Veterans and Agent Orange Update 2006 (2007) / Chapter Skim
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4 Epidemiologic Studies - New Citations for Update 2006 and Background on Repeatedly Studied Populations
4 Epidemiologic Studies - New Citations for Update 2006 and Background on Repeatedly Studied Populations
Pages 139-213
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From page 139... ...
Results on a single population may be reported concerning a multiplicity of health outcomes and in more than one publication, particularly when a study is of the cohort design with repeated follow-ups. The major purpose of the chapters on "epidemiology" or "epidemiologic studies" in Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam (VAO; IOM, 1994)
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From page 140... ...
The occupational section covers studies of production workers, agriculture and forestry workers (including herbicide and pesticide applicators) , and paper and pulp workers.
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From page 141... ...
control chlorophenols Cancer Registry Environmental Studies Ascherio 2006 Prospective Pesticides/herbicides Parkinson's Cancer Prevention et al. cohort disease Study II Nutrition Cohort Bloom 2006 Cross- Serum dioxins, Thyroid New York State et al.
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sectional serum dioxin TEQ function (TSH McMaster University (CALUX) and thyroxine)
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sectional hormone levels Studies of Vietnam Veterans Leavy 2006 Case– Service in Vietnam Prostate cancer Cancer registry of et al. control Western Australia ABBREVIATIONS: 2,4-D, 2,4-dichlorophenoxyacetic acid; ALS, amyotrophic lateral sclerosis; CALUX, Chemically Activated Luciferase Gene Expression; DNA, deoxyribonucleic acid; MCPA, 2-methyl, 4-chlorophenoxyacetic acid; NHL, non-Hodgkin's lymphoma; PCB, polychlorinated biphenyl; PCDD, polychlorinated dibenzo-p-dioxin; PCDF, polychlorinated dibenzofuran; TCDD, 2,3,7,8tetrachlorodibenzo-p-dioxin; TEQ, total toxicity equivalency; TSH, thyroid-stimulating hormone.
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From page 144... ...
exposure to Health Study herbicides McLean 2006 Cohort Nonvolatile Cancer mortality International et al. organochlorine by type collaborative study compounds of pulp and paper industry Carreon 2005 Case–control Arsenicals, Gliomas in women Upper Midwest et al.
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phenoxy Health Study herbicides, 2,4-D Torchio 1994 Cohort Farm work Cancer mortality Men licensed to use et al. agricultural pesticides in Piedmont area of Italy Reif 1989 Mixed Forestry Cancer incidence Men entered in New et al.
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, low birth weight ABBREVIATIONS: 2,4-D, 2,4-dichlorophenoxyacetic acid; 2,4,5-T, 2,4,5-trichlorophenoxyacetic acid; CNS, central nervous system; HD, Hodgkin's disease; NCI, National Cancer Institute; NHL, non-Hodgkin's lymphoma; NIOSH, National Institute of Occupational Safety and Health; PCB, polychlorinated biphenyl; PD, Parkinson's disease; SEER, Surveillance Epidemiology and End Results; TEQ, total toxicity equivalency. study is presented in this chapter, organized according to the type of study population.
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From page 147... ...
2005 Cohort Ever/never use Breast cancer incidence AHS of phenoxy herbicides; 2,4-D; 2,4,5-T; 2,4,5-TP Kamel 2005 Cohort Days exposed to Neurologic symptoms AHS et al. herbicides 't Mannetje 2005 Cohort Phenoxy herbicide Cancer mortality (full Subcohort et al.
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2006 Cohort Serum TCDD Prostate cancer AFHS level (low or high group) ADVA 2005a Cohort Deployed veterans Cancer incidence (full Male vs.
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From page 149... ...
AFHS ABBREVIATIONS: 2,4-D, 2,4-dichlorophenoxyacetic acid; 2,4,5-T, 2,4,5-trichlorophenoxyacetic acid; 2,4,5-TP, 2 (2,4,5-trichlorophenoxy) propionic acid; ADVA, Australian Department of Veterans Affairs; AFHS, Air Force Health Study; AHS, Agricultural Health Study; ALL, acute lymphocytic leukemia; CNS, central nervous system; COPD, chronic obstructive pulmonary disease; GI, gastrointestinal; HD, Hodgkin's disease; IARC, International Agency for Research on Cancer; NCI, National Cancer Institute; NHL, non-Hodgkin's lymphoma; NIOSH, National Institute for Occupational Safety and Health; PBPK, physiologically-based pharmacokinetic; PCB, polychlorinated biphenyl; SEA, Southeast Asia; SEER, Surveillance Epidemiology and End Results; STS, soft-tissue sarcoma; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; VAO, Veterans and Agent Orange.
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From page 150... ...
, and the National Cancer Institute (NCI) ; residents of Seveso; and Ranch Hand personnel.
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Available details of exposure assessment and use of exposure data are discussed in Chapter 5 of the present report. The occupational section covers studies of production workers, agriculture and forestry workers (including herbicide and pesticide applicators)
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and one in veterans of Operation Ranch Hand in which the herbicides were sprayed from planes in Vietnam (Henriksen et al., 1997)
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Serum TCDD concentrations were available for the NIOSH subjects, and serum TCDD measurements were made on a random sample of 79 referent subjects for the background unexposed levels. The median value for the sampled referents (6 pg/g)
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. Large-scale cohort mortality studies of workers exposed to herbicides in several of its plants (Bloemen et al., 1993; Bond et al., 1988; Burns et al., 2001; Ramlow et al., 1996)
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A cohort study of cancer incidence and mortality was conducted among 701 women from seven countries who were occupationally exposed to chlorophenoxy herbicides, chlorophenols, and dioxins (Kogevinas et al., 1993)
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Agricultural Health Study (AHS) The AHS is a prospective investigation of cohorts of private pesticide applicators (farmers)
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In an analysis of lung-cancer incidence, Alavanja et al.
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(2005) looked at breast-cancer incidence among private pesticide applicators' wives who were diagnosed with breast cancer between 1993 and 2000 (n 309)
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Study participants were classified according to their self-reported pesticide exposure. Data on herbicide and phenoxy herbicide exposures were included in the analysis of information pertaining to women who ever mixed or applied pesticides.
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That constitutes an important limitation in a breast-cancer study, because misclassification of established risk factors as covariates can introduce substantial bias. Upper Midwest Health Study Chiu et al.
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The resulting database has been used in studies that evaluated cancer mortality and farm work (Wiklund, 1983) ; STS and malignant lymphoma among agricultural and forestry workers (Wiklund and Holm, 1986; Wiklund et al., 1988a)
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A cohort mortality study examined men employed at a Canadian public utility (Green, 1987, 1991) , a Dutch study of forestry workers exposed to 2,4,5-T investigated the prevalence of acne and liver dysfunction (van Houdt et al., 1983)
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, additional cohorts of herbicide and pesticide applicators have been assessed for health outcomes: cancer mortality among Swedish railroad workers (Axelson and Sundell, 1974; Axelson et al., 1980) , mortality among pesticide applicators in Florida (Blair et al., 1983)
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From page 164... ...
. Rather than measuring serum dioxin levels, the authors inferred dioxin exposure of individual workers on the basis of dioxin concentrations in air and estimated exposures to polycyclic aromatic hydrocarbons by analyzing two urinary metabolites: 1-hydroxypyrene and 2-napthol.
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. An expanded case series was collected and additional case–control studies were conducted on exposure to phenoxy herbicides or chlorophenols and the risks of malignant lymphoma, NHL, and multiple myeloma (Pearce et al., 1985, 1986a,b, 1987)
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[2006] , and discussed above under the Upper Midwest Health Study.)
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(2006) investigated whether exposure to phenoxy herbicides and other pesticides was associated with incidence of HD, multiple myeloma, or STS.
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and phenoxy herbicides in the genesis of the malignancies in question. ENVIRONMENTAL STUDIES The occurrence of industrial accidents has led to the evaluation of the longterm health effects of exposure to the compounds of interest.
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to evaluate the association between individual serum TCDD and reproductive effects in women who resided in Seveso at the time of the accident in 1976. The study group consisted of 981 volunteers who were between infancy and age 40 at the time of the accident, who had resided in zones A or B, and for whom adequate serum remained from samples collected for TCDD measurements shortly after the explosion.
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For samples taken after 1977 with detectable TCDD, the TCDD exposure was back-extrapolated to 1976. Further analyses were conducted to determine correlations between individual serum TCDD levels and age at menopause in the study participants.
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; cancer mortality in four northern wheat-producing states (Schreinemachers, 2000) ; HD, NHL, multiple myeloma, and acute myeloid leukemia in various regions of Italy (Masala et al., 1996)
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This section is organized primarily by research sponsor because it is more conducive to a methodologic presentation of the articles. Exposure measures fall on a crude scale from individual exposures of Ranch Hand personnel, as reflected in serum TCDD measurements, to some statewide studies' use of service in Vietnam as a surrogate for TCDD exposure.
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From page 173... ...
To determine whether exposure to herbicides, including Agent Orange, had adverse human health effects, the Air Force made a commitment to Congress and the White House in 1979 to conduct an epidemiologic study of Ranch Hands (AFHS, 1982)
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. Blood samples were drawn for determination of serum TCDD concentrations at the cycle examinations in 1982 from 36 Ranch Hands (Pirkle et al., 1989)
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Because risk-factor data were available for only a subgroup of this cohort, the researchers were unable to adjust for confounders such as the smoking or drinking habits of all study participants. The subgroup of 1,016 Ranch Hand veterans and 1,436 Vietnam-era comparison veterans for whom serum dioxin measurements were available -- those who had attended at least one physical exam between 1982 and 1997.
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From page 176... ...
Of a total of 2,516 veterans who participated in at least one physical exam and had serum TCDD measurements (1,019 Ranch Hands and 1,497 comparisons) , 59 Ranch Hands and 81 comparisons received a diagnosis of prostate cancer in the period Jaunuary 1982–December 2003.
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From page 177... ...
has two major limitations: it has difficulty in detecting low to mod erate increases in risks of rare diseases because of the relatively small size of the Ranch Hand population, and its findings cannot be generalized to all Vietnam veterans because Ranch Hands and ground troops were exposed to different levels of herbicides in different ways. Blood measurements of dioxin .
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From page 178... ...
Such a design, coupled with the usual issues of missing data and losses to followup, complicates the reanalysis of results presented in AFHS reports and papers. 17At the time of the Cycle 1 exam, 185 Ranch Hands and 184 comparison subjects were on active duty; in addition, 210 Ranch Hand subjects and 234 comparison subjects held current military or civilian flying certificates, which have rigorous physical and mental fitness requirements (AFHS, 1984a)
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. If so, especially given the asymmetric nature of the changes in the numbers of Ranch Hand and comparison subjects, would this imply that the results reported by Akhtar et al.
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(2006) are cumulative for first prostate cancers diagnosed from 1982–2003 for those with TCDD readings.
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In particular, a recently published analysis showed an increase in cancer risk with increased dioxin body burden in Ranch Hand veterans who spent less than 2 years in Southeast Asia; a stratified analy sis was performed because years of service in Southeast Asia was identified as a risk factor for cancer in Comparison veterans. These patterns require that more sophisticated statistical models be used to study cancer in Ranch Hand veterans.
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From page 182... ...
. To examine concerns about Agent Orange more directly, CDC conducted the Agent Orange Validation Study to evaluate TCDD in US Army veterans compared with exposure estimates based on military records and with TCDD in veterans who did not serve in Vietnam (CDC, 1989a)
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From page 183... ...
Most of those publications do not discuss exposure to Agent Orange; exposure to "combat" is evaluated as the risk factor of interest. The first new VA study published since Update 2002 is the long-awaited report from a long-term health study of deployed and non-deployed veterans of US Army Chemical Corps Vietnam veterans following pilot studies (Kang et al., 2001)
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American Legion The American Legion conducted a cohort study of the health and well-being of Vietnam veterans who were members of the American Legion, a voluntary service organization for veterans. Studies examined physical health and reproductive outcomes, social–behavioral consequences, and PTSD among veterans who had served in Southeast Asia and elsewhere (Snow et al., 1988; Stellman et al., 1988a,b)
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. The first of these reports, Cancer Incidence in Australian Vietnam Veteran Study 2005 (ADVA, 2005a)
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2005c. Australian National Service Vietnam Veterans: Mortality and Cancer Incidence 2005.
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Serum Dioxin Analysis of 1987 Examination Results. Brooks AFB, TX: USAF School of Aerospace Medicine.
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2005. Cancer incidence in the Agricultural Health Study.
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2001. Serum dioxin and cognitive functioning among veterans of Operation Ranch Hand.
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American Journal of Industrial Medicine 23:729–742. Blair A, Sandler DP, Tarone R, Lubin J, Thomas K, Hoppin JA, Samanic C, Coble J, Kamel F, Knott C, Dosemeci M, Zahm SH, Lynch CF, Rothman N, Alavanja MC.
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1998. Serum dioxin, chloracne, and acne in veterans of Operation Ranch Hand.
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American Journal of Industrial Medicine 25:559–571. Calvert GM, Wall DK, Sweeney MH, Fingerhut MA.
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British Journal of Industrial Medicine 48:173–178.
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American Journal of Industrial Medicine 31(6)
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2005. Pesticide use and breast cancer risk among farmers' wives in the Agricultural Health Study.
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1991. Cancer mortality in workers exposed to 2,3,7,8-tetrachloro dibenzo-p-dioxin.
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1986. Final Report: A Case–Control Mortality Study on the Association of Soft Tissue Sarcomas, Non-Hodgkin's Lymphomas, and Other Selected Cancers and Vietnam Military Service in Pennsylvania Males.
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American Journal of Industrial Medicine 21:651–660. Hardell L
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1997. Serum dioxin and diabetes mellitus in veterans of Operation Ranch Hand.
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2005. Neurologic symptoms in licensed private pesticide applicators in the agricultural health study.
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From page 201... ...
1992. Cancer mortality from soft-tissue sarcoma and malignant lymphomas in an international cohort of workers exposed to chlorophenoxy herbicides and chlorophenols.
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1997. Cancer mortality in workers exposed to phenoxy herbicides, chlorophenols, and dioxins.
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1985. A follow-up study of cancer incidence among workers in manufacture of phenoxy herbicides in Denmark.
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2001b. Serum dioxin and peripheral neuropathy in veterans of Operation Ranch Hand.
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2006. Association between Agent Orange and birth defects: Systematic review and meta-analysis.
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2003. Ex posure to animals and selected risk factors among Canadian farm residents with Hodgkins' disease, multiple myeloma, or soft tissue sarcoma.
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1989. Estimates of the half-life of 2,3,7,8-tetrachlorodibenzo-p-dioxin in Vietnam veterans of Operation Ranch Hand.
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1991. Cancer mortality in workers exposed to chlorophenoxy herbicides and chlorophenols.
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1992. Phenoxy herbicides and chlorophenols: A case–control study on soft tissue sarcoma and malignant lymphoma.
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American Journal of Industrial Medicine 18:665–673. Thomas TL, Kang H, Dalager N
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2002. Serum dioxin concentrations and breast cancer risk in the Seveso Women's Health Study.
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1995. Paternal serum dioxin and reproductive outcomes among veterans of Operation Ranch Hand.
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1980. The mortality experience of workers exposed to tetrachlorodibenzodioxin in a trichlorophenol process accident.
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