Skin diseases associated with Agent Orange and other organochlorine exposures
Authors: Andrew T. Patterson, Benjamin H. Kaffenberger, Richard A. Keller, Dirk M. Elston
Journal: Journal of the American Academy of Dermatology (2015)

Organochlorine exposure is an important cause of cutaneous and systemic toxicity. Exposure has been associated with industrial accidents, intentional poisoning, and the use of defoliants, such as Agent Orange in the Vietnam War. Although long-term health effects are systematically reviewed by the Institute of Medicine, skin diseases are not comprehensively assessed. This represents an important practice gap as patients can present with cutaneous findings. This article provides a systematic review of the cutaneous manifestations of known mass organochlorine exposures in military and industrial settings with the goal of providing clinically useful recommendations for dermatologists seeing patients inquiring about organochlorine effects. Patients with a new diagnosis of chloracne, porphyria cutanea tarda, cutaneous lymphomas (non-Hodgkin lymphoma), and soft-tissue sarcomas including dermatofibrosarcoma protuberans and leiomyosarcomas should be screened for a history of Vietnam service or industrial exposure. Inconclusive evidence exists for an increased risk of other skin diseases in Vietnam veterans exposed to Agent Orange including benign fatty tumors, melanomas, nonmelanoma skin cancers, milia, eczema, dyschromias, disturbance of skin sensation, and rashes not otherwise specified. Affected veterans should be informed of the uncertain data in those cases. Referral to Department of Veterans Affairs for disability assessment is indicated for conditions with established associations. Organochlorine exposure is an important cause of cutaneous and systemic toxicity. Exposure has been associated with industrial accidents, intentional poisoning, and the use of defoliants, such as Agent Orange in the Vietnam War. Although long-term health effects are systematically reviewed by the Institute of Medicine, skin diseases are not comprehensively assessed. This represents an important practice gap as patients can present with cutaneous findings. This article provides a systematic review of the cutaneous manifestations of known mass organochlorine exposures in military and industrial settings with the goal of providing clinically useful recommendations for dermatologists seeing patients inquiring about organochlorine effects. Patients with a new diagnosis of chloracne, porphyria cutanea tarda, cutaneous lymphomas (non-Hodgkin lymphoma), and soft-tissue sarcomas including dermatofibrosarcoma protuberans and leiomyosarcomas should be screened for a history of Vietnam service or industrial exposure. Inconclusive evidence exists for an increased risk of other skin diseases in Vietnam veterans exposed to Agent Orange including benign fatty tumors, melanomas, nonmelanoma skin cancers, milia, eczema, dyschromias, disturbance of skin sensation, and rashes not otherwise specified. Affected veterans should be informed of the uncertain data in those cases. Referral to Department of Veterans Affairs for disability assessment is indicated for conditions with established associations. Capsule Summary•Organochlorines are highly toxic chemicals with long half-lives.•Human exposure has occurred through industrial accidents and defoliation missions during the Vietnam War.•This systematic review summarizes the dermatologic evidence of exposure associations and offers clinical guidelines for dermatologists. •Organochlorines are highly toxic chemicals with long half-lives.•Human exposure has occurred through industrial accidents and defoliation missions during the Vietnam War.•This systematic review summarizes the dermatologic evidence of exposure associations and offers clinical guidelines for dermatologists. Dermatologic ailments were the most common reason for outpatient visits to US Army medical facilities during the Vietnam War and the major cause of field days lost.1Allen A.M. Taplin D. Lowy J.A. Twigg L. Skin infections in Vietnam.Mil Med. 1972; 137: 295-301PubMed Google Scholar Although immersion foot and zoonotic tinea comprised much of the acute dermatologic morbidity, long-term effects can often relate to organochlorine exposure. During the war, herbicides were used to defoliate enemy crops and cover in a campaign designated Operation Ranch Hand (ORH), lasting from 1962 to 1971. It exposed millions of soldiers and civilians to organochlorine chemicals, predominantly Agent Orange containing 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD).2Stellman J.M. Stellman S.D. Christian R. Weber T. Tomasello C. The extent and patterns of usage of Agent Orange and other herbicides in Vietnam.Nature. 2003; 422: 681-687Crossref PubMed Scopus (132) Google Scholar Resultant skin diseases have been a persistent question with one study reporting up to 85% of exposed veterans describing a persistent skin eruption.3Health status of Vietnam veterans. II. Physical health. Centers for Disease Control Vietnam Experience Study.JAMA. 1988; 259: 2708-2714Crossref PubMed Google Scholar, 4Bogen G. Symptoms in Vietnam veterans exposed to Agent Orange.JAMA. 1979; 242: 2391Crossref PubMed Google Scholar An official review has been conducted by the Institute of Medicine with specific emphasis on systemic manifestations including cancers, fertility, and cardiovascular, metabolic, neurologic, and immunologic parameters of Agent Orange exposure, but with little emphasis on skin disease.5Institute of Medicine, Committee to Review the Health Effects in Vietnam Veterans of Exposure to HerbicidesVeterans and Agent Orange: update 2012. National Academy Press, Washington (DC)2012Google Scholar This article provides a brief description of organochlorine use, disease mechanism, and a summary of evidence for dermatologic conditions associated with organochlorine exposure. Journal articles were searched and selected on a narrative basis to provide an overview of organochlorine history and pathophysiology. Skin disease associations were assessed systematically by 2 investigators (A. T. P., B. H. K.) using search terms "Agent Orange," "dioxin," "2,3,7,8-tetrachlorodibenzo-p-dioxin," OR "TCDD" AND "skin," "cutaneous," "rash," "skin cancer," "dermatol*," "chloracne," "acne," OR "porphyria cutanea tarda" (PCT). Abstracts were reviewed by both investigators and selected for studies on 1 or more human beings. References were cross-checked for additional inclusion (Fig 1). A third investigator (D. M. E.) made final inclusion decisions for disagreements. Although numerous phenoxyherbicide formulations were used as defoliants in Vietnam and the Korean demilitarized zone, the most prominent involved a 1:1 mixture of n-butyl esters 2,4-dichlorophenoxyacetic acid and 2,4,5-trichlorophenoxyacetic acid. This particular mixture became known as Agent Orange, as herbicides were identified by colored stripes on the sides of the 55-gal transport barrels.6Schecter A. McGee H. Stanley J.S. Boggess K. Brandt-Rauf P. Dioxins and dioxin-like chemicals in blood and semen of American Vietnam veterans from the state of Michigan.Am J Ind Med. 1996; 30: 647-654Crossref PubMed Google Scholar, 7Dunagin W.G. Cutaneous signs of systemic toxicity due to dioxins and related chemicals.J Am Acad Dermatol. 1984; 10: 688-700Abstract Full Text PDF PubMed Google Scholar Agent Orange is now accepted as reference to all military phenoxyherbicides used during the era. The synthesis of the 2,4,5-trichlorophenoxyacetic acid component from 2,4,5-trichlorphenol generated the highly toxic byproduct TCDD, which remained in the mixture. Dioxins are a group of lipophilic, biologically active, chlorinated aromatic compounds produced during industrial manufacturing reactions that possess long-lasting environmental pollutant capacity.6Schecter A. McGee H. Stanley J.S. Boggess K. Brandt-Rauf P. Dioxins and dioxin-like chemicals in blood and semen of American Vietnam veterans from the state of Michigan.Am J Ind Med. 1996; 30: 647-654Crossref PubMed Google Scholar, 8Frumkin H. Agent Orange and cancer: an overview for clinicians.CA Cancer J Clin. 2003; 53: 245-255Crossref PubMed Google Scholar TCDD contamination levels varied between 1 and 50 ppm in individual barrels with an estimated average mean concentration of 13 ppm.2Stellman J.M. Stellman S.D. Christian R. Weber T. Tomasello C. The extent and patterns of usage of Agent Orange and other herbicides in Vietnam.Nature. 2003; 422: 681-687Crossref PubMed Scopus (132) Google Scholar, 7Dunagin W.G. Cutaneous signs of systemic toxicity due to dioxins and related chemicals.J Am Acad Dermatol. 1984; 10: 688-700Abstract Full Text PDF PubMed Google Scholar Although Vietnam serves as the largest organochlorine exposure historically, contact risks may still persist in occupational settings including paper mills, pesticide manufacturing, incineration/combustion, and metallurgy.7Dunagin W.G. Cutaneous signs of systemic toxicity due to dioxins and related chemicals.J Am Acad Dermatol. 1984; 10: 688-700Abstract Full Text PDF PubMed Google Scholar Another prominent large-scale dioxin exposure occurred in 1976 in Seveso, Italy, when a chemical manufacturing plant released several tons of organochlorine-laced chemicals into the surrounding towns. Thousands of residential citizens were exposed to high levels of TCDD and numerous longitudinal studies were conducted examining the effects of dioxins on human beings.5Institute of Medicine, Committee to Review the Health Effects in Vietnam Veterans of Exposure to HerbicidesVeterans and Agent Orange: update 2012. National Academy Press, Washington (DC)2012Google Scholar, 7Dunagin W.G. Cutaneous signs of systemic toxicity due to dioxins and related chemicals.J Am Acad Dermatol. 1984; 10: 688-700Abstract Full Text PDF PubMed Google Scholar Another highly publicized case of TCDD toxicity involved the 2004 assassination attempt on Ukrainian presidential candidate Viktor Yushchenko, where high dioxin levels led to substantial chloracne development (Fig 2).9Sorg O. Zennegg M. Schmid P. et al.2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) poisoning in Victor Yushchenko: identification and measurement of TCDD metabolites.Lancet. 2009; 374: 1179-1185Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar, 10Saurat J.H. Kaya G. Saxer-Sekulic N. et al.The cutaneous lesions of dioxin exposure: lessons from the poisoning of Victor Yushchenko.Toxicol Sci. 2012; 125: 310-317Crossref PubMed Scopus (22) Google Scholar, 11Serum 2,3,7,8-tetrachlorodibenzo-p-dioxin in US Army Vietnam-era veterans. Centers for Disease Control Veterans Health Studies.JAMA. 1988; 260: 1249-1254Crossref PubMed Google Scholar This article attempts to examine all organochlorine human exposures described in the literature for any available information on cutaneous toxicity in human beings. Throughout the course of ORH, almost 20 million gal of Agent Orange–containing an estimated 366 kg of TCDD–was applied to over 3.6 million acres across south Vietnam.7Dunagin W.G. Cutaneous signs of systemic toxicity due to dioxins and related chemicals.J Am Acad Dermatol. 1984; 10: 688-700Abstract Full Text PDF PubMed Google Scholar The goal was to decimate vegetation used for enemy food and concealment while clearing land near allied bases for easier defense.6Schecter A. McGee H. Stanley J.S. Boggess K. Brandt-Rauf P. Dioxins and dioxin-like chemicals in blood and semen of American Vietnam veterans from the state of Michigan.Am J Ind Med. 1996; 30: 647-654Crossref PubMed Google Scholar Despite increased effort to characterize the degree and distribution of dioxin based on military records, quantifying the extent of individual exposure to Agent Orange has proved challenging for researchers.2Stellman J.M. Stellman S.D. Christian R. Weber T. Tomasello C. The extent and patterns of usage of Agent Orange and other herbicides in Vietnam.Nature. 2003; 422: 681-687Crossref PubMed Scopus (132) Google Scholar The expensive serum dioxin test, considered to be the gold standard for organochlorine exposure, has only been used by a few high-level evidence studies to date because of its high cost and lack of resultant impact on clinical management. The Department of Veterans Affairs (VA) does not perform this test as by law the VA presumes all US service branch members who served in Vietnam or Korea during certain specified time periods were exposed to Agent Orange, along with additional military personnel who meet established time and location service criteria.12US Department of Veterans Affairs. Vietnam veterans and Agent Orange independent study course. Veterans Health Initiative. Updated June 2008. Available at: http://www.publichealth.va.gov/docs/vhi/VHIagentorange_text508.pdf. Accessed June 14, 2015.Google Scholar Incidental ground troop exposure to Agent Orange appears to have remained minimal because of the limited bioavailability and rapid photochemical degradation of TCDD, and precise delivery of TCDD by airplane spray devices.13Young A.L. Giesy J.P. Jones P.D. Newton M. Environmental fate and bioavailability of Agent Orange and its associated dioxin during the Vietnam War.Environ Sci & Pollut Res. 2004; 11: 359-370Crossref PubMed Google Scholar Several studies have demonstrated nearly identical levels of TCDD in the serum of Vietnam-stationed and control US Army veterans and the general public.13Young A.L. Giesy J.P. Jones P.D. Newton M. Environmental fate and bioavailability of Agent Orange and its associated dioxin during the Vietnam War.Environ Sci & Pollut Res. 2004; 11: 359-370Crossref PubMed Google Scholar, 14Buffler P.A. Ginevan M.E. Mandel J.S. Watkins D.K. The Air Force health study: an epidemiologic retrospective.Ann Epidemiol. 2011; 21: 673-678Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar, 15Kahn P.C. Gochfeld M. Nygren M. et al.Dioxins and dibenzofurans in blood and adipose tissue of Agent Orange-exposed Vietnam veterans and matched controls.JAMA. 1998; 259: 1661-1667Crossref Google Scholar, 16Young A.L. TCDD biomonitoring and exposure to Agent Orange: still the gold standard.Environ Sci & Pollut Res. 2004; 11: 143-146Crossref PubMed Google Scholar Despite this strong evidence, surveys have shown between 25% to 55% of Vietnam veterans believe they were significantly exposed to herbicides during their service and many present to their physicians with concerns about Agent Orange and its possible contribution to their various health problems.3Health status of Vietnam veterans. II. Physical health. Centers for Disease Control Vietnam Experience Study.JAMA. 1988; 259: 2708-2714Crossref PubMed Google Scholar, 8Frumkin H. Agent Orange and cancer: an overview for clinicians.CA Cancer J Clin. 2003; 53: 245-255Crossref PubMed Google Scholar, 14Buffler P.A. Ginevan M.E. Mandel J.S. Watkins D.K. The Air Force health study: an epidemiologic retrospective.Ann Epidemiol. 2011; 21: 673-678Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar Several groups may be at higher risk including ORH and Army Chemical Corps members both of whom personally handled the liquid herbicides. Compared with other Air Force personnel serving concurrently in Southeast Asia without direct Agent Orange exposure, this high-risk population has demonstrated a statistically significant increase in serum TCDD concentration with persistent elevations even 30 to 40 years postexposure in the Air Force Health Study (AFHS).17Kang H.K. Dalager N.A. Needham L.L. et al.Health status of Army Chemical Corps Vietnam veterans who sprayed defoliant in Vietnam.Am J Ind Med. 2006; 49: 875-884Crossref PubMed Scopus (66) Google Scholar, 18Air Force Health Study. 2005b. An epidemiologic investigation of health effects in Air Force personnel following exposure to herbicides. 2002 Follow-up Examination Results. Brooks AFB (TX): Epidemiologic Research Division, Armstrong Laboratory. Available at: http://www.nap.edu/openbook.php?record_id=11590&page=88. Accessed June 14, 2015.Google Scholar, 19Pavuk M. Patterson Jr., D.G. Turner W.E. Serum concentrations of TCDD and other dioxin-like compounds in US Air Force veterans of Operation Ranch Hand.Chemosphere. 2014; 102: 18-23Crossref PubMed Google Scholar TCDD is classified as a human carcinogen with the potential for rapid bodily absorption via inhalation, ingestion, and direct skin contact. It is extremely lipophilic and becomes distributed to all areas of the body.20Hites R.A. Dioxins: an overview and history.Environ Sci Technol. 2011; 45: 16-20Crossref PubMed Scopus (32) Google Scholar The compound is cleared slowly from human beings with a half-life estimated around 7 years, but is dose dependent.5Institute of Medicine, Committee to Review the Health Effects in Vietnam Veterans of Exposure to HerbicidesVeterans and Agent Orange: update 2012. National Academy Press, Washington (DC)2012Google Scholar Mechanistically, dioxins demonstrate their toxic influence by binding to aryl hydrocarbon receptor, a ligand-activated transcription factor. The receptor-ligand complex then migrates to the nucleus where it binds to designated DNA sequences known as xenobiotic-responsive elements and modulates the transcription of target genes.21Ikuta T. Namiki T. Fujii-Kuriyama Y. Kawajiri K. AhR protein trafficking and function in the skin.Biochem Pharmacol. 2009; 77: 588-596Crossref PubMed Scopus (30) Google Scholar, 22Sorg O. AhR signaling and dioxin toxicity.Toxicol Lett. 2014; 230: 225-233Crossref PubMed Scopus (4) Google Scholar The skin is a primary focus of these transcription effects, with rapid development of cutaneous hamartomas and associated sebaceous gland atrophy, suggesting possible interference with cutaneous basal stem cell differentiation (Fig 2).9Sorg O. Zennegg M. Schmid P. et al.2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) poisoning in Victor Yushchenko: identification and measurement of TCDD metabolites.Lancet. 2009; 374: 1179-1185Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar, 10Saurat J.H. Kaya G. Saxer-Sekulic N. et al.The cutaneous lesions of dioxin exposure: lessons from the poisoning of Victor Yushchenko.Toxicol Sci. 2012; 125: 310-317Crossref PubMed Scopus (22) Google Scholar, 23Panteleyev A. Bickers D. Dioxin-induced chloracne–reconstructing the cellular and molecular mechanisms of a classic environmental disease.Exp Dermatol. 2006; 15: 705-730Crossref PubMed Scopus (62) Google Scholar Immunohistochemical staining of epithelial walls of these cystic lesions demonstrates focal induction of CYP1A1, the predominant enzyme involved in dioxin metabolism, and repression of several enzymes that regulate sebaceous lipid synthesis.10Saurat J.H. Kaya G. Saxer-Sekulic N. et al.The cutaneous lesions of dioxin exposure: lessons from the poisoning of Victor Yushchenko.Toxicol Sci. 2012; 125: 310-317Crossref PubMed Scopus (22) Google Scholar, 22Sorg O. AhR signaling and dioxin toxicity.Toxicol Lett. 2014; 230: 225-233Crossref PubMed Scopus (4) Google Scholar TCDD has been shown to be nongenotoxic and nonmutagenic in its interaction with human DNA, but TCDD may act as a tumor promoter for other cancer initiators.5Institute of Medicine, Committee to Review the Health Effects in Vietnam Veterans of Exposure to HerbicidesVeterans and Agent Orange: update 2012. National Academy Press, Washington (DC)2012Google Scholar, 9Sorg O. Zennegg M. Schmid P. et al.2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) poisoning in Victor Yushchenko: identification and measurement of TCDD metabolites.Lancet. 2009; 374: 1179-1185Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar A multitude of studies have examined the possible immunologic impact of Agent Orange exposure to Vietnam veterans in the form of dioxin-induced immune dysfunction. Although isolated reports have detailed statistically significant differences in a single immune measure such as immunoglobulin or interleukin levels, there have been no consistent findings of reduced immunologic status after TCDD exposure.5Institute of Medicine, Committee to Review the Health Effects in Vietnam Veterans of Exposure to HerbicidesVeterans and Agent Orange: update 2012. National Academy Press, Washington (DC)2012Google Scholar, 24Kim J.S. Lim H.S. Cho S.I. Cheong H.K. Lim M.K. Impact of Agent Orange exposure among Korean Vietnam veterans.Ind Health. 2003; 41: 149-157Crossref PubMed Google Scholar, 25Baccarelli A. Mocarelli P. Patterson Jr., D.G. et al.Immunologic effects of dioxin: new results from Seveso and comparison with other studies.Environ Health Perspect. 2002; 110: 1169-1173Crossref PubMed Google Scholar Table I, Table II review published studies with 2 or greater patients, many of which show substantial weaknesses, particularly strong deviations in skin disease frequency in self-reported Agent Orange exposure or self-reported skin reactions. Table III summarizes all single case reports. The Centers for Disease Control and Prevention (CDC) Vietnam Experience study logged 4817 skin conditions other than acne possibly associated with Agent Orange exposure. Most were not corroborated when a smaller segment was examined by board-certified dermatologists.3Health status of Vietnam veterans. II. Physical health. Centers for Disease Control Vietnam Experience Study.JAMA. 1988; 259: 2708-2714Crossref PubMed Google ScholarTable IVietnam War organochlorine exposure studiesNo. of exposures/patients∗Largest sample allocated in given study.No. of controls∗Largest sample allocated in given study.Control strategyDesignNo. of years followedStart time after exposure (years), last exposure 1971AO exposure history: Serum dioxin/chloracne/SR/risk modeling/other?Cutaneous manifestations: SR/ICD/pathology/general examination/dermatologic examinationChloracne/other acnePCTMelanoma and/or NMSCOther cutaneous oncologic manifestations, soft-tissue sarcoma, or cutaneous lymphomaRash/otherWeakness of study, (not including SR data) statistical, attrition, and additional commentsLOEVietnam AF Health Study18Air Force Health Study. 2005b. An epidemiologic investigation of health effects in Air Force personnel following exposure to herbicides. 2002 Follow-up Examination Results. 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An epidemiologic investigation of health effects in Air Force personnel following exposure to herbicides. 2002 Follow-up Examination Results. Brooks AFB (TX): Epidemiologic Research Division, Armstrong Laboratory. Available at: http://www.nap.edu/openbook.php?record_id=11590&page=88. Accessed June 14, 2015.Google Scholar, 32Wolfe W.H. Michalek J.E. Miner J.C. et al.Health status of Air Force veterans occupationally exposed to herbicides in Vietnam. I. Physical health.JAMA. 1990; 264: 1824-1831Crossref PubMed Google Scholar; melanoma INC (S) in ranch hand compared to controls and in nonoccupational exposed but still measurable33Pavuk M. Michalek J.E. Schecter A. Ketchum N.S. Akhtar F.Z. Fox K.A. Did TCDD exposure or service in Southeast Asia increase the risk of cancer in Air Force Vietnam veterans who did not spray Agent Orange?.J Occup Environ Med. 2005; 47: 335-342Crossref PubMed Scopus (24) Google Scholar, 34Akhtar F.Z. Garabrant D.H. Ketchum N.S. Michalek J.E. Cancer in US Air Force veterans of the Vietnam War.J Occup Environ Med. 2004; 46: 123-136Crossref PubMed Scopus (61) Google ScholarAll cancer INC (S) DR (includes NMSC and other skin);Hyperpigmentation INC (S) with dioxin exposure but no difference between comparison subjects32Wolfe W.H. Michalek J.E. Miner J.C. et al.Health status of Air Force veterans occupationally exposed to herbicides in Vietnam. I. Physical health.JAMA. 1990; 264: 1824-1831Crossref PubMed Google Scholar; no consistent abnormalities of immunologic parameters; INC (S) skin bruises, patches, or sensitivity in comparison to controls18Air Force Health Study. 2005b. An epidemiologic investigation of health effects in Air Force personnel following exposure to herbicides. 2002 Follow-up Examination Results. Brooks AFB (TX): Epidemiologic Research Division, Armstrong Laboratory. Available at: http://www.nap.edu/openbook.php?record_id=11590&page=88. Accessed June 14, 2015.Google Scholar; benign skin neoplasms and neoplasms of uncertain behavior INC (S) sporadically, no DRDioxin exposure 15+ years out requiring modeling elimination; not always modified by body fat; not powered for rare disease associations.IIIVietnam Army Chemical Corps17Kang H.K. Dalager N.A. Needham L.L. et al.Health status of Army Chemical Corps Vietnam veterans who sprayed defoliant in Vietnam.Am J Ind Med. 2006; 49: 875-884Crossref PubMed Scopus (66) Google Scholar, 51Cypel Y. Kang H. Mortality patterns of Army chemical corps occupationally exposed to herbicides in Vietnam.Ann Epidemiol. 2010; 20: 339-346Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar, 52Kang H.K. Dalager N.A. Needham L.L. et al.US Army chemical corps Vietnam veterans health study: preliminary results.Chemosphere. 2001; 43: 943-949Crossref PubMed Scopus (13) Google Scholar, 53Dalager N.A. Kang H.K. Mortality among Army Chemical Corps veterans.Am J Ind Med. 1997; 31: 719-726Crossref PubMed Scopus (24) Google Scholar28722737Army Chemical CorpsProspective cohort3528+ for dioxin assessmentRisk modeling; dioxin serum in ≤70%ICDINC (NS) for skin cancer53Dalager N.A. Kang H.K. Mortality among Army Chemical Corps veterans.Am J Ind Med. 1997; 31: 719-726Crossref PubMed Scopus (24) Google ScholarAll cancer INC (S) but excludes NMSC17Kang H.K. Dalager N.A. Needham L.L. et al.Health status of Army Chemical Corps Vietnam veterans who sprayed defoliant in Vietnam.Am J Ind Med. 2006; 49: 875-884Crossref PubMed Scopus (66) Google Scholar (may include melanoma or lymphoma)Mortality data only not powered for rare outcomes; no skin examinationsIIIClemens et al Washington, DC VA study35Clemens M.W. Kochuba A.L. Carter M.E. Han K. Liu J. Evans K. Association between Agent Orange exposure and nonmelanotic invasive skin cancer: a pilot study.Plast Reconstr Surg. 2014; 133: 432-437Crossref PubMed Scopus (2) Google Scholar100NAStandard US incidencesRetrospective cohortNA38+SRGeneral examination43% of sampleINC (S) compared to standard rate of normative US adultsPoor matching with normative data without proper adjustment for known risk factors; questionable if 43% of patients in this study diagnosed with chloracne compared to 0% in AFHSIIIJang et al MF study39Jang M.S. Jang J.G. Han S.H. et al.Clinicopathological features of mycosis fungoides in patients exposed to Agent Orange during the Vietnam War.J Dermatol. 2013; 40: 606-612Crossref PubMed Google Scholar12192MF patients, history of AO exposureCase controlNA42+SRDermatologic examination12 of 204 cutaneous lymphoma patients with AO exposureSmall study, unclear degree of patient exposure; case series with few valuable analysesIII-IVKim et al AO impact on Korean Veterans of Vietnam24Kim J.S. Lim H.S. Cho S.I. Cheong H.K. Lim M.K. Impact of Agent Orange exposure among Korean Vietnam veterans.Ind Health. 2003; 41: 149-157Crossref PubMed Google Scholar1224154Korean Veterans not stationed in VietnamCross-sectionalNA24+SR with risk modeling confirmationGeneral examinationINC (NS); other acne INC (NS)INC (S) uroporphyrin measured, not clinically relevantEczema INC (S); seborrheic dermatitis INC (S); neurodermatitis, INC (S)Selection bias: low participation of non–Vietnam Veterans (eg, 34% participation in e