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Veterans and Agent Orange: Update 2006 (2007)

Chapter: APPENDIX C Epidemiologic Tables for Chapter 4

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APPENDIX C Epidemiologic Tables for Chapter 4 In Tables C-1, C-2, and C-3, respectively, studies are grouped according to whether their subjects had occupational exposures, had environmental exposures, or were specifically Vietnam veterans. The tables provide an overview of design aspects of those epidemiologic studies reviewed in this and earlier reports that presented results on more than one health outcome or that investigated popula- tions that have been repeatedly studied. The summaries include the study’s design type, the numbers of subjects in the study and comparison populations, and a synopsis of how subjects were selected, how data were collected, what inclusion criteria were used, and how exposure was determined. Results were discussed in the appropriate health-outcome chapter of the Veterans and Agent Orange docu- ment in which the publication was reviewed. The citations for the articles in this appendix can be found in the reference list at the end of Chapter 4. Contents of TABLE C-1 Epidemiologic Studies—Occupational Exposure Page PRODUCTION WORKERS 718 NIOSH Studies, 718 Monsanto Studies, 721 Dow Studies, 721 BASF Studies, 723 IARC Studies, 724 Studies from Other Chemical Plants, 728 AGRICULTURAL–FOREST PRODUCTS 729 Studies from the Agricultural Health Study, 729 717

718 VETERANS AND AGENT ORANGE: UPDATE 2006 Studies of Other Agricultural Workers, 731 United Farm Workers, 731 Upper Midwest Health Study, 731 Studies of Forestry Workers, 736 Studies of Herbicide–Pesticide Applicators, 736 PAPER AND PULP WORKERS 740 CASE–CONTROL STUDIES 741 TABLE C-1 Epidemiologic Studies—Occupational Exposure Study Study Group Comparison Group Reference Design Description (n) (n)a PRODUCTION WORKERS NIOSH Studies Reviewed in Update 2006 Lawson Cohort Follow-on of NIOSH cross- 176 workers 217 referent wives et al., 2004 sectional medical study wives with 513 with 604 births (Sweeny et al., 1989, 1993); births examined reproductive endpoints, in terms of exposure to TCDD at the time of conception estimated by pharmacokinetic model, in wives of chemical workers vs. referent neighbors NIOSH Studies Reviewed in Update 2002 Steenland Cohort Reexamination and 267 NIOSH 227 NIOSH et al., 2001 comparison of diabetes data workers; comparisons; from the NIOSH cohort 990 Ranch 1,275 AFHS and the AFHS; reconciled Hand subjects comparisons differences between study methods and protocols NIOSH Studies Reviewed in Update 2000 Calvert Cohort Follow-up of workers 281 260 et al., 1999 employed more than 15 years at 2 plants that manufactured substances contaminated with TCDD; evaluated associations between serum TCDD and serum glucose (diabetes), TSH, total T4, T3 continued

APPENDIX C 719 TABLE C-1 Continued Study Study Group Comparison Group Reference Design Description (n) (n)a Steenland Cohort Mortality of workers 5,132 (3,538 — et al., 1999 at 12 industrial plants subjects with that produced TCDD- exposure data contaminated materials, divided into using a job–exposure matrix septiles of to estimate TCDD exposure cumulative categories; endpoints were exposure; all cancers, lung cancer, 608 with ischemic heart disease, chloracne) diabetes, smoking-related cancer, and all other cancers Calvert Cohort Follow-up of workers 281 260 et al., 1998 employed more than 15 years before at 2 plants that manufactured TCDD- contaminated materials; to evaluate association between TCDD exposure and cardiovascular outcomes Halperin Cohort Follow-up of a cohort of 259 243 et al., 1998 TCDD-exposed workers at 2 plants that manufactured TCDD-contaminated materials; to assess association between serum TCDD and immunologic outcome variables for eligible workers and matched neighborhood controls NIOSH Studies Reviewed in Update 1998 Sweeney Cross- Non-cancer endpoints 281 260 et al., 1996, sectional for liver function, 1997/1998 gastrointestinal disorders, chloracne, serum glucose, hormone, lipid concentrations, diabetes in the group studied by Calvert et al. (1991) Halperin Cross- Surrogates for cytochrome 281 260 et al., 1995 sectional P-450 induction in group studied by Calvert et al. (1991) continued

720 VETERANS AND AGENT ORANGE: UPDATE 2006 TABLE C-1 Continued Study Study Group Comparison Group Reference Design Description (n) (n)a NIOSH Studies Reviewed in Update 1996 Calvert Cross- PCT in group studied by 281 260 et al., 1994 sectional Calvert et al. (1991) Egeland Cohort Total serum testosterone and 248 231 et al., 1994 gondadotropin in chemical production workers exposed to dioxin, in group studied by Calvert et al. (1991) NIOSH Studies Reviewed in VAO Sweeney Cohort Peripheral neuropathy in 281 260 et al., 1993 group studied by Calvert et al. (1991) Alderfer Cohort Psychological assessment 281 260 et al., 1992 to determine depression in group studied by Calvert et al. (1991) Calvert Cohort Liver and gastrointestinal 281 260 et al., 1992 systems assessment in group studied by Calvert et al. (1991) Calvert Cohort Workers employed at 1 of 2 281 260 et al., 1991 plants manufacturing TCDD- contaminated materials at least 15 years before; to assess chronic bronchitis, COPD, ventilatory function, thorax, lung abnormalities; compared with matched neighborhood controls Fingerhut Cohort Cancer mortality in 5,172 — et al., 1991 male workers from 12 plants producing TCDD- contaminated materials (1942–1984), compared with US population

APPENDIX C 721 TABLE C-1 Continued Study Study Group Comparison Group Reference Design Description (n) (n)a Monsanto Studies Reviewed in VAO Collins Cohort Mortality of workers 122 — et al., 1993 (through 1987) exposed (chloracne); and unexposed to dioxin 632 (without between March 8, 1949, and chloracne) Nov. 22, 1949, as indicated by presence of chloracne, compared with local population mortality rates Moses et al., Cohort Health outcomes in 117 109 1984 Monsanto workers (1948–1969) with chloracne reported as a surrogate for 2,4,5-T exposure, compared with health outcomes in workers without chloracne as surrogate for no exposure Suskind and Cohort Health outcomes (1979) at 204 163 Hertzberg, clinical examination among 1984 workers exposed to 2,4,5-T (1948–1969) compared with non-exposed workers at same Monsanto plant Zack and Cohort Mortality of all white 884 — Gaffey, male workers (1955–1977) 1983 employed at a Monsanto plant through Dec. 31, 1977, compared with mortality of standardized US population Zack and Cohort Mortality experience 121 — Suskind, among employees with 1980 chloracne exposed to TCP process accident in 1949 at Monsanto, compared with US male population standard Dow Studies in Update 2004 Bodner Cohort Additional 10-year follow- 2,187 — et al., 2003 up of cohort studied by Cook et al. (1986), through 1995; Dow cohort findings compared with IARC International Study and NIOSH Dioxin Registry continued

722 VETERANS AND AGENT ORANGE: UPDATE 2006 TABLE C-1 Continued Study Study Group Comparison Group Reference Design Description (n) (n)a Dow Studies Reviewed in Update 2002 Burns et al., Cohort Mortality in chemical 1,567 US population; 2001 workers who manufactured 40,600 non-exposed or formulated 2,4-D, chemical workers 1945–1994 Dow Studies Reviewed in Update 1998 Ramlow Cohort Mortality in PCP-exposed 770 US population et al., 1996 workers 36,804 non-exposed workers Dow Studies Reviewed in Update 1996 Bloeman Cohort Follow-up of cohort studied 878 US population; et al., 1993 by Bond et al. (1988), 36,804 unexposed through 1986 workers Dow Studies Reviewed in VAO Bond et al., Cohort Chloracne incidence among 2,072 Internal comparison 1989a workers potentially exposed to TCDD; association with other risk factors Bond et al., Cohort Extension of Ott et al. 2,187 — 1989b (1987), through 1984 Bond et al., Cohort Mortality (through 1982) 878 US white male 1988 among workers potentially population; 36,804 exposed to 2,4-D (1945– non-exposed 1983) compared with US employees white men and all other male employees not exposed Bond et al., Cohort Extension of Cook et al. 322 US white male 1987 (1980); mortality through population; 2,026 1982 employees without chloracne Cook et al., Cohort Extension of Cook et al. 2,187 — 1987; (1986) through 1982 Ott et al., 1987 Sobel et al., Case– STS among Dow employees 14 126 1987 control (1940–1979), compared with employees without STS, for possible association with several exposures

APPENDIX C 723 TABLE C-1 Continued Study Study Group Comparison Group Reference Design Description (n) (n)a Cook et al., Cohort Mortality experience 2,189 — 1986 (1940–1979) of men manufacturing chlorinated phenols, compared with US white men Bond et al., Cross- Differences in potentially (1) 183 (1) 732 1983 sectional exposed and non-exposed (2) 114 (2) 456 workers for TCDD during chemical production, for (1) morbidity and (2) medical examination frequency, 1976–1978 Townsend Cohort Adverse reproductive 370 345 et al., 1982 outcomes among wives of Dow employees potentially exposed to TCDD (1939– 1975), compared with wives whose husbands were not exposed Cook et al., Cohort Mortality experience 61 — 1980 (through 1978) of male workers involved in a chloracne incident (1964) from TCDD exposure, compared with mortality experience of US white men Ott et al., Cohort Mortality experience 204 — 1980 among workers exposed to 2,4,5-T in manufacturing (1950–1971), compared with mortality experience of US white men BASF Studies Reviewed in Update 2000 Zober et al., Cohort Review and summary of 154 surviving None 1997 (1953 previous BASF studies of (as of 1989) accident) morbidity and mortality in members of Cross- workers exposed to TCDD 1953 accident sectional after BASF accidents in 1953 cohort; (1988 and 1988 42 exposed cohort) (1988) extruder personnel continued

724 VETERANS AND AGENT ORANGE: UPDATE 2006 TABLE C-1 Continued Study Study Group Comparison Group Reference Design Description (n) (n)a BASF Studies Reviewed in Update 1998 Ott and Cohort Cancer incidence and 243 — Zober, 1996 mortality experience (through 1992) of workers exposed to TCDD after the BASF accident, during reactor cleanup, maintenance, or demolition (based on the cohort of Zober et al., 1990) BASF Studies Reviewed in Update 1996 Zober et al., Cohort Morbidity experience in the 158 161 1994 group studied Zober et al. (1990) BASF Studies Reviewed in VAO Zober et al., Cohort Mortality experience of 247 — 1990 TCDD-exposed workers (1954–1987) at BASF plant, compared with population of FRG Thiess et al., Cohort Mortality experience among 74 180,000 (Town); 1.8 1982 BASF employees potentially million (district); exposed to TCDD during 60.5 million (FRG); Nov. 17, 1953, accident, 2 groups of 74 each compared with population from other cohort and other workers not studies exposed IARC Studies Reviewed in Update 2006 ’t Mannetje Cohort New Zealand phenoxy 813 production et al., 2005 herbicide workers exposed workers; 699 TCDD and phenoxy sprayers herbicides IARC Studies Reviewed in Update 2000 Neuberger Austrian Morbidity up to 1993 of 159; 50 Two control groups, et al., 1999 chloracne exposed chemical workers participated in comparable to cohort assessed by health insurance examination 50 examination data and health examination, participants; laboratory measures, numbers not given interviews with participating survivors and control subjects

APPENDIX C 725 TABLE C-1 Continued Study Study Group Comparison Group Reference Design Description (n) (n)a Hooiveld Cohort Mortality (through 1991), 562 (serum 567 et al., 1998 using SMR, of Dutch factory samples for workers assessed in relation 50); 140 men to work and exposure at accident history; SMR and relative risk analyses Jäger et al., Cohort Preliminary data from 159, original Matched non- 1998 Neuberger et al., 1999 cohort; 56 exposed controls [English abstract only] screened; 49 full data Neuberger Cohort of Preliminary data from 50 Age and sex- et al., 1998 exposed Neuberger et al., 1999 matched controls; cases number not given Vena et al., Cohort 36 Worker cohorts 21,863 None 1998 from 12 countries, produced or sprayed phenoxyacid herbicides and chlorophenols, categorized in 1 of 3 TCDD or higher- chlorinated dioxin categories; non-cancer mortality (1939– 1992) analyzed by SMR comparison and Poisson multiple regression Flesch- Cohort Mortality (1952–1984) of 1,189 — Janys, 1997 German workers exposed to TCDD and other contaminants in herbicide and insecticide production; SMR and Cox regression model IARC Studies Reviewed in Update 1998 Kogevinas Cohort Mortality (through 1992) 26,615 total — et al., 1997 of workers engaged in (21,863 production or application exposed; 4,160 of phenoxy herbicides and probably composed of (1) the Saracci exposed; 592 et al. (1991) cohorts, (2) the unknown German cohorts of Becher exposure) et al. (1996), and (3) the NIOSH cohorts of Fingerhut et al. (1991) continued

726 VETERANS AND AGENT ORANGE: UPDATE 2006 TABLE C-1 Continued Study Study Group Comparison Group Reference Design Description (n) (n)a Becher Cohort Cancer mortality (through 2,479 — et al., 1996 1989) among German workers in 4 chemical factories exposed to 2,4,5-T and/or trichlorophenol (subcohorts I and II), and phenoxy herbicides and chlorophenols (subcohorts III and IV) Flesch- Cohort Cancer and circulatory 1,189 2,528 gas workers Janys et al., system mortality among 1995 chemical plant workers in Hamburg, Germany, exposed to herbicides contaminated with PCDD/F IARC Studies Reviewed in Update 1996 Kogevinas Case– Nested studies of the 11 cases, STS; 5 controls per case et al., 1995 control relationship between STS 32 cases, NHL and NHL and occupational exposures in the IARC cohort Kogevinas Cohort Cancer incidence and 701 — et al., 1993 mortality experience of female workers in 7 countries, potentially exposed to chlorophenoxy herbicides, chlorophenols, and dioxin, compared with national death rates and cancer incidence rates Lynge, 1993 Cohort Cancer incidence in the 3,390 men; — group studied by Lynge 1,071 women (1985); follow-up extended through 1987 Kogevinas Cohort STS and malignant 14,439 (13,482 3,951 non-exposed et al., 1992 lymphoma mortality in exposed, employees an international cohort of 416 probably production workers and exposed, 541 herbicide sprayers (group unknown studied by Saracci et al., exposure) 1991)

APPENDIX C 727 TABLE C-1 Continued Study Study Group Comparison Group Reference Design Description (n) (n)a IARC Studies Reviewed in VAO Bueno de Cohort Mortality experience of 2,310 — Mesquita production workers exposed et al., 1993 to phenoxy herbicides and chlorophenols in the Netherlands, compared with national rates Coggon Cohort Mortality experience 1,104, Factory — et al., 1991 among 4 cohorts of workers A; 271, potentially exposed (1963– Factory B; 1985) to phenoxy herbicides 345, Factory and chlorophenols, compared C; 519, with national (England and Factory D Wales) and local population expected numbers Manz et al., Cohort Mortality experience of 1,184 men (a) population 1991 workers (1952–1984) 399 women (b) 3,120 gas at Hamburg, Germany, workers Boehringer plant exposed to TCDD, compared with national mortality and workers from another company Saracci Cohort Mortality experience of 16,863 men; — et al., 1991 20 international cohorts 1,527 women of herbicide sprayers and production workers, compared with national expected mortality experience Coggon Cohort Mortality experience 5,754 — et al., 1986 (through 1983) among workers manufacturing and spraying MCPA (1947–1975), compared with expected number of deaths among men of England and Wales and for rural areas Lynge, 1985 Cohort Cancer incidence among 3,390 men; — Danish workers exposed to 1,069 women phenoxy herbicides compared with expected results from the general population continued

728 VETERANS AND AGENT ORANGE: UPDATE 2006 TABLE C-1 Continued Study Study Group Comparison Group Reference Design Description (n) (n)a Studies from Other Chemical Plants Reviewed in Update 2000 Hryhorczuk Cohort Morbidity (chloracne, 366 303 et al., 1998 prophyria, general health status) of workers involved in pentachlorophenol production 1938–1978, compared with unexposed workers at the same factory. Jung et al., Cohort Self-selected group 192 — 1998 of former workers at pesticide factory: physical examination, laboratory measures, questionnaires; associations between serum PCDD/F, infectious disease, immunologic measures Lymphocyte proliferation 29 highly 28 external and chromate resistance tests exposed unexposed group compared for subgroup of subgroup most highly exposed workers at the study factory and non- exposed workers in another industry Studies from Other Chemical Plants Reviewed in Update 1998 Tonn et al., Cohort Long-term immune system 11 10 1996 effects of TCDD in industrial workers (1966–1976) in production and maintenance at a German chemical factory producing 2,4,5-T Studies from Other Chemical Plants Reviewed in VAO Jennings Cohort Immunologic abnormalities 18 15 et al., 1988 among TCDD-exposed workers in a 2,4,5-T manufacturing accident, compared with matched controls

APPENDIX C 729 TABLE C-1 Continued Study Study Group Comparison Group Reference Design Description (n) (n)a Thomas, Cohort Mortality experience 1,412 — 1987 as of Jan. 1, 1981, for white men employed in fragrance and flavors plant with possible exposure to TCDD, compared with US white men and for cancers compared with local men May, 1982, Cohort Health outcomes among 41 exposed; 31 1983 workers exposed and 54 possibly probably exposed to TCDD exposed after a 1968 accident, compared with non-exposed workers Pazderova- Descriptive Development of TCDD 55 None Vejlupkova intoxication among men in et al., 1981 Prague (1965–1968) Poland Cross- PCT, chloracne, 73 workers (20 Internal comparison et al., 1971 sectional hepatotoxicity, administrators; neuropsychiatric symptoms 11 production among 2,4-D and 2,4,5-T supervisors; 28 workers, compared with production; 14 other plant workers maintenance) Bashirov, Cross- Descriptive results of 292 20 examined 1969 sectional examination of workers descriptive; 50 involved in production examined of herbicides, study of workers for examination of cardiovascular and digestive systems, compared with non- exposed controls AGRICULTURAL–FOREST PRODUCTS Studies from US Agricultural Health Study (AHS) Reviewed in Update 2006 Farr et al., Cohort AHS—age at menopause for 8,038 2006 women 35–55 Hoppin AHS—cross-sectional 2,375 et al., 2006 design to investigate the prevalence of wheeze among commercial pesticide applicators continued

730 VETERANS AND AGENT ORANGE: UPDATE 2006 TABLE C-1 Continued Study Study Group Comparison Group Reference Design Description (n) (n)a Alavanja Cohort AHS—incidence–farmers, 87,286—total; et al., 2005 spouses of farmers, 51,211 private commercial applicators applicators; 31,350 spouses; 4,725 commercial applicators Blair et al., Cohort AHS—mortality, farmers 2005 (years used pesticides 10 or 10), spouses of farmers De Roos Cohort AHS reported on rheumatoid 135 675 et al., 2005b arthritis (RA) for women applicators and spouses Engel et al., Cohort AHS, wives of private 309 2005 applicators—incidence of breast cancer Kamel AHS cross-sectional analysis 18,782 et al., 2005 of white male licensed private pesticide applicators Farr et al., AHS—menstrual 3,103 2004 cycle characteristics in premenstrual women aged 21–40 Kern et al. Cohort AHS—serum TCDD and 567 815 2004 insulin sensitivity in Air Force veterans exposure to herbicides Studies from US Agricultural Health Study (AHS) Reviewed in Update 2004 Flower Prospective Parental pesticide application 150 — et al., 2004 cohort and cancer risk in offspring of pesticide applicators in AHS cohort Alavanja Prospective Correlation between 55,332 — et al., 2003 cohort pesticide exposure (including 2,4-D and 2,4,5-T) and prostate cancer in pesticide applicators Studies from US Agricultural Health Study (AHS) Reviewed in Update 2002 Hoppin Cohort Study predicting wheeze 3,838 16,630 applicators et al., 2002 among farm pesticide applicators without wheeze applicators in AHS with wheeze

APPENDIX C 731 TABLE C-1 Continued Study Study Group Comparison Group Reference Design Description (n) (n)a Studies from US Agricultural Health Study (AHS) Reviewed in Update 2000 Alavanja Cohort Analysis of self-reported 35,879 None et al., 1998 health care visits resulting from pesticide use by Iowa and North Carolina pesticide applicators Studies of Other Agricultural Workers Reviewed in Update 2006 United Farm Workers Mills and Nested California United Farm 128 breast 640 cancer free Yang, 2005 case– Workers evaluated effects of cancer cases control specific pesticides including 2,4,D on breast cancer Mills et al., Nested California United Farm 131 2005 case– Workers evaluated effects control of specific pesticides including 2,4,D on lymphohematopoeitic cancers (LHC) Lee et al., Case– Population-based 170 stomach; 502 2004a control agricultural pesticide use and 137 esophagus adenocarcinoma of stomach or esophagus Torchio Cohort Men licensed to use 23,401 2,683 et al., 1994 agricultural pesticides in Piedmont area of Italy Reif et al., Case– Men with occupation 134 1989 control indicated entered into New Zealand Cancer Registry 1980–1984 (brain or CNS cancers) Upper Midwest Health Study Lee et al., Case– Nebraska—incidence 2005 control (gliomas) Carreon Case– Upper Midwest Health 341 (female 528 et al., 2005 Control Study evaluated effects of glioma) rural herbicide exposure (arsenicals, phenoxys) on female farmers continued

732 VETERANS AND AGENT ORANGE: UPDATE 2006 TABLE C-1 Continued Study Study Group Comparison Group Reference Design Description (n) (n)a Ruder et al., Case– Upper Midwest Health (male glioma) 2004 Control Study evaluated effects of rural herbicide exposure (arsenicals, phenoxys) on male farmers Chiu et al., Nested Examined the association 973 2,853 2004 case– between agricultural control pesticide use and familial cancer with NHL Lee et al., Nested NHL among asthmatics who 2004b case– reported previous pesticide control exposure Studies of Other Agricultural Workers Reviewed in Update 2002 Arbuckle Cohort Spontaneous abortions in 2,110 women; None et al., 2001 couples living on full-time, 3,936 family-run farms in Ontario, pregnancies Canada Masley Cross- Targeted survey of 548 None et al., 2000 sectional households in an agriculture- households; survey based rural area of 1,407 Saskatchewan, Canada individuals Curtis et al., Cohort Time to pregnancy in couples 2,012 None 1999 living on full-time, family- pregnancies run farms in Ontario, Canada Savitz et al., Cohort Male pesticide exposure 1,898 couples; None 1997 and pregnancy outcome for 3,984 full-time, family-run farms in pregnancies Ontario, Canada Studies of Other Agricultural Workers Reviewed in Update 2000 Arbuckle Cohort Spontaneous abortions in 2,110 women; None et al., 1999 couples living on full-time, 3,936 family-run farms in Ontario, pregnancies Canada Studies of Other Agricultural Workers Reviewed in Update 1998 Gambini Cohort Cancer mortality (1957– 958 — et al., 1997 1992) among rice growers in Novara Province, northern Italy Kristensen Cohort Birth defects among 192,417 births 61,351 births et al., 1997 offspring of Norwegian farmers born after 1924

APPENDIX C 733 TABLE C-1 Continued Study Study Group Comparison Group Reference Design Description (n) (n)a Faustini Cohort Immune system components 10 Internal comparison et al., 1996 and function among farmers who mixed and applied commercial formulations containing 2,4-D and MCPA Studies of Other Agricultural Workers Reviewed in Update 1996 Dean, 1994 Cohort Brain and hematopoietic Population size — cancer mortality in unclear agricultural workers, compared with non- agricultural workers in Ireland (1971–1987) Morrison Cohort Update of mortality 155,547 — et al., 1994 experience in the group studied by Wigle et al., (1990), through 1987, with addition of farmers from Alberta and Manitoba Semenciw Cohort Leukemia mortality in group 155,547 — et al., 1994 studied by Morrison et al., (1993) Blair et al., Cohort Causes of death, including 119,648 white — 1993 cancer, among farmers in 23 men; 2,400 states (1984–1988) white women; 11,446 non- white men; 2,066 non- white women Semenciw Cohort Multiple myeloma mortality 155,547 — et al., 1993 of male farmers, compared with male population of the 3 prairie provinces of Canada (1971–1987) Senthilselvn Cross- Association between 1,939 None et al., 1992 sectional pesticide exposure and asthma in male farmers continued

734 VETERANS AND AGENT ORANGE: UPDATE 2006 TABLE C-1 Continued Study Study Group Comparison Group Reference Design Description (n) (n)a Studies of Other Agricultural Workers Reviewed in VAO Morrison Cohort Mortality experience of 145,383 — et al., 1993 male Canadian farmers 45 years or older in Manitoba, Saskatchewan, Alberta (1971–1987), compared with Canadian prairie province mortality rates Eriksson Cohort Incidence of NHL, HD, Number in — et al., 1992 and multiple myeloma occupational (1971–1984) among group selected occupational unknown groups in Swedish men and women, compared with rates expected in general population Hansen Cohort Study of cancer incidence 4,015 (859 — et al., 1992 among male and female women; 3,156 Danish gardeners compared men) to incidence expected among the general population Morrison Cohort Mortality experience, male 155,547 — et al., 1992 farmers 35 years or older (1971–1987), compared with Canadian prairie province rates Ronco et al., Cohort Cancer incidence (1970– None given None given 1992 1980) among male and female Danish farm workers 15–74 years old, compared with expected number of cancers among persons economically active; cancer mortality (November 1981– April 1982) among male and female Italian farmers 18–74 years old, compared with persons in other occupational groups

APPENDIX C 735 TABLE C-1 Continued Study Study Group Comparison Group Reference Design Description (n) (n)a Lerda and Cohort Farmers exposed to 2,4-D, as 32 25 Rizzi, 1991 measured in urine, compared with non-exposed men, for differences in sperm volume, death, count, motility, abnormalities, March–June 1989 Wigle et al., Cohort NHL mortality experience 69,513 — 1990 in male farmers 35 years or older (1971–1985) in Saskatchewan, Canada, compared with age- and period-specific mortality rates expected for Saskatchewan men Corrao Cohort Cancer incidence among 642 18,839 et al., 1989 male farmers licensed (1970– 1974) to use pesticides, compared with number expected among licensed non-users Wiklund Cohort Malignant lymphoma 354,620 1,725,845 et al., 1988a incidence among agricultural and forestry workers in Sweden, compared with the general population of men; 1960 census Wiklund Cohort STS incidence among 354,620 1,725,845 and Holm, agricultural and forestry 1986 workers in Sweden, compared with the general population of men; 1960 census Wiklund, Cohort Cancer incidence (diagnosed 19,490 — 1983 1961–1973) among agricultural workers in Sweden, compared with expected rates; 1960 census Burmeister, Cohort Mortality of farmers, 6,402 13,809 1981 compared with non-farmers, Iowa (1971–1978) continued

736 VETERANS AND AGENT ORANGE: UPDATE 2006 TABLE C-1 Continued Study Study Group Comparison Group Reference Design Description (n) (n)a Studies of Forestry Workers Reviewed in Update 2002 Thörn et al., Cohort Mortality and cancer 261 243 2000 incidence in Swedish lumberjacks exposed to phenoxy herbicides Studies of Forestry Workers Reviewed in VAO Green, 1991 Cohort Mortality experience, male 1,222 — forestry workers (1950– 1982) in Ontario, compared with expected mortality of male Ontario population Green, 1987 Cohort Suicide experience in 1,222 — Canadian forestry workers by number of years in forestry trade as a surrogate for exposure to phenoxy herbicides, compared with population Van Houdt Cross- Acne and liver dysfunction 54 54 et al., 1983 sectional in 2,4,5-T–exposed and non-exposed Dutch forestry workers Studies of Herbicides–Pesticide Applicators Reviewed in Update 2006 Foster et al., Cross- Dioxin levels and thyroid 20,625 — 2005 sectional hormones in maternal serum applicators as possible contributor and spouses; to cognitive or motor 21,375 impairment in offspring children born during or after 1975 Studies of Herbicide–Pesticide Applicators Reviewed in Update 2004 Swaen Cohort Mortality follow-up in Dutch 1,341 — et al., 2004 male herbicide applicators Studies of Herbicide–Pesticide Applicators Reviewed in Update 2000 Dich and Cohort Men licensed for pesticide 20,025 — Wiklund, application in Sweden; 1998 cancer cases ascertained from cancer registry and reported standardized incidence ratio for prostate cancer

APPENDIX C 737 TABLE C-1 Continued Study Study Group Comparison Group Reference Design Description (n) (n)a Studies of Herbicide–Pesticide Applicators Reviewed in Update 1998 Heacock Cohort Fertility among British 18,016 births 1,668 births et al., 1998 Columbia workers potentially exposed to chlorophenate wood preservatives in 14 sawmills, 1955–1988; includes the cohort studied by Hertzman et al. (1997) Hertzman Cohort Mortality among British 23,829 2,658 et al., 1997 Columbia workers potentially exposed to chlorophenate wood preservatives in 11 sawmills, 1950–1985 Dimich- Cohort; Birth defects among 19,675 births 5 control subjects, Ward et al., nested offspring (1952–1988) of the among 9,512 non-anomalous 1996 case– cohort studied by Hertzman fathers birth, per case control et al. (1997) Garry et al., Cohort Chromosome abnormalities 23 fumigant 33 1996a based on the cohort of Garry applicators; et al. (1994) 18 insecticide applicators; 20 herbicide applicators Garry et al., Cohort Birth defects among 4,935 births 3,666 births with 1996b offspring (1989–1992) of among 34,772 anomalies, general male pesticide applicators in pesticide population Minnesota applicators (125 with birth anomalies) Zhong and Cohort Cancer mortality among 2,449 (1,860 — Rafnsson, various subgroups of men, 589 1996 pesticide users in Iceland women) Studies of Herbicide–Pesticide Applicators Reviewed in Update 1996 Asp et al., Cohort Mortality and cancer 1,909 — 1994 morbidity experience of male chlorophenoxy herbicide applicators (cohort studied by Riihimaki et al., 1982, 1983) in Finland (1955–1971), through 1989, compared with general population morbidity and continued mortality

738 VETERANS AND AGENT ORANGE: UPDATE 2006 TABLE C-1 Continued Study Study Group Comparison Group Reference Design Description (n) (n)a Garry et al., Cross- Health outcomes resulting 719 None 1994 sectional from exposure in male pesticide applicators in Minnesota Studies of Herbicide–Pesticide Applicators Reviewed in VAO Swaen Cohort Cancer mortality experience 1,341 — et al., 1992 (through 1987) among Dutch male herbicide applicators licensed before 1980, compared with total Dutch male population Bender Cohort Cancer mortality of 4,849 — et al., 1989 Minnesota highway maintenance workers, compared with numbers expected in white Minnesota men Wiklund Cohort Risk of cancer in cohort 20,245 — et al., 1989a studied by Wiklund et al. (1987), through 1982 Wiklund Cohort Risk of STS, HD, NHL in 20,245 — et al., 1989b cohort studied by Wiklund et al. (1987) through 1984 Wiklund Cohort Risk of STS in cohort 20,245 — et al., 1988b studied by Wiklund et al. (1987), through 1984 Wiklund Cohort Risk of HD, NHL among 20,245 — et al., 1987 Swedish pesticide applicators from date of license through 1982, compared with expected total population cases Blair et al., Cohort Mortality experience of 3,827 — 1983 white male Florida pesticide applicators compared with US and Florida men Riihimaki Cohort Cancer morbidity, mortality 1,926 — et al., 1983 in cohort (Riihimaki et al., 1982), through 1980

APPENDIX C 739 TABLE C-1 Continued Study Study Group Comparison Group Reference Design Description (n) (n)a Riihimaki Cohort Mortality among herbicide 1,926 — et al., 1982 applicators exposed to 2,4- D and 2,4,5-T in Finland, compared with expected population mortality Smith et al., Cohort Adverse reproductive 113 401 pregnancies 1982 outcomes among chemical pregnancies (non-exposed) applicators and agricultural (compounds contractors by category of other than exposure: none; compounds 2,4,5-T); 486 other than 2,4,5-T; 2,4,5-T pregnancies (2,4,5-T) Barthel, Cohort Cancer incidence (1948– 1,658 — 1981 1972) in male agricultural production workers, compared with expected population incidence rates Smith et al., Cohort Differences in adverse 459 422 1981 reproductive outcomes in chemical applicators (1973– 1979) in New Zealand, compared with agricultural contractors Axelson Cohort Additional years of follow- 348 — et al., 1980 up of cohort established in Axelson and Sundell (1974) Axelson Cohort Mortality and cancer 348, total — and Sundell, incidence among Swedish herbicide 1974 railroad workers spraying exposure; herbicides ( 45 days), 207, phenoxy compared with expected acids and deaths by age and sex combinations; (1957–1972) in Sweden 152, amitrole and combinations; 28, other herbicides and combinations continued

740 VETERANS AND AGENT ORANGE: UPDATE 2006 TABLE C-1 Continued Study Study Group Comparison Group Reference Design Description (n) (n)a PAPER AND PULP WORKERS Paper and Pulp Studies Reviewed in Update 2006 McLean Cohort IARC pulp and paper 27 never et al., 2006 workers exposure to exposed; 16 nonvolatile organochlorine ever exposed compounds Paper and Pulp Studies Reviewed in Update 2000 Schildt Case– Histopathologically verified 410 410 et al., 1999 control oral-cancer cases, matched control subjects; mailed exposure questionnaire on lifetime occupational history, oral cancer risk factors, pesticide use, smoking, SES, place of residence Rix et al., Cohort Cancer incidence in blue- 14,788 (14,362 — 1998 collar workers at 3 Danish identified for paper mills, compared follow-up) with population rates from national population and mortality registers Paper and Pulp Studies Reviewed in VAO Jappinen Cohort Cancer incidence (through 152 ~135,000 and 1987) in male Finnish Pukkala, pulp and paper workers 1991 (1945–1961), compared with rates in local central hospital district Henneberger Cohort Mortality experience through 883 — et al., 1989 August 1985, white men employed in Berlin, New Hampshire, pulp and paper industry, compared with mortality expected in US white men Solet et al., Cohort Mortality (1970–1984) 201 — 1989 in white male United Paperworkers International Union members, compared with expected number of deaths in US men

APPENDIX C 741 TABLE C-1 Continued Study Study Group Comparison Group Reference Design Description (n) (n)a Robinson Cohort Mortality experience through 3,572 — et al., 1986 March 1977, white male workers employed in 5 paper and pulp mills, compared with expected number of deaths in US population CASE–CONTROL STUDIES Case–Control Studies Reviewed in Update 2006 De Roos Nest case– AHS limited to female 135 675 et al., 2005a control participants to determine association of 2,4-D and rheumatoid arthritis De Roos Case– Investigation of PCBs and 100 100 et al., 2005b control other organchlorines and risk of NHL Hartge Case– Estimate the effects of 1,057 1,321 et al., 2005 control residential herbicide exposure on NHL risk. Heilier Case– Endometriosis among 50 women (25 21 et al., 2005 control Belgian surgical patients w/ peritoneal vs healthy gynecological endometriosis, patients 25 w/ deep adenomyotic nodules McDuffie Case– Test contradictory results in 513 1506 et al., 2005 control studies of phenoxyherbicides and NHL, rubber gloves use by farmers when mixing or applying pesticides Chen et al., Case– Residential exposure to 2006 control pesticides and chemicals Chen et al. Case– Parental occupational 253 394 2005 control exposure to pesticide and childhood germ cell-tumors (GCTs) Oh et al., Case– South Korean study 84 31 2005 control evaluated male fertility- dioxin exposure with air monitoring continued

742 VETERANS AND AGENT ORANGE: UPDATE 2006 TABLE C-1 Continued Study Study Group Comparison Group Reference Design Description (n) (n)a Park et al., Case– Investigated the association 2005 control between occupational factors and mortality from neurodengerative diseases Reynolds Case– Evaluated breast-cancer risk 79 women 52 women et al., 2005a control associated with body burden diagnosed with diagnosed with levels of PCDDs and PCDFs invasive breast benign breast cancer conditions Reynolds Case– Evaluated association 2,216 cases in 4,388 controls et al., 2005b control between cancers diagnosed state cancer matched on DOB at 0–4 years in 1990–1997 registry and sex and maternal exposure matched to to “probable human California birth carcinogens” (including certificate cacodylic acid) during gestation at residence based on application of GIS approach to pesticides data from CPUR Tango et al., Case– Examined multiple 2004 control pregnancy outcomes in Japan—infant deaths from congenital defects Magnani Case– Mortality study that et al., 1987 control examined five cancer— esophageal, pancreatic, cutaneous melanoma, kidney, and brain in deceased male residents Case–Control Studies Reviewed in Update 2000 Ekström Case– All new cases of 565 1,164 et al., 1999 control histologically confirmed gastric adenocarcinoma in 2 areas in Sweden; age- and sex-matched control group randomly selected by computerized population register

APPENDIX C 743 TABLE C-1 Continued Study Study Group Comparison Group Reference Design Description (n) (n)a Hardell and Case– Male cases, 25 years or older, 404 741 Eriksson, control with histopathologically 1999 confirmed NHL during 1987–1990 in northern and central-Sweden; age-matched controls from National Population Registry García Case– Match-paired study of 261 261 et al., 1998 control congenital malformations or defects in an agricultural region of Spain Case–Control Studies Reviewed in Update 1998 Blatter Case– Multicenter Dutch study of 222 764 et al., 1997 control paternal occupation and risk of spina bifida in offspring (1980–1992) Liou et al., Case– Occupational and 120 240 1997 control environmental risk factors and PD in Taiwan (1993–1995) Tatham Nested Occupational risk factors 1,048 1,659 et al., 1997 case– (population based) for control subgroups of NHL patients based on the CDC Selected Cancers Study (CDC, 1990a,b,c,d) Nanni et al., Case– Occupational and chemical 187 977 1996 control risk factors (population- based) in northeastern Italy for CLL and NHL (1987–1990) Schulte PMR Neurodegenerative diseases Based on et al., 1996 Analysis, and occupational risk factors 130,420 death Nested from 27 states certificates case– control Seidler Case– PD and rural factors, 380 379 neighborhood et al., 1996 control including exposure to controls; 376 herbicides and wood regional controls preservatives, in Germany continued

744 VETERANS AND AGENT ORANGE: UPDATE 2006 TABLE C-1 Continued Study Study Group Comparison Group Reference Design Description (n) (n)a Case–Control Studies Reviewed in Update 1996 Hardell Case– Association between 105 335 et al., 1994 control occupational exposures, parameters related to NHL in white men in Sweden Mellemgaad Case– Cases of renal-cell carcinoma 365 396 et al., 1994 control (20–79 years) in Denmark, compared with population- based sample without cancer for identification of occupational risk factors Nurminen Case– Structural defects in infants 1,306 1,306 et al., 1994 control born to mothers engaged in agriculture in first trimester, compared with those from mothers not in agricultural work during the first trimester Brown Case– Multiple myeloma 173 650 et al., 1993 control (population-based) in Iowa men, for association with pesticide exposures Persson Case– Risk factors potentially 31 HD; 93 204 et al., 1993 control associated with HD and NHL NHL in men identified from the Regional Cancer Registry in Sweden Semchuk Case– PD cases (36–90 years of 75 men; 55 150 men; 110 et al., 1993 control age) in Canada, compared women women with population-based sample, for association with occupational exposure to herbicides and other exposures Zahm et al., Case– NHL and pesticide exposure 206 824 1993 control in white women diagnosed from July 1, 1983, to June 30, 1986 McDuffie Case– Pesticide exposure in male 273 187 et al., 1990 control cases of primary lung cancer in Saskatchewan, Canada, compared with age-, sex-, and location of residence– matched control subjects

APPENDIX C 745 TABLE C-1 Continued Study Study Group Comparison Group Reference Design Description (n) (n)a Case–Control Studies Reviewed in VAO Cantor Case– NHL (population-based) in 622 1,245 et al., 1992 control Iowa and Minnesota men, association with farming exposures Smith and Case– STS, malignant lymphomas 82 82 other cancers; 82 Christophes, control in men diagnosed 1982–1988 population 1992 in Australia, compared with other cancers, for association with exposure to phenoxy herbicides and chlorophenols Brown Case– Leukemia (population based) 578 1,245 et al., 1990 control in Iowa and Minnesota men for association with farming exposures Eriksson Case– Male cases of STS (25–80 218 212 et al., 1990 control years) diagnosed 1978–1986 in central Sweden, compared with population-based sample without cancer, for association with occupational exposure to phenoxyacetic acids and chlorophenols Wingren Case– Male cases of STS (25–80 71 315 population et al., 1990 control years) diagnosed 1975–1982 based; 164 other in southeast Sweden, cancers compared with 2 referent groups: population-based sample and other cancers, for association with phenoxyacetic acids and chlorophenols Zahm et al., Case– White men 21 years or 201 725 1990 control older diagnosed with NHL (1983–1986) in Nebraska, compared with residents of the same area without NHL, HD, multiple myeloma, CLL for association with herbicides (2,4-D) on farms continued

746 VETERANS AND AGENT ORANGE: UPDATE 2006 TABLE C-1 Continued Study Study Group Comparison Group Reference Design Description (n) (n)a Alavanja PMR Mortality experience, USDA 1,411 — et al., 1989 Analysis, forest–soil conservationists nested (1970–1979) evaluated case– for specific cancer excess; control case–control study of specific cancers identified from PMR analysis Boffetta Nested Multiple myeloma (national), 282 1,128 et al., 1989 case– compared with other cancer control controls, for association with exposures including pesticides and herbicides LaVecchia Case– Italian men and women with 69 HD; 153 396 et al., 1989 control HD, NHL, and multiple NHL; 110 myeloma (1983–1988), multiple compared with population of myeloma Italy, for occupational and herbicide use associations Persson Case– HD, NHL among living 54 HD; 106 275 et al., 1989 control men and women in Sweden, NHL compared with subjects without cancers, for association with occupational exposures, including phenoxy herbicides Woods and Case– NHL from the study of 576 694 Polissar, control Woods et al. (1987), 1989 association with phenoxy herbicides in farmworkers Alavanja PMR USDA extension agents 1,495 — et al., 1988 Analysis, mortality experience nested (1970–1979), evaluated case– for specific cancer excess; control case–control study of specific cancers identified from PMR analysis Dubrow Case– NHL, HD (death certificates, 61 NHL; 304 et al., 1988 control 1958–1983) among white 15 HD male residents of Hancock County, Ohio, compared with a random sample of those dying from other causes, for association with farming

APPENDIX C 747 TABLE C-1 Continued Study Study Group Comparison Group Reference Design Description (n) (n)a Hardell and Case– Male cases of STS (25–80 55 330 population Eriksson, control years) diagnosed between based; 190 other 1988 1978–1983 in northern cancers Sweden, compared to two referent groups: population based, and with other cancers, for association with occupational exposure to phenoxyacetic acids and chlorophenols Musicco Case– Brain gliomas diagnosed 240 (1) 465 et al., 1988 control 1983–1984 in men and (2) 277 women in Italy, compared with (1) patients with non-glioma nervous system tumors and (2) patients with other neurologic diseases, for association with chemical exposures in farming Olsson and Case– NHL (1978–1981) in 167 50, same area; Brandt, control Swedish men, compared with 80, other parts of 1988 2 groups of men without Sweden NHL for association with occupational exposures including phenoxy acids Hardell Case– Kaposi’s sarcoma in AIDS 50 50 et al., 1987 control patients (23–53 years) in Sweden, compared with controls, for association with TCDD and pesticide exposure Pearce Case– Expansion of study by Pearce 183 338 et al., 1987 control et al. (1986b) of NHL to include ICD 200 diagnosed cases and additional controls, for association with farming exposures continued

748 VETERANS AND AGENT ORANGE: UPDATE 2006 TABLE C-1 Continued Study Study Group Comparison Group Reference Design Description (n) (n)a Woods Case– STS or NHL in men 20–79 128 STS; 576 694 et al., 1987 control years old (1983–1985) in NHL western Washington State, compared with non-cancer population sample, for association with occupational exposure to phenoxy herbicides and chlorinated phenols Hoar et al., Case– STS, NHL, HD in Kansas 133 STS; 121 948 1986 control (1976–1982), compared with HD; 170 NHL non-cancer control subjects, for association with 2,4-D, 2,4,5-T, and other herbicides in white men 21 years or older Morris Case– Multiple myeloma (1977– 698 1,683 et al., 1986 control 1981) in four SEER areas, compared with population control subjects, for risk factors associated with the disease, including farm use of herbicides Pearce Case– Male multiple myeloma 76 315 et al., 1986a control cases diagnosed 1971–1981 in New Zealand, compared with control subjects with other cancers, for potential association with phenoxy herbicides and chlorophenols Pearce Case– NHL cases (ICD-9 202) in 83 168 other cancer; et al., 1986b control men diagnosed 1977–1981 in 228 general New Zealand, compared with population control group sample with other cancers and population sample, for association with occupational exposure to phenoxy herbicides and chlorophenols Smith and Case– Update of Smith et al. 51 update 315 (407) Pearce, control (1983), diagnoses through cases (133, 1986 1982 combined with data from Smith et al., 1983)

APPENDIX C 749 TABLE C-1 Continued Study Study Group Comparison Group Reference Design Description (n) (n)a Vineis et al., Case– STS cases in men and 37 men; 85 men; 1986 control women diagnosed 1981– 31 women 73 women 1983 in northern Italy, compared with population sample of control subjects, for association with phenoxy herbicide exposure Blair and Case– Leukemia cases by cell type 1,084 2,168 White, 1985 control in Nebraska (1957–1974), compared with non-leukemia deaths, for association with agricultural practices Pearce Case– Malignant lymphoma, 734 2,936 et al., 1985 control multiple myeloma in men diagnosed 1977–1981 in New Zealand, compared with men with other cancers, for association with agricultural occupations Balarajan Case– STS (1968–1976) diagnosed 1,961 1,961 and control in men in England and Acheson, Wales, compared with men 1984 with other cancers, for association with farming, agriculture, forestry occupations Donna Case– Ovarian cancer in women 60 127 et al., 1984 control (1974–1980), compared with women without ovarian cancer, for association with herbicide use Hardell Case– Primary liver cancer 98 200 et al., 1984 control diagnosed 1974–1981 in men (25–80), residing in northern Sweden, compared with population-based control subjects, for association with occupational exposure to phenoxyacetic acid and chlorophenols continued

750 VETERANS AND AGENT ORANGE: UPDATE 2006 TABLE C-1 Continued Study Study Group Comparison Group Reference Design Description (n) (n)a Smith et al., Case– STS in New Zealand 82 92 1984 control residents (1976–1980), compared with subjects without cancer, for association with occupational exposures, including phenoxy herbicides Burmeister Case– Multiple myeloma, NHL, 550 multiple 1,100; et al., 1983 control prostate, stomach cancer myeloma mortality (1964–1978) in 1,101 NHL; 2,202; white men 30 years or older, compared with mortality 4,827 prostate; 9,654; from other causes, for 1,812 stomach 3,624 association with farming practices, including herbicide use, in Iowa Hardell and Case– HD diagnosed (1974–1978) 60 335 Bengtsson, control in men (25–85) in northern 1983 Sweden, compared with population-based sample without cancer, for association with occupational exposure to phenoxyacetic acid and chlorophenols Smith et al., Case– Preliminary report, men with 80 92 1983 control STS reported 1976–1980 in New Zealand, compared with control subjects with other cancers, for association with phenoxyacetic acid exposure Burmeister Case– Leukemia deaths (1964– 1,675 3,350 et al., 1982 control 1978) in white men 30 years or older in Iowa, compared with nonleukemia deaths, for association with farming Cantor, Case– NHL in Wisconsin men 774 1,651 1982 control (1968–1976), compared with men dying from other causes, for association with farming

APPENDIX C 751 TABLE C-1 Continued Study Study Group Comparison Group Reference Design Description (n) (n)a Hardell Case– Nasal, nasopharyngeal 44 nasal; 27 541 et al., 1982 control cancers diagnosed nasopharyngeal 1970–1979 in men (25–85) residing in northern Sweden, compared with controls selected from previous studies (Hardell and Sandstrom, 1979; Hardell et al., 1981), for association with occupational exposure to phenoxyacetic acid and chlorophenols Carmelli Case– Cases of spontaneous 134 311 et al., 1981 control abortion (1978–1980), compared with live births, for association with paternal exposure to 2,4-D Eriksson Case– Cases of STS diagnosed 110 219 et al., 1979, control 1974–1978 in southern 1981 Sweden, compared with population-based sample without cancer, for association with occupational exposure to phenoxyacetic acid and chlorophenols Hardell, Case– (1) Cases of STS (Hardell (1) 221 154 1981 control and Sandstrom, 1979) and (2) 154 541 malignant lymphomas (Hardell et al., 1981), compared with colon cancer cases, and (2) colon- cancer cases compared to population-based controls for association with occupational exposure to phenoxyacetic acids and chlorophenols Hardell Case– Cases of malignant 60 HD 338 et al., 1980 control lymphomas (HD, NHL, 109 NHL Hardell unknown) diagnosed (1974– et al., 1981 1978) in men (25–85) in northern Sweden, compared with population-based controls, for association with occupational exposure to phenoxyacetic acid and continued chlorophenols

752 VETERANS AND AGENT ORANGE: UPDATE 2006 TABLE C-1 Continued Study Study Group Comparison Group Reference Design Description (n) (n)a Blair and Case– Cases in Nebraska (1957– 1,084 2,168 Thomas, control 1974), compared with deaths 1979 from other causes, for association with agricultural practices Hardell and Case– Cases of STS (26–80 years) 52 206 Sandstrom, control diagnosed (1970–1977) in 1979 northern Sweden, compared with population-based controls, for association with occupational exposure to phenoxyacetic acid and chlorophenols ABBREVIATIONS: 2,4-D, 2,4-dichlorophenoxyacetic acid; 2,4,5-T, 2,4,5-trichlorophenoxyacetic acid; AHS, Agricultural Health Study; CDC, Centers for Disease Control and Prevention; CLL, chronic lymphocytic leukemia; COPD, chronic obstructive pulmonary disease; FRG, Federal Re- public of Germany; HD, Hodgkin’s disease; IARC, International Agency for Research on Cancer; ICD, International Classification of Diseases; MCPA, methyl-4 chlorophenoxyacetic acid; NIOSH, National Institute for Occupational Safety and Health; NHL, non-Hodgkin’s lymphoma; PCDD, polychlorinated dibenzodioxin; PCDF, polychlorinated dibenzofurons; PD, Parkinson’s disease; PCP, pentachlorophenol; PCT, porphyria cutanea tarda; PMR, proportionate mortality ratio; SEER, Surveil- lance, Epidemiology, and End Results program of National Cancer Institute; SES, socioeconomic status; SIR, standardized incidence ratio; SMR, standardized mortality ratio; STS, soft-tissue sarcoma; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; TCP, 2,4,5-trichlorophenol; TSH, thyroid-stimulating hormone; T3, triiodothryonine; T4, thyroxine; USDA, US Department of Agriculture; Update 2006, Veterans and Agent Orange: Update 2006 (IOM, 2007); Update 2004, Veterans and Agent Orange: Update 2004 (IOM, 2005); Update 2002, Veterans and Agent Orange: Update 2002 (IOM, 2003); Update 2000, Veterans and Agent Orange: Update 2000 (IOM, 2001); Update 1998, Veterans and Agent Orange: Update 1998 (IOM, 1999); Update 1996, Veterans and Agent Orange: Update 1996 (IOM, 1996); and VAO, Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam (IOM, 1994). a The dash (—), comparison group based on a population (e.g., US white men, country rates); details are given in the text for population specifics. Contents of TABLE C-2 Epidemiologic Studies—Environmental Exposure Page Seveso Studies, 753 Times Beach/Quail Run Studies, 756 Studies in Vietnamese, 757 Other Environmental Studies, 758

APPENDIX C 753 TABLE C-2 Epidemiologic Studies—Environmental Exposure Study Study Group Comparison Reference Design Description (n) Group (n)a Seveso Studies Reviewed in Update 2006 Baccarelli et al., Population Investigate health status of 101 chloracne 211 control 2005 based chloracne cases, TCDD- cases chloracne exposure relationship, and factors modifying TCDD toxicity Eskenazi et al., Population Seveso Women’s Health Study 616 None 2005 based examining the relationship of TCDD (serum dioxin) and age at menopause Landi et al., 2005 Population Effects of CYP1A1, 62 59 based CYP1B1 variant genotypes and haplotypes on mRNA expression and EROD activity in lymphocytes Warner et al., Population Examined the age of 282 2004 based menarche in SWHS women who were premenarcheal at the time of the explosion Seveso Studies Reviewed in Update 2004 Baccarelli et al., Population mRNA concentrations, AhR, 62 59 2004 based ARNT, CYP1A1, CYP1B1 genes, and EROD activity in peripheral blood lymphocytes in a Seveso, Italy cohort Eskenazi et al., Cohort Relationship between serum 899 None 2004 TCDD concentration and age at exposure in SWHS participants Eskenazi et al., Cohort Association between maternal 888 None 2003a serum TCDD and birth outcome SWHS participants Landi et al., 2003 Population Effect of TCDD-mediated 62 59 based alterations in AhR-dependent pathway in Seveso Zone A and B residents Baccarelli et al., Population Immunologic effects in 62 59 2002 based Seveso residents, compared with previous published results continued

754 VETERANS AND AGENT ORANGE: UPDATE 2006 TABLE C-2 Continued Study Study Group Comparison Reference Design Description (n) Group (n)a Eskenazi et al., Cohort Association between 381 None 2002a menstrual cycle characteristics and serum TCDD in SWHS participants Eskenazi et al., Cohort Association between 601 None 2002b endometriosis and serum TCDD concentration in SWHS participants Seveso Studies Reviewed in Update 2002 Warner et al., Cohort Association between 15 981 2002 individual serum TCDD and breast cancer risk in SWHS participants Seveso Studies Reviewed in Update 2000 Bertazzi et al., Cohort Mortality (through 1996) of 804, Zone A; 232,745 2001 residents in 3 exposure zones 5,941, Zone B; 38,624, Zone R Pesatori et al., Cohort Mortality (through 1991) of 805, Zone A; 232,747 1998 residents in 3 exposure zones 5,943, Zone B; 38,625, Zone R Seveso Studies Reviewed in Update 1998 Bertazzi et al., Cohort Cancer incidence among 45,373 Total: 232,747 1997, 1998 residents of contaminated 805, Zone A; zones (A, B, R) after 15 years 5,943, Zone B; of follow-up, through 1991 38,625, Zone R Mocarelli et al., Cohort Sex ratio among offspring of (1) 74 births — 1996 Seveso Zone A residents (1) (28 boy, 48 1977–1984, (2) 1985–1994 girl) (2) 124 births (60 boy, 48 girl) Seveso Studies Reviewed in Update 1996 Bertazzi et al., Cohort Cancer incidence in residents 724, Zone A; 181,579 1993 (20–74 years) of contaminated 4,824, Zone B; zones (A, B, R) exposed to 31,647, Zone R TCDD on July 10, 1976, compared with neighboring residents in nonexposed areas

APPENDIX C 755 TABLE C-2 Continued Study Study Group Comparison Reference Design Description (n) Group (n)a Pesatori et al., Cohort Cancer incidence in Seveso ~20,000 167,391 1993 residents (1–19) in first postaccident decade, compared with age-matched residents of neighboring non- exposed areas Seveso Studies Reviewed in VAO Bertazzi et al., Cohort Mortality for exposed children 306, Zone A; 95,339 1992 (1976–1986), compared with 2,727, Zone B; children in non-exposed areas 16,604, Zone R Pesatori et al., Cohort Cancer incidence (1976–1986) Data in Data in 1992 in zone A, B, R, compared person-years person-years with non-exposed areas Assennato et al., Cohort Dermatologic, laboratory 193 chloracne 123 1989a results in children during periodic exams Assennato et al., Cohort Health outcomes in workers 36 36 1989b assigned to cleanup or referent group after Seveso accident Bertazzi et al., Cohort Mortality experience 556, Zone A; 167,391 1989a,b (1976–1986) in Zone A, B, 3,920, Zone B; R residents, compared with 26,227, Zone R non-exposed residents in neighboring towns Barbieri et al., Cohort Prevalence of peripheral 152 123 1988 nervous system involvement among Seveso residents with chloracne, compared with residents of non-exposed areas Mastroiacovo Cohort Birth defects to Zone A, 26, Zone A 12,391 et al., 1988 B, R mothers with live and 435, Zone B stillbirths, compared with 2,439, Zone R mothers from non-exposed areas Mocarelli et al., Cross- Laboratory measures of serum 69, Zone A; 241, subset of 1986 sectional and urine in Seveso Zone 528, Zone B; Zone R A and B children measured 874, Zone R over 6 years (1977–1982), compared with Zone R children continued

756 VETERANS AND AGENT ORANGE: UPDATE 2006 TABLE C-2 Continued Study Study Group Comparison Reference Design Description (n) Group (n)a Ideo et al., 1985 Cross- Enzyme activity among 117 adults 127 adults sectional residents of Seveso Zone B and an uncontaminated community Tenchini et al., Cross- Cytogenetic analysis, maternal 19 16 1983 sectional and fetal tissue among Seveso exposed, compared with control sample Ideo et al., 1982 Cross- Hepatic enzymes in exposed 16, Zone A; 51, 60 Bristo sectional children, compared with Zone B Assizio normal 26 Cannero Caramaschi Cohort Chloracne among Seveso 146 182 et al., 1981 children, compared with children with no chloracne, association with other health outcomes between chloracne and no chloracne groups Filippini et al., Cohort Prevalence of peripheral 308 305 1981 neuropathy on 2 screening examinations in Seveso residents, compared with residents of non-exposed areas Bisanti et al., Descriptive Selected health outcomes in 730, Zone A; None 1980 residents of Zone A, B, R 4,737, Zone B; 31,800, Zone R Boeri et al., 1978 Cohort Neurologic disorders in 470, Zone A 152, Zone R exposed residents on July 10, 1976, compared with residents of non-exposed areas Times Beach/Quail Run Studies Reviewed in VAO Evans et al., Cross- Retesting for skin delayed- 28 15 1988 sectional type hypersensitivity among non-responders in earlier test (Stehr et al., 1986) Stockbauer et al., Cohort Adverse reproductive 402 births 804 births 1988 outcomes (1972–1982) among mothers potentially exposed to TCDD-contaminated areas of Missouri (1971) compared with births among non- exposed mothers

APPENDIX C 757 TABLE C-2 Continued Study Study Group Comparison Reference Design Description (n) Group (n)a Hoffman et al., Cohort Health effects (1971–1984) 154 155 1986; Stehr- in Quail Run Mobile Home Green et al., Park residents compared with 1987 residents of noncontaminated mobile home parks Webb et al., 1987 Cross- Pilot, Missouri residents 68 36 sectional exposed to TCDD in the high-exposed low-exposed environment (1971) for health effects, comparing potentially high-exposed to low-exposed residents Stehr et al., 1986 Cross- Pilot, Missouri residents 68 36 sectional exposed to TCDD in the high-exposed low-exposed environment (1971) for health effects, comparing potentially high-exposed to low-exposed residents Studies in Vietnamese Reviewed in Update 1996 Cordier et al., Case– Hepatocellular carcinoma 152 241 1993 control (1989–1992) in men living in Vietnam, compared with other hospitalized patients, for association with a range of exposures, including herbicides Studies in Vietnamese Reviewed in VAO Dai et al., 1990 Cohort Infant mortality (1966–1986) 5,609 3,306 in 2 South Vietnam villages exposed to Agent Orange spraying, compared with infant mortality in an unsprayed area Phuong et al., Case– Birth defects, hydatidiform 15 birth 104 1989a control mole, compared with normal defects; 50 134 births (1982) in Ho Chi Minh hydatidiform City, for association with moles maternal exposure to Agent Orange and TCDD continued

758 VETERANS AND AGENT ORANGE: UPDATE 2006 TABLE C-2 Continued Study Study Group Comparison Reference Design Description (n) Group (n)a Phuong et al., Cohort Reproductive anomalies 7,327 births 6,690 births 1989b among births to women (May 1982–June 1982) living in heavily sprayed areas with herbicides in southern Vietnam, compared with births among women from Ho Chi Minh City Constable and Review Summaries, reproductive Hatch, 1985 outcomes among Vietnamese populations, including 9 unpublished studies Other Environmental Studies Reviewed in Update 2006 Chen et al., 2006 Investigated the prevalence of hypertension in Taiwanese residents near municipal waste incinerators for a least 5 years Lee C-C et al., Cohort From prior survey identified 85 subjects (52 33 2006 residence near Taiwan from exposure) PCP factory to examine associations fatty liver and hepatic function and PCDD/Fs in serum De Roos et al., Studied associations for 100 100 2005a TEQs overall from PCBs, furans, and dioxins were NHL cases serum levels had been determined Hartge et al., Population- Identified cases of NHL from 1,321 1,057 2005 based four SEER registries (Iowa, case– Los Angeles County, Detroit, control Seattle) during 1998–2000 McDuffie et al., Case– NHL in men in Canada 513 1,056 2005 control exposed to phenoxy herbicides Mills and Yang, Nested Breast cancer in Californian 128 640 2005 case– farm labor union members control Mills et al., 2005 Nested Lymphohematopoietic 131 139,000 case– cancer (NHL leukemia) in control Californian Hispanic farm workers

APPENDIX C 759 TABLE C-2 Continued Study Study Group Comparison Reference Design Description (n) Group (n)a Pahwa et al., Case– HD, multiple myeloma, STS 316 HD cases 1,056 2006 control diagnosed 1991–1994 in men 342 multiple 19 years of age living in six myeloma cases Canadian provinces, exposed 357 STS cases to phenoxy herbicides and other pesticides Vermeir et al., Cross- Flemish Environmental and 2005 sectional Health Study on neuro- behavior and dioxin-like compounds Wang et al., 2005 Cross- Thyroid function in newborns 118 sectional with exposure to PCBs Other Environmental Studies Reviewed in Update 2004 Fierens et al., Population- Association between serum 194 63 2003 based, dioxin, prevalence of diabetes, cross- endometriosis in several sectional Belgian towns Fukuda et al., Ecologic Correlation between 426 164 2003 cohort incinerator dioxin emissions municipalities municipalities and mortality in 803 Japanese with plants without plants municipalities Other Environmental Studies Reviewed in Update 2002 Revazova et al., Cohort Cytogenetic effects in women 15 possibly 30 non- 2001 exposed to different amounts exposed exposed but of dioxin while living in workers; living close to Chapaevsk, Russia plant Revich et al., Cohort Dioxin exposures in Children Samara 2001 Chapaevsk, Russia, and and adults in region and all various health outcomes in Chapaevsk, of Russia children and adults Russia Other Environmental Studies Reviewed in Update 2000 Schreinemachers, Cross- Cancer mortality rates in 4 — — 2000 sectional northern wheat-producing states using wheat acreage per county as surrogate for exposure continued

760 VETERANS AND AGENT ORANGE: UPDATE 2006 TABLE C-2 Continued Study Study Group Comparison Reference Design Description (n) Group (n)a Other Environmental Studies Reviewed in Update 1998 Gallagher et al., Case– Community-based study of 226 BCC; 180 406 1996 control primary BCC and primary SCC SCC in Alberta, Canada Lovik et al., Cohort Immune system parameters 24 10 1996 in hobby fishermen in the Frierfjord, southeastern Norway Masala et al., Case– Multicenter study, NHL, HD, 421 HD; Internal 1996 control multiple myeloma, AML by 1,822 NHL; comparison region in Italy 325 multiple by region myeloma; 263 AML Waterhouse PMR NHL, HD, CLL in rural 42 men; 32 4 controls per et al., 1996 analysis, Michigan women case nested case– control Svensson et al., Cohort Mortality and cancer 2,896 East 8,477 West 1995 incidence experience in 2 coast coast cohorts of Swedish fishermen Weisglas- Cohort Immunologic effects of pre- 105 breast-fed 102 bottle-fed Kuperus et al., and postnatal PCB or TCDD 1995 exposure in 207 Dutch infants from birth to 18 months Wolf and Cross- Effects of inhalation 221 189 Karmaus, 1995 sectional exposure to TCDD and related compounds in wood preservatives on cell-mediated immunity in German day care center employees Other Environmental Studies Reviewed in Update 1996 Butterfield et al., Case– Possible environmental risk 63 68 1993 control factors associated with young- onset PD Peper et al., 1993 Descriptive Environmental exposure 19 None in Germany to dioxins and furans, potential association with adverse neuropsychological effects

APPENDIX C 761 TABLE C-2 Continued Study Study Group Comparison Reference Design Description (n) Group (n)a Other Environmental Studies Reviewed in VAO Lampi et al., Nested Cancer incidence in Finland 56 colon 688 1992 case– community residents exposed cancer; 40 control/ to chlorophenol-contaminated bladder cancer; Cohort water and food (1987), 8 STS; 7 HD; compared with residents of 23 NHL; 43 other communities; several leukemia cancers, compared with population controls, for association with potential risk factors, including food and water consumption Vineis et al., Ecological Presentation rates (1985– 63 HD; 253 No non- 1991 1988) NHL, HD, STS in men NHL; 49 STS exposed and women (15–74) living control in provinces in Italy where phenoxy herbicides are used in rice weeding and defined in 2 categories Fitzgerald et al., Cohort Health outcomes in group 377 — 1989 exposed to electrical transformer fire (1981), compared with standardized rates among upstate New York residents Jansson and Cohort, Case study of facial cleft 20,595 71,665 Voog, 1989 case study (April–August 1987), births after births before facial cleft (1975–1987), incineration incineration compared with expected 6 case study rates in Swedish county with incinerators Cartwright et al., Case– Living NHL cases (1979– 437 724 1988 control 1984) in Yorkshire, England, compared with other hospitalized patients, for association with a range of exposures including fertilizers, herbicides continued

762 VETERANS AND AGENT ORANGE: UPDATE 2006 TABLE C-2 Continued Study Study Group Comparison Reference Design Description (n) Group (n)a Michigan Descriptive Comparison of Michigan County rates State and Department of county rates, for STS and national rates Public Health, connective tissue cancer 1983 mortality (1960–1981), compared with state and national rates, for potential excess in areas where dioxin could be in the environment Gordon and Shy, Case– Agricultural chemical 187 985 1981 control exposures and potential association with cleft palate– lip in Iowa and Michigan, compared with other live births Hanify et al., Ecological Study of adverse birth 9,614 births 15,000 births 1981 design outcomes (1960–1966), compared for association with 2,4,5-T spraying (1972–1977) Nelson et al., Ecological Prevalence of oval cleft — — 1979 design palate in high, medium, and low 2,4,5-T-sprayed areas in Arkansas (1948–1974) US EPA, 1979 Ecological Spontaneous abortion (1972– 2,344 births 1,666 births, design 1977) in herbicide-sprayed nonsprayed areas around Alsea, Oregon area; 4,120 compared with spontaneous Births, urban abortion in nonsprayed areas area ABBREVIATIONS: 2,4,5-T, 2,4,5-trichlorophenoxyacetic acid; AhR, aryl hydrocarbon receptor; AML, acute myelogenous leukemia; ARNT, arylhydrocarbon receptor nuclear transporter; BCC, basal-cell carcinoma; CYP1A1, cytochrome p450 1A1; CYP1B1, cytochrome P450 1B1; EROD, 7-ethoxyresorufun-O-deethylase; HD, Hodgkin’s disease; NHL, non-Hodgkin’s lymphoma; PCB, polychlorinated biphenyl; PD, Parkinson’s disease; SCC, squamous-cell carcinoma; SWHS, Seveso Women’s Health Study; STS, soft-tissue sarcoma; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; Up- date 2006, Veterans and Agent Orange: Update 2006 (IOM, 2007); Update 2004, Veterans and Agent Orange: Update 2004 (IOM, 2005); Update 2002, Veterans and Agent Orange: Update 2002 (IOM, 2003); Update 2000, Veterans and Agent Orange: Update 2000 (IOM, 2001); Update 1998, Veterans and Agent Orange: Update 1998 (IOM, 1999); Update 1996, Veterans and Agent Orange: Update 1996 (IOM, 1996); US EPA, United States Environmental Protection Agency; and VAO, Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam (IOM, 1994). a The dash (—) indicates the comparison group is based on a population (e.g., US white men, country rates), with details given in the text for specifics of the actual population.

APPENDIX C 763 Contents of TABLE C-3 Epidemiologic Studies—Vietnam Veterans Exposed Page STUDIES OF AMERICAN VIETNAM VETERANS 763 Reports from Air Force Health Study (AFHS) of Ranch Hand Veterans, 763 CDC Studies, 767 Department of Veterans Affairs Studies, 769 American Legion Studies, 771 State Studies, 772 Other Studies of American Vietnam Veterans, 774 STUDIES OF AUSTRALIAN VIETNAM VETERANS 775 STUDIES OF VIETNAM VETERANS FROM OTHER COUNTRIES 777 TABLE C-3 Epidemiologic Studies—Vietnam Veterans Exposed Study Comparison Reference Design Description Study Group (n) Group (n)a STUDIES OF AMERICAN VIETNAM VETERANS Reports from the Air Force Health Study (AFHS) on Ranch Hand Veterans Reviewed in Update 2006 Pavuk Cohort Focus on prostate cancer using 59 81 et al., 2006 information on serum TCDD and years of service in Southeast Asia (SEA) AFHS, Air Force Health Study—2002 2005 exam cycle Ranch Hand veterans Ketchum Cohort Ranch Hand mortality analysis 1,262 Ranch 19,078 and summarizing current all-cause and Hand veterans comparison Michalek, cause-specific post-service mortality veterans 2005 rates for veterans sprayed between 1962 to 1971 Pavuk Cohort Examine cancer incidence in 1,482 No et al., 2005 Air Force veterans who served comparison in Southeast Asia and who were group not occupationally exposed to herbicides Kern et al., Cohort Observe whether insulin sensitivity ? ? 2004 was related to TCDD in Vietnam veterans exposed to Agent Orange and other herbicides in Vietnam from 1962 to 1971 continued

764 VETERANS AND AGENT ORANGE: UPDATE 2006 TABLE C-3 Continued Study Comparison Reference Design Description Study Group (n) Group (n)a Reports from AFHS Reviewed in Update 2004 Akhtar Cohort Follow-up to Ketchum et al. (1999), 1,189 net Ranch 1,776 net et al., 2004 comparing cancer incidence among Hands for comparison Ranch Hands with Vietnam veterans external analysis; subjects who served in Southeast Asia but 1,009 net Ranch for external did not spray herbicides and with Hands for analysis; US national cancer rates internal analysis 1,429 net comparison subjects for internal analysis Barrett Cohort Serum TCDD measurement and 1,109 1,493 et al., 2003 psychological functioning among Ranch Hand veterans Michalek Cohort Correlation for TCDD elimination 343 No et al., 2003 and Ranch Hands with diabetes comparison group Pavuk Cohort Study to examine the relationship 1,009 1,429 et al., 2003 between serum TCDD and thyroid function in Ranch Hand veterans Barrett Cohort Based on tests of cognitive 937 Ranch Hand 1,052 et al., 2001 functioning in 1982 and dioxin Ranch Hand concentrations measured in 1987 comparisons and 1992, analyzed association between serum dioxin levels and cognitive functioning Michalek Cohort Based on physical examination 1,109 Ranch 1,493 et al., through 1992 and medical records Hand Ranch Hand 2001a reviewed through March 1993, comparisons association between serum dioxin levels and hepatic abnormality Michalek Cohort Based on physical examination in 761 Ranch Hand 1,086 et al., 1982, 1985, 1987, 1992, and 1997 Ranch Hand 2001b and medical records through 1997, comparisons association between serum dioxin and peripheral neuropathy Michalek Cohort Based on physical examination in 953 Ranch Hand 1,280 et al., 1982, 1985, 1987, and 1992 and Ranch Hand 2001c medical records through 1997, comparisons association between serum dioxin and hematologic function

APPENDIX C 765 TABLE C-3 Continued Study Comparison Reference Design Description Study Group (n) Group (n)a Steenland Cohort Re-examine and compare diabetes 267 NIOSH 227 NIOSH et al., 2001 data from the NIOSH cohort and workers; comparisons the United States Air Force Ranch 990 Ranch 1,275 in order to reconcile differences Hands Ranch Hand between the two study methods and comparisons protocols. Reports from AFHS Reviewed in Update 2000 AFHS, Cohort 266 Health-related endpoints, 995 1,299 2000 including assessments of 10 clinical areas: general health, neoplasia, neurologic, psychological, gastrointestinal, cardiovascular, hematologic, endocrine, immunologic, pulmonary Longnecker Cohort Based on physical examination and — 1,197 and medical records review through Michalek, 1992, association between serum 2000 dioxin and diabetes mellitus among comparison group (no Ranch Hands) Ketchum Cohort Based on physical examination and 980 Ranch Hand 1,275 et al., 1999 medical records review through Ranch Hand 1992, association between serum comparisons dioxin and cancer, skin cancer, cancer other than skin cancer Michalek Cohort Further elucidate relationship 871 Ranch Hand 1,121 et al., between dioxin and diabetes Ranch Hand 1999a mellitus, effect of dioxin body comparisons burden on sex-hormone-binding globulin and insulin and fasting glucose Michalek Cohort Based on physical examinations 914 Ranch Hand 1,186 et al., in 1982, 1985, 1987, and 1992, 372 (lymphocyte Ranch Hand 1999b immunologic response and exposure counts comparisons to dioxin among Ranch Hand and conducted) 491 comparison cohorts (lymphocyte counts conducted) Burton Cohort Based on physical examination 930 Ranch Hand 1,200 et al., 1998 and medical record review through Ranch Hand 1992, association between serum comparisons dioxin and occurrence and timing (relative to Southeast Asia service) of chloracne and acne continued

766 VETERANS AND AGENT ORANGE: UPDATE 2006 TABLE C-3 Continued Study Comparison Reference Design Description Study Group (n) Group (n)a Michalek Cohort Updates, all-cause and cause- 1,261 Ranch 19,080 et al., specific post-service mortality Hand Ranch Hand 1998b (through 1993) among veterans comparisons of Operation Ranch Hand, using standardized mortality ratios Michalek Cohort Prospective study, exposure 1,208 veterans; 1,549 et al., and long-term health, survival, 903 offspring veterans; 1998c reproductive outcome 1,254 offspring Michalek Cohort Third report in a series investigating 859 1,223 et al., dioxin body burden and preterm 1998d birth, intrauterine growth retardation, infant death among offspring of Ranch Hand veterans Reports from AFHS Reviewed in Update 1998 Michalek Cohort Paternal serum dioxin levels and 859 children: 1,223 et al., infant death among Ranch Hand 323 background children 1998a offspring exposure; 267 low exposure; 269 high exposure Henriksen Cohort Relationship between serum dioxin 989 1,276 et al., 1997 and glucose, insulin, and diabetes mellitus in Ranch Hands through 1992 AFHS, Cohort Mortality update, Ranch Hands 1,261 19,080 1996 through the end of 1993 in the Michalek AFHS cohort (1983, 1984b, 1985, et al., 1986, 1989, 1991a, 1995) 1998b Henriksen Cohort Serum dioxin and reproductive 1,045 1,224 et al., 1996 hormones in Ranch Hands, 1982, participants participants 1985, 1987, and 1992 (1982); 474 (1982); 532 provided semen provided semen Reports from AFHS Reviewed in Update 1996 AFHS, Cohort Mortality updates of Ranch Hands 1,261, original 19,101, 1995 who sprayed herbicides in Vietnam, cohort original compared with Air Force C-130 cohort air and ground crew veterans in Southeast Asia who did not spray herbicides

APPENDIX C 767 TABLE C-3 Continued Study Comparison Reference Design Description Study Group (n) Group (n)a Wolfe Cohort Paternal serum dioxin and 932 1,202 et al., 1995 reproductive outcomes of Ranch Hand veterans, compared with Air Force veterans from Southeast Asia who did not spray herbicides Reports from AFHS Reviewed in VAO AFHS, Cohort Reproductive outcomes of AFHS 791 942 1992 participants AFHS, Cohort Baseline morbidity, follow-up 1,208 baseline 1,668 1984a, examination results baseline 1987, 1990, 1991b AFHS, Cohort Mortality updates, Ranch Hands 1,261 (original 19,101 1983, who sprayed herbicides in Vietnam, cohort) (original 1984b, compared with Air Force C-130 cohort) 1985, 1986, air and ground crew veterans in 1989, Southeast Asia who did not spray 1991a herbicides Michalek Cohort Mortality of Ranch Hands, 1,261 19,101 et al., 1990 compared with Air Force C-130 air and ground crew veterans in Southeast Asia Wolfe Cohort Health status of Ranch Hands at 995 1,299 et al., 1990 second follow-up, compared with Air Force C-130 air and ground crew veterans in Southeast Asia CDC Studies Reviewed in Update 2006 Boehmer Cohort Vietnam Experience Study—post- 18,313 et al., 2004 service mortality CDC Studies Reviewed in VAO Decoufle Cohort Association between self-reported 7,924 7,364 et al., 1992 health outcomes and perception of exposure to herbicides based on Vietnam Experience Study O’Brien Cohort Interview report and mortality for 8,170 7,564 et al., 1991 NHL based on Vietnam Experience Study continued

768 VETERANS AND AGENT ORANGE: UPDATE 2006 TABLE C-3 Continued Study Comparison Reference Design Description Study Group (n) Group (n)a CDC, Case– Selected Cancers Study: population- 1,157 NHL; 1,776 1990a control based case–control study of all men 342 STS; 310 born 1921–1953; cases diagnosed HD; 48 nasal area covered by 8 cancer registries, carcinoma; 80 controls selected by random-digit nasopharyngeal dialing carcinoma; 130 primary liver cancer CDC, Case– Selected Cancers Study: population- 1,157 1,776 1990b control based case–control study of all men born 1921–1953; cases diagnosed in area covered by 8 cancer registries, controls selected by random-digit dialing for NHL CDC, Case– Selected Cancers Study: STS 342 1,776 1990c control CDC, Case– Selected Cancers Study: HD, nasal 310 HD; 48 nasal 1,776 1990d control cancer, nasopharyngeal cancer, carcinoma; 80 primary liver cancer nasopharyngeal carcinoma; 130 primary liver cancer CDC, Cohort Vietnam Experience Study: random 2,490 1,972 1989b sample, US Army enlisted men, 1965–1971 CDC, Cohort Vietnam Experience Study: random 2,490 1,972 1988a sample, US Army enlisted men, 1965–1971, psychosocial outcomes CDC, Cohort Vietnam Experience Study: physical 2,490 1,972 1988b health outcomes CDC, Cohort Vietnam Experience Study: 12,788 children 11,910 1988c reproductive outcomes children CDC, 1987; Cohort Vietnam Experience Study: 9,324 8,989 Boyle mortality et al., 1987 Erickson Case– CDC birth defects study, children 7,133 4,246 et al., 1984 control born in the Atlanta, Georgia, area a,b 1968–1980, comparing paternal Vietnam experience and potential Agent Orange exposure for birth defects cases and normal controls

APPENDIX C 769 TABLE C-3 Continued Study Comparison Reference Design Description Study Group (n) Group (n)a Department of Veterans Affairs Studies Reviewed in Update 2006 Kang et al., Cohort Army Chemical Corp; serum 1,499 1,428 2006 TCDD, Vietnam veterans {sprayers vs. not sprayers} vs not Vietnam vet Department of Veterans Affairs Studies Reviewed in Update 2002 Kang et al., Cohort Health of Army Chemical Corps 2,872 2,737 2001 Vietnam veterans, compared with Army Chemical Corps veterans who did not serve in Vietnam Kang et al., Cohort Self-report pregnancy outcomes for 3,392 women; 3,038 2000a female Vietnam veterans, compared 1,665 women women; with contemporary veterans not with indexed 1,912 deployed to Vietnam; odds ratios pregnancy women with calculated for reproductive history indexed and various birth defects pregnancy Kang et al., Cohort Gynecologic cancers among female 484 5,946 2000b Vietnam veterans, compared with veteran controls Department of Veterans Affairs Studies Reviewed in Update 1998 Dalager Cohort Morbidity and mortality experience 2,872 2,737 and Kang, (1968–1987), Army Chemical 1997 Corps Vietnam veterans, compared with US men; extension of Thomas and Kang (1990) Mahan Case– Lung cancer among Vietnam 329 269 et al., 1997 control veterans (1983–1990) 111 McKinney Cross- Tobacco use in veterans and non- 15,000 — et al., 1997 sectional veterans by 1987 NMES Bullman Cohort Mortality of veterans with non- 34,534 — and Kang, lethal (combat and noncombat) 1996 wounds sustained during the Vietnam war Watanabe Cohort Mortality experience (1965–1988) 33,833 36,797 and Kang, of Army and Marine Corps Vietnam 1996 veterans; extension of Breslin et al. (1988) and Watanabe et al. (1991) Dalager Case– HD Cases diagnosed 1969–1985 283 404 et al., control among Vietnam-era veterans 1995b continued

770 VETERANS AND AGENT ORANGE: UPDATE 2006 TABLE C-3 Continued Study Comparison Reference Design Description Study Group (n) Group (n)a Watanabe Cohort Post-service mortality among 10,716 9,346 and Kang, Marine Vietnam veterans 1995 Department of Veterans Affairs Studies Reviewed in Update 1996 Dalager Cohort Update of Thomas et al. (1991) 4,586 5,325 et al., through Dec. 31, 1995 1995a Bullman Case– Association between testicular 97 311 et al., 1994 control cancer and surrogate measures of exposure to Agent Orange in male Vietnam veterans Department of Veterans Affairs Studies Reviewed in VAO Bullman Case– PTSD cases in Vietnam veterans, 374 373 et al., 1991 control compared with Vietnam veterans without PTSD, for association with traumatic combat experience Dalager Case– NHL cases diagnosed 1969–1985 201 358 et al., 1991 control among Vietnam-era veterans, compared with cases of other malignancies among Vietnam- era veterans, for association with Vietnam service Eisen et al., Cohort Health effects in male monozygotic 2,260 2,260 1991 twins serving in the armed forces during Vietnam era (1965–1975) Thomas Cohort Mortality experience (1973–1987) 4,582 5,324 et al., 1991 among female Vietnam veterans, compared with female non-Vietnam veterans and for each cohort compared with US women Watanabe Cohort Mortality experience (1965–1984) 24,145 Army (1) 27,145 et al., 1991 in Army and Marine Corps Vietnam 5,501 Marines Army veterans, compared with: (1) 4,505 branch-specific (Army and Marine) Marines Vietnam-era veterans, (2) all (2) 32,422 Vietnam-era veterans combined, (3) combined the US male population Vietnam era (3) US male population

APPENDIX C 771 TABLE C-3 Continued Study Comparison Reference Design Description Study Group (n) Group (n)a Bullman Cohort Mortality experience in Army I 6,668 deaths 27,917 et al., 1990 Corps Vietnam veterans, compared deaths with Army Vietnam-era veterans Farberow Case– Psychological profiles, military 22 Vietnam 21 Vietnam et al., 1990 control factors associated with suicide suicides; 19 MVA; 20 and MVA fatalities in Los Angeles Vietnam-era Vietnam-era County Vietnam-era veterans suicides MVA (1977–1982) Thomas Cohort Morbidity and mortality experience 894 — and Kang, (1968–1987) in Army Chemical 1990 Corps Vietnam veterans compared with US men True et al., Cross- PTSD and Vietnam combat 775 1,012 1988 sectional experience among Vietnam-era veterans Breslin Cohort Mortality experience (1965–1982) 24,235 26,685 et al., 1988 in Army and Marine Corps Vietnam Burt et al., veterans, compared with Vietnam- 1987 era veterans who did not serve in Southeast Asia, standardized by age and race; nested NHL case–control study Kang et al., Case– STS cases (1975–1980) diagnosed 217 599 1987 control at the Armed Forces Institute of Pathology, compared with controls identified from patient logs of referring pathologists or their departments, for association with Vietnam service and likelihood of Agent Orange exposure Kang et al., Case– STS (1969–1983) in Vietnam- 234 13,496 1986 control era veterans, for association with branch of Vietnam service as a surrogate for Agent Orange exposure American Legion Studies Reviewed in VAO Snow et al., Cohort PTSD in association with traumatic 2,858 Study group 1988 combat experience among subdivided American Legion members serving for internal in Southeast Asia (1961–1975) comparison continued

772 VETERANS AND AGENT ORANGE: UPDATE 2006 TABLE C-3 Continued Study Comparison Reference Design Description Study Group (n) Group (n)a Stellman Cohort Physical health, reproductive 2,858 3,933 et al., outcomes among American Legion 1988b members who served in Southeast Asia (1961–1975), for association with combat and herbicide exposure Stellman Cohort Social, behavioral outcomes among 2,858 3,933 et al., American Legion members who 1988c served in Southeast Asia (1961– 1975), association with combat and herbicide exposure State Studies Reviewed in Update 2006 Engel et al., Cohort AHS examine phenoxy herbicides 309 30,145 2005 and breast cancer incidence among farmer wives in Iowa and North Carolina Kirrane Cross- AHS in Iowa and North Carolina; 31,173 et al., 2005 sectional phenoxy herbicide exposure and retinal degeneration in wives of farmers Lee et al., Population Continues Ward et al., 1997 170 502 2004 based study on diet. Evaluate risk of (adenocarcinoma /case- the stomach and oesophageal of stomach) control adenocarcinomas associated with 137 (oesophagus) farming and agricultural pesticide use in eastern Nebraska State Studies Reviewed in Update 1998 Clapp, Case– Selected cancers identified 245 999 1997 control (1988–1993) among Massachusetts Vietnam veterans, compared with Massachusetts Vietnam-era veterans with cancers of other sites; update of Clapp et al., 1991 State Studies Reviewed in Update 1996 Visintainer Cohort Mortality experience (1965–1971) 3,364 deaths 5,229 deaths et al., 1995 in male Michigan Vietnam veterans, compared with non-Vietnam veterans from Michigan

APPENDIX C 773 TABLE C-3 Continued Study Comparison Reference Design Description Study Group (n) Group (n)a State Studies Reviewed in VAO Fiedler and Cohort New Jersey: outcomes in select 10 Pointman I 17 Pointman Gochfeld, group of herbicide-exposed 55 Pointman II I 1992 Army, Marine, and Navy Vietnam 15 Pointman Kahn et al., veterans, compared with veterans II 1992a,b,c self-reported as unexposed Clapp Case– Massachusetts: selected cancers 214 727 et al., 1991 control identified (1982–1988) among Vietnam veterans, compared with Massachusetts Vietnam-era veterans with cancers of other sites Deprez Descriptive Maine: Vietnam veterans, compared 249 113 Atomic et al., 1991 with atomic test veterans and test veterans general population, for health status and reproductive outcomes Levy, 1988 Cross- Massachusetts: PTSD in chloracne 6 25 sectional as indicator of exposure to TCDD; control Vietnam veterans Anderson Cohort Wisconsin: mortality experience, 110,815 white 342,654 et al., veterans compared with non- male veteran white male 1986a veterans (Phase 1); mortality deaths; 2,494 non-veteran experience of Vietnam veterans and white male deaths; Vietnam-era veterans, compared Vietnam-era 109,225 with non-veterans and other veteran deaths; white veterans (Phase 2) 923 white male male other (superseded by Anderson et al., Vietnam veteran veteran 1986b) deaths deaths Anderson Cohort Wisconsin: mortality experience in 122,238 — et al., Vietnam-era veterans and Vietnam Vietnam-era 1986b veterans, compared with US veterans; 43,398 men, Wisconsin men, Wisconsin Vietnam veterans non-veterans, and Wisconsin other veterans Goun and Case– Pennsylvania: STS, NHL, selected 349 349 Kuller, control rare cancer cases, compared with Deceased 1986 controls without cancer for Vietnam experience in men (1968–1983) Holmes Cohort West Virginia: mortality experience 615 Vietnam — et al., 1986 (1968–1983) of veterans, Vietnam veterans veterans, Vietnam-era veterans, 610 Vietnam era compared with non-veterans; veterans Vietnam veterans compared with Vietnam-era veterans continued

774 VETERANS AND AGENT ORANGE: UPDATE 2006 TABLE C-3 Continued Study Comparison Reference Design Description Study Group (n) Group (n)a Pollei et al., Cohort New Mexico: chest radiographs 422 105 1986 of Agent Orange Registry Vietnam veterans, compared with radiographs of control Air Force servicemen, for pulmonary and cardiovascular pathology Kogan Cohort Massachusetts: mortality experience 840 Deaths 2,515 deaths and Clapp, (1972–1983) among white male in Vietnam- 1985, 1988 Vietnam veterans, compared with era veterans non-Vietnam veterans and all other non-veteran white men in Massachusetts Lawrence Cohort New York: mortality experience in (1) 4,558 17,936 et al., 1985 (1) Vietnam-era veterans, compared (2) 555 941 with non-veterans and (2) Vietnam veterans, compared with Vietnam- era veterans Rellahan, Cohort Hawaii: health outcomes in 232 186 1985 Vietnam-era (1962–1972) veterans residing in Hawaii, associated with Vietnam experience Wendt, Descriptive Iowa: health effects and potential 10,846 None 1985 exposure to Agent Orange among veterans who served in Southeast Asia Greenwald Case– New York: STS cases, compared 281 281 live et al., 1984 control with controls without cancer for controls; Vietnam service and herbicide 130 exposure including Agent Orange, deceased dioxin, or 2,4,5-T controls Newell, Cross- Texas: preliminary (1) cytogenetic, (1) 30; (2) 32; (1) 30; (2) 1984 sectional (2) sperm, (3) immune response (3) 66 32; (3) 66 tests in Vietnam veterans, compared with controls Other Studies American Vietnam Veterans Reviewed in VAO Tarone Case– Testicular cancer (18–42 years old) 137 130 et al., 1991 control cases, January 1976–June 1981, compared with hospital controls, for association with Vietnam service

APPENDIX C 775 TABLE C-3 Continued Study Comparison Reference Design Description Study Group (n) Group (n)a Aschengrau Case– Cases with late adverse pregnancy 857 congenital 998 and control outcomes compared with normal anomalies Monson, control births, for association 61 stillbirths; 48 1990 with paternal Vietnam service neonatal deaths (1977–1980) Goldberg Cohort Male twin pairs who served in 2,092 2,092 et al., 1990 Vietnam era (1965–1975), for association between Vietnam service and PTSD Aschengrau Case– Association between husband’s 201 1,119 and control military service and spontaneous Monson, abortion at or by 27 weeks, 1989 compared with women delivering at 37 weeks STUDIES OF AUSTRALIAN VIETNAM VETERANS Studies of Australian Vietnam Veterans Reviewed in Update 2006 ADVA, Cohort Cancer incidence from 1982 to 59,179 total; 2005a 2000 among Australian male Army, 41,084 (Army); Navy, and Air Force veterans who 13,538 (Navy); served in Vietnam between May 4,570 (Air Force) 1962 and July 1973 ADVA, Cohort Retrospective mortality study of 59,179 2005b male Australian personnel who served between May 1962 and July 1973 vs. Australian men in general community ADVA, Cohort Retrospective cohort study of male 43,969 total; 2005c National Service personnel who 19,240 veterans; served in the Vietnam era between 24,729 1966 and July 1973. Examined all non-veterans deaths identified from the end of service to 31 December 2001 and all cancers diagnosed from 1982 to 31 December 2000 Leavy Case– Cancer registry of Western Australia 606 471 et al., 2006 control and prostate cancer; deployment to Vietnam continued

776 VETERANS AND AGENT ORANGE: UPDATE 2006 TABLE C-3 Continued Study Comparison Reference Design Description Study Group (n) Group (n)a Studies of Australian Vietnam Veterans Reviewed in Update 2000 AIHW, Cohort Validation of the male veterans’ 6,842 — 1999 study (CDVA, 1998a) by medical documents, doctors’ certification, records on a disease or death registry CDVA, Cohort Self-reported data on male members 49,944 mailed; — 1998a of the Australian Defence Force 39,955 and the Citizen Military Force responded who landed in Vietnam or entered Vietnamese water. Questions on physical (including reproductive history) and mental health, and that of their partner(s) and children CDVA, Cohort Self-reported data on female 278 mailed — 1998b members of the Australian Defence 225 responded Force and the Citizen Military Force who landed in Vietnam or entered Vietnamese water. Questions on physical (including reproductive history) and mental health, and that of their partner(s) and children Studies of Australian Vietnam Veterans Reviewed in Update 1998 Crane Cohort Mortality experience (through 59,036 men — et al., 1994) of Australian veterans who 484 women 1997a served in Vietnam Crane Cohort Mortality experience (through 1994) 18,949 24,646 et al., of Australian national servicemen 1997b who served in Vietnam O’Toole Cross- Survey of self-reported health status 641 — et al., sectional (1989–1990) of Australian Army 1996a,b,c Vietnam veterans Studies of Australian Vietnam Veterans Reviewed in VAO Field and Cohort Tasmanian Vietnam veterans, 357 281 Kerr, 1988 compared with neighborhood controls for adverse reproductive and childhood health outcomes Fett et al., Cohort Mortality experience in Vietnam 19,205 25,677 1987a veterans, compared with Vietnam- era veterans through 1981

APPENDIX C 777 TABLE C-3 Continued Study Comparison Reference Design Description Study Group (n) Group (n)a Fett et al., Cohort Cause-specific mortality experience 19,205 25,677 1987b in Vietnam veterans, compared with Vietnam-era veterans through 1981 Forcier Cohort Mortality in Vietnam veterans by 19,205 Internal et al., 1987 job classification, location, time of comparison service Donovan Case– Congenital anomalies in children 8,517 8,517 et al., 1983, control (1969–1979), compared with 1984 infants born without anomalies, for association with paternal Vietnam service STUDIES OF VIETNAM VETERANS FROM OTHER COUNTRIES Other Vietnam-Veteran studies Reviewed in Update 2004 Kim H-A Cohort Immunotoxicologic effects of 51 (24 veterans– 36 et al., 2003 Agent Orange exposure on Korean patient; 27 Vietnam veterans veterans–normal) Kim J-S Cross- Agent Orange exposure and Korean 1,224 154 et al., 2003 sectional Vietnam veterans Mo et al., Cohort Skin and general disease patterns 332 None 2002 among Korean Vietnam veterans Other Vietnam-Veteran studies Reviewed in Update 1998 Chinh Cohort Antinuclear antibodies and sperm 25 63; 36 et al., 1996 autoantibodies among Vietnamese veterans who served 5–10 years in a “dioxin-sprayed zone” ABBREVIATIONS: 2,4,5-T, 2,4,5-trichlorophenoxyacetic acid; AFHS, Air Force Health Study; CDC, Centers for Disease Control and Prevention; CDVA, Commonwealth Department of Veterans’ Affairs; HD, Hodgkin’s disease; MVA, motor vehicle accidents; NIOSH, National Institute for Occupational Safety and Health; NHL, non-Hodgkin’s lymphoma; NMES; National Medical Expenditure Survey; PTSD, posttraumatic stress disorder; SMR, standardized mortality ratio; STS, soft-tissue sarcoma; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; Update 2006, Veterans and Agent Orange: Update 2006 (IOM, 2007); Update 2004, Veterans and Agent Orange: Update 2004 (IOM, 2005); Update 2002, Veterans and Agent Orange: Update 2002 (IOM, 2003); Update 2000, Veterans and Agent Orange: Update 2000 (IOM, 2001); Update 1998, Veterans and Agent Orange: Update 1998 (IOM, 1999); Update 1996, Veterans and Agent Orange: Update 1996 (IOM, 1996); and VAO, Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam (IOM, 1994). a Comparison group based on a population (e.g., US white men, country rates); details are given in the text for population specifics.

Next: APPENDIX D Committee to Review the Health Effects in Vietnam Veterans of Exposure to Herbicides (Sixth Biennial Update) and Staff Biographies »
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From 1962 to 1971, the U.S. military sprayed herbicides over Vietnam to strip the thick jungle canopy that could conceal opposition forces, to destroy crops that those forces might depend on, and to clear tall grasses and bushes from the perimeters of U.S. base camps and outlying fire-support bases.

In response to concerns and continuing uncertainty about the long-term health effects of the sprayed herbicides on Vietnam veterans, Veterans and Agent Orange provides a comprehensive evaluation of scientific and medical information regarding the health effects of exposure to Agent Orange and other herbicides used in Vietnam. The 2006 report is the seventh volume in this series of biennial updates. It will be of interest to policy makers and physicians in the federal government, veterans and their families, veterans' organizations, researchers, and health professionals.

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