Veterans and Agent Orange Update 2008 (2009) / Chapter Skim
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5 Epidemiologic Studies - New Citations and Background on Repeatedly Studied Populations
5 Epidemiologic Studies - New Citations and Background on Repeatedly Studied Populations
Pages 104-201
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From page 104... ...
Results of a study of a single population may be reported in connection with a multiplicity of health outcomes and more than one publication, particularly if a study is of the cohort design with repeated follow-ups. The major purpose of the chapters on epidemiology or epidemiologic studies in the original Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam (VAO)
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From page 105... ...
The occupational-studies 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 106... ...
Adult brain Patients with new et al., 2008 from JEM, self-reported tumors diagnosis of glioma occupational history or meningioma Solomon Cross- Pesticides; herbicide Neurologic Men born between et al., 2007 sectional users were 40% of "other symptoms 1933–1977 identified pesticides" users in 1991 census in rural areas of England and Wales Environmental Studies Abdelouahab Cross- Serum concentrations of Thyroid Men and women who et al., 2008 sectional POPs, including dl PCBs homeostasis consume freshwater 105, 118, 156 fish from Canadian lakes Brighina Case–control Herbicides, discussion PD PD patients from et al., 2008 of 2,4-D Wisconsin, Iowa, South Dakota, North Dakota Chao et al., Cross- Serum concentrations of Menstrual- Healthy Taiwanese 2007 sectional PCDDs, PCDFs, PCBs cycle mothers (18–40 years characteristics old) Chevrier et Birth cohort 34 PCBs, including dl Thyroid Pregnant women in al., 2008 PCBs 118, 156 levels during Salinas Valley, CA pregnancy Cok et al., Case–control Serum concentrations of Male infertility Surgical patients 2008 PCDDs, PCDFs, dl PCBs from Ankara University, School of Medicine, Turkey
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From page 107... ...
and Canada Dhooge Cross- Serum concentrations Reproductive 101 Flemish men et al., 2006 sectional of TCDD (5 months parameters 20–40 years old after PCB, dioxin food contamination episode in Belgium) Eriksson Population- Herbicides; specific NHL Swedish patients et al., 2008 based phenoxy herbicides, with diagnosis of case–control including 2,4,5-T; 2,4-D; NHL December 1, MCPA 1999–April 30, 2002 Hancock Family-based Self-reported herbicide PD PD patients, family et al., 2008 case–control or chlorophenoxy acid or members (with, ester use without PD)
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From page 108... ...
Massachusetts Spinelli Population- Serum concentrations of NHL Residents of British et al., 2007 based dl PCBs 105, 118, 156; Columbia, Canada case–control non-dl PCBs Teitelbaum Population- Self-reported lifetime Breast cancer Women living on et al., 2007 based residential use of lawn Long Island, New case–control and garden pesticides York (unspecified) Toft et al., Cross- Endocrine-disrupting Semen quality Inuits, three 2007 sectional compounds; dl activity European populations by CALUX, AHR competitive activity Tsuchiya Case–control Serum TEQ of dioxin Endometriosis, Infertile Japanese et al., 2007 (sum of dl compounds)
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From page 109... ...
The results, with comments related to their reliability or limitations, appear in the appropriate outcome-specific sections of Chapters 6–9. TABLE 5-2 Citations on Study Populations New in Update 2008 with Results on Multiple Health Outcomes Health Study Exposure Measures(s)
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From page 110... ...
Author Design Results Reported Study Population Everett Cross- Serum concentrations of Hypertension NHANES (1999– et al., sectional PCBs, including dl PCBs 118 2002, 1999–2004) 2008a,b and 126 Ha et al., Cross- Serum concentrations of Cardiovascular NHANES 2007 sectional PCDDs, PCDFs, dl and non-dl disease (1999–2002)
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From page 111... ...
, and the National Cancer Institute (NCI) ; residents of Seveso; and Ranch Hand personnel.
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From page 112... ...
Author Study Design Having Results Reported Study Population Gupta et al., Longitudinal Serum Serum testosterone, AFHS (sprayers 2006 prospective concentrations of benign prostatic vs nonsprayers) cohort TCDD hyperplasia Michalek Prospective Serum Diabetes, cancer AFHS (calendar and Pavuk, cohort concentrations of period of service, 2008 TCDD days spraying, years in SEA)
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From page 113... ...
Pelclová Case–control Serum Endothelial dysfunction, Poisoned Czech et al., 2007 concentrations of impaired microvascular production TCDD reactivity workers Saldana Cohort Pesticides, Gestational diabetes AHS et al., 2007 including 2,4-D; 2,4,5-T; 2,4,5-TP; dicamba Samanic Cohort Dicamba Cancer incidence AHS et al., 2006 Urban et al., Case series Serum Polyneuropathy, other Poisoned Czech 2007 concentrations of neurologic effects production TCDD workers Valcin et al., Cohort Herbicides Chronic bronchitis AHS (nonsmoking 2007 women) Weselak Cohort In utero exposure Cough, asthma, allergy Ontario Farm et al., 2007 to phenoxy Family Health herbicides, Study including 2,4-D; 2,4-DB; MCPA; dicamba Environmental Studies Baccarelli Cohort Serum Neonatal thyroid function Seveso births et al., 2008 (residential- concentrations of (TSH)
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From page 114... ...
propionic acid; AFHS, Air Force Health Study; AHS, Agricultural Health Study; ALL, acute lymphocytic leukemia; CLL, chronic lymphocytic leukemia; CNS, central nervous system; GIS, geographic information system; HD, Hodgkin's disease; MCPA, 2-methyl-4-chlorophenoxyacetic acid; NHL, non-Hodgkin's lymphoma; PCB, polychlorinated biphenyl; PD, Parkinson's disease; SEA, Southeast Asia; STS, softtissue sarcoma; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; THS, thyroid-stimulating hormone; VA, Department of Veterans Affairs. aThroughout the report the same alphabetic indicator following year of publication is used con sistently for the same article when there were multiple citations by the same first author in a given year.
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From page 115... ...
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 116... ...
Veterans who took place in the defoliation activities became the first subpopulation of Vietnam veterans to receive special attention with regard to Agent Orange and have become known as the Ranch Hand cohort within the Air Force Health Study (AFHS)
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From page 117... ...
A retrospective matched-cohort study design was used to examine morbidity and mortality; follow-up was scheduled to continue until 2002. Records from the National Personnel Records Center and the US Air Force Human Resources Laboratory were searched and cross-referenced to identify all Ranch Hand personnel (AFHS, 1982; Michalek et al., 1990)
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From page 118... ...
. Blood samples for determination of serum TCDD concentrations were drawn at the cycle examinations in 1982 from 36 Ranch Hands (Pirkle et al., 1989)
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From page 119... ...
investigated diabetes and cancer incidence in Vietnam veterans and Vietnam-era veterans. The study population consisted of Air Force veterans who served in Operation Ranch Hand and in SEA during the period 1962–1971 and participated in at least one physical examination in 1982, 1985, 1987, 1992, 1997, or 2002.
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From page 120... ...
Serum TCDD results from the AFHS demonstrate that the Ranch Hands in general were, indeed, more highly exposed than the SEA veterans, but the SEA veterans had serum TCDD concentrations that tended to exceed background values in the US population. The AFHS is perceived by many to be the central piece of research for decision making by the committees preparing the VAO reports.
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From page 121... ...
.19 After CDC developed an assay for measuring serum TCDD levels in the late 1980s that AFHS adopted as a proxy, more issues arose. One of these was the effect of measurement error in the estimation of TCDD half-life, an issue because this value was used to es timate a common baseline serum dioxin level for each study participant.
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From page 122... ...
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. 17 At 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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From page 123... ...
. If so, especially given the asymmetric nature of the changes in the numbers of Ranch Hand and comparison subjects, would it imply that the results reported by Akhtar et al.
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From page 124... ...
(2006) are cumulative for first prostate cancers diagnosed from 1982 to 2003 for those with TCDD readings.
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From page 125... ...
These patterns require that more sophisticated statistical models be used to study cancer in Ranch Hand veterans. Consistent with the protocol, study investigators continue to question the underlying assumptions of all analyses, explore new ways to analyze data, and collaborate with specialists to determine whether exposure to Agent Orange adversely affected the health of Ranch Hand veterans.
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From page 126... ...
That involved determining the proximity of troops to Agent Orange spraying by using military records to track troop movement and the HERBS tapes to locate herbicide-spraying patterns. The CDC birth-defects study developed an exposure-opportunity index to score Agent Orange exposure (Erickson et al., 1984a,b)
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From page 127... ...
. Department of Veterans Affairs Numerous cohort and case–control studies are discussed in detail in VAO, Update 1996, Veterans and Agent Orange: Update 1998 referred to as Update 1998 (IOM, 1999)
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, a computer database containing health information on Vietnam veterans who voluntarily undergo physical examinations at a VA hospital. The AOR was set up in 1978 to monitor Vietnam veterans' health complaints or problems that could be related to Agent Orange exposure during military service in Vietnam.
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From page 129... ...
. In 1986, PL 99-972 was enacted, requiring that an epidemiologic study be conducted to examine long-term adverse health effects in female Vietnam veterans as a result of their exposure to traumatic experiences, exposure to such herbicides as Agent Orange or other chemicals or medications, or any other similar experience or exposure during such service.
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From page 130... ...
The combined roster of all female personnel from the military branches was considered by the researchers to be relatively complete. Comparisons were female veterans identified through the same process as the female Vietnam veterans but who had not served in Vietnam during their military service.
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From page 131... ...
Since Update 2006, Cypel and Kang (2008) have conducted a mortality study of female Vietnam veterans and compared their mortality with that in a control group of women who were in military service but did not participate in the Vietnam War.
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From page 132... ...
The authors concluded that Agent Orange exposure was a likely contributor to TCDD concentrations in Vietnam veterans who had a history of spraying herbicides.
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From page 133... ...
VAO and Update 1998 discuss them in detail; most did not discuss exposure to Agent Orange, and exposure to "combat" was evaluated as the risk factor of interest. American Legion The American Legion, a voluntary service organization for veterans, conducted a cohort study of the health and well-being of Vietnam veterans who were members.
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From page 134... ...
VAO summarized those studies, and no new studies have been published. The 1997 Institute of Medicine request for proposals for historical-exposure reconstruction has led to the development of new methods for estimating Vietnam veterans' exposures to Agent Orange.
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From page 135... ...
The study involved 720 veterans who served in Vietnam and 25 veterans who did not. The exposure index was based on Agent Orange spraying patterns in military regions in which Korean personnel served, time–location data on the military units stationed in Vietnam, and an exposure score derived from self-reported activities during service.
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From page 136... ...
However, the concentrations reported in the Korean veterans study are significantly lower than those reported in American Vietnam veterans in the 1988 CDC Agent Orange Validation Study, which was nonetheless unable to distinguish Vietnam veterans from non-Vietnam veterans on the basis of serum dioxin (CDC, 1988b)
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From page 137... ...
The committee reviewed many epidemiologic studies of occupationally exposed groups for evidence of an association between health risks and exposure to TCDD or to the herbicides used in Vietnam, primarily the phenoxy herbicides 2,4-D and 2,4,5-T. TCDD is an unwanted byproduct of 2,4,5-T production but not of 2,4-D production.
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From page 138... ...
Other occupationally exposed groups included were pulp and paper workers exposed to dioxins through bleaching processes that use chlorinated compounds and sawmill workers exposed to chlorinated dioxins that can be contaminants of chlorophenates used as wood preservatives. Production Workers National Institute for Occupational Safety and Health Starting in 1978, an extensive set of data on chemical production workers potentially contaminated with TCDD in 1942–1984 has been compiled by NIOSH.
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From page 139... ...
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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(1989, 1993) in a study of three birth outcomes -- birth weight, preterm delivery, and birth defects -- in offspring, by comparing serum TCDD concentrations in the NIOSH cohort with those in a reference population.
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From page 141... ...
The Dow cohorts have been followed as part of the NIOSH and IARC cohorts since 1991 and 1997, respectively. Dow also has conducted a cohort study of its manufacturing workers exposed to pentachlorophenol (PCP)
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From page 142... ...
The authors used their data to estimate worker exposures at the time of exposure termination by using several pharmacokinetic models. They concluded that their findings were consistent with those of other studies that reported high serum dioxin concentrations in chlorophenol workers after occupational exposures.
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From page 143... ...
. A cohort study of cancer incidence and mortality was conducted in 701 women in seven countries who were occupationally exposed to chlorophenoxy herbicides, chlorophenols, and dioxins (Kogevinas et al., 1993)
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From page 144... ...
Waste-Incineration Worker Studies A study of infectious-waste–incineration plant workers in Japan used serum dioxin concentrations to document higher PCDD and PCDF exposures of workers than of controls (Kumagai and Koda, 2005)
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From page 145... ...
. Rather than measuring serum dioxin, both studies 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-naphthol.
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From page 146... ...
Other Chemical Plants Studies have reviewed health outcomes in UK chemical workers exposed to TCDD as a result of an industrial accident in 1968 (Jennings et al., 1988; May, 1982, 1983) , 2,4-D production workers in the former Soviet Union (Bashirov, 1969)
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From page 147... ...
Exposure of those groups has been classified by using approaches similar to those noted above for agricultural workers, for example, by using the number of years employed, job category, and occupational title. Agricultural Health Study The US Agricultural Health Study (AHS)
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From page 148... ...
This quantitative approach has the potential to improve the accuracy of exposure classification for the cohort but has not yet been used in published epidemiologic studies. In phase II (a 5-year follow-up of farmers, 1999–2003)
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From page 149... ...
, reported on the relationship between self-reported incident diabetes and pesticide and herbicide exposure in 31,787 licensed pesticide applicators and their spouses. Physician-diagnosed incident diabetes was assessed during a follow-up questionnaire.
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From page 150... ...
The new analyses provided no evidence of greater use of pesticides in cases than in controls, and there was no breakdown of specific agents. Ontario Farmers The Ontario Farm Family Health Study (OFFHS)
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From page 151... ...
All birth defects were combined for study analyses, and exposure was examined by pesticide class, family, and active ingredient for two 3-month periods -- before and after conception. Mortality Study of Male Canadian Farm Operators The Mortality Study of Canadian Male Farm Operators evaluated the risk to farmers of death and of specific health outcomes: NHL (Morrison et al., 1994; Wigle et al., 1990)
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From page 152... ...
The resulting database has been used in studies that evaluated cancer mortality and farm work (Wiklund, 1983) ; STS and malignant lymphoma in agricultural and forestry workers (Wiklund and Holm, 1986; Wiklund et al., 1988a)
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From page 153... ...
, a Dutch study of forestry workers exposed to 2,4,5-T investigated the prevalence of acne and hepatic dysfunction (van Houdt et al., 1983) , a study evaluated cancer incidence in a group of New Zealand forestry workers (Reif et al., 1989)
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From page 154... ...
Only one study has provided information on serum TCDD concentrations in herbicide applicators. Smith AH et al.
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From page 155... ...
, mortality and reproductive effects in British Columbia sawmill workers potentially exposed to chlorophenate wood preservatives used as fungicides (Dimich-Ward et al., 1996; Heacock et al., 1998; Hertzman et al., 1997) , and cancer risk in pesticide users in Iceland (Zhong and Rafnsson, 1996)
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From page 156... ...
An expanded case series was collected, and additional case–control studies of exposure to phenoxy herbicides or chlorophenols and the risks of malignant lymphoma, NHL, and multiple myeloma were conducted (Pearce et al., 1985, 1986a,b, 1987)
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From page 157... ...
; PD associated with occupational risk factors (Semchuk et al., 1993) ; birth defects in offspring of agriculture workers (Nurminen et al., 1994)
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From page 158... ...
The data presented do not allow direct comparison of dioxin concentrations in soil as a function of distance from the industrial facilities. However, the highest TCDD concentrations in the Chapaevsk study (those nearest the plant)
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From page 159... ...
have not changed the exposure-assessment approach. A number of studies of the Seveso population have used lipid-adjusted serum TCDD concentrations as the primary exposure metric (Baccarelli et al., 2002; Eskenazi et al., 2002a,b, 2003, 2004; Landi et al., 2003)
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From page 160... ...
, studies have examined specific health effects associated with TCDD exposure in Seveso residents: chloracne, birth defects, spontaneous abortion, and crude birth and death rates (Bisanti et al., 1980) ; chloracne and peripheral nervous system conditions (Barbieri et al., 1988)
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From page 161... ...
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 40 years old at the time of the accident, who had resided in Zone A or B, and for whom adequate serum remained from samples collected for TCDD measurements shortly after the explosion.
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From page 162... ...
Those findings demonstrate a significant association between zone of residence and serum TCDD, but much of the variability in TCDD concentration is still unexplained by the models. Previously reviewed studies have examined associations between serum TCDD and menstrual cycle (Eskenazi et al., 2002a)
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From page 163... ...
(2006) published a meta-analysis addressing an association between exposure to Agent Orange and birth defects.
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From page 164... ...
Researchers also conduct analyses of the NHANES data for epidemiologic studies and health science research. Since Update 2006, several studies have been published that draw upon NHANES data as the basis for their analyses.
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From page 165... ...
. Several epidemiologic studies have been conducted in association with industrial-facility emissions or in regions with documented variation in dioxin exposures.
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From page 166... ...
(2004) found generally quite high correlations between concentrations of dioxins and related compounds in breast and abdominal fat in the same woman, this suggested that they could be used interchangeably in epidemiologic studies.
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From page 167... ...
2005a. Cancer Incidence in Australian Vietnam Veteran Study 2005.
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2008. IOM announces new Vietnam veterans and Agent Orange committee to prepare 2008 update.
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From page 169... ...
2005. Cancer incidence in the Agricultural Health Study.
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From page 170... ...
American Journal of Industrial Medicine 16:119–125. Assennato G, Cannatelli P, Emmett E, Ghezzi I, Merlo F
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From page 171... ...
2001. Serum dioxin and cognitive functioning among veterans of Operation Ranch Hand.
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From page 172... ...
American Journal of Industrial Medicine 32(3)
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From page 173... ...
1998. Serum dioxin, chloracne, and acne in veterans of Operation Ranch Hand.
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From page 174... ...
1989a. Comparison of Serum Levels of 2,3,7,8-Tetrachlorodibenzo-p-dioxin with Indirect Estimates of Agent Orange Exposure Among Vietnam Veterans: Final Report.
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2008. Agent Orange exposure, Vietnam War veterans, and the risk of prostate cancer.
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From page 176... ...
American Journal of Industrial Medicine 31(6)
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From page 177... ...
2005b. Rheumatoid arthritis among women in the Agricultural Health Study: Risk associated with farming activities and exposures.
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From page 178... ...
American Journal of Industrial Medicine 22:305–312. Eriksson M, Hardell L, Carlberg M, Akerman M
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From page 179... ...
2007. Serum dioxin concentrations and risk of uterine leiomyoma in the Seveso Women's Health Study.
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From page 180... ...
2004. Cancer risk and parental pesticide application in children of Agricultural Health Study participants.
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From page 181... ...
1991. A cohort mortality study of forestry workers exposed to phenoxy acid herbicides.
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From page 182... ...
American Journal of Industrial Medicine 21:651–660. Hansen ES, Lander F, Lauritsen JM.
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From page 183... ...
1997. Serum dioxin and diabetes mellitus in veterans of Operation Ranch Hand.
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From page 184... ...
1991. Cancer incidence among pulp and paper workers exposed to organic chlorinated compounds formed during chlorine pulp bleaching.
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From page 185... ...
2007a. Neurologic symptoms in licensed pesticide applicators in the Agricultural Health Study.
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From page 186... ...
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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From page 187... ...
American Journal of Public Health 75:277–279. Lawson CC, Schnorr TM, Whelan EA, Deddens JA, Dankovic DA, Piacitelli LA, Sweeney MH, Connally LB.
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From page 188... ...
2007. Pesticide use and colorectal cancer risk in the Agricultural Health Study.
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From page 189... ...
1995. Indices of TCDD exposure and TCDD body burden in veterans of Operation Ranch Hand.
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From page 190... ...
2001a. Serum dioxin and hepatic abnormalities in veterans of Operation Ranch Hand.
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From page 191... ...
2008. Incident diabetes and pesticide exposure among licensed pesticide applicators: Agricultural Health Study, 1993–2003.
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From page 192... ...
2005. Did TCDD exposure or service in Southeast Asia increase the risk of cancer in Air Force Vietnam veterans who did not spray Agent Orange?
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1993. Some occupational exposures as risk factors for malignant lymphomas.
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From page 194... ...
American Journal of Industrial Medicine 51(4)
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From page 195... ...
2006. Cancer incidence among pesticide applicators exposed to dicamba in the Agricultural Health Study.
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American Journal of Industrial Medicine 9:305–321. Stellman SD, Stellman JM.
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. American Journal of Industrial Medicine 23:845–858.
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From page 198... ...
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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From page 200... ...
1995. Paternal serum dioxin and reproductive outcomes among veterans of Operation Ranch Hand.
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From page 201... ...
2004a. Assessing possible exposures of ground troops to Agent Orange during the Vietnam War: The use of contemporary military records.
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