involves the investigation of multiple risk factors for disease with standard multiple regression techniques. Schroeder's paper on various chemical and physical properties of finished drinking water and cardiovascular disease mortality exemplifies the univariate approach (198). In this study, average annual age-adjusted mortality rates from cardiovascular disease for the period 1949-1951 for white males aged 45-64 years were plotted as a function of the average drinking water hardness in the 48 contiguous United States plus the District of Columbia. Bivariate correlation coefficients were computed for four categories of cardiovascular disease and for all causes of death combined; �148 John R. Wilkins III and Nancy A. Reiches four of the five correlation coefficients were negative in sign and were statistically significant at the p < 0.01 level. A similar analysis of coronary heart disease and 21 constituents of water in the 163 largest U.S. cities yielded highly significant (negative) correlation coefficients for magnesium, calcium, bicarbonate, sulfate, fluoride, dissolved solids, specific conductance, and pH, prompting Schroeder to write "the data offer a clue to an environmental influence associated with the nature of public water supplies which affects adversely the course of degenerative cardiovascular diseases in the United States." This particular approach (i.e., the use of bivariate correlation coefficients to measure association between some factor and some disease) has some notable limitations. First, the magnitude of a correlation coefficient can be affected significantly by the size of the geographic unit used for analysis. Although the phenomenon is not always appreciated, the simple aggregation of geographic areas into larger units will usually result in an increase in the size of the correlation coefficient, an increase which can, in reality, be quite large. As Blalock (18) explains, a shift from smaller to larger geographic units will tend to reduce the effect of so-called nuisance variables, variables that are causally related to Y (the dependent variable of interest, i.e., disease) but that are unidentifiable and/or unmeasurable. Thus, as geographic areas are aggregrated they become more homogeneous with respect to the nuisance variables, which in turn allows the single independent variable of interest (X) to account for, or "explain," a greater proportion of the variation in Y. It is not surprising, therefore, that a fairly high (negative) correlation between hardness of drinking water and cardiovascular disease can be obtained when comparisons are made on a state-by-state basis, while the association, in general, disappears as the geographic unit of study gets smaller and smaller (43). Another important consideration is that the correlation coefficient itself does not measure the strength of an association, but merely reflects the degree of dispersion of the data points about a straight line. Since it is the regression, not the correlation, coefficient that measures the effect of changes in X on Y, its use is preferred as a measure of association between factor and disease. Further, the magnitude of a regression coefficient (i.e., the slope of a line in a bivariate analysis) is theoretically not influenced by shifts in the size of the geographic unit of study. The univariate approach discussed above, whether correlation or regression coefficients are used, cannot deal with the complex of factors related to the occurrence of human disease. Consequently, in order to help identify the cause (or causes) of environmentally related illness, a multivariate approach must be employed. In general, this involves the application of standard multiple regression techniques, a strategy based Epidemiologic Approaches to Chemical Hazard Assessment 149 on the assumption that disease rates (e.g., county-level cancer mortality rates) can be expressed as a linear or nonlinear function of a set of demographic, socioeconomic, and environmental characteristics of the population(s) in question. To illustrate, once maps of county-level cancer mortality data reveal geographic clusters of elevated death rates for specific neoplasms, multiple regression studies may be performed to identify those demographic, socioeconomic, and environmental characteristics of the apparent high-risk populations that are statistically related to the cancer death rates (2723, 76). The county-level cancer mortality data [their origin described earlier (137)] are treated as dependent variables in regression equations, and relevant county-level demographic, socioeconomic, and environmental data are entered as independent or predictor variables. Statistical significance of regression coefficients indicates which variables are significantly associated with the cancer rates, while the sign of each coefficient indicates the direction of the association. The county-level demographic, socioeconomic, and environmental data are obtained from such sources as U.S. Census publications and computer tapes. Quantities such as percentage of the population that is nonwhite, percentage that is urban, percentage residing on farms, population density, median family income, median number of school years completed by the adult population, percentage foreign stock, and various industrial indexes [derived from the U.S. Census of Manufactures (279)] are typically included in regression equations. For example, after controlling for the effects of demographic and socioeconomic differences, Blot and Fraumeni (21) found lung cancer mortality rates in white men to be significantly high in those U.S. counties where the paper, chemical, petroleum, and transportation industries tended to concentrate. Interestingly, death rates from lung cancer among white females were found not to be significantly associated with any of the industrial indices examined, a result consistent with the hypothesis that occupational exposures account for a measurable proportion of all lung cancer deaths. A methodologically similar study by Blot and Fraumeni (23) reported a statistically significant (positive) association between cancer of the urinary bladder among white males and the geographic concentration of the chemical and printing industries. As with their lung cancer study, industrial indices were found not to be related to bladder cancer mortality in white females. Comparable studies, one of which describes their method in detail (22), have investigated demographic, socioeconomic, and industrial correlates of oral (22) and esophageal (76) cancers. The initial focus of the multivariate approach described above is on a specific disease (or possibly on a group of diseases). In other words. �150 John R. Wilkins III and Nancy A. Reiches given a specific health outcome, a study is made to identify demographic, socioeconomic, and environmental factors of potential etiologic significance. It is possible, however, to reverse this logic by asking the following question: Given an a priori interest in a specific risk factor, what disease or group of diseases could be related to the factor in question? Thus, the initial focus of a correlation study might be on some environmental variable, perhaps a certain chemical exposure, rather than on a specific health effect. This approach, which generally utilizes the same multiple regression techniques discussed above, has been applied primarily to the investigation of various industries and/or occupations suspected of being cancer hazards (87,211), including the chemical (102), petroleum (79), metal electroplating (17), and furniture (32) industries. Studies of this kind have also addressed the possible cancer risk associated with the contamination of water by asbestos (739), fluoride (105), and organic chemicals (228)', of air by arsenical compounds (20); and of soil by uranium mill tailings (136). c. Nature of the Ecologic Study. The correlation studies referred to above, whether analyzed in univariate or multivariate fashion, share a very important characteristic: the data employed, and this relates to both the independent and the dependent variables, are in aggregate form, i.e., they (the data) are organized at a group level, thus providing information about human populations in a collective sense. Quantities derived from U.S. Census data, such as the proportion of a county population employed in a given industry, illustrate the point. Thus, investigations that rely on group- or aggregate-level data are commonly referred to as "ecologic studies," a descriptor having origins in the social sciences (61, 89, 150, 184). Ecologic studies, by virtue of their use of aggregate-level data, possess various limitations. A major concern in this regard pertains to the interpretation of the results of an ecologic analysis. First and foremost, since study subjects cannot be classified on an individual basis with respect to the study variables, any results suggesting an association between some factor and some disease must be regarded as indirect and therefore not conclusive. It should be appreciated that the interpretation of ecologic data is subject to an "ecologic fallacy," in this case, the error of ascribing to individuals associations or characteristics based on an analysis of aggregate-level data. This particular fallacy, the "aggregative fallacy," pertains to improper inferences made from the aggregate to the disaggregate (212). Improper inferences may also be made in the other direction, i.e., from the disaggregate to the aggregate; this type of ecologic fallacy is referred to as the "atomistic fallacy" (2/2). Ecologic studies, therefore, cannot be used to test formally some hypothesis of cause and effect. Epidemidogic Approaches to Chemical Hazard Assessment 151 They can, however, be used quite successfully to generate clues to the etiology of disease, clues that are pursued by more rigorous methods of study. Ecologic analyses are fraught with other methodologic problems. These include: 1. Inability to incorporate the concept of a latent period. It will usually not be possible with routine data to construct a proper temporal relationship between measures of the hypothesized cause and measures of the hypothesized effect, i.e., it may not be possible to take into account a latent period—the time between the biologic onset of disease and its clinical manifestation (792). For example, in studies (720, 170) of cancer and organic chemical contamination of public drinking water supplies, data on the hypothesized cause (drinking water) pertained to 1963 and data on the hypothesized effect (cancer mortality) pertained to the 20year period, 1950-1969. In this case, for the measure of cause to precede in time in an appropriate fashion the measure of effect, the drinking water data should have pertained to a time period well before the 19501969 vicennium. The actual magnitude of a latent period to incorporate into such an analysis depends, of course, on the specific chemical agent and disease in question, as well as on the nature of the exposure. Moreover, if the study period overlaps with the latency period, regardless of when population exposures occurred, the full effect of the exposure cannot be determined because not all cases of disease attributable to the exposure will have had time to become manifest. 2. Artificial nature of the boundaries of geographic units of study. Geographic areas demarcated by natural boundaries such as mountain ranges or major rivers, as contrasted to areas defined by political or administrative boundaries, are more likely to be homogeneous with respect to demographic and environmental characteristics of etiologic significance, and thus would be more likely to define areas of high (or low) disease occurrence. The boundaries of most (though not all) states, counties, cities, etc. do not coincide with natural boundaries. Therefore, the artificial and arbitrary nature of politically established geographic areas creates problems in ecologic analyses because such boundaries may either subdivide homogeneous regions or combine heterogeneous ones (140). Further, it may not even be possible to obtain data on all variables of interest for a given type of areal unit. This creates a comparability problem, which may be compounded if the political/administrative boundaries shift over time. Such changes may then preclude any investigation of the temporal relationship between an exposure and a disease (209). 3. Difficulties in measuring human exposures to toxic chemicals in ecologic studies. With the kind of data typically available for use in ecologic studies it will usually only be possible to employ fairly crude �152 Epidemiologic Approaches to Chemical Hazard Assessment John R. Wilkins ffl and Nancy A. Reiches measures of human exposure to toxic chemicals. In general, such measures will be indirect (rather than direct) and qualitative (rather than quantitative). Since ecologic measures of exposure are in aggregate form, like the other variables in an ecologic study, they cannot be truly representative of the exposure experience of individuals comprising the study population. This aspect of conducting epidemiologic studies of chemical hazards is discussed in more detail in Section IV. 4. Effects of population migration. Migration of people between geographic areas will affect adversely the sensitivity of an ecologic study. As Polissar (178) points out, a geographic area assumed to'be inhabited entirely by a so-called exposed population is actually inhabited by some who are and by some who are not exposed to the agent or factor in question because of in-migration of unexposed people. Polissar demonstrates how one measure of disease risk, the Standardized Mortality (or Morbidity) Ratio (SMR), can be affected by differing degrees of migration. He shows, with some simplifying assumptions, that the SMR is a function of (i) the proportion of the exposed population that is truly exposed because they have not migrated, (ii) the size of the exposed population, (iii) the rate of death or disease in the control (unexposed) population, and (iv) the ratio of death or disease in the exposed population to that in the control (unexposed) population. Polissar also shows that the magnitude of excess risk observed in ecologic studies in the presence of migration varies with the age of the population, the particular disease in question, the duration of the latency period, and the type of geographic unit used for study. 5. Some technical issues. Most of the technical (statistical) problems in ecologic analyses relate to assumptions associated with any multiple regression problem. In many cases, underlying assumptions of the general linear (or nonlinear) model cannot be met strictly by the data. These include assumptions of normality with respect to predictor and dependent variables, homoscedasticity of variances, and independence of observations. Fortunately, the regression model is quite robust with respect to the first two assumptions, i.e., they can be violated substantially before the validity of results is threatened. The third assumption, however, can pose serious problems. In many instances, the distributions of two or more predictor variables are not independent, which means that they are correlated. This situation adversely affects the estimates of the regression coefficients and their subsequent interpretation. In many cases, however, this problem, called multicollinearity, can be solved by the use of two-stage or even three-stage least squares, rather than ordinary least squares, regression. Perhaps the most serious problem in ecologic analyses relates to the question of specification of the model to be evaluated. If a predictor 153 variable that is significantly related to the dependent variable is omitted (owing to lack of data or lack of knowledge that the variable is important), specification errors will result. If the omitted variable is correlated with a variable that is specified in the equation, the included variable will appear to be more strongly related to the dependent measure than is actually the case. If this occurs, a variable might erroneously be associated with the disease under consideration. Errors of this type in hypothesisgenerating studies can be dangerous, since they will mislead the investigator and probably result in an untenable etiologic hypothesis. Unfortunately, there is rarely enough knowledge available at the time of a preliminary study to determine whether a specification error has indeed occurred. However, the possibility emphasizes the caution noted earlier that causal inferences cannot be drawn from correlational results, but that such findings must be regarded as tentative. Once descriptive epidemiologic tools have generated hypotheses regarding the potential adverse effects of chemical exposures on human health, studies will then be conducted to'test formally such hypotheses. Studies of this type, "analytic" studies, require individual-level data on the traits and characteristics of study subjects. With such disaggregate data it will be possible, as it is not in ecologic studies, to classify each study subject with respect to the study variables. III. TESTING ETIOLOGIC HYPOTHESES: AN OVERVIEW OF ANALYTIC APPROACHES In this section the major analytic approaches typically employed to estimate potential associations between an exposure and a defined health outcome are discussed. The two primary methods can be distinguished on the basis of how the study samples are selected. In the case-control approach, individuals with a specific disease are compared with persons believed to be free of the condition under study. The cohort approach evaluates the occurrence of disease within a group defined in terms of characteristics prior to the diagnosis of disease. Both cohort and casecontrol methods can be defined further on the basis of whether the study is conducted retrospectively or prospectively. Many case-control studies are conducted retrospectively, i.e., the data collected are historical in nature. However, it is also possible to conduct prospective case-control analyses, in which the sample is accumulated over time as new cases of the disease occur. Cohort studies can also be conducted forward or backward in time. In either case, the distinguishing characteristic of such analyses is the long-term observation of a group of people, which is accomplished by prospective monitoring of the study subjects or by �154 John R. Wilkins IH and Nancy A. Reiches historically tracing the experience of the sample over a defined time interval. Prospective cohort studies are sometimes referred to as concurrent studies, while historical cohort analyses may be called nonconcurrent (123). The major features of each analytic model and some of their relative advantages and disadvantages are now described. A. Case-Control Studies Case-control studies are an excellent method for evaluating the relationship of an exposure or hypothesized etiologic factor to the occurrence of disease. In its most fundamental form, the purpose of a case-control study is to determine whether individuals with a disease are more (or less) likely to possess some characteristic (or exposure) than persons without the disease. These studies are designed to assess whether exposure to some factor of interest places individuals at higher risk of disease than those individuals not exposed. Statistical techniques applied to data from case-control studies can evaluate risk associated with two or more levels of exposure. Perhaps most fundamental to the conduct of a case-control study are those issues that bear on the selection of the study subjects. In selecting cases it is essential to confirm that the potential subject is indeed a case, i.e., that he or she strictly meets the diagnostic criteria of the condition under study. With respect to studies of cancer, for example, such confirmation could be in the form of microscopic pathologic analysis of a tissue sample, rather than merely a clinical or radiologic diagnosis. Even under conditions of laboratory confirmation, misclassification can occur, so it is important to minimize this bias, where feasible (63). Furthermore, it has been suggested that cases have a reasonable probability that their disease might have been caused by the hypothesized agent, and not by another identifiable factor (109). Cases can be identified through several sources. These include all persons (or more usually a probability sample of persons) diagnosed during a specified period of time in a given community or in a single hospital or group of hospitals. Often it is more practical to identify cases through the records of one or just a few medical care facilities. However, this can introduce a bias into the sample, since there are systematic selection factors that guide certain individuals to a particular facility. If such a bias is present, study cases will not be representative of the entire population of persons with the disease, possibly leading to erroneous inferences about the etiologic factor of concern. In principle, sampling cases from a general population has great theoretical appeal, but can be laborious and expensive. To the extent possible, the assumption of rep- Epidemiologic Approaches to Chemical Hazard Assessment 155 resentativeness should be met or the possible extent of bias estimated. Even with a condition such as cancer, certain nonrandom cases do escape medical attention. The question of selecting appropriate controls poses even more difficult questions. Simply defined, a control is an individual with no clinical evidence of the disease under study. Ideally, the control group will be a representative sample of disease-free persons. Furthermore, it is desirable that the controls be members of the same general population from which the cases derive. Control groups can be selected from several sources. These include hospital patients, residents of the same geographic area as the cases, and relatives or other associates of the cases. Selecting cases from the same geographic area is appropriate if the cases are representative of that population. Hospital controls are often used since they are a relatively easy source to obtain. The major disadvantage of this source is simply that hospitalized persons are ill and may therefore be unrepresentative of the general population with respect to a complex of illness-related factors. This may introduce a particular type of selection bias, especially if many of the controls are of a similar diagnostic group. This effect may be minimized by choosing controls from several diagnostic categories (41, 135). The extent of selection bias has long been known (94) and has been comprehensively discussed (10). Although selection biases do not necessarily invalidate study findings, one must carefully interpret whether an observed association is likely to be real or spurious (34, 58). Another significant issue with regard to the selection of cases and controls involves the question of matching. Since the purpose of a casecontrol study is to measure the effect of a defined exposure, it is desirable to eliminate by design those factors that might potentially confound the results. Matching is a process of selecting controls known to be similar to the cases with regard to specific characteristics such as age, race, sex, or socioeconomic status. Effects of variables known to be associated with both the disease and the study factors can be controlled by matching (752). The primary disadvantage of matching is that the etiologic role of the matching variable cannot be evaluated, since, by definition, cases and controls are alike with regard to that characteristic. Also, matching can increase the complexity of a study, with respect to both design and analysis (13, 14,143). Finally, there is a risk of overmatching or unnecessary matching. In general, inappropriate matching can reduce the statistical efficiency of the case-control comparison (757, 200). Collecting accurate and valid information on exposure for both cases and controls is a crucial aspect of case-control studies, since resulting estimates of risk are directly related to these measures. The precise �156 Epidemiologic Approaches to Chemical Hazard Assessment John R. Wilkins III and Nancy A. Reiches meaning of exposure (to be expanded on in Section IV) must be defined, with regard to both intensity and duration. Most importantly, the exposure information must be comparable, with respect to reliability and validity, for cases and controls. If the data are incomplete, spurious associations will result. Medical or vital statistics records and interviews with study subjects provide the major sources of exposure data; both sources entail potential biases. For example, as discussed earlier, there are possible sources of error with public records, such as death certificates. Clinical records may exhibit some of the same problems, or they may simply be incomplete with regard to data concerning the exposure of interest. Since the purpose of the record is to chart the clinical course of disease, information required to study other phenomena may not be available (72). Additionally, questions of validity of data recorded in the medical record have been raised (7/5). Finally, reliable (reproducible) abstracting of clinical data from existing records cannot always be achieved (28). Despite these potential limitations, the medical record remains a key source of data regarding exposure; its intrinsic value in the study of disease etiology is unchallenged (779). Data collected by interviewing cases and controls also presents some possible biases, but this method also assumes great importance in epidemiologic analyses. Information obtained through personal interviews (or self-administered questionnaires) is subject to the pitfalls of faulty respondent memory, unintentional errors in reporting, or outright prevarication. Bias might occur, for example, if the occurrence of disease has prompted the respondent to recall certain related information that might otherwise have been forgotten. If corresponding information does not emerge for the control, a bias is introduced (194). Further, the passage of time since the relevant event might affect the validity of the reported information (270). In other instances respondents might have been unaware of exposure and consequently are unable to report it. A number of studies have been conducted to evaluate the reliability and validity of self-reported data, many of which offer encouraging results (67, 114, 187). Errors in the collection of exposure data or noncomparabilities of data between cases and controls can result in serious misclassification problems, i.e., erroneously determining an individual's exposure status. The result of misclassification is an inaccurate estimate of risk. It has long been appreciated that even random and independent errors can reduce the measured association between exposure and outcome (33, 164). This topic has been reviewed extensively, and methods to adjust for misclassification under specified conditions have been proposed (45,85,110). Careful attention to study design can preclude or diminish many errors 157 of misclassification. Standardized provisions for data collection may at least ensure a high degree of reliability, a major prerequisite for validity. The analysis of data from a case-control study is primarily a comparison between cases and controls regarding the presence of hypothesized etiologic factors in each group. Results of these analyses indicate whether there is an association between the factor and disease. In principle, one desires to estimate the relative risk associated with exposure (i.e., the incidence rate among those with the factor divided by the incidence rate for persons without the factor). However, the method by which cases and controls are assembled does not include all exposed and all unexposed individuals. Consequently, the incidence rates of interest cannot be calculated. If, however, assumptions about the representativeness of cases and controls can be met, a measure known as the odds ratio can be computed as an estimate of relative risk (46, 47). In the simplest case, data from a casecontrol study can be presented in the form of a 2 x 2 table, with columns representing the classification of cases and controls, and rows representing the presence or absence of the exposure factor (Fig. 1). The odds ratio, given by the expression (ad)/(bc), summarizes the probabilities of having or not having disease. The statistical properties of the odds ratio have been analyzed extensively. Numerous methods have been proposed for tests of significance (83, 230) and for approximating confidence intervals (46, 96, 214). Furthermore, there are techniques to adjust the odds ratio for the effects of confounding variables through stratification (75, 90, 135). Appropriate statistical management of the odds ratio also depends on the degree of matching in the study design (148). In addition to stratification, control can be introduced by logistic Status of study subject Case Control ' Present a b Absent c d a + c b + d Exposure • a+b+c+d Fig. 1. Cross-classification of subjects in a case-control study. �158 John R. Wilkins in and Nancy A. Reiches Epidemiologic Approaches to Chemical Hazard Assessment models, which permit adjustment for variables that were not matched in the study design (31, 180). The epidemiologic literature is replete with examples of investigations employing the full range of study designs and analytic techniques described above. For example, death certificates were used as a primary source of data in an analysis of sinonasal cancer among males (193), for which several chemical agents are hypothesized etiologic factors. Exposure to a variety of agents was inferred from occupational data on the death certificate; complete occupational histories and quantitative exposure data were not available. However, probability of exposure to nickel, cutting oils, and wood dust was estimated from occupational titles and industry of work. The odds ratio computed for nickel exposure was not statistically significant, but was with respect to cutting oils and wood dusts. An example of the evaluation of a multiplicity of factors can be found in an ambitious study of bladder cancer (706). The effects of several exposures, including tobacco, coffee, various nutrients and nitrates in food, and occupation were estimated. A logistic model was used to deal with the multivariate design, thereby affording an opportunity to measure the independent effects of exposures, their interaction, and the effects of confounding variables. The applicability of case-control studies to provide preliminary information that might account for an unusual cluster of cases is demonstrated by an analysis of mortality from pancreatic carcinoma (775). Although the findings are somewhat constrained by the limited residential and occupational information available on the death certificate, a significant odds ratio was obtained for persons who worked in oil refining or paper manufacturing. A small effect was detected among persons living near refineries. A study of this type is useful for defining requirements for a more extensive interview study and is particularly interesting because of the implication of occupational and ambient environmental risk. Finally, the conduct of an interview study is shown in an analysis of exposure to artificial sweeteners (157), and the use of more than one control series is demonstrated in another investigation of pancreatic cancer (729). B. Cohort Studies The second major approach in analytic epidemiology is the cohort study, of which the primary design features are discussed here. Although cohort studies differ from case-control studies with respect to the way in which study subjects are selected, the majority of issues that pertain to the validity and analysis of data obtained in cohort studies are equivalent 159 to the issues considered with respect to the case-control method. Specifically, similar and equal attention should be given to the representativeness of the sample, the effects of both disease status and exposure misclassification, other selection biases, sources of exposure data, and problems of confounding variables. Indeed, many of the statistical approaches to the resulting data are the same, or entail the same assumptions, and therefore are not considered in detail here. The basic concept of a cohort study is relatively straightforward. A sample of a population is selected, and it is determined which members of the cohort possess the study characteristic or are exposed to the hypothesized etiologic agent. The cohort is then followed over time, and the incidence rate of the disease under consideration is calculated for the exposed group and for the unexposed group. If the rate of disease is higher among those exposed, an association between the risk factor and disease is inferred. In the retrospective, or nonconcurrent, cohort approach, the period of observation is historical, a method often used to study specially exposed groups such as industrial populations. Several examples of this method will be discussed in the context of measuring response by computing standardized and proportionate mortality ratios (Section IV). One difficulty in retrospectively assembling a cohort is in assuring that all members can be identified. Sometimes, comprehensive data are not available (37, 221), thus limiting the generalizability of the findings. In addition to special exposure groups, cohorts can be defined because they can be followed over time and because methods for identifying outcomes of interest are available. Examples of groups that have been studied include persons enrolled in prepaid medical care plans, groups of insured persons, obstetric populations, and volunteer groups. Additionally, a cohort may be defined on the basis of geography, such as all members of a specifc community. One of the most crucial aspects of a cohort study relates to followup, i.e., the task of determining outcome, usually the appearance of morbidity or mortality. It is important that determination of outcome be equally complete for exposed and unexposed cohort members, or for cohort members in each level of exposure in the nondichotomous case. Otherwise, measures of association between exposure and disease will be biased. Therefore, it is important to establish a follow-up (or tracing) mechanism that applies equally to all study subjects, whether the surveillance entails review of routine records or special data collection efforts. The length of follow-up is also a significant determinant in the results of a cohort study. If follow-up is not sufficiently long, cases of the study �160 John R. Wilkins III and Nancy A. Reiches disease will not have yet become clinically apparent (especially if the latent period is long), and the rates of disease will therefore be underestimated. Comparisons of findings under two different follow-up periods have been reported. One such example involves two analyses of a cohort of workers exposed to beta-naphthylamine and benzidine (750, 757). The time-of-measurement effect has also been discussed in a theoretical framework (257). The consequences of losing some proportion of persons during followup can be considerable, particularly if the losses are not random. If losses are biased with respect to outcome, the absolute rates of the study condition will be influenced, but their relative relationship to each exposure category will remain the same. Substantial losses, however, can distort the measurement of risk. A more serious situation will result if followup losses are biased with respect to exposure category, since this will affect the relative rates of disease between exposure groups. In some circumstances it is possible to estimate the effect of follow-up losses, particularly if the date on which an individual leaves the cohort is known. There are many examples of cohort studies designed to evaluate the effects of environmental exposures. Despite limitations in data availability, results of these investigations can be very revealing. For example, analysis of a cohort of persons engaged in the manufacture of mustard gas was limited in that only 84% of the cohort could be traced (755). To compensate, additional calculations were made under the extreme conservative assumption that all persons untraced were alive at the termination of the follow-up interval. Even under these conditions, a positive association was detected. The relative advantages and disadvantages of case-control versus cohort studies can be summarized briefly. Case-control studies are reasonably efficient and inexpensive to conduct. Comparatively few subjects are required, since the study begins with the identification of cases. This efficiency is particularly apparent in etiologic investigations of rare diseases, although the same advantage can accrue to retrospective cohort studies. By contrast, it is impractical, if not impossible, to assemble a large enough cohort to study in prospective fashion the occurrence of a rare condition, since the probability of any cohort member exhibiting the disease is extremely small. Case-control studies also offer an advantage with respect to time, since it is not necessary to wait for the development of new disease. Analytically, the major disadvantage of a case-control study is that relative risk cannot be measured directly, and there is controversy regarding the most appropriate estimation and testing of the odds ratio. Further difficulties, such as selection of the most appropriate control group, have been alluded to above and are discussed extensively in the literature (41, 108, 109). Epidemiologic Approaches to Chemical Hazard Assessment 161 By comparison, cohort studies have the advantage of classifying persons with respect to exposure prior to the development of disease. This can minimize (although not necessarily eliminate) problems of bias and misclassification. Most significantly, cohort analyses can yield actual incidence rates, thereby providing a direct measure of risk. The primary disadvantages of the cohort method relate to obstacles encountered in the follow-up of a large number of study subjects. Prospective cohort studies are expensive to execute and generally represent very large-scale undertakings. Consequently, they are not efficient for exploring new hypotheses; their strength lies in the provision of additional evidence after a specific hypothesis has been posited. IV. CRUCIAL ASPECTS OF ENVIRONMENTAL STUDY DESIGN To estimate accurately health risks resulting from chemical exposures, the relation between the amount or concentration of the agent in the critical organ or tissue (i.e., the dose) and the proportion of the population at risk manifesting a specified biological effect (i.e., the response) must be determined. In the following two subsections, epidemiologic approaches (and attendant problems) with respect to making measurements of dose and response in human populations are examined. A. Measurement of Dose Perhaps the most problematic aspect of designing epidemiologic studies of chemical hazards in human populations involves the measurement of dose. Although attention in this regard centers (properly) on considerations of the intensity, duration, and mode of external exposure to environmental chemicals, the problem of dose estimation is actually much more complex. The difficulty is easily appreciated by considering the many factors, conditions, and forces that affect the actual degree of external exposure, and thus, ultimately, the amount of toxicant reaching the critical organ or tissue. Therefore, if at first just those factors that determine the transport and fate of chemicals in the ambient environment are considered, many relevant questions may be posed. For example, what is (are) the source (sources) of the chemical agent in question? Is it a point or a nonpoint source? In what amounts and at what frequency is the substance discharged into the environment? Is the substance primarily of natural or anthropogenic origin, or a combination of the two? What are the patterns of use and of disposal of the material? Once the substance enters the human environment, how does it behave in air, in water, in soil, in �162 John R. Wilkins III and Nancy A. Reiches biota? To what extent is the substance transported between the various environmental compartments? To what extent will the chemical undergo a transformation in either air, water, soil, or biota? If a transformation does occur, will the product be more hazardous or less hazardous than the parent material? Is it possible to identify populations that are most likely to be exposed and/or most likely to be exposed to the highest levels of the substance? Are there subgroups of the population that are particularly sensitive to the agent in question? And once human exposure does occur, what information is available on the absorption of the agent into the body, on the distribution of the agent in plasma and tissue, and on the pathways and rates of excretion? Before proceeding further, the difference between exposure and dose must be clarified. Unfortunately, the distinction is not always made. Exposure to a given chemical substance refers simply to the extent of contact between the toxicant and those surfaces of the human body where absorption may occur. Thus, measures of exposure, i.e., measures of external exposure, are expressed in terms of the concentration of the agent in environmental media (air, water, food) that interface with relevant body membranes (11). Dose, on the other hand, refers to the amount or concentration of the toxicant in a critical organ or tissue [the critical organ or tissue being that which exhibits the first or the most serious effect (77, 765)]. It is the dose that must be obtained in order to quantify health risks resulting from chemical exposures. In general, however, the amount or concentration of a toxicant in a critical organ or tissue cannot be measured directly. Thus, dose must be measured in some indirect fashion and in such a way that the index used will result in an observed dose-response curve that accurately depicts, in both qualitative and quantitative terms, the true or actual dose-response relation for the substance in question. Surrogate measures of dose, then, will generally be derived from data either generated by some form of biological monitoring [the "systematic collection of human or other biological specimens for which analysis of pollutant concentrations, metabolites, and biotransformation products is of immediate application" (77)] or by some form of environmental monitoring [the "systematic collection, analysis, and evaluation of environmental samples, such as air, water, or food for pollutants" (77)]. 7. Biological Monitoring Given the usual inability to measure directly dose of the toxicant at the effector site, it would seem appropriate to assume that levels of the toxicant (or of its metabolites) in blood or other accessible tissue(s) would correlate with levels in the critical organ or tissue and thus could serve Epidemiologic Approaches to Chemical Hazard Assessment 163 as a reliable and valid index of dose. If so, data derived from measurements made on human tissues or excreta could be used to clarify dose-response relationships. For example, levels of lead and other heavy metals (such as cadmium and mercury) in blood (755, 233), urine (233), hair (97), or nails (107) have been used in the past as dose indices. Other tissues or excreta, including breast-milk (756), adipose tissue (275), expired air (44), and others (77), are at present amenable to biological monitoring. Unfortunately, there are relatively few applications in epidemiologic studies of chemical hazards (42, 88). However, there is a growing opportunity and need for a greater integration of toxicologic and epidemiologic data for purposes of health hazard assessment, as evidenced by recent papers (55, 275, 229). For a more detailed discussion of biological monitoring per se, see references 77 and 236. 2. Environmental Monitoring Most surrogate measures of dose 'used in epidemiologic studies are actually measures of external exposure to some agent, since they are usually derived from some sort of environmental data. Further, indices of dose based on such data may be divided into two categories: those that can be characterized as simple classifications and those that are based on Haber's law. a. Simple Classification Schemes. Measures of external exposure to toxic chemicals should, ideally, reflect the intensity, duration, and mode of the particular exposure. Further, such measures should be quantitative in nature, should accurately summarize the exposure experience over time of any individual study subject, and should reflect the amount or concentration of the toxicant in the critical organ or tissue. In order to develop such measures, detailed, extensive, and individualized environmental data are required. Such data, however, are not, for a number of reasons, usually available. For one thing, the substance or group of substances in question may have only recently come to be thought of as hazardous, in which case ambient and/or occupational environments will probably not have been routinely monitored in past time periods. Further, there may exist no analytical techniques capable of measuring the substance or substances in air, water, soil, and/or biota; or, if analytical methods are available, they may be grossly inadequate. Also, there may be no mechanism, practical or otherwise, to link levels of exposure to the environmental contaminant(s) in question with specific individuals. Consequently, when numerical estimates of external exposure cannot be calculated for individual study subjects, for whatever reason, �164 John R. Wilkins III and Nancy A. Reiches what may be described as simple classification schemes are developed instead. Although these simple schemes may be devised from either qualitative or quantitative environmental data, they generally take the form of ordinal-level measurements, measurements that do provide a rank ordering of exposure categories but do not provide an indication of the "distance" between categories. Further, exposure classification schemes of this sort are usually (but not always) employed in aggregate population studies, i.e., in studies comparing morbidity and/or mortality rates among large geographic units such as states, counties, communities, etc. When the classification scheme is based on qualitative information only, the exposure variable itself will likely be constructed as a simple high/medium/low, or a simpler high/low dichotomy. For example, in the prevalence study of chronic obstructive respiratory disease by Detels et al. (55), several lung function parameters were compared between the populations comprising two California communities. The "high" exposure community was described as "chronically exposed to relatively high levels of photochemical/oxidant-type pollutants," and the other, the "low" exposure community, was "subjected to low levels of chemical ambient air pollutants." In addition to high/low schemes and variations thereof such as exposed/ unexposed, aggregate populations have also often been categorized in terms of their degree of urbanization. Since U.S. Census data make this a relatively straightforward procedure, many studies report comparisons of morbidity and/or mortality rates among "urban" and "rural" populations, as well as among populations classified in similar ways (such as, for example, SMSA1 county with central city/SMSA county without central city/non-SMSA county). A number of studies employing this general approach, including notably several studies of air pollution, have focused on the differences in sex- and site-specific cancer death rates between urban and rural populations. In this regard, attention has centered on the cancer death rates among populations characterized by differing levels of urbanization. After a review of several such studies the general conclusion, as Carnow and Meier (55) point out, is that mortality from respiratory cancer is roughly twice as high in urban areas as in comparable rural areas, results consistent with the hypothesis that the higher levels of airborne carcinogens generally found in urban areas are etiologically involved in pulmonary neoplasms. Similarly, recent studies of organic chemical contamination of drinking water supplies report the classification of numerous aggregate populations with respect to various raw water source and treatment characteristics, 'Standard Metropolitan Statistical Area. Epidemiologic Approaches to Chemical Hazard Assessment 165 from which several types of comparisons have been made (225). For example, sex- and site-specific cancer mortality (and in some cases cancer incidence) rates in populations served surface water have been compared to cancer rates in populations served groundwater. Populations served chlorinated water have been compared to populations served unchlorinated water, and so forth. Although the interpretations of these studies differ, the results of all of them to date seem to suggest a slightly elevated risk of certain gastrointestinal and urinary tract cancers in populations consuming drinking water containing the highest levels of trace organic chemical contaminants. Because the schemes previously discussed are generally based on qualitative information only, they may be improved somewhat by using quantitative environmental measurements to assist in the construction of exposure classes. Studies of air and water pollution, again, illustrate the approach. Morris et al. (156) compared mortality between two small Pennsylvania communities, one of which was in close proximity to a coal-fired electric power plant (and therefore presumably had higher levels of air pollution than the other). Unlike the study by Detels et al. (55), which assigned exposure categories (high/low) without, apparently, using quantitative environmental measurements, Morris and co-workers used specific air quality indices (dust fall, sulfation rate, suspended particulates, and sulfur dioxide levels) to verify that a significant difference in air quality existed between the two study populations. Similar air quality measurements have been used to assign communities some air pollution exposure ranking in a number of other studies (38, 77). Studies of the organic chemical content of public drinking water supplies by the U.S. Environmental Protection Agency (USEPA) have provided quantitative measurements on the levels of various waterborne organic chemical contaminants, data that have been used in several epidemiologic studies (225). To summarize, the simple classification schemes previously discussed (1) are based on either qualitative or quantitative environmental data, (2) take the form of ordinal-level measurements, (3) are usually used in aggregate population studies, and (4) are perhaps the crudest of techniques available for measuring human exposures to chemical hazards. It is, however, possible under certain circumstances to refine these simple schemes. For example, in epidemiologic studies of occupational hazards, in which "exposure" data of some kind are usually available for individual study subjects, qualitative information such as the occupation and/or industry of each worker can form the basis of the classification scheme. This "occupational title" (OT) approach, as described by Gamble and Spirtas (52), assigns workers to categories of jobs that are functionally similar (i.e., jobs that involve the same equipment or process) and/or �Epidemiologic Approaches to Chemical Hazard Assessment 166 167 John R. Wilkins III and Nancy A. Reiches that are materially similar (i.e., jobs that involve similar products). Appropriate morbidity and/or mortality measures can then be compared among the various groups of workers, since the groups can be thought of as fairly homogeneous with respect to occupational exposures. For example, in a study of mortality among workers in a rubber tire manufacturing plant, McMichael et al. (146) needed to identify 60 separate OTs in order to characterize the work histories of approximately 1500 men. In their analyses, the 60 OTs were grouped into 16 major work areas and the frequency of employment in each OT group (i.e., the "rate of exposure" to each work area or OT group) was compared among the case and a control series for 7 cancer and 2 noncancer causes of death. The strongest associations were observed between several neoplasms and those work areas most likely to have involved the greatest exposures to organic and inorganic chemicals. Notably, exposure to solvents at several stages of tire building was associated with lymphatic leukemia. Other studies by McMichael and co-workers (144, 147) of the rubber industry, including one that focuses on leukemia and exposure to solvents (147), illustrate the OT approach. The OT approach has also been employed in a study of steel workers (124), and in studies of occupational exposures to asbestos (752) and chloromethyl methyl ether (54). The OT approach has several advantages. First, even in the absence of quantitative environmental sampling data it is possible to characterize systematically chemically complex environments, such as those encountered in rubber tire manufacturing plants. Second, what is usually a very large number of specific jobs can be reduced to a manageable number (at least from a statistical point of view) of fairly uniformly exposed OT groups. Also, the results of such an analysis can be quite useful in either generating or refining hypotheses of cause-and-effect relationships, because it is not necessary to state a priori an interest in some specific health effect, nor is it necessary to have a clear understanding of the induction and latency periods involved. Furthermore, if the results of a study employing the OT approach identify a particularly hazardous work area, intervention strategies may be implemented without knowledge of the specific chemical substances responsible. Additional studies could focus in detail on' the process and/or product related to the apparent high-risk work area in attempts to identify the specific causal agent or agents. Before attention is turned to other ways of measuring external exposure to chemicals in epidemiologic studies it is important to realize that the classification of aggregate populations into ordinal-level exposure categories involves, at least implicitly, the following assumptions: • The degree of exposure among the individuals comprising each class is uniform, or nearly so. • The designated categories make a clear distinction between the groups with respect to exposure levels. In order to gain some insight into the implications of these assumptions, imagine that two well-defined communities (A and B) are selected for study. Imagine further that Community A is in very close proximity to a point source of pollution, say a lead smelter, and that the mere existence of this smelter serves as the basis for labeling Community A the "highexposure" population. Community B, without smelter, is therefore considered the "low-exposure" population. If it is then assumed that the only difference between the two populations is the existence of the smelter, the situation may be conceptualized with the help of a simple sketch (see Fig. 2). Inspection of the figure suggests that exposure to lead in both communities is not precisely uniform, but rather the definitions, high/low, reflect an average amount of population exposure. Certainly, exposure levels in each community vary about a mean, and these means are significantly different from each other. (For simplicity, the distributions have been given a "normal" shape, although the actual distributional form is more likely to be log-normal.) Since, in this case, the exposure classification scheme reflects a sizable difference between the mean population exposure levels—i.e., the exposure definition employed discriminates between the two populations—a comparison of lead-related health measures will be valid. Consider, however, two reasons why this hypothetical situation is not realistic. First, even if the actual (true) underlying distributions of exposure to lead for the study populations are significantly different, the "looseness" or imprecision of simple classification schemes such as with smelter/without smelter, high/low, etc. can, in the general case, create categories that are not homogeneous (with respect to exposure) like those portrayed in Fig. 2. In other words, a certain amount of misclassification will occur, weakening the "purity" of comparing health effect measures between the two groups. Second, it is quite unlikely that Exposure classification Low Kgh (-jt.immunity B j. A Fig. 2. >^ Community A "" s > >. s / * k-rff k Degree of exposure Hypothetical example of lead exposure in two populations. �168 John R. Wilkins III and Nancy A. Reiches we will be able, realistically, to find two or more well-defined populations so vastly different with respect to the degree of exposure to the agent in question, thus compounding the effects of misclassification. This is certainly true for chemical contaminants like lead and organic pesticides that are widely distributed in nature. Further, while the hypothetical communities A and B are rank-ordered in terms of exposure to lead, the "distance" between categories, i.e., the actual degree of difference between A and B with respect to lead exposure, cannot, with such a scheme, be estimated without more information. And, in the particular case of community-wide exposure to lead, exposed/unexposed categories would be unjustified since there are numerous pathways of exposure including food, water, and air. What, then, are the epidemiologic implications of employing simple exposure classification schemes? For one, there are statistical implications. Artifact (resulting from the way in which exposure classification schemes are constructed) and/or the "natural" or environmental characteristics of the agent in question will tend to result in the mixing of individuals with different exposure experiences, thus creating heterogeneous rather than homogeneous exposure categories. The greater the degree of "mixing," i.e., the more "impure" the comparison, the more alike the comparison groups will be in terms of exposure, which in turn means they will be more alike with respect to any health effect truly related to the particular exposure. Consequently, the difference between the comparison groups (with respect to the measure of effect) will diminish, compromising the sensitivity of the study. Health effects, particularly modest ones, may therefore go undetected, possibly giving the illusion of "safety." b. Variations on Haber's Law (Unweighted Models of Cumulative Exposure). A common way to model human exposures to environmental chemical involves the application of Haber's law, an elementary concept in toxicology. This approach can be taken when quantitative environmental data are available and when it is possible to relate such data to individual study subjects, as is often the case in epidemiologic studies of workplace chemical hazards. Mathematically, Haber's law states that the magnitude of toxic effect £ is a function of the product of the intensity of exposure (in concentration units Q and the duration of exposure (in time units /), so that £ = C x t (75). With this concept it is possible to compute, for each person in a study population, an index of total cumulative exposure (TCE) by simply summing the product C x t for each period of exposure to the substance in question (if exposure levels change over time) over the entire study period. The (artificial) data in Table I illustrate the calculations for two Epidemiologic Approaches to Chemical Hazard Assessment 169 TABLE I Calculation of Individual Total Cumulative Exposures Worker i 1 Job./ Intensity of exposure, C (arbitrary units) Duration of exposure, / (arbitrary units) 1 2 3 1 2 3 1 3 9 Total cumulative exposure for worker 1:2 = 2 5 15 Total cumulative exposure for worker 2: C x i 1 6 27 34 4 5 90 99 (of n) hypothetical workers, each having worked for varying amounts of time in three different jobs entailing differing degrees of exposure to a single chemical substance. Since C and t are given equal weight in the computations, this particular method is often referred to as a simple or unweighted model of cumulative exposure. Once the total cumulative exposures are computed for each study subject, categories of TCE are then created, and appropriate morbidity and/or mortality measures compared across the classes. For example, in a study of coke oven workers (142) an index of total cumulative exposure to coal tar pitch volatiles (CTPV) was computed for each worker as follows: TCEworker,-= 2 (mean level of exposure, job j) all jobs x (duration of exposure, job j) Mortality rates for all causes of death combined, for all cancers combined, and for lung cancer were then compared across four (increasing) categories of total cumulative exposure, for white and for nonwhite workers. Notably, mortality from all cancers combined and from lung cancer increased sharply with increasing total cumulative exposure to CTPV among the nonwhite coke oven workers, results suggesting a dose-response relation. �170 Epidemiologic Approaches to Chemical Hazard Assessment John R. Wilkins HI and Nancy A. Reiches The applicability and validity of the simple, unweighted model of cumulative exposure rest on several assumptions. First, it is assumed that quantitative environmental data are available for all relevant time periods and that such data are accurate. Unfortunately, the quantitative characterization of local environments (ambient or occupational) over long periods of time is often not possible. In order to investigate properly the cause or causes of chemically related illness, measures of which (like death rates) are usually contemporary, information must be obtained on exposures occurring prior to the development of the disease. For diseases with substantial induction and/or latent periods, exposure levels dating back years and perhaps decades are required. Even when data on historical conditions are available, the accuracy and representativeness of such data can be questionable, reducing individual exposure histories to crude "guesstimates." Second, when satisfactory environmental monitoring data are available, it is assumed that it will be possible to select the most appropriate way to summarize exposure levels. Since, by nature, the concentration of most toxics in air, water, soil, etc. will fluctuate over time, so will human exposures. Depending on the substance in question, levels of the agent in environmental media may vary by the hour, by the day, by the week, by the month, and by the year, which raises several questions. Will simple arithmetic means appropriately summarize exposure levels? Would time-weighted averages be better? Should sharp peaks over the short term be given more, less, or equal weight, compared to steady, consistent, long-term trends? Although the answers are not usually clear, they are important questions, questions that relate to yet another assumption of the model: since simple cumulative models of exposure give equal weight to C and t, the rate of exposure can be ignored. The essence of this assumption is that the risk of disease would be the same for a given TCE achieved as a result of high exposure over the short term or as a result of low exposure over the long term. Exposure-time units, which are analogous to the familiar and widely used concept of person-time units (201), may be accumulated in virtually an infinite variety of ways: 100 exposure-time units = 1 exposure unit x 100 time units = 100 exposure units x 1 time unit. The problem here arises because, at least for certain types of chemical exposures, the risk of disease for a given TCE is not independent of the mode of exposure. For example, in a study of asbestos workers (66, 68) the risk of respiratory cancer was, on average, about twice as high for men who had had intermittent (and relatively high) asbestos exposures compared to men who had had steady (and relatively low) asbestos exposures. Since the mean total cumulative exposures in both groups were about the same (230.7 versus 236.0 exposure- 171 time units), this finding suggests that the rate at which exposures are accumulated must be taken into account. Another aspect of this "transient dose states" problem is something that has been referred to as the wasted dose phenomenon (197). Because disease in this particular model is viewed as dependent on the maximum TCE, i.e., dependent on the highest level or category of cumulative exposure achieved, the possibility of a "lower effective dose" is not considered, as Schneiderman et al. (197) point out. Exposures occurring after the biologic onset of disease (disease presumably resulting from the TCE up to that point) continue to be added to a person's cumulative exposure. Since the TCE responsible for disease would be overestimated by including exposures occurring during the latent period, the risk of disease would be underestimated at any TCE above the causative or "effective" TCE. Clearly, the longer the latency, the greater the discrepancy between the effective TCE and the TCE employed in the analysis, and thus the greater the underestimation of risk (as long as exposuretime units are accumulated beyond the time of biologic onset of the disease). Underestimation of risk may also occur when the exposure period and the follow-up period overlap. As Enterline (66) views it, a "dose-response fallacy" can occur because entry into the highest TCE categories can only occur for study subjects who survive long enough, i.e., to the end of the follow-up period. As he suggests, "a high dose and death tend to be incompatible states." Although one possible remedy here, at least for occupational studies, is to limit the investigation to retired persons only, this type of study entails other kinds of problems. On the other hand, risks may be overestimated when the disease of interest has a latent period and when the amount of time elapsed from the onset of exposure is not taken into account. In this case, persons falling into the lowest cumulative exposure classes will tend to be those with the least amount of exposure time, thereby artificially reducing the risk in the lower TCE classes and, accordingly, artificially inflating the risk in the higher TCE classes. As Pasternack and Shore suggest (171), a solution would be to simultaneously assign persons to their rightful category of TCE and to the appropriate category of time since exposure began, thus controlling for differences across TCE classes with respect to length of time exposed. Finally, the simple, unweighted model of cumulative exposure cannot be used to study chemically complex environments, i.e., when exposures to more than one chemical agent occur simultaneously. This is not surprising since, in general, the investigation of health risks resulting from multiple chemical exposures is quite difficult. One reason for this is that the �172 John R. Wilkins III and Nancy A. Reicbes Epidemiologic Approaches to Chemical Hazard Assessment necessary environmental data are rarely available (225). Another reason, as Saracci points out (795), is that it may be impossible to study enough subjects to isolate the effects of exposure to one agent in the presence of one or more other agents, particularly when the statistical analysis involves the cross-classification of the sample into contingency tables. And third, even if a large enough sample could be obtained, choice of the most appropriate statistical approach would be a matter of judgment. In point of fact, studies of interaction may be based on either additive models of disease risk (189, 190) or on multiplicative models (100). See also references 777, 797, 223 for a more thorough discussion of synergy and antagonism. Recent attempts have been made to refine the epidemiologic study of the health effects resulting from multiple chemical exposures (205), an area of research in which the knowledge base is rudimentary at present. areas used as the weights. This method is also discussed by Land and McGregor (727). Other attempts have been made to take latency into account by either partially weighting late exposures or by ignoring them altogether (i.e., giving them zero weight). This is the so-called lagged-exposure model, which assumes that exposures occurring a certain number of years prior to disease or death may be discounted. Mazumdar and Redmond (747) discuss this technique as applied to their study of lung cancer in men exposed to coal tar pitch volatiles. Pasternack and Shore (777) discuss the application of the lagged-exposures approach to actually estimating the average latent period in a set of data. c. Other Variations on Haber's Law (Weighted Models of Cumulative Exposure). A major deficiency of the unweighted model is that it does not take into account the concept of a latent period, i.e., the notion of an "effective" cumulative exposure is not addressed. In seeking to measure an effective cumulative exposure it has been argued that some portion of exposure occurring during the exposure period may legitimately be discounted, i.e., differentially weighted, because the portion of exposure in question presumably plays little or no causal role. A strong case can probably be made that contemporary risks are independent of very recent exposures, particularly for diseases with substantial latent periods. The central issue, of course, is the lack of knowledge about when the biologic onset of disease occurs, which severely limits the estimation of latency. One approach to this problem involves, first, making certain assumptions about the temporal pattern of disease occurrence following a single exposure, i.e., assumptions are made about the latent period. After making assumptions about the shape, the standard deviation, and the central tendency of the distribution of latent periods, the distribution itself is used to derive a series of weights, which in turn are applied to the cumulative exposures in appropriate time periods. For example, in the Lundin et al. (126) study of lung cancer mortality in underground uranium miners, weights were derived by, first, assuming that the time between the first exposure to underground uranium mining and death from lung cancer was log-normally distributed with a standard deviation of 0.1761 and a median latency of 10 years. Data on the miners were used to estimate median latency, while estimates of the shape and the spread of the distribution were based on those observed for leukemia following a single high exposure to atomic radiation (16, 727). The log-normal density function was then integrated over the relevant time intervals and these 173 B. Measurement of Response As described earlier, the morbidity or mortality rate is a useful measure of the risk of disease or death in a population. In practice, however, there are often situations in which a rate, in its usual form, cannot be computed as a measure of response in a population to a given exposure. In other situations the computed rate is not reliable and therefore should not be employed. For example, the problem of unreliable rates is common in the study of cancer. Although cancer is a leading cause of death, the actual probability of an individual dying of cancer in a given year is quite small. If the population under study is not sufficiently large the resulting rate, particularly the age-specific rate, will be quite unstable, and the confidence interval encompassing that rate will be very large. A measure called the standardized mortality ratio (SMR) is commonly used in such situations. The major advantage of the SMR is the introduction of information from a large, stable population. Using this method it is possible to compare the mortality experience of a defined subgroup with the total population. The SMR is computed as a ratio of the observed number of deaths in the study population to the number of deaths that are expected to occur in that group. It is with respect to the denominator of this ratio that the concept of a standard population is required. To compute the SMR it is not necessary to know the number of deaths that occur in each age group of the study population; one only needs to know the number of persons at risk in each age group. An expected number of deaths is generated by multiplying this figure by the age-specific mortality rate of the standard population. Both observed and expected numbers of deaths are then summed over all ages, and the ratio computed. The SMR is interpreted with respect to its deviation from unity. To the extent that it exceeds unity, the risk of death is said to be greater in the study population. Statistical properties of the SMR are known and �174 Epidemiologic Approaches to Chemical Hazard Assessment 175 John R. Wilkins III and Nancy A. Reiches therefore significance testing is possible. In this regard, tables containing critical values of SMRs are published2 (6). The choice of a standard population is not a trivial matter, nor is the most appropriate selection always obvious. For example, a comparison of death rates for different socioeconomic groups in a population might use as a standard the highest socioeconomic group (207). Resulting SMRs for lower groups would then reflect the assumption that excess deaths occur because living conditions, medical care, etc., are inadequate. Interpretively, this raises different issues than might surface if the entire population had served as the standard. In selecting a standard population, attention should be given to the purpose of the comparison and to its potential limitations. SMRs are frequently utilized in the study of defined occupational groups. One such investigation evaluated the mortality experience of iron foundry workers (53). Death rates in this cohort were compared to rates for the general U.S. male population. Potentially confounding variables, such as length of employment in the industry and race, were considered. Although silicosis has historically been a health problem in the foundry industry, unusually high mortality from chronic respiratory disease was not observed in this analysis. However, it cannot be discerned from the data whether this was a result of exposure to low levels of silica-containing dusts, or of insufficient numbers of workers with long exposure histories, or of too short a follow-up interval to allow for the clinical expression of disease and subsequent death of cohort members. Overall, this investigation revealed lower total mortality in the worker population. This finding is not unusual in occupational studies, a phenomenon discussed later (8, 155). A similarly designed study of workers in a chemical company was intended to determine whether socioeconomic status or job classification was related to overall or cause-specific mortality (769). This type of study is important because it recognizes the variability of individual characteristics within a broadly defined worker cohort. SMRs were computed using the U.S. white male population as the standard. Overall mortality was lower than expected, but certain malignancies (such as urinary organ neoplasms) yielded high SMRs. Stratification of the data by socioeconomic level showed statistical differences: low SMRs in the high socioeconomic group. Differences with respect to job category were also detected. For example, plant mechanics and machinists had more malignancies than expected, while inorganic chemical production workers 2 Although this discussion pertains to mortality, morbidity data can be treated in the same way. showed a decreased rate of cancer. Additionally, the analysis addressed the question of age at entry to the study and age at death. This approach is significant because it presents the investigator with a new set of paths to follow to explain notable trends in the health of industrial populations. Careful stratification of the cohort is particularly important, since, as the study of the chemical workers demonstrates, there is measurable heterogeneity within the cohort. For example, the low rate of cancer mortality in the high socioeconomic group might reflect a lower prevalence of smoking. Once the specific mortality pattern of a well-defined group is understood, there is opportunity for careful testing of such hypotheses. Other investigations have also used the approach of employing data on job classifications and have reported increased rates of malignant disease for specific categories (124, 125, 168). This has been noted for mechanics and machinists in more than one industry. In addition to SMRs, a measure called the proportional mortality ratio (PMR) has been used in a large number of analyses, particularly in studies of occupational groups. The PMR differs from the SMR in that the demographic composition of the population at risk is not known. Rather, the PMR represents the proportion of total deaths attributable to a specific cause in a study population. Consequently, the PMR is not a rate. It is simply a measure of the relative importance of a given cause of death, not a measure of the risk of death (154). Despite this inherent limitation, PMRs do have a role in epidemiologic analyses. First, the data necessary to compute a PMR are relatively easy to obtain—they are essentially only the data that would normally constitute the numerator of a mortality rate. Hence, PMR studies are sometimes referred to as "numerator studies." Second, although the absolute risk of death cannot be determined, knowledge of the relative importance of a cause of death can lead to testable hypotheses about potential etiologic factors. That is, if a cause of death is proportionately greater in one group than in another, exposures unique to the former might explain the observed differential. The validity of a PMR study depends on the extent to which certain assumptions are met by the data. The difficulty is that the assumptions cannot be tested empirically, since they require data that are not available, namely population data. The basic assumption is that the relationship between the PMRs of two groups being compared is equivalent to the relationship between the actual mortality rates in the populations. If this latter information were known, however, there would be no need to compute PMRs; rather the rates or SMRs could be compared directly. There is a danger of erroneous interpretation of PMRs if this assumption is not tenable or if the PMR is inappropriately interpreted as a measure of risk. For example, consider a hypothetical case of two study populations, �176 John R. Wilkins UI and Nancy A. Reiches in each of which 1000 total deaths are observed. Also assume that 200 deaths in each group are due to cancer. The PMR for each group would thus be 0.20. Clearly, cancer assumes the same relative importance in each group—20% of all deaths. But if the population of the second group is larger, the actual death rate from cancer would be smaller than in the first group. That is, the risk or probability of dying of cancer can vary even if its proportionate contribution to total mortality is the same. Consequently, in interpreting PMRs one must not be tempted by the false impression that the comparative risk of death is being analyzed. There are many examples of PMR studies in the literature. One such analysis investigated mortality patterns among employees exposed to poly vinyl chloride (PVC) (40). Since the population at risk could not be determined, the proportional mortality in various subgroups of the worker population was compared to similarly defined PMRs for the U.S. population. A comparison of these figures is an indication of whether or not relative excess mortality has occurred in the study population. In this particular investigation, there appeared to be an excess number of cancer deaths among both white males and white females. For the reasons already given, however, this finding must be interpreted with caution. The suggestion, however, of excess cancer mortality does provide a lead for more definitive investigation, thereby demonstrating the value of PMR analyses. The importance of such analyses is similarly demonstrated in a study of mortality among workers in a newspaper printing factory (92). This example is noteworthy because it demonstrates that PMR analysis can be an efficient method for very preliminary investigation of a new hypothesis. This study was undertaken following anecdotal reports of a high incidence of bladder cancer among the printing workers. In the particular group studied there was no evidence that bladder cancer assumed unusual importance as a cause of death, although the PMR for all neoplasms combined was very high. However, this appeared to be the result of a large number of deaths from lung cancer, implicating smoking rather than an industrial hazard. The comparability (and differences) of the PMR and SMR methods is demonstrated in an analysis of workers exposed to low levels of methylene chloride for up to 30 years (75). Specifically, the investigators wanted to determine whether this cohort exhibited high rates of mortality from ischemic heart disease, since exposure to chlorohydrocarbons may result in increased cardiac sensitivity (183). Since population data were not available for this group prior to 1964, a PMR approach was adopted. The post-1964 cohort was analyzed by an SMR approach. Proportional mortality ratios did not reveal any unusual mortality trends for any of Epidemiologic Approaches to Chemical Hazard Assessment 177 the 17 major diagnostic categories that were analyzed. Further breakdown of the data for specific malignancies also failed to show any statistically significant differences. In the second part of the analysis, two different standard populations were selected. The first was the group of all other males working in the same plant; the second was a general population standard. The results obtained exemplify the point noted earlier regarding the effect of a particular control population on study findings. With respect to the industrial standard, the methylene chloride-exposed group did not have significantly different SMRs for any major cause of death studied. However, when compared to the general population, significantly fewer deaths than expected were observed for malignant neoplasms and circulatory diseases. Specifically, ischemic heart disease mortality was reduced. While it has been emphasized that PMRs are not direct risk-assessment measures, their usefulness for preliminary screening of data is generally accepted. The methylene chloride study, however, demonstrates a case in which potentially erroneous conclusions might have been drawn if only the PMR analysis were available. In this study the PMRs and SMRs are not directly comparable, since the data for each were derived from different time periods. However, one might argue that the differences are small and that the conflicting results reflect the method of analysis. The findings of this investigation do not negate the relative value of PMR analysis, nor do they wholly validate the SMR approach. Rather, they point out the need for cautious interpretation. There are in the literature several rigorous comparisons of the two approaches described here (52, 118, 181). Although these issues will not be discussed in detail, it is important to recognize, at least in concept, some of the primary constraints. Some, such as the choice of the standard population and the failure of PMRs to measure risk, have been previously alluded to. Other problems of the SMR have also been identified (80, 81, 145). For example, the SMR does not reflect the effect of a hypothesized hazard on life expectancy; it counts only the number of deaths, not the ages at which they occur (87). It has been demonstrated that populations with different life expectancies can yield the same SMR. Additionally, the SMR is dependent on the age distribution of the study population. If younger workers have a lower mortality rate than the standard population, the SMR will not correctly estimate the probability of death, since this probability is not precisely (mathematically) equivalent to the mortality rate (74). These two figures are related, however, and consequently one can compute the degree of age dependence in the SMR (39). Finally, the SMR is not independent of the length of follow-up of the study cohort. That is, if calculated periodically during follow-up, the SMR is not expected �John R. Wilkins III and Nancy A. Reiches Epidemiologic Approaches to Chemical Hazard Assessment to remain constant. If the risk of death in the study group is high, SMRs might exceed 1.00 early in the study, but decline as follow-up continues. A final point about the measurements of outcome that have been discussed in this subsection relates to a question of sample selection bias known as the "healthy worker effect." A variety of data indicate that the fact that persons are healthy enough to be employed intrinsically predicts that their mortality experience will be more favorable than that of the general population. This effect was first identified nearly 100 years ago and has been widely recognized in contemporary epidemiology (86, 166). Furthermore, it has been demonstrated that the magnitude of the bias is related to the age distribution of the industrially employed cohort and to the specific causes of death being considered (65). In addition to the fitness of workers at the time of employment, the issue is further complicated by the fact that the composition of the cohort is influenced by the dynamics of individuals leaving the industry for health-related reasons. The empirical effects of these questions on SMRs has been reported. One of the more comprehensive analyses involved a study of all PVC workers in Great Britain (75). The findings supported an association between exposure to the vinyl chloride monomer and angiosarcoma of the liver; furthermore, it was demonstrated that the observed rates of mortality were indeed related to the selection of workers into the industry, their continued employment, and the length of time the cohort was followed. The cause-specific nature of these biases has been shown in a study of workers in five chemical plants, using an approach designed to minimize selection effects on the resultant SMRs (202). sometimes provide sufficient information for designing intervention strategies, thus interrupting the causal chain of events even if they are not fully known. Even with this inherent strength, epidemiologic assessment of health risks resulting from chemical exposures can be enhanced by incorporating knowledge derived from theoretical studies of the pathogenesis of cancer. In this' section we do not provide a comprehensive discussion of the molecular theories of carcinogenesis; rather, we highlight a few general principles that bear on the design of epidemiologic investigations and the interpretation of their results. Of particular importance in this context are the concepts of initiation and promotion. These terms were coined in the 1940s to define operationally the extended period between the initial exposure to a carcinogen and the expression of a malignancy (755,188). Early empirical demonstrations of this process involved the direct application of a confirmed chemical carcinogen (usually a polycyclic hydrocarbon) to the skin of a mouse— the initiation phase. Tumor promotion was accomplished by the application of another chemical agent, which was by itself incapable of inducing neoplasia (9). Although this general procedure has been refined in recent years, it still provides one of the fundamental models for studying chemically induced cancer. Subsequent experiments have confirmed that certain compounds, such as benzo[o]pyrene and methylcholanthrene, possess both initiation and promotion activity, and therefore are complete carcinogens (26, 27). The various stages of carcinogenesis have been demonstrated in organs other than the skin. For example, a breast cancer model in rats and mice has indicated that application of a carcinogen without the appropriate hormones does not result in a malignant tumor (79). Additionally, both initiating and promoting agents have been identified for tumors of the dog and rat bladder, the mouse lung and forestomach, and the rat colon, bone marrow, liver, and thyroid (777). In each case the initiator is an agent whose metabolites can react with DNA. The corresponding promoters range from natural products to normal circulating hormones. There are several general characteristics of the multistage carcinogenic process that have implications for the ultimate control of malignant disease in human populations. One important finding in this regard is that the process of initiation is not reversible, while the process of promotion is. This bears directly on the potential for prevention of neoplastic disease. That is, if the exposure is discontinued before cells in the target tissue develop the ability to multiply in the absence of the promoter, then formation of a tumor may be avoided. Reduction of risk of lung cancer following cessation of cigarette smoking may be an example of this type of intervention (174). The declining risk suggests that promoters are the cancer-causing elements in cigarette smoke. 178 V. RELATING MEASURES OF DOSE TO MEASURES OF RESPONSE There are several important aspects of the process by which the functional relationship between measures of dose and measures of response is determined. For example, in the case of cancer this process is influenced by the investigator's assumptions regarding the underlying biologic mechanisms of carcinogenesis. Although cancer has been recognized as a distinct disease for thousands of years, only recently has there developed some understanding of the mechanisms responsible for the transformation of a normal cell into a malignant one. Clearly, an elucidation of the biologic mechanisms of carcinogenesis will substantially increase the potential for prevention and control of neoplastic disease. The lack of this type of evidence, however, does not thoroughly preclude the ability to intervene; associations discovered in epidemiologic investigations can 179 �180 John R. Wilkins III and Nancy A. Reiches The concepts of initiation and promotion are inextricably bound to the phenomenon of latency. The importance of accounting for the latent period is well understood in epidemiologic research. Investigators attempt to introduce appropriate temporal relationships between measures of dose and measures of response. The latent period is a general feature of the natural history of neoplasia, whether the relevant exposure is chemical, radiologic, or viral. In the practice of epidemiologic research, however, the concept of a latent period and the temporal relationships between initiation and promotion phases pose various difficulties. In general, the duration of the latency period is unknown. Furthermore, the relationship between dose level and duration of latency is uncertain. Experiments with laboratory animals have indicated that an increased dose does shorten latency, and attempts have been made to quantify this relationship (7). However, the same mathematical model does not appear to hold for human populations (121). For example, in a study of bladder cancer among persons occupationally exposed to dyestuff intermediates, no relation between dose and latency could be detected (36). These findings have led to speculation that the duration of the latent period is affected by variables other than the dose of the initiator. Some of these factors are probably endogenous characteristics of the host, such as levels of pituitary hormones and the genetic makeup of the host (12). Other modifiers are thought to be exogenous and may include dietary constituents (153, 163). To the extent that these factors are unknown, the assessment of risk in human populations becomes more complicated, since the variation in dose rate over time, the reversibility of initiation, and the distinction between initiation and promotion must be accounted for if causal inferences are to result. Although a number of diverse quantitative approaches to modeling carcinogenesis in human populations have been proposed, none is entirely consistent with available empirical evidence (48, 227). Many of these models have incorporated information regarding the age distribution of cancer cases and have measured the effective duration of exposure before onset of disease over a wide range of ages (5, 56). By this method the comparative risk of exposure to the same agent at different ages could be analyzed in relation to dose, duration of latency, and the effect of altering various promoters. VI. CONCLUSION The purpose of this article has been to discuss some of the concepts fundamental to the epidemiologic evaluation of potential health risks stemming from chemical contamination of the human environment. These Epidemiologic Approaches to Chemical Hazard Assessment 181 methods assume a central role in any comprehensive attempt to understand the effects of chemical exposures on human health. Combined with evidence derived from the fields of chemistry and toxicology, the quantification of human risk should ultimately result in substantially improved methods for intervening in the process of disease causation. The epidemiologic approach is characterized by its systematic examination of patterns of exposure and response in human populations. Since the occurrence of disease is not a random phenomenon, epidemiologic investigation is uniquely suited to the generation and testing of etiologic ./hypotheses. The development of clues to explain chemically related illness I generally begins with descriptive methods, whose major purpose is to i detect variations in disease occurrence with respect to time and/or place. <f Observed secular trends may reflect alterations in exposure to environmental hazards. Notable geographic differences in disease occurrence may result from the presence of a risk factor in some populations and its absence in others. Once observed temporal or geographic patterns are established as real (as opposed'to artifactual), epidemiologic investigation may proceed to a variety of aggregate population studies, usually entailing correlation or regression techniques. In this phase of the process, attention focuses on the identification of demographic, socioeconomic, and environmental factors that may have etiologic implications. Although the methodologic problems associated with ecologic analyses are well recognized, the method has substantial utility for generating hypotheses that may subsequently be tested by more rigorous methods. If descriptive epidemiologic studies suggest a potentially adverse effect from a chemical exposure, investigations can then be designed to test formally the possible association between the agent and the disease. The analytic methods employed in this phase of epidemiologic inquiry incorporate data for individual study subjects, as opposed to aggregate or summary data for a population. Although the two primary methodologic approaches, case-control and cohort studies, differ with regard to the assemblage of subjects, they share a number of characteristics. In both cases, the desired endpoint is some quantitative (statistical) measure of risk associated with the exposure in question. Concern for proper classificatinn_nf_stiidy suhjectsj\jth_respect to exposunTand disease, selection of appropriate^ comparison groups, the requirement of reliable and valid ""exposure data", jmd the needto control_gonfounding factors are common" elements in both approaches.^ATtEough there are a variety of advantages and disadvantages intrinsic to both methods, the choice for a particular study depends on the hypothesis to be tested, the availability of necessary data, the rarity of the disease under consideration, and the prevalence and intensity of the exposure factor. �182 John R. Wilkins III and Nancy A. Reiches To a great extent, the applicability of results from case-control or cohort studies is dependent on the method by which exposure (and by implication, dose) is measured. The exposure variable may range from a simple qualitative classification to a more complex quantitative estimate of total cumulative exposure. What is important to recognize is that the measurement of exposure must be consistent with an underlying biologic theory of disease causation. For example, studies of malignant neoplasms must account for periods of latency and possible differential effects between initiating and promoting agents. Finally, methodologic attention must focus on appropriate measures of response to a chemical contaminant. Quantitative measures, such as standardized and proportional mortality ratios, need to be carefully constructed and statistically analyzed. Each aspect of the epidemiologic approach we have described is itself an area that continues to be subjected to intense critical scrutiny. For example, there is a rich literature regarding the statistical properties of the odds ratio, the choice of controls for case-control studies, the appropriate length of follow-up for cohort analyses, etc. That controversy exists in each area does not invalidate the overall approach; rather, it enhances the investigator's ability to reach critical decisions about all phases of study design, execution, data analysis, and interpretation. Perhaps more than for anything else, the epidemiologic method can be recommended for its vigilance regarding the possibility of alternative explanations to account for any observed finding. In the ideal case, the interpretation of epidemiologies data guards against the chance that a hazardous exposure is judged to '- 'safe." Epidemiologic analyses thus contribute to the control of disease by quantifying the probability that a chemical exposure may pose risk to human health, and by specifying the co-occurring conditions under which such risk might exist. If a hazard is confirmed, appropriate intervention strategies may be devised to interrupt the causal chain, thereby reducing morbidity and mortality. In this context the epidemiologic approach is fundamental to the assessment of chemical exposures, their effects on human health, and the benefits to society that might result from reduced environmental contamination. References 1. Albert, R. E., and Altshuler, B. (1973). In "Radionuclide Carcinogenesis" (C. L. Sanders, R. H. Busch, and J. E. Ballow, eds.), pp. 223-253. U.S. At. Energy Comm., Oak Ridge, Tennessee. 2. Alderson, M. R., and Meade, T. W. (1967). Br. J. Prev. Soc. Med. 21, 22-29. 3. Alter, M., Loewenson, R., and Harshe, M. (1973). J. Chronic Dis. 26, 755-767. Epidemiologic Approaches to Chemical Hazard Assessment 183 4. Armenian, H. K., and Lilienfeld, A. M. (1974). Am. J. Epidemiol. 99, 92-100. 5. Armitage, P., and Doll, R. (1961). In "Proceedings of Fourth Berkeley Symposium on Mathematical Statistics and Probability," pp. 19-38. Univ. of California Press, Berkeley. 6. Bailer, J. C., and Ederer, F. (1964). Biometrics 201, 639-643. 7. Barna-LIoyd, G. (1978). Science 202, 469. 8. Beaumont, J. J., and Weiss, N. S. (1980). Am. J. Epidemiol. 112, 775-786. 9. Berenblum, I., and Shubrik, P. (1947). Br. J. Cancer 1, 379-380. 10. Berkson, J. (1946). Biometrics 2, 47-53. 11. Berlin, A., Wolff, A. H., and Hasegawa, Y., eds. (1977). "International Workshop on the Use of Biological Specimens for the Assessment of Human Exposure to Environmental Pollutants." Martinus Nijhoff Publishers, The Hague, Netherlands. 12. Bielschowsky, F. (1955). Br. J. Cancer 9, 80-83. 13. Billewicz, W. Z. (1964). Br. J. Prev. Soc. Med. 18, 167-173. 14. Billewicz, W. Z. (1965). Biometrics 21, 623-644. 15. Birch, M. W. (1964). J. K. Stat. Soc., Ser. B 26, 313-324. 16. Bizzozero, O. H., Jr., Johnson, K. G., and Ciocco, A. (1966). N. Engl. J. Med. 274, 1059-1102. 17. Blair, J., and Mason, T. J. (1980). Arch. Environ. Health 35, 92-94. 18. Blalock, H. M., Jr. (1964). "Causal Inferences in Nonexperimental Research." Univ. of North Carolina Press, Chapel Hill. 19. Blot, W. J., Brinton, L. A., Fraumeni, J. F., Jr., and Stone, B. J. (1977). Science 198, 51-53. 20. Blot, W. J., and Fraumeni, J. F., Jr. (1975). Lancet 1, 142-144. 21. Blot, W. J., and Fraumeni, J. F., Jr. (1976). Am. J. Epidemiol. 103, 539-550. 22. Blot, W. J., and Fraumeni, J. F., Jr. (1977). J. Chronic Dis. 30, 745-757. 23. Blot, W. J., and Fraumeni, J. F., Jr. (1978). JNCI, J. Nat. Cancer Inst. 61, 10171023. 24. Blot, W. J., Fraumeni, J. F., Jr., Mason, T. J., and Hoover, R. N. (1979). Environ. Health Perspect. 32, 53-58. 25. Blot, W. J., Mason, T. J., Hoover, R., and Fraumeni, J. F., Jr. (1977). In "Origins of Human Cancer. Book A> Incidence of Cancer in Humans" (H. H. Hiatt, J. D. Watson, and J. A. Winsten, eds.), pp. 21-32. Cold Spring Harbor Laboratory, Cold Spring Harbor, New York. 26. Boutwell, R. K. (1964). Prog. Exp. Tumor Res. 4, 207-250. 27. Boutwell, R. K. (1974). CRC Crit. Rev. Toxicol. 2, 419-423. 28. Boyd, N. F., Patu, J. L., Ginsburg, A. D., and Myers, R. E. (1979). J. Chronic Dis. 32, 327-332. 29. Boyland, E. (1967). Proc. R. Soc. Med. 60, 93-99. 30. Boyland, E. (1967). Prog. Exp. Tumor Res. 11, 222-234. 31. Breslow, N. E., Day, N. E., Halvorsen, K. T., Prentice, R. L., and Sabai, C. (1978). Am. J. Epidemiol. 108, 299-307. 32. Brinton, L., Stone, B. J., Blot, W. J., and Fraumeni, J. F., Jr. (1976). Lancet 2, 628. 33. Bross, I. D. J. (1954). Biometrics 10, 478-486. 34. Carlson, H. A., and Bell, E. T. (1929). J. Cancer Res. 13, 126-135. 35. Carnow, B. W., and Meier, P. (1973). Arch. Environ. Health 27, 207-218. 36. Case, R. A. M., Hosker, M. E., McDonald, D. B.. and Pearson, J. T. (1954). Br. J. Ind. Med. 11, 75-104. 37. Case, R. A. M., and Lea, A. J. (1955). Br. J. Prev. Soc. Med. 9, 62-72. �185 John R. Wilkins HI and Nancy A. Refches Epidemiologic Approaches to Chemical Hazard Assessment 38. Chapman, R. S., Shy, C. M., and Finklea, J. F. (1973). Arch. Environ. Health 27, 138-142. 39. Chiang, C. L. (1961). Biometrics 17, 57-78. 40. Chiazze, L., Nichols, W. E., and Wong, O. (1977). JOM, J. Occup. Med. 19, 623628. 41. Cole, P. (1979). J. Chronic Dis. 32, 15-34. 42. Colucci, A. V., Hammer, D. I., Williams, M. E., Hinners, T. A., Pinkerton, C., Kent, J. L., and Love, G. J. (1973). Arch. Environ. Health, 27, 151-154. 43. Comstock, G. W. (1979). Am. J. Epidemiol. 110, 375-400. 44. Conkle, J. P., Camp, B. J., and Welch, B. E. (1975). Arch. Environ. Health 30, 290295. 45. Copeland, K. T., Checkoway, H., McMichael, A. J., and Holbrook, R. H. (1977). Am. J. Epidemiol. 105, 488-495. 46. Cornfield, J. (1951). JNCl, J. Nat. Cancer Inst. 11, 1269-1275. 47. Cornfield, J., and Haenszel, W. (1960). J. Chronic Dis. 11, 523-534. 48. Crump, K. S. (1975). Biometrics 35, 157-167. 49. Cutler, S. J., and Ederer, F., eds. (1961). "End Results and Mortality Trends in Cancer: Part I. End Results in Cancer," Nat. Cancer Inst. Monogr. 6. U.S. Gov. Printing Office, Washington, D.C. 50. Cutler, S. J., Scotto, J., Devesa, S. S., and Connelly, R. R. (1974). JNCI, J. Nat. Cancer Inst. S3, 1565-1575. 51. Davis, D. L., and Magee, B. H. (1979). Science 206, 1356-1357. 52. Decoufle, P., Thomas, T. L., and Pickle, L. W. (1980). Am. J. Epidemiol. Ill, 263269. 53. Decoufle, P., and Wood, D. J. (1979). Am. J. Epidemiol. 109, 667-675. 54. DeFonso, L. R., and Kelton, S. C. (1976). Arch. Environ. Health 31, 125-130. 55. Detels, R., Rokaw, S. N., and Coulson, A. H. (1979). Am. J. Epidemiol. 109, 3358. 56. Doll, R. (1971). J. R. Stat. Soc. Part 2, 134, 133-166. 57. Doll, R. (1977). Nature (London) 265, 589-596. 58. Doll, R., and Hill, A. B. (1952). Br. Med. J. 2, 1271-1286. 59. Doll, R., Muir, C., and Waterhouse, J., eds. (1970). "Cancer Incidence in Five Continents." Springer-Verlag, Berlin and New York. 60. Dorn, H. F., and Moriyama, I. M. (1964). Am. J. Public Health 54, 400-406. 61. Duncan, O. D., and Davis, B. (1953). Am. Sociol. Rev. 18, 665-666. 62. 'Edwards, J. H. (1961). Ann. Hum. Genet. 25, 89-93. 63. Ehrlich, D., Li-Sik, M., and Modan, B. (1975). J. Chronic Dis. 28, 359-364. 64. Engel, L. W., Strauchen, J. A., Chiazze, L.. and Heid. M. (1980). Am. J. Epidemiol 111, 99-112. 65. Enterline, P. E. (1975). JOM, J. Occup. Med. 17, 127-128. 66. Enterline, P. E. (1976). JOM, J. Occup. Med. 18, 150-156. 67. Enterline, P. E., and Capt, K. G. (1959). Am. J. Public Health 49, 205-212. 68. Enterline, P. E., Decoufle, P., and Henderson, V. (1972). JOM, J. Occup. Med. 14, 897-903. 69. Epstein, S. S. (1974). Cancer Res. 34, 2425-2435. 70. Fabsitz, R., and Feinleib, M. (1980). Am. J. Epidemiol. Ill, 315-328. 71. Feigl, P., Breslow, N. E., Laszlo, J., Priore, R. L., and Taylor, W. F. (1981). JNCI. J. Nat. Cancer Inst. 67, 1017-1024. 72. Feinstein, A. R., Pritchett, J. A., and Schimpff, C. R. (1969). Arch. Intern. Med. 123, 448-461. 73. Filov, V. A., Golubev, A. A., Liublina, E. I., and Tolokontsev, N. A. (1979). "Quantitative Toxicology." Wiley, New York. 74. Fleiss, J. R. (1973). "Statistical Methods for Rates and Proportions." Wiley, New York. 75. Fox, A. J., and Collier, P. F. (1976). Br. J. Prev. Soc. Med. 30, 225-230. 76. Fraumeni, J. F., Jr., and Blot, W. J. (1977). J. Chronic Dis. 30, 759-767. 77. French, J. G., Lowrimore, G., and Nelson, W. C. (1973). Arch. Environ. Health 27, 129-133. 78. Friedlander, B. R., Hearne, T., and Hall, S. (1978). JOM, J. Occup. Med. 20, 657666. 79. Furth, J. (1975). In "Cancer: A Comprehensive Treatise" (F. F. Becker, ed.), pp. 75-120. Plenum, New York. 80. Gaffey, W. R. (1975). JOM, J. Occup. Med. 17, 128. 81. Gaffey, W. R. (1976). JOM, J. Occup. Med. 18, 157-160. 82. Gamble, J., and Spirtas, R. (1976). JOM, J. Occup. Med. 18, 399-404. 83. Gart, J. J. (1971). Rev. Int. Stat. Inst. 39, 148-169. 84. Gittelsohn, A., and Senning, J. (1979). Am. J. Public Health 69, 680-689. 85. Goldberg, J. D. (1975). JASA, J. Am. Stat. Assoc. 70, 561-567. 86. Goldsmith, J. R. (1975). JOM, J. Occup. Med. 17, 126-127. 87. Goldsmith, J. R. (1977). JOM, J. Occup. Med. 19, 533-539. 88. Goldstein, I. F. (1981). Environ. Res. 25, 236-240. 89. Goodman, L. A. (1953). Am. Sociol. Rev. 18, 663-664. 90. Goodman, L. A. (1969). J. R. Stat. Soc., Ser. B 31, 485-498. 91. Goodman, R. A., Maton, K. A., Nolan, T. F., Bregman, D. J. and Hinman, A. R. (1982). JAMA, J. Am. Med. Assoc. 247, 793-7%. 92. Greenberg, M. (1972). Br. J. Ind. Med. 29, 15-20. 93. Guralnick, L. (1966). J. Chronic Dis. 19, 979-990. 94. Guy, W. A. (1856). J. R. Stat. Soc. 19, 12-27. 95. Haenszel, W. (1975). In "Persons at High Risk of Cancer: An Approach to Cancer Etiology and Control" (J. F. Fraumeni, Jr., ed.), pp. 361-371. Academic Press, New York. 96. Haldane, J. B. S. (1955). Ann. Hum. Genet. 20, 309-311. 97. Hammer, D. I., Finklea, J. F., Hendricks, R. H., Shy, C. M., and Horton, R. J. M. (1971). Am. J. Epidemiol. 93, 84-92. 98. Higginson, J. (1979). Science 205, 1363. 99. Higginson, J., and Muir, C. S. (1979). JNCI, J. Nat. Cancer Inst. 63, 1291-1298. 100. Hogan, M. D., Kupper, L. L., Most, B. M., and Baseman, J. K. (1978). Am. J. Epidemiol. 108, 60-67. 101. Hoover, R. (1979). Ann. N.Y. Acad. Sci. 329, 50-60. 102. Hoover, R. and Fraumeni, J. F., Jr. (1975). Environ. Res. 9, 196-207. 103. Hoover, R., Mason, T. J., McKay, F. W., and Fraumeni, J. F., Jr. (1975). Science 189, 1005-1007. 104. Hoover, R., Mason, T. J., McKay, F. W., and Fraumeni, J. F., Jr. (1975). In "Persons at High Risk of Cancer: An Approach to Cancer Etiology and Control" (J. F. Fraumeni, Jr., ed.), pp. 343-360. Academic Press, New York. 105. Hoover, R., McKay, F. W., and Fraumeni, J. F., Jr. (1976). JNCI, J. Nat. Cancer Inst. 57, 757-768. 106. Howe, G. R., Burch, J. D., Miller, A. B., Cook, A. M., Esteve, J., Morrison, B., Gordon, P., Chambers, L. W., Fodor, G., and Winsor, G. M. (1980). JNCI, J. Nat. Cancer Inst. 64, 701-713. 184 �186 Epidemiologic Approaches to Chemical Hazard Assessment John R. Wilkins III and Nancy A. Reiches 107. Jenkins, D. (1977). In "The Use of Biological Specimens for the Assessment of Human Exposure to Environmental Pollutants" (A. Berlin, A. H. Wolff, and Y. Hasegawa, eds.), pp. 215-220. Martinus Nijhoff Publishers, The Hague, Netherlands. 108. Jick, H., and Miettinen, O. S. (1973). N. Engl. J. Med. 289, 63-67. 109. Jick, H., and Vessey, M. P. (1978). Am. J. Epidemiol. 107, 1-7. 110. Keys, A., and Kihlberg, J. K. (1963). Am. J. Public Health S3, 1656-1665. 111. Kmet, J. (1970). J. Chronic Dis. 23, 305-324. 112. Knobloch, H., and Pasamanick, B. (1958). Am. J. Public Health 48, 1201-1208. 113. Knox, E. G. (1971). Br. Med. Bull. 27, 43. 114. Kolonel, L. N., Hirohata, T., and Nomina, A. M. Y. (1977). Am. J. Epidemiol. 106, 476-484. 115. Koran, L. M. (1975). N. Engl. J. Med. 293, 642-646. 116. Kotin, P. (1970). J. Chronic Dis. 23, 293-304. 117. Kupper, L. L., and Hogan, M. D. (1978). Am. J. Epidemiol. 108, 447-453. 118. Kupper, L. L., McMichael, A. J., Symons, M. J., and Most, B. M. (1978). J. Chronic Dis. 31, 15-22. 119. Kurland, L. T., and Molgaard, C. A. (1981). Sci. Am. 245, 54-63. 120. Kuzma, R. J., Kuzma, C. M., and Buncher, C. R. (1977). Am. J. Public Health 67, 725-729. 121. Land, C. E., and McGregor, D. H. (1977). In "Prevention and Detection of Cancer" (H. E. Nieburgs, ed.), Vol. 1, Part 1, pp. 831-843. Dekker, New York. 122. Lewis, M. S. (1980). J. Chronic Dis. 33, 703-712. 123. Lilienfeld, A. M., and Lilienfeld, D. E. (1980). "Foundations of Epidemiology," 2nd ed. Oxford Univ. Press, London and New York. 124. Lloyd, J. W., and Ciocco, A. (1969). JOM, J. Occup. Med. 11, 299-310. 125. Lloyd, J. W., Lundin, F. E., Jr., Redmond, C. K., and Geiser, P. B. (1970). JOM, J. Occup. Med. 12, 151-157. 126. Lundin, F. E., Jr., Archer, V. E., and Wagoner, J. F. (1979). In "Energy and Health" (N. E. Breslow and A. S. Whittemore, eds.), pp. 243-264. Soc. Ind. App. Math., Philadephia, Pennsylvania. 127. Maclennan, R., Muir, C., Steinitz, R., and Winkler, A. (1978). "Cancer Registration and its Techniques," IARC Sci. Publ. No. 21. Int. Agency Res. Cancer, Lyon. 128. MacMahon, B., and Pugh, T. F. (1970). "Epidemiology: Principles and Methods." Little, Brown, Boston, Massachusetts. 129. MacMahon, B., Yen, S., Trichopoulos, D., Warren, K., and Nardi, A. (1981). N. Engl. J. Med. 304, 630-633. 130. Mancuso, T. F., and Coulter, E. J. (1959). Am. J. Public Health 49, 1525-1536. 131. Mancuso, T. F., and El-Attar, A. A. (1967). J. Occup. Med. 9, 277-285. 132. Mancuso, T. F., and El-Attar, A. A. (1967). J. Occup. Med. 9, 147-162. 133. Manning, K. P., Skegg, D. C. A., Stell, P. M., and Doll, R. (1981). Clin. Otolaryngol. 6, 165-170. 134. Mantel, N. (1967). Cancer Res. 27, 209-220. 135. Mantel, N., and Haenszel, W. (1959). JNCI, J. Nat. Cancer Inst. 22, 719-748. 136. Mason, T. J., Fraumeni, J. F., Jr., and McKay, F. W. (1972). JNCI, J. Nat. Cancer Inst. 49, 661-664. 137. Mason, T. J., and McKay, F. W. (1974). "U.S. Cancer Mortality by County: 19501969," DHEW Publ. No. (NIH) 74-615. U.S. Govt. Printing Office, Washington, D.C. 138. Mason, T. J., McKay, F. W., Hoover, R., Blot, W. J., and Fraumeni, J. F., Jr. (1975). "Atlas of Cancer Mortality for U.S. Counties: 1950-1969," DHEW Publ. No. (NIH) 75-780. U.S. Govt. Printing Office, Washington, D.C. 139. 140. 141. 142. 143. 144. 145. 146. 147. 148. 149. 150. 151. 152. 153. 154. 155. 156. 157. 158. 159. 160. 161. 162. 163. 164. 165. 166. 167. 187 Mason, T. J., McKay, F. W., and Miller, R. W. (1974). JAMA, J. Am. Med. Assoc. 228, 1019-1020. Mausner, J. S., and Bahn, A. K. (1974). "Epidemiology: An Introductory Text." Saunders, Philadelphia, Pennsylvania. Mazumdar, S., and Redmond, C. K. (1979). In "Energy and Health" (N. E. Breslow and A. S. Whittemore, eds.), pp. 265-282. Soc. Ind. Appl. Math., Philadelphia, Pennsylvania. Mazumdar, S., Redmond, C. K., Sollecito, W., and Sussman, N. (1975). /. Air Pollut. Control Assoc. 25, 382-389. McKinlay, S. M. (1974). Appl. Stat. 23, 372-383. McMichael, A. J., Andjelkovic, D. A., and Tyroler, H. A. (1976). Ann. N.Y. Acad. Sci. 271, 125-137. McMichael, A. J., Haynes, S. A., and Tyroler, H. A. (1975). JOM, J. Occup. Med. 17, 128-131. McMichael, A. J., Spirtas, R., Gamble, J. F., and Tousey, P. M. (1976). JOM, J. Occup. Med. 18, 178-185. McMichael, A. J., Spirtas, R., Kupper, L. L., and Gamble, J. F. (1975). JOM, J. Occup. Med. 17, 234-239. McNemar, Q. (1947). Psychometrika 12, 153-157. Medical Services Study Group of the Royal ,ColIege of Physicians of London (1978). Br. Med. J. 2, 1063-1065. Menzel, H. (1950). Am. Social. Rev. 15, 674. Miettinen, O. S. (1970). Am. J. Epidemiol. 91, 111-118. Miettinen, O. S. (1974). Am. J. Epidemiol. 100, 350-353. Miller, J. A., Kline, B. E., Rusch, H. P., and Baumann, C. A. (1944). Cancer Res. 4, 153-158. Monson, R. R., Peters, J. M., and Johnson, M. N. (1974). Lancet 2, 397-398. Morgan, R. W., Kaplan, S. D., and Gaffey, W. R. (1981). JOM, J. Occup. Med. 23, 13-21. Morris, S. C., Shapiro, M. A., and Waller, J. H. (1976). Arch. Environ. Health 31, 248-254. Morrison, A. S., and Buring, J. E. (1980). N. Engl. J. Med. 302, 537-541. Mottran, J. C. (1944). J. Pathol. Bacterial. 56, 181-185. Muir, C. S. (1975). In "Persons at High Risk of Cancer: An Approach to Cancer Etiology and Control" (J. F. Fraumeni, Jr., ed.), pp. 293-305. Academic Press, New York. National Center for Health Statistics (1978). "Physician's Handbook on Medical Certification: Death, Birth, Fetal Death," DHEW Publ. No. (PHS) 78-1108. U.S. Govt. Printing Office, Washington, D.C. National Center for Health Statistics (1978). "Vital Statistics: Instructions for Classifying the Underlying Cause of Death, 1979," Part 2a. U.S. Govt. Printing Office, Washington, D.C. Naus, J. I. (1965). J. Am. Stat. Assoc. 60, 532-538. Newberne, P. M., Weigert, J., and Kula, N. (1979). Cancer Res. 39, 3986-3991. Newell, D. J. (1963). Biometrics 19, 187-188. Nordberg, G. F. (1976). "Effects and Dose-Response Relationships of Toxic Metals." Elsevier, Amsterdam. Ogle, W. (1885). "45th Annual Report of the Registrar-General of Births, Deaths, and Marriages in England." Registrar-General, London. Ohno, Y., Aoki, K., and Aoki, N. (1979). Int. J. Epidemiol. 8, 273-280. �188 Epidemiologic Approaches to Chemical Hazard Assessment John R. Wilkins III and Nancy A. Reiches 168. Ott, M. A., Holder, B. B., and Langner, R. R. (1975). Arch. Environ. Health 30, 333-339. 169. Ott, M. A., Holder, B. B., and Langner, R. R., (1976), JOM, J. Occup. Med. 18, 171-177. 170. Page, T., Harris, R. H., and Epstein, S. S. (1976). Science 193, 55-57. 171. Pastemack, B. S., and Shore, R. E. (1977). In "Environmental Health: Quantitative Methods" (A. Whittemore, ed.), pp. 49-71. Soc. Ind. Appl. Math., Philadelphia, Pennsylvania. 172. Percy, C., Garfinkel, L., Krueger, D. E., and Dolman, A. B. (1974). Public Health Rep. 89, 418-428. 173. Percy, C., Stanek, E., and Gloeckler, L. (1981). Am. J. Public Health 71, 242-250. 174. Peto, R. (1977). In "Origins of Human Cancer. Book A. Incidence of Cancer in Humans" (H. H. Hiatt, J. D. Watson, J. A. Winsten, eds.), pp. 1403-1428. Cold Spring Harbor Laboratory, Cold Spring Harbor, New York. 175. Pickle, L. W., and Gottlieb, M. S. (1980). Am. J. Public Health 70, 256-259. 176. Pike, M. C., and Smith, P. G. (1980). Biometrics 24, 541-556. 177. Pilot, H. C., and Sirica, A. E. (1980). Biochim. Biophys. Ada 60S, 191-196. 178. Polissar. L. (1980). Am. J. Epidemiol. Ill, 175-182. 179. Pollack, E. S., and Horm, J. W. (1980). JNCI, J. Nat. Cancer Inst. 64, 1091-1103. 180. Prentice, R. (1976). Biometrics 32, 599-606. 181. Redmond, C. K., and Breslin, P. P. (1975). JOM, J. Occup. Med. 17, 313-317. 182. Reiches, N. A., and Savitz, D. A. (1980). Am. J. Epidemiol. 112, 425. 183. Reinhardt, C. F., Azar, A., Maxfield, M. E., Smith, P. E., and Mullin, L. S. (1971). Arch. Environ. Health 22, 265-279. 184. Robinson, W. S. (1950). Am. Social. Rev. 15, 351-357. 185. Roels, H. A., Buchet, J. P., Lauwerys, R. R., Bruax, P., Claeys-Thoreau, F., Lafontaine, A., and Verduyn, G. (1980). Environ. Res. 22, 81-94. 186. Rogan, W. J., Bagniewska, A., and Damstra, T. (1980). N. Engl. J. Med. 302, 14501453. 187. Rogot, E., and Reid, D. D. (1975). Int. J. Epidemiol. 4, 51-54. 188. Rons, P., and Kidd, J. G. (1941). J. Exp. Med. 73, 365-371. 189. Rothman, K. J. (1974). Am. J. Epidemiol. 99, 385-388. 190. Rothman, K. J. (1976). Am. J. Epidemiol. 103, 506-511. 191. Rothman, K. J. (1978). Am. J. Epidemiol. 108, 347-349. 192. Rothman, K. J. (1981). Am. J. Epidemiol. 114, 253-259. 193. Rousch, G. C. (1980). Am. J. Epidemiol. Ill, 183-193. 194. Sackett, D. L. (1979). J. Chronic Dis. 32, 51-68. 195. Saracci, R. (1978). Int. J. Epidemiol. 7, 101-111. 196. Sartwell, P. E. (1950). Am. J. Hyg. 51, 310-318. 197. Schneiderman, M. A., Decoufle", P., and Brown, C. C. (1979). Ann. N.Y. Acad. Sci. 329, 92-130. 198. Schroeder, H. A. (1960). JAMA, J. Am. Med. Assoc. 172, 1902-1908. 199. Segi, M., and Kurihara, M. (1972). "Cancer Mortality in 24 Countries." Japan Cancer Society, Nagoya. 200. Seigel, D. G., and Greenhouse, S. W. (1973). J. Chronic Dis. 26, 219-225. 201. Sheps, M. C. (1966). Milbank Meml. Fund Q. 44, 69-91. 202. Shindell, S., Weisberg, R. F., and Giefer, E. E. (1978). JOM, J. Occup. Med. 20, 807-811. 203. Siegel, J. S. (1974). Demography 11, 1-23. 204. Silverberg, E. (1982). Co—Cancer J. Cttn. 30, 15-31. 205. 206. 207. 208. 209. 210. 211. 212. 213. 214. 215. 216. 217. 218. 219. 220. 221. 222. 223. 224. 225. 226. 227. 228. 229. 230. 231. 232. 233. 234. 235. 236. 189 Smith, A. H., Waxweiler, R. J., and Tyroler, H. A. (1980). Am. J. Epidemiol. 112, 787-797. Smith, R. J. (1980). Science 209, 998-1002. Spiegelman, M., and Marks, H. H. (1966). Hum. Biol. 38, 280-292. Spirtas, R. and Kaminski, R. (1978). JOM, J. Occup. Med. 20, 427-429. Stavraky, K. M. (1976). J. Chronic Dis. 29, 435-444. Stolley, P. D., Tonascia, J. 'A., Sartwell, P. E., Tockman, M. S., Tonascia, S., Rutledge, A., and Schinnar. R. (1978). Am. J. Epidemiol. 107, 226-235. Stone, B. J., Blot, W. J., and Fraumeni, J. F., Jr. (1978). JOM, J. Occup. Med. 20, 472-477. Susser, M. (1973). "Causal Thinking in the Health Sciences." Oxford Univ. Press, London and New York. Tassignon, J. P. (1979). JOM, J. Occup. Med. 21, 10. Thomas, D. G. (1975). Comput. Biomed. Res. 8, 423-446. Thomas, J. A. (1979). Fed. Proc., Fed. Am. Soc. Exp. Biol. 38, 1873-1874. Till, M. M., Hardisty, R. M., Pike, M. C., and Doll, R. (1967). Br. Med. J. 3, 755758. Toxic Substances Strategy Committee (1980). "Toxic Chemicals and Public Protection." U.S. Govt. Printing Office, Washington, D.C. Unger, M., and Olsen, J. (1980). Environ. Res. 23, 257-263. United States Bureau of Commerce (1966). "1963 Census of Manufactures." U.S. Govt. Printing Office, Washington, D.C. Vianna, N. J., and Greenwald, P. (1972). Ann. Intern. Med. 77, 169-180. Wada, S., Miyanishi, M., Nishimoto, Y., Kambe, S., and Miller, S. W. (1968). Lancet 1, 1161-1163. Wallenstein, S. (1980). Am. J. Epidemiol. Ill, 367-372. Walter, S. D., and Holford, T. R. (1978). Am. J. Epidemiol. 108, 341-346. Waterhouse, J., Muir, C. S., and Correa, P., eds. (1976). "Cancer Incidence in Five Continents." IARC Sci. Publ. 15. Int. Agency Res. Cancer, Lyon. Waxweiler, R. J. (1981). Envrion. Health Perspect. 42, 51-56. Weinstock, M. A. (1981). Int. J. Epidemiol. 10, 289-293. Whittemore, A. S. (1978). Adv. Cancer Res. 27, 55-58. Wilkins, J. R., Ill, Reiches, N. A., and Kruse\ C. W. (1979). Am. J. Epidemiol. 110, 420-448. Woods, J. S. (1979) Fed. Proc., Fed. Am. Soc. Exp. Biol. 38, 1891-18%. Woolf, B. (1955). Ann. Hum. Genet. 19, 251-253. Wu, M. (1980). J. Chronic Dis. 33, 207-213. Wynder, E. L., and Gori, G. B. (1977). JNCI, J. Nat. Cancer Inst. 58, 825-832. Wysowski, D. K., Landrigan, P. J., Ferguson, S. W., Fontaine, R. E., Tsongas, T. A., and Porter, B. (1978). Am. J. Epidemiol. 107, 27-35. Young, J. L., Asire, A. J., and Pollack, E. (1978). "SEER Program: Cancer Incidence and Mortality in the United States, 1973-1976," Nat. Cancer Inst. DHEW Publ. No. (NI-H) 78-1837. U.S. Govt. Printing Office, Washington, D.C. Young, J. L., Percy, C. L., and Asire, A. J., eds. (1981). "Surveillance, Epidemiology, and End Results: Incidence and Mortality Data, 1973-1977," Nat. Cancer Inst. Monogr. 57, DHHS Publ. No. (NIH) 81-2330. U.S. Govt. Printing Office, Washington, D.C. Zielhuis, R. L. (1979). In "The Use of Biological Specimens for the Assessment of Human Exposure to Environmental Pollutants" (A. Berlin, A. H. Wolff, and Y. Hasegawa, eds.), pp. 341-355. Martinus Nijhoff Publishers, The Hague, Netherlands. � Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Alvin L. Young Collection on Agent Orange Description An account of the resource <p style="margin-top: -1em; line-height: 1.2em;">The Alvin L. Young Collection on Agent Orange comprises 120 linear feet and spans the late 1800s to 2005; however, the bulk of the coverage is from the 1960s to the 1980s and there are many undated items. The collection was donated to Special Collections of the National Agricultural Library in 1985 by Dr. Alvin L. Young (1942- ). Dr. Young developed the collection as he conducted extensive research on the military defoliant Agent Orange. The collection is in good condition and includes letters, memoranda, books, reports, press releases, journal and newspaper clippings, field logs and notebooks, newsletters, maps, booklets and pamphlets, photographs, memorabilia, and audiotapes of an interview with Dr. Young.</p> <p>For more about this collection, <a href="/exhibits/speccoll/exhibits/show/alvin-l--young-collection-on-a">view the Agent Orange Exhibit.</a></p> Text A resource consisting primarily of words for reading. Examples include books, letters, dissertations, poems, newspapers, articles, archives of mailing lists. Note that facsimiles or images of texts are still of the genre Text. Box The box containing the original item. 052 Folder The folder containing the original item. 1387 Series The series number of the original item. Series III Subseries II Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Creator An entity primarily responsible for making the resource Kang, Han K. Alvin L. Young Barclay M. Shepard Date A point or period of time associated with an event in the lifecycle of the resource 1984-05-01 Title A name given to the resource Typescript: Health Effects of Agent Orange Exposure Subject The topic of the resource soft tissue sarcoma AOWG veteran health and hygiene ao_seriesIII https://www.nal.usda.gov/exhibits/speccoll/files/original/e2e570d4f610e7605bedc7e2617927bd.pdf 6c8b9205aedaaf306a0c0df9afa774f8 PDF Text Text Item ID Number 01336 Author Smith, Pamela W. Corporate Author Science Policy Research Division, Library of Congress, Report/Article TitlO Agent Orange: Veterans' Complaints Concerning Exposure to Herbicides in South Vietnam, Issue Brief Number IB80040 Journal/Book Title Year 1982 Month/Day APHI 20 Color n Number of Images DeSOriptOU Notes 21 Date originated: 09/06/79, Date Updated: 04/20/82. Includes a table of military projects involving agents orange, purple, pink, or green, with dates and descriptions of projects. Also includes a table of the signs, symptoms, and disorders reported after occupational exposure to TCP, 2,4,5-T or TCDD. Item gives an overview of background and policy analysis, health effects, perseonnel exposure, veterans' problems, Department of Defense efforts, health studies, the Interagency Work Group and Agent Orange Working Group, Congressional action, and legislation and hearings Thursday, May 03, 2001 Page 1336 of 1403 �AGENT ORANGE: VETERANS' COMPLAINTS CONCERNING EXPOSURE TO HERBICIDES IN SOUTH VIETNAM ISSUE BRIEF NUMBER IB80040 AUTHOR: Pamela W. Smith Science Policy Research Division THE LIBRARY OF CONGRESS CONGRESSIONAL RESEARCH SERVICE MAJOR ISSUES SYSTEM DATE ORIGINATED 09/06/79 DATE UPDATED 04/20/82 FOR ADDITIONAL INFORMATION CALL 287-5700 0426 �CRS- 1 IB80040 UPDATE-04/20/82 ISSUE DEFINITION From 1962 to 1971, the United States Air Force (USAF) sprayed various herbicide mixtures (chemicals that kill plants) in South Vietnam. The purpose of the spraying was to defoliate jungle growth to deprive the Communist forces of ground cover, and to destroy enemy crops to restrict food supplies. The most extensively used of these herbicide mixtures was known as Agent Orange, a 50:50 mix of two common herbicides called 2,4,5-T and 2,4-D (2,4,5-trichlorophenoxyacetic' acid and 2,4-dichlorophenoxyacetic acid). A third chemical present in the mixture in small amounts was TCDD, an inevitable by-product of the manufacture of 2,4,5-T. This chemical, called tetrachlorodibenzo-para-dioxin or simply "dioxin," is highly toxic to laboratory animals when administered in its pure form. Acute (short-term) toxicity values in humans have not been established, although Gosselin et al., in the 1976 edition of Clinical Toxicology of Commercial Products, puts TCDD in a class of chemicals for which the "probable lethal dose" for humans would be less than 5 mg/kg, or about 7 drops for a 150 Ib (70 kg) person. CRS has been unable to locate any report of a human death from exposure to pure TCDD. The human health effect that has been most consistently documented following exposure to small amounts of TCDD as a contaminant in other compounds is a skin condition known as chloracne. There is other, less consistent, evidence of damage to the liver and the nervous system in humans. Extensive testing on laboratory animals has been done to determine possible long-term effects of exposure to TCDD. It can induce cancer in some strains of rats and mice (carcinogenicity) , cause fetal death in several species (fetotoxicity) and birth defects in developing mouse fetuses (teratogenicity), but has been found not to cause genetic changes in mammalian cells (mutagenicity). The American Medical Association's Council on Scientific Affairs concluded that "there is no scientific evidence that 2,4-D, 2,4,5-T or TCDD has caused reproductive difficulties or hazards in the human. " Congressional interest was triggered by receipt of reports from Vietnam veterans who believed they had been harmed by exposure to herbicides, particularly Agent Orange. The 96th Congress held numerous hearings on the use of herbicides in South Vietnam, and various initiatives to deal with the problem were introduced. P.L. 96-151 was enacted to direct the Veterans Administration (VA) to conduct an epidemiological study on Vietnam veterans to determine whether there may be adverse human health effects associated with exposure to phenoxy herbicides and/or dioxin. This study and other studies planned will help elicit answers to the scientific questions posed by the Veterans Administration in determining whether or not the veterans' medical problems, allegedly due to exposure to Agent Orange and associated herbicides used in Vietnam, are compensable. Following recommendations made by the Interagency Work Group on Phenoxy Herbicides (now the Agent Orange Working Group), legislation was introduced in the 97th Congress to expand the scope of the VA's epidemiological study of the health effects of Agent Orange to include other factors related to military service in Vietnam. The legislation also allows veterans with medically certifiable conditions that might possibly have been caused by exposure to Agent Orange to receive medical care in VA facilities. The bill (H.R. 3499) was considered by the House and Senate in June 1981, put into final form in October, and signed by the President Nov. 3, 1981. Its title is the Veterans' Health Care, Training, and -Small Business Loan Act of 1981 (P.L. 97-72). �CRS- 2 IB80040 UPDATE-04/20/82 BACKGROUND AND POLICY ANALYSIS History During the summer of 1969, the first reports of human birth defects allegedly attributed to Agent Orange appeared in Vietnamese newspapers. Based on these allegations and the results of a study sponsored by the National Cancer Institute that showed that 2,4,5-T contaminated with TCDD caused birth defects in laboratory animals, the USAF stopped spraying 2,4,5-T in South Vietnam by early 1971. Although the Department of Defense maintains that only a limited number of U.S. military personnel can be positively identified as having been exposed to 2,4,5-T in South Vietnam (i.e., crews of aircraft that were used to spray herbicides), it is theoretically possible that large numbers of both military personnel (from the United States, South Vietnam, North Vietnam, Australia, and New Zealand) and civilians (especially South Vietnamese peasants) were exposed to 2,4,5-T through the USAF spraying program. A growing number of U.S. veterans who served in South Vietnam have begun to attribute the cause of various chronic ailments which they are now experiencing (especially nervous disorders, cancers, and birth defects in their offspring) to exposure to 2,4,5-T in South Vietnam, and many have filed claims with the VA for compensation. The VA has not yet awarded compensation to veterans for any claims related to 2,4,5-T exposure because of the lack of valid human data to prove a cause and effect relationship between exposure to 2,4,5-T and/or TCDD and specific health effects (except for chloracne). TCDD Contamination The industrial production "of 2,4,5-T always results in some TCDD contamination although TCDD levels can be reduced to about 0.01 parts per million (ppm) with current technology. Because it was not widely recognized until the late 1960s that 2,4,5-T could contain hazardous amounts of TCDD, manufacturers did not start reducing the level of TCDD in 2,4,5-T until the USAF was already winding down its herbicide spraying program. The average TCDD levels in the 2,4,5-T - containing herbicide mixtures used in South Vietnam were approximately 2 ppm in Agent Orange (which accounted for approximately 96% of the 2,4,5-T used in South Vietnam), approximately 32.8 ppm in Agent Purple, and 65.6 ppm in Agents Pink and Green (Agents Purple, Pink, and Green contained the remaining 2,4,5-T used in South Vietnam). The herbicides procured by the USAF were code named after the colored band that was placed around each 55 gallon drum in order to identify the contents. / Health Effects — Animal Data Although TCDD is well established as one of the most toxic chemicals known for acute (short-term) effects, there is no consensus in the scientific community over the -Chronic (long-term) effects on humans of exposure to low levels of TCDD (such as those levels found in the herbicides used in South Vietnam) . Statistically significant animal experiments have demonstrated that �CRS- 3 IB80040 UPDATE-04/20/82 2,4,5-T containing low levels of TCDD and/or TCDD alone have caused various tumors in mice and rats. A recently-released National Toxicology Program bioassay of TCDD confirms these earlier reports that TCDD is carcinogenic in some laboratory animals. Thymic atrophy (without a corresponding loss in immune function) and severe weight loss have been observed in many species after TCDD exposure. In some species, acute exposure to TCDD can cause liver damage. Birth defects such as cleft palate and kidney abnormalities have been reported in baby mice when the mothers were exposed during pregnancy. A National Toxicology Program animal study of male reproductive effects of exposure to TCDD, however, has failed to reveal a statistically significant increase in reproductive abnormalities in TCDD-exposed animals or birth defects in the TCDD-exposed male animals' offspring. Although there is some experimental evidence that TCDD may cause mutations (changes in the cell's genetic material that may produce birth defects in as-yet-unconceived offspring), these experiments have been few, they have been done mainly on non-mammalian species or in vitro (in test tubes), and they have basically been inconclusive. Some investigators feel that humans are less sensitive than animals to the toxic effects of TCDD. There is wide variation of" responses to TCDD among different species, and the mechanisms of its toxicity and metabolism are not understood. More work needs to be done to clarify whether human exposure to TCDD can produce the same health effects with the same potency as those observed in animal studies. Health Effects. -- Human.TData. If a cause and effect relationship is to be scientifically established between human exposure to a chemical and chronic health effects, a study which meets the following minimum criteria must be conducted to prove that such a relationship exists: a group of people (the "study group") must be identified that has already been exposed to the chemical under study (it would help to know the level of exposure); this study group must be large enough to detect chronic effects with statistical significance (to find an effect that occurred in 1 out of 100 people, one would need to examine at least 100 people); a control group must be found that ideally would differ from the study group only by never having been exposed to the chemical under study (thus, any differences in chronic health effects between the study and control groups could be attributed only to exposure to the chemical under study); and, due to the long latency period for many chronic effects, the study and control groups must be followed for as many years after exposure as it takes for the chronic effects to show up (i.e., in carcinogenicity studies, subjects must be followed for a minimum of 10 to 20 years after exposure to the suspect carcinogen). These exacting criteria are not met by most of the studies that have explored the relationship between human exposure to TCDD and/or 2,4,5,-T and subsequent health effects. Only for chloracne has such a cause and effect relationship been well established. Workers who have been exposed to TCDD and/or 2,4,5-T in industrial explosions or who have had other occupational exposure are frequently found to have a skin condition known as chloracne — which resembles normal acne except that it is caused by chemical exposure. Chloracne can appear from weeks to months after initial exposure and while mild cases (blackheads) may clear in a matter of months, severe cases (inflammatory lesions and scars) may last up to 30 years after exposure has ceased. While the severity of chloracne is not thought to correlate precisely with the intensity or duration of exposure to TCDD and/or 2,4,5-T, chloracne is associated so �CRS- 4 IB80040 UPDATE-04/2'0/82 closely with exposure that some scientists argue that patients who have not exhibited chloracne are unlikely to have suffered other toxic effects of TCDD and/or 2,4,5-T exposure. Studies of these exposed workers have also indicated a variety of other health problems. For example, the United States Air Force Technical Report on the Toxicology, Environmental Fate, and Human Risk of Herbicide Orange and its associated Dioxin (1978) listed a number of symptoms, signs, or disorders that had been reported after occupational exposure to TCP (trichlorophenol, 2,4,5-T's precursor), 2,4,5-T, or TCDD (see Appendix). As noted, these studies, which reported symptoms associated with human exposure to dioxin, were not conducted in such a way as to prove a cause-and-effect relationship between exposure to TCDD and/or 2,4,5-T and any of these effects, but they may be indicative of such a relationship. Several of the above studies have focused on investigating cancer rates among exposed workers. These studies do not show a clear cause/effect relationship between carcinogenicity associated with exposure to TCDD and/or 2,4,5-T because very few exposed workers (with the exception of those in Nitro, West Virginia) have been followed for more than ten years (the latency period for most cancers being 15 to 40 years after exposure) and the results have been equivocal. However, they support a continuing suspicion and indicate a need for further study. When the scientific panel of the Interagency Work Group on Phenoxy Herbicides reviewed five research papers by European scientists, it concluded that despite the studies' limitations, they do "show a correlation between exposure to phenoxy acid herbicides and an increased risk of some forms of cancer." A soft-tissue "sarcoma study has been proposed that will be conducted jointly by the Armed Forces Institute of Pathology and the National Cancer Institute. Studies that have been conducted in non-industrial settings have not been able to prove a cause and effect relationship between exposure to TCDD and/or 2,4,5-T and specific health effects. The National Academy of Sciences (NAS) was directed by Congress P.L. 91-441, sec. 506 (c) to conduct a study on the effects of herbicides in South Vietnam, including health effects. This NAS study, as well as at least three other similar studies that were conducted in South Vietnam during the early 1970s, were unable to find adequate data upon which to reach any conclusions concerning a causal effect between exposure to herbicides and any health effects, including birth defects. An explosion in a Hoffman-LaRoche chemical plant in Seveso, Italy in July 1976 caused thousands of people to be exposed to varying doses of TCDD as a toxic cloud drifted across the Italian countryside in a cone-shaped pattern about a mile long and half a mile wide. Some 5400 people lived in the two zones most directly affected, with an additional 40,000 people potentially exposed. Animals began to die 2 to 3 days after the incident with over 1,100 animals killed by direct exposure to TCDD. Over 700 people were evacuated from their homes. Chloracne was reported in 187 people, mostly children, and it tended to heal rapidly. Long-term human health effects of exposure to TCDD at Seveso are still being studied. Preliminary findings reported in 1979 by Hoffman-LaRoche revealed that Seveso residents had suffered liver damage but that there was no permanent breakdown in liver function. They also reported that rates of spontaneous abortions, fetal malformations, congenital defects, chromosome aberrations, reactions to infectious disease, and morbidity and mortality were not affected by TCDD exposure. As reported by the American Medical Association's Council on Scientific Affairs, "The most recent progress report on the long-term epidemiologic survey of the residents of the Seveso area emphasizes the preliminary nature of their �. . CRS- 5 IB80040 UPDATE-04/20/82 findings and reiterates the conclusions of prior investigators. Except for the skin, no organs or body functions were impaired. No derangement of gestation, no fetal lethality and loss, no gross malformations-, no growth retardation at term and no cytogenetic abnormalities have yet occurred." Health effects of domestic use of 2,4,5-T have been kept under surveillance by various Government agencies for some years. In April 1970, the Departments of Agriculture, Interior, and Health, Education and Welfare jointly announced the suspension of certain uses of 2,4,5-T following studies indicating that it was a teratogen. On Apr. 21, 1978, the Environmental Protection Agency (EPA) issued a Rebuttable Presumption Against Registration (RPAR) on 2,4,5-T, finding that the herbicide had exceeded certain risk criteria and inviting comments from interested parties. The RPAR was based on toxicological data from animal studies showing a correlation between 2,4,5-T exposure and cancer and birth defects. One of the comments received was from Alsea, Oregon, claiming that there was a high incidence of miscarriage among area women following spraying of the local forests with 2,4,5-T. EPA investigated this claim and reported its conclusion that the incidence of spontaneous abortion over a 6-year period in Alsea was higher than the rates in two other regions of Oregon that had lower rates of 2,4,5-T usage. Based on the combination of evidence from the animal studies and the Alsea study, EPA announced the emergency suspension of the domestic use of 2,4,5-T on forests, pastures, and rights-of-way on Feb. 28, 1979. The Alsea study has been criticized on methodological grounds by various groups, and its results are rejected by a number of writers. EPA hearings on cancellation of 2,4,5-T began in June 1979. On Mar. 24, 1981, EPA and Dow Chemical requested a recess in the hearing to discuss the possiblity of negotiating a settlement. The recess has been extended while the negotiations continue. Herbicide Spraying in Vietnam Approximately 107 million pounds of herbicides were aerially disseminated on 6 million acres of South Vietnam (an area about the size of Connecticut) from January 1962 to February 1971. Approximately 276,000 gallons of Agents Green, Pink, and Purple were sprayed in South Vietnam prior to 1965 when they were replaced by Agent Orange. Approximately 11 million gallo.ns of Agent Orange were then sprayed in South Vietnam — making it the most widely used herbicide of the war. Ninety percent of Agent Orange was sprayed on 2.9 million acres of inland forests and mangrove forests for defoliation, 8% was sprayed on enemy crops for crop destruction, and the remaining 2% was sprayed around base perimeters, cache sites, waterways, and communications lines. The Air Force continued to operate its herbicide spraying program in South Vietnam until the late 1960s when the National Cancer Institute released results of an animal bioassay that showed 2,4,5-T to be teratogenic and/or fetotoxic in rodents, and newspapers in South Vietnam started reporting health problems among the rural populations who had been exposed to such herbicides. The Air Force first restricted the use of Agent Orange to areas remote from populations in October of 1969, then stopped all airplane spraying of Agent Orange in early 1970 and all helicopter spraying of Agent Orange by 1971. All remaining herbicide stocks were gathered and stored at either Gulfport, Mississippi or Johnston Island in the Pacific until they were incinerated at sea in 1977. The following table outlines major military projects involving handling of Agents Orange, Purple, Pink, or Green in South Vietnam. the �CRS-6 IB80040 UPDATE-04/2'0/82 MILITARY PROJECTS INVOLVING AGENTS ORANGE, PURPLE, PINK, OR GREEN PROJECT DATES DESCRIPTION AGILE 1960-68 Selection of herbicides., and development and evaluation of defoliation techniques. RANCH HAND 1962-71 Aerial spraying of herbicides in South Vietnam. Various USAF Projects 1962-70 'Development and testing of aerial spray equipment. PACER IVY 1971 Air Force Logistics Command Project 1972-77 PACER HO 1977 Redrumming and movement of surplus herbicide from South Vietnam to Johnston Island. Maintenance of herbicide inventory and research on options for disposal. Dedrumming of herbicide inventory and at-sea incineration of Agent Orange. Each of these projects involved some human exposure to the herbicide 2,4,5-T and its contaminant, TCDD. The difficulty lies in determining who may have been exposed and at what level. �CRS-7 IB80040 UPDATE-04/20/82 Personnel Exposed The early trials that were conducted in South Vietnam to improve aircraft spray systems (1960 to early 1962) were conducted by USAF personnel assigned to the Special Aerial Spray Flight Division, Langley AFB, Va. (USAF personnel engaged in the herbicide program did not receive permanent change of station assignments to South Vietnam until 1964 -- thus making it more difficult to track personnel who may have been exposed to herbicides). During late 1962 and early 1963, the Crops Division at Fort Detrick and the USAF Armament Laboratory at Eglin Air Force Base, Florida were involved in efforts to provide improvements in spray system components in support of Operation RANCH HAND. Most of the personnel involved in the actual handling of herbicide drums were Vietnamese. However, a USAF flight mechanic or crew chief was responsible for ensuring that the aircraft were properly loaded and that the spray systems were functional. Each herbicide aircrew consisted of a pilot and a copilot (both usually officers) and a flight mechanic/spray unit operator (usually enlisted). The aircrews were frequently joined by South Vietnamese and U.S. observers. As noted in a USAF report, "within the aircraft, it was not uncommon to have herbicide leakage from around the numerous hose connections joining the spray tank and pumps with the wing and aft spray booms. In hot weather, the odor of herbicide within the aircraft was decidedly noticeable." The USAF has data on 6,542 herbicide spraying missions that took place between August 1965 and February 1971 on its "HERBS" computer tape. These data were compiled on a mission-by-mission basis from reports and files in various commands and offices in South Vietnam and the United States. The HERBS tape contains the following data for each mission: date; mission number; location; province and UTM coordinates; type of herbicide (basically, Agents Orange, White, or Blue); quantity of herbicide; area covered; purpose of mission (defoliation, crop destruction, etc.); and type of aircraft (plane or helicopter). The NAS used the HERBS tape in its evaluation of the effects of herbicides on South Vietnam. After evaluating the HERBS data, the NAS concluded that the HERBS tape accounted for approximately 86% of all herbicide operations in South Vietnam and that "despite certain recognized deficiencies," the HERBS tape is "a reliable source for an assessment of the major part of the herbicide operation in South Vietnam" and "is the best and in fact the only available comprehensive computation of the major part of the herbicide operations conducted in the Vietnam war." When the DOD suspended all use of 2,4,5-T in South Vietnam, the USAF was left with an inventory of 2.22 million gallons of unused Agent Orange (1.37 million gallons which had been shipped to South Vietnam and 0.85 million gallons which were waiting to be shipped at the Naval Construction Battalion Center at Gulfport, Mississippi). In April 1972, the 1.37 million gallons of Agent Orange were moved from South Vietnam to Johnston Island in the Pacific Ocean for storage. The total amount of TCDD in the remaining Agent Orange stock was approximately 44.1 pounds. Problems began to arise in both locations as drums reportedly began to leak and the USAF expressed concern over further leakage problems that could occur if a tornado hit the Mississippi site or if a typhoon hit the Pacific site. After exploring a number of options, the USAF decided to dispose of the Agent Orange by burning it at high temperatures at sea on the Dutch incinerator ship named the "Vulcanus." The Agent Orange was drained from the drums at each site and �CRS- 8 IB80040 UPDATE-04/20/82 transferred to the Vulcanus. The empty drums were then rinsed with diesel fuel and crushed. The rinse fluid was combined with the Agent Orange for incineration at sea. A total of 15,480 drums of Agent Orange were processed at the Mississippi site between May 24, 1977, and June 10, 1977, by approximately 110 USAF officers/technicians from the five Air Logistics Centers of the Air Force Logistics Command (located at Kelly AFB Texas; Hill AFB, Utah; Warner Robbins AFB, Georgia; Tinker AFB, Oklahoma; and McCellan AFB, California). A total of 24,795 drums of Agent Orange were processed at the Johnston Island site between July 27, 1977, and Aug. 23, 1977. Approximately 100 civilian employees hired by a contractor performed the dedrumming process. At both the Johnston Island and Mississippi sites, workers were provided with daily changes of work clothes and some with protective clothing. The Agent Orange was incinerated at sea in the period from July to September 1977. Results of industrial hygiene studies conducted at the time of the disposal operation by the U.S. Air Force (Gulfport) and the Battelle Memorial Institute (Johnston Island) revealed no immediate adverse health effects among the personnel involved in the operation. Department of Defense, Efforts The USAF has stated that it can now identify 1,264 servicemen who were directly exposed to Agent Orange as they handled herbicide., containers and flew spraying missions in South Vietnam. The Air Force has initiated a health effects study of Air Force personnel involved in operation "Ranch Hand," who sprayed Agent Orange in Vietnam. The Department of Defense (DOD) believes that these individuals had at least 1000 ti-mes more exposure .to Agent Orange than the average ground troops. The epidemiological study will try to determine whether a causal relationship can be established between exposure to the 2,4-D/2,4,5-T mixture and long-term health effects. Although the study was originally scheduled to begin in October 1979, peer review of its protocols forced delays. The University of Texas School of Public Health, the U.S. Air Force Scientific Advisory Board and the Armed Forces Epidemiological Board reviewed the study protocols and recommended modifications. Then the Air Force asked the National Academy of Sciences (NAS) to review the protocols. On May 6, 1980, the NAS announced recommendations that the scope and duration of the study be expanded to increase the likelihood of obtaining definitive data. NAS also expressed concern about the public perception of credibility and impartiality of a study conducted internally by the Air Force. The Interagency Work Group's Scientific Panel, however, has recommended that the study, as designed by the Air Force, be conducted because, despite its limitations, it provides "a focus as to the type of health effects that may possibly occur in other (ground troop) personnel." The Ranch Hand study is proceeding in several phases and will continue for 20 years. The first phase consists of a detailed medical history questionnaire, which has been administered to the Ranch Handers in their homes by trained interviewers from Louis Harris and Associates. A carefully matched control group, selected from military records held by the Air Force, has also been interviewed. The first data from the questionnaire should be available by mid-summer 1982. Also underway is the second phase of the study, a 3-day series of physical examinations, including a battery of psychological tests, which will be given to both the study group and the controls. The contractor for this phase is Kelsey-Seabold of Houston. The exams are scheduled to be completed by September 1982, with preliminary findings available 2 to 3 months later. Follow-up exams will be conducted at 1, 3, 5, 10, and 20 years. A mortality analysis on the Ranch Hand group is �, , , CRS- 9 IB80040 UPDATE-04/20/82 in progress at the Air Force School of Aerospace Medicine, with data anticipated around August 1982, and a mortality tracking program will be continued throughout the study. Information on the health status of the veterans, as shown by the questionnaires and the physical examinations, will provide data for a morbidity analysis. Many of the veterans who have filed claims with the VA for compensation for health effects caused by exposure to TCDD in South Vietnam did not hold jobs that caused direct exposure to 2,4,5-T. They claim that their exposure occurred indirectly either by being sprayed with overhead planes (although substances other than herbicides were also sprayed from planes) or by being exposed to 2,4,5-T in the environment. According to the DOD, military personnel did not usually enter areas sprayed with Agent Orange until 4 to 6 weeks after treatment. However, a recent General Accounting Office investigation concluded that a large number of Marines in the I Corps section of Vietnam from 1966-1969 were in, or close to, areas sprayed with Agent Orange on both the day of spraying and within 4 weeks afterward. Some Army units were also close to Agent Orange spraying. The Department of Defense has recently made progress in identifying ground troops that may have been exposed to Agent Orange. Two Army and one Marine battalion - 31st Engineer Battalion, 2050 troops; 1st Squadron, 9th Calvary (Air Mobil), 2300 troops and 3rd Battalion, 1st Marines, have been identified as being in areas of Agent Orange operations. Exact numbers, locations, and identities of individuals who may have been sprayed are impossible to determine. Veterans' Problems and Veterans^ .Administration E_f_fO'rts The first reports of veterans' concerns over health effects of exposure to 2,4,5-T began to appear in late 1977 and early 1978, following media coverage of several veterans' claims. Veterans have associated a number of illnesses with exposure to 2,4,5-T, including skin conditions, fatague, nervousness, numbness in extremities, vision and/or hearing impairments, birth d'efects in offspring, reduced libido, miscarriages, impotency, respiratory problems, gastro-intestinal tract disturbances, and various cancers, as well as a variety of other illnesses. As of Apr. 1, 1982, the VA had received 13064 claims for damage reportedly related to in-service exposure to herbicides? 2986 claims have been made due only to exposure to the herbicides and not for any specific condition; 10078 claims have been filed for specific conditions related to herbicide exposure, but 3469 of these have not had the diagnosis con-firmed by medical authority. Of the 6609 claims with a confirmed diagnosis, 923 (13.7%) have been allowed for reasons other than Agent Orange exposures and 5686 (86.3%) have been denied. Approximately 93% or 858 of the total 923 claims allowed were for service-connected skin conditions, and the remaining 7% or 65 claims were allowed for cancer, psychiatric and neurological conditions, and various other miscellaneous disabilities. The 5686 claims denied fall into the following categories (many claims have more than one claimed diagnosis): 3055 for various skin conditions; 2335 for nervousness, headache, or fatigue; 886 for paralysis or numbness; 751 for gastro-intestinal or genito-urinary conditions; 399 for various malignancies; 356 for impaired sexual activity; 394 for eye, ear, nose, and throat conditions; 274 for lung conditions; 227 for cardiovascular conditions; and 137 for miscellaneous conditions. The VA has not awarded compensation for the claims of chronic illnesses related to Agent Orange exposure because of the lack of valid human data to prove a �CRS-10 IB80040 UPDATE-04/20/82 cause and effect relationship between exposure to a 2,4,5-T/2,4-D mixture and/or TCDD and specific chronic health effects. Previously, the difficulty of determining which veterans' were or were not exposed to Agent Orange was also a factor in denying compensation, but more recently the VA has conceded exposure for all veterans who were in Vietnam. The VA is maintaining a registry of all Vietnam veterans who have come to VA hospitals and health care facilities expressing concern about possible herbicide-related health problems. Each such veteran, whether experiencing any health problems or not, is given a physical examination; currently, some 2700-2800 exams are being conducted each month. Data from all the exams is being computerized into a central Agent Orange Registry in addition to the individual records being maintained at the local VA facilities. As of Mar. 25, 1982, 81,670 veterans had received the initial exam, and about 61,000 of the records had been coded into the computer. Information from the registry is being analyzed to determine if the veterans have an increased rate of any particular diseases. Thus far, nothing unusual or unexpected has turned up. Treatment of any health problems uncovered by the exams is handled under normal VA procedures regarding service-connection, ability to pay for medical care, etc., with the exception that special guidelines have been issued for the handling of conditions possibly related to Agent orange. In the Federal Register of Dec. 2, 1981, pursuant to Public Law 97-72, the VA issued guidelines for use by its physicians to "assist them in making determinations in individual cases as to whether a disability may have been caused" by exposure to Agent Orange. Even though treatment may be given for some conditions, the VA specified that "In accordance with congressional intent, a determination to furnish care under this authority does not establish that the condition for which medical care is provided is service-connected" for purposes of compensation or vocational rehabilitation eligibility. Three additional VA activities on Agent Orange include participation in the tissue registry, the Chloracne Task Force, and investigations into TCDD residues in body fat tissue of veterans. When VA facilities perform surgery or autopsies on Vietnam veterans, tissue samples are taken and sent to the Armed Forces Institute of Pathology where a special tissue registry is being maintained. Examination of approximately 800 specimens has so far shown no significant clustering of tumors or other particular disease features. The Chloracne Task Force was established in response to a congressional request to sift out those cases of skin conditions that either resemble or are truly Chloracne. Those veterans whose medical records show a definite possibility of Chloracne will be invited to come to non-VA clinics for re-examination by dermatologists who have an expert knowledge of the disease. The VA has conducted a study to determine if TCDD can be detected in the body fat tissues of Vietnam veterans at any higher levels than in veterans who were not in Vietnam. Dioxin in body fat is measured in parts per trillion, levels which are at the technological limits of available detection methods. The test requires surgical removal of tissue from the abdomen and chemical analysis of the sample on gas chromatography/high resolution mass spectrometry instruments. The results of the study were inconclusive, and the VA has decided that the reliability of the procedure is not sufficient to warran-t its use in attempting to verify dioxin exposure. An additional problem is that dioxin contamination is so ubiquitous (from domestic herbicide use and from its formation in municipal incinerators) that it may likely be found in everyone's fat tissue. As mandated in P.L. 96-151, the Veterans' Affairs Amendments, the VA is currently preparing to perform an epidemiological study of Vietnam veterans exposed to Agent Orange. Although the study's protocol has been developed �CRS- 11 IB80040 UPDATE-04/20/82 and validated by an independent group, the VA will perform the testing and collect the data, with oversight by a non-VA scientific committee. Procurement of an independent contractor for the study's protocol was delayed for 14 months by a protest filed by the National Veterans Law Center (NVLC) . The NVLC alleged that not only was the .VA violating procurement law, but also the study as currently contemplated did not comply with the requirements of P.L. 96-151. On Feb. 2, 1981, the General Accounting Office concluded its investigation and denied the NVLC protest. On May 5, 1981, the VA announced the awarding of a contract to the University of California at Los Angeles (UCLA) School of Public Health for the design of the epidemiological study. UCLA submitted its first draft of the protocol to the VA in August 1981; it was peer-reviewed by the VA Advisory Committee on Health-Related Effects of Herbicides, by the Office of Technology Assessment, and by the Science Panel of the Agent Orange Working Group. All the review groups judged the draft protocol to be inadequate and not in compliance with the contract. UCLA has since modified the protocol, expanding on problem areas and incorporating the suggestions of the review groups; its final submission to the VA is due April 29, 1982. As with the Ranch Hand study, this epidemiological study will have two main parts: a questionnaire on health status and medical and occupational history, and a physical exam with laboratory workup. The study group will be 18,000 veterans, divided into 3 cohorts of 6000 each. Two of the cohorts will have had Vietnam service, and will be distinguished as having a high or a low likelihood of herbicide exposure. The third cohort will be veterans with non-Vietnam military service. Inclusion of the third group will generate data about the health effects of Vietnam service in addition to the information expected about herbicide-related health effects. The study will commence with a pilot project to field test its procedures.and the questionnaire. P.L. 96-151 also mandated the VA to conduct a comprehensive review and scientific analysis of the worldwide literature on Agent Orange and other phenoxy herbicides. JRB Associates prepared the review under contract, and the VA published the 2-volume study in October 1981. The VA is now preparing to contract for an update to the literature review, to reflect new reports and data -that have appeared. The Interagency Work Group on Phenoxy Herbicides and Contaminants, established in December 1979, recommended that the Centers for Disease Control (CDC) perform a case-control study to see if there is an increased incidence of specific malformations in children of Vietnam veterans. The population to be studied is a group of 7500 children who have birth defects and who are registered in CDC's Birth Defects Program (in operation since the late 1960s). Information on the families of these children, gained by extensive interviews and questionnaires, will be compared with that for 300 normal controls. The data will be analyzed to see what risk factors in the parents' lives, including military service in Vietnam, may be related to increased incidence of malformations in their children. CDC has completed a pilot study on a representative sample of the two groups to test the questionnaire and the procedures for finding the families. The main study will be started in late April 1982, and a preliminary report on the issue of Vietnam service is expected in the fall of 1983. Detailed analysis of the data on all risk factors will take several years to complete. On Sept. 22, 1980, the Work Group held its first public meeting to discuss problems and proposals related to exposure to herbicides. On Jan. 19, 1981, the Secretary of Health and Human Services established the "Advisory Committee on Special Studies Relating to the Possible Long-Term Health Effects of Phenoxy Herbicides and Contaminants" to advise the Secretary and �CRS- 12 IB80040 UPDATE-0'4/20/82 the Chair of the Interagency Work Group on Herbicides concerning the Advisory Committee's oversight of the conduct of the Ranch Hand Study being conducted by the Air Force. In its seventh report to the White House, the Work Group's Scientific Panel concluded that: While it is difficult to accept logically that a single causative factor -- Herbicide Orange -- could be responsible for such a diverse set of health effects as alleged by Vietnam veteran claims to the VA , there is no definitive evidence that permits selective exclusion of some of these illnesses. Further, it is possible that some of these health effects are occurring as a consequence of Vietnam^ service but not due to exposure to Herbicide Orange. The Science Panel is not aware of any data that suggest a modification of its previous recommendation that the •focus of a study of Vietnam veterans should be broadened to consider Vietnam service as the exposure factor rather than focus solely on Herbicide Orange exposure.... The Science Panel is in receipt of data which indicate that there is at best a remote chance of accurate identification of specific ground troops who were exposed to Herbicide Orange.... The Panel is therefore of the opinion that design of a scientifically valid Herbicide Orange study of ground troops may not be possible. If the focus of a study of Vietnam veterans is broadened to consider Vietnam service as the exposure factor, a study of ground troops is necessary and a scientifically valid study can be designed. On July 17, 1981, the Interagency Work Group was renamed and its membership expanded. Now called the Agent Orange Working Group, it is part of the Cabinet Council on Human Resources. The Department of Health and Human Services is the lead agency. Because the VA currently recognizes only chloracne as a human health effect that can be proven to be caused by exposure to 2,4,5-T, veterans may have difficulty being compensated for even those effects for which there is strong animal evidence (i.e., cancer and birth defects caused in utero which are those birth defects that cannot be caused by the father and require the mother and fetus to be exposed during the actual pregnancy). Veterans who claim compensation for health effects which are not supported by strong animal data (i.e., mutations -- which could cause genetic defects in the father's sperm that would affect children conceived after exposure) may have an even tougher case to argue. The veteran's question then becomes: How much evidence is required to prove the right to compensation? On whom does the burden of proof lie (the veteran or the VA)? .If more evidence is needed, who will generate it? And finally, what constitutes fair treatment of veterans while the necessary data are being gathered? Congressional Action of the 96th Congress The 96th Congress responded to the problems of establishing a cause and effect relationship between veterans' exposure to herbicides in South Vietnam and the various health problems they are now experiencing by holding hearings and enacting legislation. �CRS- 13 IB80040 UPDATE-04/20/82 The Subcommittee on Oversight and Investigations, of the House Committee on Interstate and Foreign Commerce held hearings on June 24 and 25, 1979, to hear testimony from veterans who allegedly have been affected by herbicide exposure and from the Veterans Administration regarding its efforts to unequivocally determine the relationship between herbicide exposure and health effects. The Subcommittee on Medical Benefits and Facilities of the House Committee on Veterans' Affairs held two sets of hearings on the hazards associated with TCDD, veterans' complaints of health effects associated with Agent Orange exposure, and Veterans Administration's efforts to resolve the Agent Orange problem. The Senate Veterans' Affairs Committee also held hearings to Agent Orange problem. examine the As a step to gain access to records to locate veterans who may have been exposed to herbicides in-service, Title V of H.R. 2282, the Veterans' Disability Compensation and Survivors' Benefits Amendments of 1979, requires the Director of the National Institute for Occupational Safety and Health, upon request by the VA (or other appropriate agency) to request the current mailing address from the Internal Revenue Service of persons whom the VA certifies may have been exposed to occupational hazards. H.R. 2282 was passed in lieu of its companion bill, S. 689, and became Public Law 96-128 on Nov. 28, 1979. Title III of H.R. 3892, the Veterans' Affairs amendments, directs the Veterans Administration to conduct an epidemiological study of the long-term health effects on individuals from exposure to dioxins in Vietnam, upon the Office of Technology Assessment's (OTA) approval of its protocol. Its companion bill, S. 1039, was incorporated in H.R. 3892 as an amendment, and the measure was enacted by Congress and signed by the President on Dec. 20, 1979 (P.L. 96-151) . If enacted, S. 2096 would have directed the Secretary of Health, Education, and Welfare (now, Health and Human Services) to undertake an epidemiological study to determine the long-term adverse human health effects associated with exposure to dioxins produced during the manufacture of phenoxy herbicides. This bill proposed to investigate the long-term health effects of exposure to dioxins, in general, not just to Agent Orange. As similarly incorporated in H.R. 3892, S. 2096 would have required that the study's protocol be approved by the Congressional Office of Technology Assessment. This bill was presented to the President on Dec. 21, 1979, and vetoed by him on Jan. 2, 1980. President Carter vetoed the bill because the White House counsel believed that such a procedure violated the separation of power between the legislative branch and the executive branch. He did not feel that the Department of Health and Human Services' study protocol should be subject to approval by a congressional agency. Title X of H.R. 5288, the Veterans' Rehabilitation Program and Veterans' Educational Assistance Program would have directed the Secretary of Health and Human Services to conduct a study of veterans and other groups exposed to the herbicide known as "Agent Orange" to determine if there may be adverse health effects associated with such exposure. Like H.R. 3892 (P.L. 96-151) and S. 2096, the bill called for OTA approval of the study's protocol. The bill also would have required the Secretary of Health and Human Services to coordinate its efforts with other studies in the Federal Government. During the debate on S. 1188, its companion bill, the Disabled Veterans' Rehabilitation Act, the Senate adopted an amendment offered by Senator �CRS-14 IB80040 UPDATE-04/20/82 Cranston to expand the study on health effects of exposure to Agent Orange to include other factors related to service in Vietnam. The Senate also adopted an amendment offered by Senator Heinz requiring the VA to promulgate regulations regarding guidelines to resolve veterans' disability claims based on exposure to Agent Orange. The ' amendments were striken by the House because they were considered to be "non-germane" to the primary focus of the bill. S. 1872 (the Vietnam Veterans' Act); H.R. 6050 (the Vietnam Veterans' Act); H.R. 6377 (the Vietnam Era Veterans Agent Orange Act); each would have established a presumption of service-connected disability for health effects in Vietnam veterans (and birth defects in their children) exposed to Agent Orange. H.R. 8238 (Independent Agent Orange Study) would have directed the Veterans Administrator to request the National Academy of Sciences to conduct a study on veterans exposed to Agent Orange. H.R. 8300 would have expanded the scope of the Agent Orange study currently being coordinated by the VA and would have established deadlines for promulgating regulations related to Agent Orange exposure claims. These bills received no action. LEGISLATION P.L. 97-72, H.R. 3499 Veterans' Health Care, Training and Small Business Loan Act of 1981. Amends title 38, U.S. Code, to extend the Vietnam-era veterans' readjustment counseling program, to provide medical care for Vietnam veterans exposed to herbicide defoliants (including Agent Orange), to recover the cost of certain health care provided by the VA, and authorizes the VA to expand the scope of its epidemiological study on the health effects of Agent Orange, and other purposes. Introduced May 7, 1981; referred to Committee on Veterans' Affairs. Committee consideration and mark-up session held May 12. Reported to House (amended) by Committee on Veterans' Affairs (H.Rept. 97-79) May 19. Passed House (amended) June 2, 1981. Received in the Senate June 3. Senate struck all after the Enacting Clause and substituted the language of S. 921, June 16. Passed Senate in lieu of S. 921 with amendments, June 16, 1981. House concurred in Senate amendments with amendments Oct. 2, 1981. Senate agreed to House amendments Oct. 16, 1981. Signed into law Nov. 3, 1981. H.R. 523 (Roe) Amends Title 38, U.S. Code, to waive the 1-year limitation on claims for compensation from the Veterans Administration for disabilities and diseases incurred in or aggravated by military service in the case of claims by veterans who served in Southeast Asia during the Vietnam era for compensation for disabilities resulting from exposure to the phenoxy herbicides known as Agent Orange or other phenoxy herbicides. Introduced Jan. 5, 1981; referred to Committee on Veterans' Affairs. H.R. 1173 (Montgomery, by request) Amends section 307 of P.L. 96-151, by assigning the responsibility of designating a protocol for, and conducting an epidemiological study of, veterans who were exposed to Agent Orange, to an independent scientific agency. Introduced Jan. 22, 1981; referred to Committee on Veterans' Affairs. H.R. 1962 (Oilman) �- . , CRS- 15 IB80040 UPDATE-04/20/82 Amends the Veterans Health Programs Extension and Improvement Act of 1979 to require the Veterans Administration and the National Academy of Sciences to enter into an agreement under which the Academy will conduct an epidemiological study of veterans exposed to Agent Orange. Introduced Feb. 19, 1981; referred to Committee on Veterans' Affairs. H.R. 2157 (Mottl) Expands the scope of a study required to be conducted by the Administrator of Veterans' Affairs concerning the effect on humans of exposure to the chemical known as Agent Orange. Introduced Feb. 25, 1981: referred to Committee on Veterans' Affairs. VA requested Executive comment Mar. 2, 1981. Referred to Subcommittee on Hospitals and Health Care Apr. 28. Hearings held Apr. 30. Subcommittee consideration and mark-up session held. Clean bill forwarded to full committee. H.R. 2297 (Downey) Amends Title 38, United States Code, to waive the 1-year limitation on claims for compensation from the Veterans Administration for disabilities and disease incurred in or aggravated by military service in the case of claims by veterans who served in Southeast Asia during the Vietnam era for compensation for disabilities resulting from exposure to the phenoxy herbicides known as "Agent Orange" or other phenoxy herbicides. Introduced Mar. 4, 1981; referred to Committee on Veterans' Affairs. H.R. 2493 (Daschle) Amends Title 38, United States Code, to provide a presumption of service connection for the occurrence of certain diseases in veterans who were exposed to herbicides in Southeast Asia during the Vietnam era. Introduced Mar. 12, 1981; referred to Committee on Veterans' Affairs. H.R. 2953 (Daschle) Entitles veterans exposed to Agent Orange during the Vietnam era to specified medical benefits. Extends the period during which veterans of such era may initially request psychological readjustment counseling. Extends specified educational assistance without delimiting periods for vocational training for specified veterans determined to be in need of such assistance. Introduced Apr. 1, 1981; referred to Committee on Veterans' Affairs. Referred to Subcommittee on Hospitals and Health Care Apr. 28. Hearings held Apr. 28. Subcommittee consideration and mark-up session held Apr. 30, 1981. H.R. 3163 (Railsback) Requires the Secretary of Health and Human Services to arrange for an independent epidemiological study of persons exposed to Agent Orange. Introduced Apr. 8, 1981; referred to Committee on Energy and Commerce. Referred to Subcommittee on Health and the Environment Apr. 9, 1981. S. 636 (Cranston et al.) Entitles the United States to recover the costs of certain medical care and services furnished to a veteran for a non-service-connected disability when disability is covered by another form of insurance or compensation. Permits the expansion of the scope of the epidemiological and literature �CRS- 16 IB80040 UPDATE-04/20/82 study of the long term adverse health effects of exposure to Agent Orange during the Vietnamese conflict to include the effects of other factors. Introduced Mar. 5, 1981; referred to Committee on Veterans' Affairs. S. 689 (Heinz) Amends section 307 of the Veterans Health Programs Extension and Improvement Act of 1979 to require the promulgation of regulations containing guidelines for resolving claims for veterans benefits based on exposure, to Agent Orange, and for other purposes. Introduced Mar. 12, 1981; referred to Committee on Veterans' Affairs. Hearings held Apr. 30, 1981. S. 921 (Simpson) Extends the authority of the Administrator of Veterans' Affairs to contract for hospital care or medical services in Puerto Rico and the Virgin Islands without reference to patient loads or incidence of provision of medical services for veterans treated by the Veterans' Administration in the contiguous 48 States. Introduced "Apr. 8, 1981; referred to Committee on Veterans' Affairs. Reported with amendment May 15, 1981 (S.Rept. 97-89); H.R. 3499 passed in lieu (see P.L. 97-72 above) June 16, 1981. S. 1345 <Heinz) Authorizes the Administrator of the Veterans' Administration to provide hospital or nursing home care to a veteran for treatment of a condition associated with exposure to Agent Orange during service in Vietnam. Extends the Vietnam-era veterans' readjustment counseling program. Directs the Administrator to expand the scope of the epidemiological study of long term adverse health effects of other factors involved in such service. Introduced June 8, 1981; referred to Committee on Veterans' Affairs. S. 1953 (Specter) Amends title 38, United States Code to provide a presumption of service connection for the occurrence of certain diseases in veterans who were exposed to phenoxy herbicides while serving in Southeast Asia during the Vietnam era. Introduced Dec. 15, 1981; referred to Committee on Veterans Affairs. HEARINGS U.S. Congress. House. Committee on Interstate and Foreign Commerce. Subcommittee on Oversight and Investigations. Agent Orange: exposure of Vietnam veterans. Hearing, 96th Congress, 2d session. Sept. 25, 1980. 249 p. Involuntary exposure to Agent Orange and other toxic spraying. Hearings, 96th Congress, 1st session. June 26 and 27, 1979. 256 p. U.S. Congress. House. Committee on Veterans' Affairs. Ad Hoc Subcommittee. Status of Vietnam veterans in the Bay area. Hearing, 96th Congress, 2d session. Apr. 10, 1980. 64 p. U.S. Congress. House. Committee on Veterans' Affairs. Subcommittee on Hospitals and Health Care. �% .. , CRS- 17 IB80040 UPDATE-04/20/82 Legislation to improve medical programs administered by the Veterans Administration (H.R. 2157, H.R. 2953, and H.R. 2999). Hearings, 97th Congress, 1st session. Apr. 28, 1981. 54 p. U.S. Congress. House. Committee on Veterans' Affairs. .Subcommittee on Medical Facilities and Benefits. Herbicide "Agent Orange". Hearing, 95th Congress, 2d session. Oct. 11, 1978. 62 p. Oversight hearing to receive testimony on Agent Orange. Hearing, 96th Congress, 2d session. Feb. 25, 1980. 121 p. ----- Oversight hearing to receive testimony on Agent Orange. Hearing, 96th Congress, 2d session. July 22, 1980. 459 p. --—•- Scientific community report on Agent Orange. Hearing, 96th Congress, 2d session. Sept. 16, 1980. 145 p. U.S. Congress. House. Committee on Veterans' Affairs. Subcommittee on Oversight and Investigations. Current status of Agent Orange studies. Hearing, 97th Congress, 1st session. May 6, 1981. 385 p. U.S. Congress. Senate. Committee on Veterans' Affairs. Agent Orange update and appendix: Agent Orange activities (part II). Hearing, 96th Congress, 2d session. Sept. 10, 1980. 1368 p. Oversight on issues related to Agent Orange and other herbicides. Hearing, 97th Congress, 1st session. Nov. 18, 1981. (not yet printed) • VA health resources and program extensions and appendix: Agent Orange activities. Hearing, 96th Congress, 1st session, on S. 741 and S. 196. Apr. 10,. 1979. 462 p. • Veterans' Programs Extension and Improvement Act of 1981. Hearing, 97th Congress, 1st session, on S. 26 (titles II and III, only), S. 380, S. 458, S. 636, S. 689, S. 872, S. 914, S. 921, and related bills. Apr. 30, 1981. 685 p. • Vietnam veterans' readjustment. Hearings, 96th Congress, 2d session. Feb. 21, Mar. 4, and May 21, 1980. Part 2. 595-2082 p. ADDITIONAL REFERENCE SOURCES American Medical Association. Council on Scientific Affairs. Health effects of "Agent Orange" and dioxin contaminants (Executive Summary). 1981. 6 p. Behrens, Richard, et al. Comments from CAST (Council on Agricultural Science and Technology): Dioxin. 1978, 9 p. Bucfc, Craig. The Death of a nation. Aug. 28, 1978: 49-50, 52-55. New west, v. 3, �CRS-18 IB80040 UPDATE-04/20/82 Cookson, Clive. "Emergency" ban on 2,4,5-T herbicide in U.S. Nature, v. 278, Mar. 8, 1979: 10'8-110. Davis, Donald E. et al. Comments from CAST (Council on Agricultural Science and Technology): Agent orange. 1978. 5 p. Galston, Arthur W. Herbicides: a mixed blessing. v. 29, February 1979: 85-90. Bioscience, International Agency for Research on Cancer. IARC monographs on the evaluation of the carcinogenic risk of chemicals to man: 2,5,5-T, vol. 15, August 1977. JRB Associates. Review of literature on herbicides, including phenoxy herbicides and associated dioxins. Washington, Veterans Administration, 1981. 2v. Laporte, Joan-Ramon. Multinationals and health: reflections on the Seveso catastrophe. International journal of health services, v. 8, no. 4, 1978: 619-632. National Research Council. The effects of herbicides in South Vietnam: Part A. Summary and conclusions. Washington, National Academy of Sciences, 1974. AD-774-749. 398 p. Peterson, Jeannie. Seveso: 1978: 232-239. the event. Ambio, v. 7, no. 5-6, Reggiani, G. Localized contamination with TCDD - Seveso, Missouri, and other areas. In: Halogenated biphenyls, terphenyls, naphthalenes, dibenzodioxins and related products, ed. Renate D. Kimbrough. Amsterdam, New York, Oxford, Elsevier/North-Holland Biomedical Press, 1980. Severe, Richard. Seveso: lessons from an escape. June 17, 1978: 101-102, 104-106, 108. U.S. Economist, v. 2.67, General Accounting Office. Health effects of exposure to herbicide orange in South Vietnam should be resolved, Apr. 6, 1979. CED-79-22. U.S. ground troops in South Vietnam were in areas sprayed with herbicide orange. Nov. 16, 1979. FPCD-80-23. Young, Alvin et al. The toxicology, environmental fate and human risk of herbicide orange and its associated dioxin. The Surgeon General, U.S. Air Force, Washington, D.C. October 1978. Walsh, John. Seveso: the questions persist where dioxin created a wasteland. Science, v. 197, Sept. 9, 1977: 1064-1067. Whiteside, Thomas. Defoliation. New York, Ballantine, •- The pendulum and the toxic cloud. New Haven, Yale 1970. �, .. k CRS-19 IB80040 University Press, 1979. Zimmerman, David R. Agent Orange: Vietnam's lingering poison. American health, v. 1, no. 1, Mar./Apr. 1982: 68-72. UPDATE-04/20/82 �Signs, Symptoms, and Disorders Reported After Occupational Exposure to TCP, 2,4,5-T or TCDD 0) O -C I/I Q> Q> O> flj o *D 10 ID V 3C Source *j e o <U in 0) o C ~O (U C V) ID -C O) —. <D 1_ C7I a ro (U J_ V) <u L. O a> >- C ID •— i>- «O Q. >- v. Poland et al. (62) j: o. o- 4 11 8 o >ID — o> a: o < 5 18 30 I a. u a> 17 8 20 48 17 C o (U 0) o c as 0) -C U C — flj D ID 10 — Q. a) •z. a (D </> c m ID cn — c .E o -a JD < a) i_ a. l- o X — Q) 4-1 U •— O E C O a) 0) Q 22 + 87 Hardell (33) K i m m i g and Schulz Jirasek et al. (37) o (/I i- >— a> 3c Dugois et al. (24) Kramer (4g) (D — in Q. L. a B l e i b e r g et al. (1*0 tfl E *-> tj* 3 Baader and Bauer (6) Bauer et al. (9) U (U ID V. > »- V) 31 3 + 12 19 78 Jirasek et al. (33) Pazderova et al. (61) M i u r a et al. (54) 23 O l i v e r (57) 27 2 + Ter Beek et al. (79) Zelikov and Danilov (88) Total number of cases reported c 53 + 1 •f 1 17 15 18 0 47 75 275 0 91 47 17 23 a Number entries in table reflect the number of cases in which sign, symptom or disorder was reported. °+ - Sign, symptom or disorder reported but number of cases not given. c Numbers do not include cases represented by "+" and totals may represent some double counting due to the overlap to studies by Jirasek et al. and Pazderova et al. SOURCE: Young, Alvin et al. The Toxicology, Environmental Fate, and Human Risk of Herbicide Orange and Its Associated Dioxin, p. VI-14. (Numbers in parentheses identify sources in Young's bibliography.) � Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Alvin L. Young Collection on Agent Orange Description An account of the resource <p style="margin-top: -1em; line-height: 1.2em;">The Alvin L. Young Collection on Agent Orange comprises 120 linear feet and spans the late 1800s to 2005; however, the bulk of the coverage is from the 1960s to the 1980s and there are many undated items. The collection was donated to Special Collections of the National Agricultural Library in 1985 by Dr. Alvin L. Young (1942- ). Dr. Young developed the collection as he conducted extensive research on the military defoliant Agent Orange. The collection is in good condition and includes letters, memoranda, books, reports, press releases, journal and newspaper clippings, field logs and notebooks, newsletters, maps, booklets and pamphlets, photographs, memorabilia, and audiotapes of an interview with Dr. Young.</p> <p>For more about this collection, <a href="/exhibits/speccoll/exhibits/show/alvin-l--young-collection-on-a">view the Agent Orange Exhibit.</a></p> Text A resource consisting primarily of words for reading. Examples include books, letters, dissertations, poems, newspapers, articles, archives of mailing lists. Note that facsimiles or images of texts are still of the genre Text. Box The box containing the original item. 051 Folder The folder containing the original item. 1336 Series The series number of the original item. Series III Subseries II Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Creator An entity primarily responsible for making the resource Smith, Pamela W. Description An account of the resource <strong>Corporate Author: </strong>Science Policy Research Division, Library of Congress, Congressional Research Service Date A point or period of time associated with an event in the lifecycle of the resource April 20 1982 Title A name given to the resource Agent Orange: Veterans' Complaints Concerning Exposure to Herbicides in South Vietnam, Issue Brief Number IB80040 Subject The topic of the resource dioxin Agent Orange Controversy AOWG VA ao_seriesIII Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Alvin L. Young Collection on Agent Orange Description An account of the resource <p style="margin-top: -1em; line-height: 1.2em;">The Alvin L. Young Collection on Agent Orange comprises 120 linear feet and spans the late 1800s to 2005; however, the bulk of the coverage is from the 1960s to the 1980s and there are many undated items. The collection was donated to Special Collections of the National Agricultural Library in 1985 by Dr. Alvin L. Young (1942- ). Dr. Young developed the collection as he conducted extensive research on the military defoliant Agent Orange. The collection is in good condition and includes letters, memoranda, books, reports, press releases, journal and newspaper clippings, field logs and notebooks, newsletters, maps, booklets and pamphlets, photographs, memorabilia, and audiotapes of an interview with Dr. Young.</p> <p>For more about this collection, <a href="/exhibits/speccoll/exhibits/show/alvin-l--young-collection-on-a">view the Agent Orange Exhibit.</a></p> Text A resource consisting primarily of words for reading. Examples include books, letters, dissertations, poems, newspapers, articles, archives of mailing lists. Note that facsimiles or images of texts are still of the genre Text. Box The box containing the original item. 036 Folder The folder containing the original item. 0779 Series The series number of the original item. Series III Subseries I Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Creator An entity primarily responsible for making the resource Jemison, Terry L. Source A related resource from which the described resource is derived U. S. Medicine Date A point or period of time associated with an event in the lifecycle of the resource January 1 1983 Title A name given to the resource Agent Orange: Exposure 'Tackled' Subject The topic of the resource veteran health and hygiene dioxin AOWG human exposure ao_seriesIII Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Alvin L. Young Collection on Agent Orange Description An account of the resource <p style="margin-top: -1em; line-height: 1.2em;">The Alvin L. Young Collection on Agent Orange comprises 120 linear feet and spans the late 1800s to 2005; however, the bulk of the coverage is from the 1960s to the 1980s and there are many undated items. The collection was donated to Special Collections of the National Agricultural Library in 1985 by Dr. Alvin L. Young (1942- ). Dr. Young developed the collection as he conducted extensive research on the military defoliant Agent Orange. The collection is in good condition and includes letters, memoranda, books, reports, press releases, journal and newspaper clippings, field logs and notebooks, newsletters, maps, booklets and pamphlets, photographs, memorabilia, and audiotapes of an interview with Dr. Young.</p> <p>For more about this collection, <a href="/exhibits/speccoll/exhibits/show/alvin-l--young-collection-on-a">view the Agent Orange Exhibit.</a></p> Text A resource consisting primarily of words for reading. Examples include books, letters, dissertations, poems, newspapers, articles, archives of mailing lists. Note that facsimiles or images of texts are still of the genre Text. Box The box containing the original item. 036 Folder The folder containing the original item. 0758 Series The series number of the original item. Series III Subseries I Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Creator An entity primarily responsible for making the resource Holden, Constance Source A related resource from which the described resource is derived Science Date A point or period of time associated with an event in the lifecycle of the resource December 4 1981 Title A name given to the resource Reviewers Pan Agent Orange Study Plan Subject The topic of the resource AOWG VA veteran health and hygiene study criticism ao_seriesIII https://www.nal.usda.gov/exhibits/speccoll/files/original/bb3b2e854afbbc1197cdafdddc181e61.pdf 6e9735a9c96a014fc47e12c23a1c99ff PDF Text Text Item ID Number 00578 Author Custis, Donald L Corporate Author Report/Article TltlB Typescript: Statement of Donald L. Curtis, M.D., Chief Medical Director, Department of Medicine and Surgery, Veterans Administration, Before the Subcommittee on Oversight and Investigations, Committee on Veterans' Affairs, House of Representatives, September 15,1982 Journal/Book Title Year Month/Day Color Number of Images DeSCrlptOII NotOS n 20 Alvin L Your| gfiled tnis item under the category "Human Exposure to Phenoxy Herbicides and TCDD" Tuesday, February 20, 2001 Page 578 of 680 �I. ; - i «PV ' u, - , > ..v?../.^J^T.of, , .,,, ' .' •. , DONALD L.CUSTIS.M.D., 1 1 . -., ' CHIEF MEDICAL DIRECTOR, T *V DEPARTMENT OF MEDICINE AND SURGERY { V ( , , * ir:^TER/^ ^^WAT!9N ^*> ^;-( , _ * ,v ^ f r '."-•,' ^BEFORE THE , t SUBCOMMITTEE ON OVERSIGHT AND INVESTIGATIONS, COMMITTEE ON VETERANS'AFFAIRS HOUSE OF REPRESENTATIVES September 15, 1982 < I * > * » , / f 1 < r "t ', » * '1 t, *<t i* " ' t V ' * • > ' ' . * ' '*' '» .1 Mr. Chairman and Members of the Committee: f tv t"*, s Good morning. 1 » < '» •> *.» , v ' . On behalf of the Veterans Administration, we are pleased to have the Opportunity to appear before you today to provide an update on the status of both VA's Agent Orange-related activities and the Readjustment Counseling Program. We are continuing efforts to resolve the complex medical and scientific questions concerning Agent Orange. In the interim, we are providing medical care and treatment, as well as information to Vietnam veterans. We believe that a great deal of progress has been mode in both areas since we last appeared before this committee on May 6, 1981. Mr. Chairman, we are aware that both the Agent Orange issue and readjustment to civilian fife remain key concerns for many Vietnam veterans. A great deal still needs to be done to resolve both of these concerns. Let me reemphasize, however, that the Veterans Administration has never lost sight of the special needs of the Vietnam veteran. �2. \ V,, . *?fr Aoent Oronge Program T \rT* • l " * w ' ' *;/- . IT?- ; \ <;«v " , ^ ' * On June 30, 1982, Robert P. Nimmo, Administratpr approved a revised Department of Medicine and Surgery program of Agent Orangerelated activities. The most significant activity which was approved is a pilot study as a preliminary to the full epidemiological study provided for by Congress. Other major efforts included are the Vietnam veterans identical twin study, a mortality study, and specially-related research projects. Approval was also given for the establishment of the Agent Orange Projects Office within the Department of Medicine and Surgery. This office will coordinate and monitor a variety of epidemiological projects. Efforts are now underway to identify key epidemiologic staff who will be responsible for these efforts. The core staffing will consist of an Epidemiologist, Biostatistician, Statistical Programmer, Health Science Specialist for Quality Assurance, on Administrative Assistant and supporting clerical staff. In addition, approval was given for continuation and improvement of the Agent Orange Registry, chloracne activities, a follow-up to the literature analysis, a monograph series, establishment of a Vietnam service indicator in the Patient Treatment File (RTF), and a retrospective study of dioxins and furans in human adipose tissue. STATUS OF VA EPIDEMIOLOGY STUDY; The epidemiology protocol submitted to the VA by the UCLA School of Public Health on April 29, 1982, has now been reviewed by the VA Advisory Committee on Health-Related �3. Effects of Herbicides, the Agent Qronge Working Group (AOWG) and the Office of Technology Assessment. The protocol is currently being reviewed by a committee of the .Academy of Sciences (MAS). The VA has been advised that HAS is now in the jes of this review process. It |s expected that the report will be completed and > '' - , f\ forw.a/jted to. tjh$ Veterans Administration shortly* Following incorporation of the .yarjous ^eYlewers/ comments, we will solicit bids for a contract for the conduct of a pilot * * * » ' *-, study. We anticipate having that solicitation in place before this December. " i ' «u The purpose of the pilot.study w|U be to permit us to "fine-tune" the protocol for the conduct of the frjll-^cale epidemiology study which will study a population of approximately 18,000 veterans. The pilot study has become the focal point of recent activity by the VA, the Army Agent Orange Task Force (AAOTF) and the AOWG. < The AOWG has appointed a subcommittee of its Science Panel to establish procedures for cohort selection for the epidemiology pilot study. The VA has brought in bipstatistica) consultants to work with this subcommittee and with the AAOTF. The Subcommittee is now in the process of preparing its final report to the Science Panel. Health Care Tr« Veterans, Administration is implementing the medical core and treatment provisions of Public Low 97-72, the "Veterans' Health Care, Training, and Small Business Loan Act of 1^81." Shortly after the law was signed, interim guidelines for the implementation of » ' .. these provisions were issued to all VA health care facilities. Those guidelines were also '- . . •• . ' "-' • „ - ' • ' -i ' • ' , - • 'f- ' ' . . y published In in the Federal Register on December 5, 1981, to provide Vietnam veterans and the general public with the opportunity to comment. �. • . . . . . . . . . , . Under the provisions of the guidelines, each veteran who served in the Republic of • ' ' . . ' .' . <>.. ".'•.-' • • . . - . . • . - ; .'" ' • ' • , . : - , • • Vietnam and who requests VA medical care Is being provided a complete medical history, physical examination and appropriate diagnostic studies/When it is determined that a condition exists requiring treatment, the responsible staff physician makes a determination as to whether the condition resulted from a cause other than the specified exposure to Agent Orange. The guidelines include a description of those conditions which I determined cannot ordinarily be considered to be due to such exposure. • ' * .' . •: • ' . - . . • : 'i - - ' -' •• • • Ultimately, it is left to the treating physician to exercise professional judgment in determining whether the veteran should be provided care under this authority. Agent Orange Registry '• -• • • . , - • ' ' -:• ;••• ' • ' - : •>' : . ' • : • . • • ' . ft. .:• ' : .'• r. " : ':• Since the initiation of the Agent Orange Registry in 1978, approximately 91,000 veterans • • " • • - . . • • • ' f ', • have received an Agent Orange examination at VA health care facilities. The VA has provided approximately 20,000 follow-up examinations for Agent Orange. The basic registry process involving a comprehensive physical examination, completion of a questionnaire and informing the veteran of the results of the examination verbally and in writing, are continuing to be followed by all health care facilities. The monthly report, transmitted by VA health care facilities and compiled at VA Central Office, is still an effective tool in measuring the numbers of examinations (initial and follow-up) being performed at the facilities and the number of pending examinations. * . The4 Environmental Medicine Office is continuing to monitor the numbers of pending examinations to assure that the veteran is provided the Agent Orange examination and related treatment in a timely manner. Facilities reporting •Vjut-of-line" situations, that .:.'••• ' -., r •• . . -.SV' '.;• • .:. • r ' . ' - " ' '.• , is, facilities with examinations pending more than 30 days or having more than 50 . , ' ' . . ' • ' . • • * • * .-- ; ' • • - k •'»•.'• ' : •'•••• • • ; : ' • : • '•"•"'• .-;.^'< • .•• '••(•• examinations pending during any reporting period ore contacted by program officials at �5. V^A Central Office and directed to'take Immediate action to reduce the number of pending examinations to comply with Central Office guidelines. •ij^iSj,.^ i H i' 1 ^ t~ ** s £ i I* r ^- / 5 *** ' w ^5 t tsT^^j)*'^ £, { ij T** ' J$ ^ ~*** ** i, ' * * 'Improvements In our registry procedures will enable the VA to match Agent Orange Registry records with records of hospitalization in the Patient Treatment File (PTF) system so that correlations can be made regarding the types of diagnoses Vietnam V '» * ! « ' » ' • * f > «' s '« 1' ii»'l»'J* H ' ' " • !' veterans are fpresenting forf treatment at VA health care facilities. t » -si j f *' *A* The VA is cooperating with the Department of Defense with regard to Agent Orange examinations for active duty personnel. Instructions will be mailed to all VA health care facilities for processing an active duty service member's request for an examination and for processing the forms. The results from this examination will be entered into the Agent Orange Registry. Twins Study j\ " \" / < • < ' < • >' • • '. The VA has recently given approval for the development of a comprehensive protocol i that will involve studying identical twins. The proposed study would involve identical twin veterans where one twin served In Vietnam during the period of Herbicide Orange spraying and where the twin sibling did not serve in Southeast Asia. This study will be designed to investigate whether the current psychological and physical health of Vietnam veterans was adversely affected by their military experience in Vietnam. Veterans Administration researchers at our St. Louis VA Medical Center have proposed the study and ore currently developing the protocol. We would anticipate that If the protocol survives the scrutiny of appropriate scientific reviews, we will launch into the physical examinations of some 450 pairs of identical twins in late 1983 and should have an initial report of findings by October 1984. .. : .c T i, • . *.- • ' . i j > . ..••„• / • • : . - •" • .- • i •• ' . .• . . .•" i '• ..'-•• •: '.. �Vietnam. yeteranJAortality Studies • • • , . . . • < ••"••. '^^-t&ffi&S^ ":"' . ' "•'.'.• ' " A carefully-designed and well-executed mortality analysis of Vietnam" veterans will provide background to many questions raised by the Agent Orange exposure issue in particular as well as the possible health effects of service in Vietnam in general, the Vietnam Mortality Study is designed to analyze and compare cteatH rates arid cause-ofdeath profiles of veterans with service in Vietnam and comparable veterans with no service in Vietnam. The studies will use existing computer records to assemble a cohort of veterans and . ' . . - • • ' • ' • • "'"-. v",/;.•••• ' • ' ' : ; - • • • " '"*!'•••'•;.-j '•• ,. . •,. . -•(.•'•i-- ' ': , • ' : ; ' - • : : ••*, determine their mortality experience. It should be noted that the mortality studies will provide mortality information which may prove useful primarily in suggesting areas for further scientific study. These mortality studies will be conducted by researchers at the Veterans Administration Central Office in Washington, DC. The collection and coding of death certificates and the abstracting of military records will be done by VA contractors. We are currently evaluating submitted proposals and hope to sign contracts for these efforts shortly. It is anticipated that it will take approximately two years to complete the mortality studies. Retrospective Study of Dioxins and Furons in "Adipose Tissue of Vietnam-Era Veterans The Environmental Protection Agency has been collecting adipose tissue from the U.S. general population. This National Adipose Tissue Bank was initiated in 1968 and now contains specimens from approximately 6,000 individuals. Represented within this bank is adipose tissue from approximately 3dO males born between 1938 and 1952. It is estimated that �7. approximately 200 of these males may have served in the U.S. military during the ,'i&V&<'-iU^,'"Ti£l^ Vietnam"erei and that as many as 70 may have lervecl in Vietnam. . ~ : fef M%fi^^ ••'^'" •^'^•: "We are currently developing an agreement by which the VA would support an interogency iludy to be conducted at theJ^PA 6ioxin Laboratory in Bay St. Louis, Mississippi. This K^:!>!M?^ V*n^ ' - . - • '--'">;?"<^ ^•••'^('' will be a retrospective study of chlorinated aioxins and furans in human adipose tissue. The study is designed to establish 'background levels of 2, 3, 7, 8-TCDD in the U.S. male population. In addition, this study may serve as a means of determining whether service in the military and especially in Vietnam has had an effect on the levels of TCDD in the ^.J^'i ' - JM > , ! < , > « f?''V«, ' • * , * < " '»f i *> ' ' ' '"^ ' adipose tissue. if' „ \t r < i t ?. '«V * * ' ' V i , * I" •' ^v i » " ' " ' The proposed effort would involve a jointly-funded program between the VA and EPA to & £*_ 1 • f - y * * * 1 ! A 3 " i *.* ! i # ^ ^ develop the research protocol and appropriate sampling and analytical methods. The actual analyses of the human tissues will be costly and time consuming. Data should be forthcoming within two-three years. « ,» ^ < ••••• • .; ' •' ' ; • : • • • • Chloracne Activities The review of skin conditions to identify questionable cases which may be chloracne is •' • •'•-••':'••-:• ':,'•: '• .•'•: : i--> v 'v.'' : -'.';. ; • ' continuing. •'' ' .'•;• •.' , ." ' : . . •'•... Over 3,200 Rating Decision Sheets on skin condition claims have been reviewed by VA Central Office physicians. The medical records of questionable cases were reviewed by a dermatologist consultant at the Washington VA Medical Center who tentatively identified 12 cases requiring a further clinical review which will include a . • ; r': : ' : ' -•-' •• : ' v -••-.'••• • • • physical examination of those individuals. ••-.-. ' .. • I .>.. . • . . • • • • • . : • . < • ! : ( : • ' ; : - . t / V K - ''• We are now In the process of making arrangements for the physical examinations, •,i i ' ; • . ' » - • • : ' . . - - ' • ;•;•:'./ . ; - , ' : .-• including dermatology examinations, of these individuals at selected non-VA clinics. I r-:. ^.;-,;-:;- •;;£..;•;<*'^'.-^^V^/v^^U-' ^ ' J ^ v »^ .-•»:•-•:.: • }• • r.f-- ':.< ?'• •". . '•'•'• : 0, anticipate that these examinations will be conducted during October. >, •"••"..<. ,<' �8. •-• • ••>..-"•' •- "Tt '• '-,.'• , V i '% • }.- >• J t ;»•-< We intend to continue our review of Rating Decision Sheets provided by VA Central ' Office Compensation and Pension Service to determine possible chlorocne cases and recommend selected claimants for special dermatojogical examination. Additionally, we will review and analyze Agent Orange Registry data relating to types of skin conditions being reported by participants. -.- •• ••.-..•• ' ', * ' ij. i • i< < f ' ' I am confident that our current emphasis on chloracne-related activities will assist us in more effectively identifying and treating skin conditions which may be the result of exposure to Agent Orange. Vietnam Service Indicator for Patient Treatment File The Patient jreatment File (PTF) maintained by the Department of Medicine and Surgery has great potential for epidemiological research related to Vietnam veterans. A major problem with this automated, file is that there has been no entry to identify those veterans who actually served in Vietnam. .' • . " -s" The establishment of such an indicator, in most instances, will require a hand search of the individual veteran's service record. This would best be accomplished by a contract with an organization which has a proven record of expertise with this type of effort. ' ' " . " . ' \ We intend to conduct a study to determine the feasibility and cost of obtaining a V A - K - - . . . . . . . . • •- ; •-.•!•• , ., - ' . ' - • " , • . . • • • . - • . - . - • • • • ' • • • • • • • "• : ; . veteran's service history. Based upon the results obtained, we will then decide whether to obtain this information for all Vietnam-era veterans in the PTF. �Speciolly-Solicited Reseorch Activities *r* c-r— j ^ r i r~ ~ Medical Research Services has recently approved 10 new Agent Orange research studies f *" t •* that will investigate the impact on basic biological processes of low levels of exposure to Mfr ? * **T^ * * * ' . . - components of Agent Orange. Two other ongoing studies address these issues also. The Studies include analysis of the impact of Agent Orange components on: o Over cell function '" t, v I j -I f ii s jr. 0 ( f Skin cell chemistry relating to chloracne o * Neurobehavioral function ' •, t f * > « '«!, ' . -x V » " • ' The basis of the design( of each of these biological studies includes exposing a test ........ "' . ' *• i , biological system to one or more components of Agent Orange, and subsequently •3 • '••?*••.! . ; ' ; : ^ ;, - £*.••:'•:* •- ' ' * *"'• 'f.\::t^ ;'r' •••'• '.':. • , . . : . . , . . _ • measuring abnormalities of biological function. ~f\ -^ " - ' ; • . • • • • . . . . • • " ••'<-. : : ': •";'• ;"i.-!:^^;-,y V-' '.•.'•*' . i r . . . y ' v < - . , •.. •X^:.;{j,4;:>:.-- .--s ,; ; v/* -• ... ',,:?;;•,'',.;.-; ;.y>/. N j i : ^ :.-.;-v:: rn :•.• ..' • The chemicals used in these experiments which are the main component parts of Agent '• ''.'• ' '- • ' ' l ' * : ' • U. :••"'.'• V-",> •/"•!•»:•''«•" yV'-C-V;! • :.!Vi''.'>V '.-;. ' ,: ',' ? (• ':•:' : '•''•••'.'•l^..? ' ! ' • - • • . ; ' • ' ' < - . . „ ' .''"fi'v •'. v i* -<i '.^ Jl'*'!*,'* i'-. ' t •'. '. - ' '• " '' Orange are: 2.4-dichlorophenoxyacetic acid (2,4-D) and 2,4,5-trichiorophenoxyocetic " ; s- {. . .-' : * -i 'i .; f i -^ . ,. ; V-. ' 5 • * ^ , - ; , : • ^VU-i. 'i .^ . , . . . . acid (2,4,5,-T). In addition to these chemicals, Agent Orange (and some other herbicides used less frequently in Vietnam) contained varying amounts of a contaminant commonly referred to as TCDO (dioxin) which will also be a focus of studies to determine whether and how delayed toxicity is manifested after low-dose exposure. Such studies may provide clues for clinicians as to what medical tests would best identify delayed, toxic effects, if any, of exposure of veterans to herbicides in Vietnam. The biological systems thought to be affected by exposure to TCDD are: 6 Liver function; When animals are exposed to TCDD and related compounds, these chemicals are stored in the liver and produce acute liver damage. It ]' • . . ^- �10. would appear likely that any delayed harmful effects of exposure to low closes of »uch compounds would be manifested by subtle changes fn the biochemistry •«f the liver. Seven of the funded research studies will investigate the delayed impact of exposure to Agent Orange components and the contaminant TCDD on various aspects of liver cell functions in a variety of •'•'".-.• species. t' o ' ' , " ,- ' • ' , ,' • -.. . ' . • - - • -• ;, • • . ' .• •. . .' .. • . . .' • . • .. •. • . . •• -, . Skin: Chloracne is the one documented effect of low-dose exposure to Agent Orange in humans. One study will analyze the underlying biochemical events that lead to ch lor acne in a mouse model and in human tissue culture cells. o the nervous systems: Acute accidental poisoning with TCDD in man has led • j- ' •- • • • ' ? ' ' ' • ' • ' . " ' • • • •- '•• • • .' • .'•*•*"' • .' • ' r< . i . , . .' - ';j f to a variety of usually-acute neuromuscular abnormalities. Four studies will ; •.. V. • - • ; , , - , - • : • • ••' > i . , • . •• •' ' •'• • •'• , '. ' " *iiV : • ' ' • ; ' • • systematically investigate the effect of the components of Agent Orange on neuromuscular function, sleep and behavior in a variety of animal models. A new effort to solicit and support research on the special health problems facing Vietnam veterans has just begun. The Research and Development Office has sent forward to all VA medical facilities a solicitation for research studies dealing with disorders affecting Vietnam veterans and their families. It is anticipated that a significant number of new studies submitted in response to this solicitation will be supported in Fiscal Year 1983. • • - • - - • . • • > ' • . .. .- - - / : - i : Monograph Series - .-•. ' >,••• -•• "' .;«:. -:.-, ..,-. • ;•;.. • „ • ' • • ;, •• /• :/: • • . , . • * ' - . " ; • • , • Funding has been provided during FY 1982 for the preparation of a monograph series designed to provide useful scientific information on environmental factors that may have affected the'health of military personnel serving in Vietnam. �II. -&#!^^^ ore planned on the following subjects: Monographs :^/ri;* •'wf1^^ Literoture Anolysis • -|V.i.' :,. . chloracne, birth defects and genetic ' ../; ' --;.-N.-:-••--t^:. .... .::•.., . ',-v;v. ' ' v:• ^l^^fc^^^V^^ ;.«:4^;-;;utf,^*^feM]tt^:^ ..,.. : Mr. Chairman, as you may know, the comprehensive literature review of worldwide scientific literature on Agent 6range and other phenoxy herbicides used in Vietnam has *'•:•'."'', • ;•»' . • ' • ' • ' • ' - ' - - . . • • • . been completed in accordance with the provisions of Public Law 96-151, ... ' .-., . ;,. .. •.. . ,. , - • . '.',•;..•: .-<*..• - v.-',,..-...'., •;•''; - • : . .. , .-,, . . . . . . . We have .!••.; ' distributed this two-volume report (which includes an annotated bibliography and analysis of1,200i scientific papers)^widelyWithin imeVA. Copies have also been provided .to rnembers of the White-House established Agent Orange Working Group, the Advisory Committee on Health-Related Effects of Herbicides, the National Academy of Sciences, the Office of Technology Assessment, the Departments of Agriculture and Defense, Surgeon General of the U.S. Air Force, Library of Congress, the Centers for Disease Control and other individuals, organizations, and scientific research groups. The successful completion of this review represents a step forward on the Jong road to understanding the complex health issues related to the use of herbicides. It will undoubtedly serve as an invaluable scientific resource which will assist scientists and others in identifying areas suitable for additional research. We jntend to periodically update this report and to augment it with a detailed critical assessment of all publications addressing herbicide exposure with particular emphasis on health consequences in humans. It is estimated that about 400 publications have appeared since October 1981. A critical review of these recent reports is needed in -•,•••• •.•;,!'.. • • :*> .:.-•=..-.'-, : --•:. • :•• ••-:,,".^;„. •!:^f,'.-.. : --:--r-' -• •• ' , ' order to keep this effort current. The Veterans Administration will take necessary steps to ensure that the literature review and analysis remains as current as possible. �12. Armed Forces Institute of Pathology (AFIP) The Veterans Administration Is continuing to cooperate with the Armed Forces Institute of Pathology in providing biopsy and autopsy materials for analysis to the Institute. This special registry was established in 1978 with the purpose of analyzing tissue samples to determine what diseases Vietnam veterans are suffering from, as reflected in biopsies or The VA has repeatedly emphasized the importance of the AFIP Registry and will continue to urge VA health care facilities to send pathological material obtained from any Vietnam veteran. . ; v: Education Activities Mr. Chairman, our environmental physicians, as Agent Orange coordinators at our major VA health care facilities, remain the key link in examining and advising the veteran concerned about exposure to Agent Orange. In order to ensure that these health care staff remain completely abreast of the latest developments, nationwide conference calls ore held on a regular basis. When required, special conference calls are scheduled on significant developments requiring their immediate attention. In addition to the conference calls, relevant Agent Orange-related literature is periodically sent to the immediate attention of environmental physicians. Staff support within the Environmental Medicine Office is available to assist in the explanation of .specific documents. or to answer questions which may be raised by the information received from VA Central Office. �13. Environmental physicians ore encouraged to participate in important scientific meetings : '• " --• , - * • • I<in Ag«nt Orange and other environmental substances in order to keep abreast of scientific «nd medical developments. Members of our own VA Central Office staff * i played a key role In the planning and organizing of an "International Symposium on ' ,, . - < ' " * •. , .Chlorinated Dioxins and Related Compounds" which was held in Arlington, Virginia, on October 25-29, 1981. On October 12-1 A, 1982, Or. Barclay M. Shepard, my special assistant, and Dr. Alvin L. Young will actively participate in the "3rd International t * Symposium on Chlorinated Dioxins and Related Compounds" which will be held in Salzburg, Austria. ) hove been advised that several of our environmental physicians are /also planning to attend. Through such participation I am confident that our health care 'ftaff will remain professionally current with the latest findings on the short and longrange effects of Agent Orange and other environmental substances. VA Public information Activities As part of our effort to inform Vietnam veterans, their families, and other concerned individuals and organizations about Agent Orange and the assistance provided by the VA, we produced and distributed to all VA field stations a videotape entitled "Agent Orange: '< A Search for Answers." '* • , While a recent internal survey indicated that many thousands of people have viewed the program on television or in numerous groups of individual showings, we are encouraging grepter use of the film. ' : ' ' We are very pleased to report that this videotape has received considerable acclaim from critics. The Health Education Communication Association and the Network for Continuing Medical Education presented an award of merit to the VA for Outstanding �14. i t, . . - , . , • . : , . ' ; • ,.'•;••• /.',•• . , -••• . ' ' • " ' •••'. ochievement in the use of television for education in the health sciences." The International Television Association (ITVA) awarded its Golden Reel of Excellence for the vltteotape's "highly-effective form of communication, which helped Ifie user ,>;;l>i';•• ,: • ' •''•••. • ••'.\ . ..:•••: ..• •'•'•>>.'.w ft)$-.;::, •';''•:i.?W^'ify^.-lc-1'; •^i~::*';p-^*i^>\}•:*£,•: f ';"• ;•:-. • organization better achieve its stated goals." the program also was cited by ITVA for • • .-. : • . • • ' • • • • •:-,•• . ' • . : -;;:.,- ''fe v -!i;-v;-fjK^:i^^^':^ ; i.-3. : ';^ ^ : |pv»v v !^».••;>:•'/•; i;.i^l;/,.;,< • ' . : . creativity, innovative techniques, and high-production value. In addition, the program also received an Emmy Award from the National Academy of television Arts and Sciences. We are delighted by this recognition and encourage all interested individuals to view this program. * The VA takes seriously its obligation to keep veterans informed about Agent Orange. We have also pursued other avenues to provide information and education to concerned Vietnam veterans and their families and VA employees on matters related to Agent Orange. . Early this year, an automated mailing list was developed from the Agent Orange Registry. In June, letters were sent to these veterans along with the first two of a new series of printed information material on Agent Orange. One of these pamphlets was devoted primarily to Public Law 97-72. A third pamphlet has been issued and a fourth is ,-, • .. . i, . :. - . , .. . -<:•...... - • ' ;.-. ••;.:..•:•:; . - ....-• , , • • ••-< ' , . - . . . - . . . ' -•• r • • . .-=.-. in production. VA officials have participated in public seminars, news media interviews and other public forums dealing with the subject of Agent Orange. 5,. ;/. ..-• ' • • " ' : . . , • : • • • < • ; ' • • • :;c;.-x •' • •'••... •''-• • .'.' • • • • • ;.?; • • "':-'-•. •+-*\v • • . • ' • - <•;,.', VA Liaison with State Agent Orange Activities At the present time, 18 states have initiated programs directly related to the Agent Orange issue. The VA is continuing its efforts to maintain an effective, ongoing �15. J » ' , ,,• , " • . . ' ; . ' • relationship with each of these state programs. One of the prime responsibilities of our Agent Orange Research and Education Office is to insure that current and accurate information regarding VA Agent' Orange-related activities is disseminated on a timely * * * <, ' '] ' ' 1 ' r -t " . ' ' • ' • '•' basis to the various states,' as well as to veteran service organizations, government agencies, and interested parties. We consider }t to be an essential part of our program to * - "' " I • ••" ; • insure that the veteran population as a whole, and those who serve them at all levels, are fully Informed both with regard to the current body of knowledge regarding the possible adverse effects of dioxins, as well as the status of VA Agent Orange programs. V" - ': ;' " ' i'V* ' ' ^ .1 ,""'.'' To this end, the VA has provided the states with copies of all pertinent Agent Orange materials and we have extended to officials from all of these states an open invitation to attend the VA Advisory Committee meetings. Several of the states sent delegations to ' . ' • • , - ' ' , • . ' ' ' ' / ' . " . . . ' • •" . . -i, • the meeting held on August 31. The efforts are of a continuous nature and are beneficial to all concerned parties. As new states become involved in the Agent Orange issue, VA will include them in its information exchange program. White House Agent Orange Working Group (AOWG) We are pleased to report that the Veterans Administration is continuing to play an active role in the White House Agent Orange Working Group and its Science Panel. This committee was established in July 1981 when the Interogency Group to Study the Possible Long-Term Health Effects of Pnenoxy Herbicides and Contaminants was expanded and elevated in status to the Cabinet Council level. �$"' 16. .v *>, The AOWG brings together policy officials and scientists from throughout the federal : • r _, " >;'.,,, •." , . - • - r • " - . . • ' .'. *-*.-.- . . - • • • . . : -.'•• •-•-v.%»*i. . :..;'"'<• •',;••'',•• ;...•,>•', ,.v >"'•'; :" ••" • • ', ' ; ,.• • •••"•• ' '" establishment to identify ongoing research activities on Agent Orange and related (*• " matters and to develop and organize the means to carry out additional needed scientific \ - research. £ * '> > • • • • •'-••'• ••••• •'/•>»• :•:•;-: ; :V r -i;y :••.;•>. K .-.i:-'7'-:%tf^H-:f:/ v,;. ':• -V^ i'. •:. v^,...:. ,1,-,^ ,-U-' . ^ , j v . i ;, ^ 4.,t!,s.; ' The Department of Health and Human Services (DHHS) is the lead agency in the working / group. • ' •• - . • . • • • • • • • : . , . . . - \ ; . . • ' . • - ' • • • . . : -/->,,^,,'f'- . • ; . • ' . . : = . ;..- :•,., I',.,,--;.:,.., i.! ,- y - ,. : In addition to DHHS and VA, the AOWG includes representatives from the Departments of Defense, Agriculture, and Labor, Environmental Protection Agency, • •• •' •'• • . ' •••'•- • ; • • : • : • •••::.'=• ' : • . . ' . •^ • Office of Management and Budget, Council of Economic Advisors, Office of Science and Technology and Office of Policy Development. The AOWG has been very helpful to the VA in the review of our planned epidemiological study, mortality study, and other important research efforts. Through the AOWG mechanism, the VA also has been able to contribute to the success of Agent Orange research efforts conducted or sponsored by other federal departments and agencies. The more important of these research efforts are the U.S. Air Force's "Operation Ranch Hand" study and the Centers for Disease Control's Birth Defects Study. We view our participation as vital to the scientific process and as fully consistent with > • • • • . . ••>.>-:•,.-,..••. , , .-•:,•,.•,, ,-,. ;.;.,:•:,,-,. .•.',.:;-..,,*•.•••?>•• •..;:.1,^., v -, , ( . ••, •.-•:;... u: ,...,....,. the President's goal of ensuring "... that the full resources of the federal government . .-,,. .. ,.„,.,..;-x > •:.i,r-: *•: ' ' - y ...!.ys. .•-. . ; are available to support the working group's continuing efforts." i. Advisory Committee on Health-Related Effects of Herbicides This committee, established in 1979, continues to meet quarterly at VA Central Office for the purpose of assembling and analyzing information which the VA needs to formulate medical policy and procedures on"the complex questions surrounding veterans' herbicide exposure. �17. During recent meetings the committee has discu&sed the VA epidemiological study and herbicide Ijterdture review,' the VA-*olicited in-house research program regarding Agent 1 /• ^ , iilj Orange and Agent Blue, the VA mortality study, international dioxin symposiums, the Air Force t^ealth'Study, the CDC Birth Defects &udy, the proposed VA Twin Study/the * * ' * , t r AFIP Agent Orange' ftetfistry, the VA rVioribg/aph series, and many'btheir-research f- *-, ' . activities and rrtottersdf concern to Vietnam veterans dnd scientists searching for answers to the (difficult qUeirfions1 raised oi>obt'the possible human health effects of herbicides. "'>•• : ':'':';".>-v,-;'1, ^^v^-i^^'^^^^'^f^^V^^Sv!^?;'-/.1''' • ; . • • " ' ' : ; ' : - ' • ' ! • ;••• "•< '- ; .-'-'^ • ' • " : ""; ' %- • The committee 'has been particularly helpful in advising the VA on the literature review and the epidemiological study. The literature review, published October 1981, was the subject of several sessions and considerable time and attention have been devoted to a critique of the proposed epidemiological study design. Verbatim transcripts are prepared and made available to appropriate government offices and interested organizations and individuals. A copy of each transcript also is sent to all environmental physicians. ; ;:; Policy Coordinating Committee In recognition of the importance of the Agent Orange issue, the Administrator has reorganized and elevated in status the Policy Coordinating Committee (PCC) which was * * • . . . . . ' thCjAgency's central coordinating point for Agent-Orange related activities. The PCC develops policy for review and approval by the Administrator. It now is composed of the top leadership of the major departments and staff offices within the VA. Mr. Everett Alvarez, Jr., Deputy Administrator, chairs the PCC. �18. I wish to conclude this port of my testimony on Agent Orange, Mr. Chairman, by again expressing the total commitment of the Veterans Administration to attempting to resolve the many issues relating to Agent Orange. Although there is no way that we, or anyone, can guarantee that ultimate and conclusive answers will be found to the extremely-complex medical and scientific issues stemming from the use of the defoliant Agent Orange in Vietnam, nevertheless, we will continue to vigorously pursue the search for those answers. These efforts will center not only on our own research initiatives, but will be closely interfaced with the intensive research now underway by other federal, public and private institutions. Readjustment Counseling The Vietnam-era Veterans Readjustment Counseling Program has seen a number of important developments in recent months. In January, the Veterans Administration vested responsibility for this program in a new independent professional service—the Readjustment Counseling Service—and established that service on the same administrative level as Medical, Surgical, Nursing, Prosthetics, etc. A new program director was appointed by the Administrator of Veterans Affairs on February 10, 1982, following an intensive and thoughtful search and selection process. The±new Director of the Readjustment Counseling Service, psychiatrist, Arthur S. Blank, Jr., M.D., too Vietnam veteran and has been psychiatric consultant to the program since its earliest planning stages in 1979. �19. A^third leadership jnitjative ^was taken on Jun? |f, 198?, when a new position was created, C^hief pf^CpMn^eling Services, andean «*per4t clinician Dr. Raymond M. Scurfield from the Brentwood VA Medical Center was hired for this position. w Underscoring the significance » the^., A^n^jr^is^rator attaches to _the Readjustment / rj Counseling Program Is ;|he establishment |n November 1981 of a high-level Agency wide ' °" < i stee/ing commijtee tp.monitpr the^program, , , j-f ^ Improving the management. and^prganlzatjpn. :of the Vet Center Program has been one of our top priorities. In addition to augmenting our Central Office program management group, we have taken steps to strengthen the offices of pur six Regional Coordinators who oyers.ee. Vet Center operations in tl)eir .respective regions. During the developmental phase of the program, each of these important offices was staffed by a Regional Coordinator and a single secretary. Each Regional Office now has an Assistant Coordinator for Administrative Services, and we are further strengthening the Regional Coordinators' staffs with the appointment of an Assistant Coordinator for Clinical Services and an additionalI secretary. From an organizational standpoint, the most important development of recent months has been the publication of a new program circular, which clarifies lines of authority and responsibility. It contains several key elements: ~a. The responsibilities of the Director and the Readjustment Counseling Service ;.•.:../ ' • . . ' • . • ' • ' • ' • . - : • ' ' , • :•*'•' '"'•.•'• '• ' " .- • .;• •'.••'•'.". •- .-• • ... . •;.'..".••,.«: ."..:.. Staff In Central Office for overall supervision and management of the program are . spelled out. The Director and his staff have direct operational control of the Vet Center system through the Regional Coordinators and, within Central Office, ,„ report to the Deputy ACMD for Professional Services and to the Chief Medical Director through the Associate Deputy Chief Medical Director. �20. b. The responsibilities of the Regional Coordinator's staff are also clarified. We have established clear lines of authority and responsibility from Vet Centers to the . : • ' 'V ;•-• . :,-. ••^vi^'-,-.^.. • Regional Coordinator's staff to the Readjustment Counseling Service in Central Office. The Regional Coordinators are responsible for selection and all supervision , of the Team Leaders, and the program director is responsible for selection and all supervision of the Regional Coordinators. We have also spelled out the relationship (. • • $ * " > " " - ' '•- ^ ' between Vet Centers and their local VA Medical Center parent facilities. The : . •• • . ' • • - ; - . ..." '• -: •':"' •i •;:'. > . "••;]'.•?•'. V •;•'•'. •,'• •' • circular directs that the parent VA medical center is responsible for providing the Vet Center all required support services. On professional matters, the medical center's role with respect to the Vet Center operations is to be consultative and collaborative only. ; ' ' 'TV ' . •: . ' . . . . ' . . • \- ' ; ' ' • • ' '•• , . .. ..'''.- -•'. ' '. :,.' - ;• . . . . . As part of our reconstituting of the management and organization of the readjustment counseling program, we have instituted financial and accounting procedures which track all program funds and maintain their earmarked character at the local level. 1 '• • •• ''• ' * . . ' • ••' ' " • ' • ' , • • ' • ' ' ,• • ' • , i ' ' t * ' ' '• ' • . . ' ':• . * • • ' • " ' .'*• . ' • ' > - ' , ' . ' •' .• : • -. . ' *• . • " . " . . - . " " As you know, Mr. Chairman, we have also established a mechanism to contract with private sector providers to furnish readjustment counseling services to Vietnam-era - ' '. ^ ' . . . • ' ' ' • • -• • ~ • . . . veterans who do not have access to one of our Vet Centers. We are using a decentralized model with a contracting committee at each of 122 medical centers. The contracting committee includes two members of a Vet Center staff in each instance. As of August 31, over 300 contracts had been awarded. We are currently evaluating the quality and effectivenss of this new mode of service delivery. £ " • • ' . _ _ That concludes my statement, Mr. Chairman. I will be pleased to answer any questions you or members of the committee may have. � Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Alvin L. Young Collection on Agent Orange Description An account of the resource <p style="margin-top: -1em; line-height: 1.2em;">The Alvin L. Young Collection on Agent Orange comprises 120 linear feet and spans the late 1800s to 2005; however, the bulk of the coverage is from the 1960s to the 1980s and there are many undated items. The collection was donated to Special Collections of the National Agricultural Library in 1985 by Dr. Alvin L. Young (1942- ). Dr. Young developed the collection as he conducted extensive research on the military defoliant Agent Orange. The collection is in good condition and includes letters, memoranda, books, reports, press releases, journal and newspaper clippings, field logs and notebooks, newsletters, maps, booklets and pamphlets, photographs, memorabilia, and audiotapes of an interview with Dr. Young.</p> <p>For more about this collection, <a href="/exhibits/speccoll/exhibits/show/alvin-l--young-collection-on-a">view the Agent Orange Exhibit.</a></p> Text A resource consisting primarily of words for reading. Examples include books, letters, dissertations, poems, newspapers, articles, archives of mailing lists. Note that facsimiles or images of texts are still of the genre Text. Box The box containing the original item. 031 Folder The folder containing the original item. 0578 Series The series number of the original item. Series III Subseries I Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Creator An entity primarily responsible for making the resource Custis, Donald L. Title A name given to the resource Typescript: Statement of Donald L. Curtis, M.D., Chief Medical Director, Department of Medicine and Surgery, Veterans Administration, Before the Subcommittee on Oversight and Investigations, Committee on Veterans' Affairs, House of Representatives, Septe Subject The topic of the resource VA Agent Orange Registry health studies AOWG ao_seriesIII