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Agent Orange, a herbicide used during the Vietnam War, contains components such as 2,4,5-trichlorophenoxyacetic acid (2,4,5-T), 2,4-dichlorophenoxyacetic acid (2,4-D), and the contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin. The toxicity associated with Agent Orange arises from both acute exposure and long-term effects of these chemicals. The primary populations affected are United States service members who participated in Operation Ranch Hand and residents in Vietnam, Cambodia, and Laos. Despite the low prevalence of exposure due to the specific populations involved, the long-term health implications of Agent Orange exposure have been significant. The Agent Orange Act of 1991 led to comprehensive investigations and studies to understand the health effects better. Participants in the course gain insights into the critical role of the healthcare team in managing cases related to Agent Orange exposure. By learning about the identification, care, and improved outcomes for affected individuals, participants understand how interprofessional collaboration enhances patient care. Collaborative efforts between various healthcare disciplines are essential for recognizing the signs and symptoms of both acute and remote dioxin exposure. Objectives: Screen patients with potential dioxin exposure for long-term health effects and complications associated with Agent Orange toxicity. Implement appropriate diagnostic tests and treatment protocols tailored to the specific needs of patients exposed to Agent Orange. Differentiate between the health effects of Agent Orange exposure and other similar environmental or occupational toxicants. Collaborate with an interprofessional team to provide holistic care and improve patient outcomes for those affected by Agent Orange exposure. Access free multiple choice questions on this topic.

From 1961 to 1971, during the Vietnam War, the chemical herbicide known as "Agent Orange" was sprayed in massive quantities across Vietnam, Laos, and Cambodia to clear foliage and crops benefitting the Viet Cong as part of the United States Air Force's Operation Ranch Hand and Army Chemical Corps operations.[1][2] The name Agent Orange originates from the orange stripe on the storage barrels. Agent Orange was one of several "Rainbow Herbicides" used during these operations. Studies examining the link between Agent Orange and developmental disorders led to the official discontinuation of its use in 1970.[2] Health concerns in returning Vietnam veterans eventually led to the 1991 Agent Orange Act, tasking the National Academy of Medicine to investigate the health effects of Agent Orange exposure.[1] This activity reviews the potential health impacts of Agent Orange exposure in at-risk populations and an approach to their care. This activity includes a discussion of herbicides and dioxin-related compounds similar to Agent Orange; for clarity, subsequent mentions of "Agent Orange" refer to all dioxin-contaminated herbicides used throughout the Vietnam War.

Agent Orange comprises equal parts of the chlorophenoxy herbicides 2,4-dichlorophenoxyacetic acid (2,4-D) and 2,4,5-trichlorophenoxyacetic acid (2,4,5-T). The obligatory byproduct of 2,4,5-T production is 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a highly toxic carcinogen. TCDD contaminated many herbicides containing 2,4,5-T used in Vietnam from 1961 to 1971. The 6 herbicides used during this timeframe were collectively called the "Rainbow Herbicides." Of this group, Agent Blue was the only herbicide that lacked 2,4,5-T.[1] Approximately 77 million liters of TCDD-containing herbicides were dispersed during the war, 95% of which was released via aerial application by Operation Ranch Hand fixed-wing aircraft. The remaining 5% was spread by ACC operations using ground sprayers near troop encampments or by helicopters, similar to Operation Ranch Hand missions.[3] Agent Orange exposure may have occurred during its handling, distribution, or from secondary contacts. The planning and execution of herbicide spraying missions during Operation Ranch Hand were strict; spray missions did not occur with friendly forces in the area and were often deep in hostile territory. Antipersonnel ordinance from escort aircraft was used in targeted areas to suppress hostile ground fire, and friendly units were prohibited from entering areas immediately after spraying due to possible unexploded ordinance.[4] Multiple safeguards and strict adherence to protocols made direct spraying of United States and Allied forces, or their passage through recently sprayed areas, very unlikely.[5] In contrast, handlers of the chemicals took minimal protective precautions due to the historical presumption that the herbicides were not a human health hazard. Direct exposure routes included indirect and direct cutaneous contact (from contaminated clothing and foliage), inhalation, and ingestion.[1] The half-life of TCDD in the environment varies with many factors, including sun exposure; the half-life ranges from hours to days on foliage and up to several years if absorbed into soil.[3]

Agent Orange was utilized primarily from 1961 to 1971 in Vietnam and from 1967 to 1971 in the Korean Demilitarized Zone (DMZ). The United States (US) Army Chemical Corps (ACC) herbicide sprayers operated from ground or helicopter-mounted chemical sprayers, including near installations in the Korean DMZ. Operation Ranch Hand personnel may be risk-stratified by job classification, which is predictive of the degree of exposure.[6] Groups at the highest risk of significant exposure during these periods include: US ACC herbicide sprayers and handlers US Air Force Operation Ranch Hand personnel Higher risk: sprayer-console operators and flight engineers Moderate risk: aircraft mechanics, crew chiefs, and support personnel Lower risk: pilots and navigators Local populations of contaminated regions in Vietnam, Cambodia, and Laos In addition to the above higher-risk groups, military units deployed near heavily sprayed areas had an increased chance of potential exposure. These units include: Units stationed in the "III Corps Military Region" of Vietnam [3] The Republic of Korea 9th and Capital Divisions [7] Veterans from other US-allied combat units, including Australia, New Zealand, and Thailand Personnel stationed in US or Royal Thai military bases in Thailand from 1962 to 1975 These veterans who were potentially exposed to Agent Orange due to their proximity to heavily sprayed areas constitute a tremendous number of individuals with difficult-to-assess exposures, which is a controversial issue. For example, in 1988, the Centers for Disease Control Veterans Health Studies attempted to use military records and self-reported exposure to identify US Army veterans possibly exposed to Agent Orange and, similar to other studies, found nearly identical serum TCDD levels in veterans who served in heavily-sprayed areas compared to non Vietnam veterans.[3] This supports the prevailing belief that most military personnel who served in Vietnam were not heavily exposed to Agent Orange or TCDD, except for those who directly handled or sprayed herbicides.[3][4]

These veterans who were potentially exposed to Agent Orange due to their proximity to heavily sprayed areas constitute a tremendous number of individuals with difficult-to-assess exposures, which is a controversial issue. For example, in 1988, the Centers for Disease Control Veterans Health Studies attempted to use military records and self-reported exposure to identify US Army veterans possibly exposed to Agent Orange and, similar to other studies, found nearly identical serum TCDD levels in veterans who served in heavily-sprayed areas compared to non Vietnam veterans.[3] This supports the prevailing belief that most military personnel who served in Vietnam were not heavily exposed to Agent Orange or TCDD, except for those who directly handled or sprayed herbicides.[3][4] Determining the impact of Agent Orange on local populations is also highly controversial, as controlling for confounding effects from decades of war on these populations is incredibly difficult, if not impossible. However, the soil where Agent Orange was stored or loaded onto aircraft was contaminated with TCDD.[8] Over time, residents may have been exposed to TCDD in soil and water entering the food supply through contaminated animal and plant life.[9][10] Ten US Air Force bases handled most of the Agent Orange entering the country and were located in the following cities, from north to south: Da Nang Pleiku Phu Cat Tuy Hoa Nha Trang Cam Ranh Phan Rang Bien Hoa Tan San Nhut Binh Thuy An additional population who may be adversely affected by Agent Orange includes the children of those directly exposed to Agent Orange, in whom birth and developmental defects were a subject of concern. The generational impact of these exposures is a topic of continued study.[1][2]  Given that the contaminant, TCDD, is the most likely component of Agent Orange to cause consequential adverse health events, other comparable populations include known exposures from dioxin-like chemicals or similar herbicides. These populations include industrial chemical workers with occupational exposure, those in British Malaya exposed to "triaxone" in 1952, and individuals subjected to environmental contamination in West Virginia (1949), Missouri (1971), and Seveso, Italy (1976).[1][11][12]

An additional population who may be adversely affected by Agent Orange includes the children of those directly exposed to Agent Orange, in whom birth and developmental defects were a subject of concern. The generational impact of these exposures is a topic of continued study.[1][2]  Given that the contaminant, TCDD, is the most likely component of Agent Orange to cause consequential adverse health events, other comparable populations include known exposures from dioxin-like chemicals or similar herbicides. These populations include industrial chemical workers with occupational exposure, those in British Malaya exposed to "triaxone" in 1952, and individuals subjected to environmental contamination in West Virginia (1949), Missouri (1971), and Seveso, Italy (1976).[1][11][12] Identifying veterans exposed to Agent Orange outside of direct occupational exposure presents several challenges. Serum TCDD levels remotely measured after exposure may not be a reliable predictor of exposure.[3][7] The Korean Veterans Health Study employed a self-reported perceived exposure index and an objective measure of exposure based on the proximity of military units to herbicide-sprayed areas. The self-reported exposures in this and other studies were less reliable than if an objective measure of exposure was used.[7] For example, reports of troops directly sprayed by aircraft were likely insecticides for mosquito control during a similar period but without the same strict controls as herbicide spray missions.[4] This example highlights the limitations of relying solely on self-reported data due to recall bias, especially when combined with self-reported health outcomes.[1][3] However, veterans self-reporting personally spraying or handling herbicides during service was a reasonably reliable indicator of exposure.[3][13]

Agent Orange comprises 2,4-D and 2,4,5-T plus the contaminant TCDD. Most research on Agent Orange pertains to the effects of TCDD due to its consistent contamination of 2,4,5-T and the profoundly toxic nature of dioxins. 2,4-D had longstanding use as an herbicide before Agent Orange, and its toxicity is well-described within its class of chlorophenoxy herbicides. 2,4-Dichlorophenoxyacetic Acid 2,4-Dichlorophenoxyacetic Acid (2,4-D) is a chlorophenoxy herbicide marketed since the 1940s to kill broadleaf weeds. 2,4-D has generally low toxicity, and poisoning is rare. Severe toxicity requires substantial acute ingestion or chronic exposure to high herbicide concentrations. Acutely, 2,4-D is a corrosive substance that uncouples cellular oxidative phosphorylation. Poisoning classically causes gastrointestinal, muscular, and neurotoxicity. These toxic manifestations include but are not limited to acute gastritis, upper gastrointestinal bleeding, acute kidney injury, rhabdomyolysis, ataxia, hypotonia, seizures, and coma.[14][15][16][17][18] Cutaneous and inhalational exposure may cause mild gastrointestinal symptoms and progressive mixed sensory-motor peripheral neuropathy.[15][17] Chronic exposure to high concentrations of 2,4-D may induce hepatic, renal, and neurologic injury. Despite this, 2,4-D is not clearly carcinogenic.[19] One study of a population exposed to 2,4-D observed genotoxic damage in the lymphocytes of smokers compared to nonsmokers and provided results that suggested a potentiation of the genotoxic effects of known carcinogens.[20] Results from another study suggested a possible association with non-Hodgkin lymphoma.[21] 2,4,5-Trichlorophenoxyacetic Acid and 2,3,7,8-Tetrachlorodibenzo-p-dioxin Agent Orange exposure is associated with various diseases, differing from nonTCDD-contaminated herbicides. Health complications related to 2,3,7; TCDD; and Agent Orange exposure remain controversial and are a subject of continued study. The National Academy of Medicine originally published a comprehensive consensus study report on the health impacts of Agent Orange on United States veterans in 1994; the 11th biennial update of the report was issued in 2018.[1]

Agent Orange exposure is associated with various diseases, differing from nonTCDD-contaminated herbicides. Health complications related to 2,3,7; TCDD; and Agent Orange exposure remain controversial and are a subject of continued study. The National Academy of Medicine originally published a comprehensive consensus study report on the health impacts of Agent Orange on United States veterans in 1994; the 11th biennial update of the report was issued in 2018.[1] The effects of acute exposure to Agent Orange are due to the contained chlorophenoxy herbicides 2,4-D and 2,4,5-T, as well as TCDD. These effects include acute liver injury, acute pancreatitis, amenorrhea, chloracne, porphyria cutanea tarda, and wasting syndrome.[11][22][23][24][25] See Image. Porphyria Cutanea Tarda. The predominant biological mechanism of TCDD toxicity has been connected with the high affinity of TCDD to the cytosolic aryl hydrocarbon receptor (AhR), a ligand-dependent transcription factor.[26][27] Dioxins bind to the AhR and activate it, inducing translocation to the nucleus to induce or suppress a diverse library of genes. This process and its consequences are not fully understood due to the complex pathways involving the AhR, though numerous studies and reviews examine the AhR and its function.[28] Some of the cellular functions and pathways altered by TCDD activation of AhR include cell cycle progression, cellular adhesion and migration, the function of receptor tyrosine kinases, and the expression and function of nuclear hormone receptors, growth factors, and growth factor receptors. Additionally, epigenetic changes result from dioxin toxicity. Several in vitro and animal study results have demonstrated altered expression of deoxyribonucleic acid methyltransferases and subsequent changes in gene expression linked with congenital malformations after maternal exposure.[29][30] Other epigenetic mechanisms include changes in noncoding ribonucleic acids and histones.[31][32][33] The potential consequences of these changes are a subject of debate and ongoing study. The diseases reportedly associated with Agent Orange exposure vary significantly among sources, as does the strength of the evidence itself. These associations rely heavily on occupational and environmental data from other herbicide and dioxin-like exposures to extrapolate the potential health impacts of Agent Orange.

When evaluating patients with suspected exposure to Agent Orange, a comprehensive medical history should be obtained, and a physical examination should be performed. To assess the risk of exposure to Agent Orange in military veterans, obtain specific details of their service history, including service in Operation Ranch Hand or the ACC and handling or spraying of herbicides during service in Vietnam, the Korean DMZ, or Thai military bases. Veterans should also be questioned regarding signs or symptoms of acute dioxin exposure, such as chloracne. Vietnam veterans who did not serve in the ACC or Operation Ranch Hand and did not personally handle herbicides are at significantly lower risk of substantial exposure to Agent Orange. However, they may have been exposed during service in highly sprayed areas. The "III Corps" combat region of South Vietnam encompasses the southwestern territory surrounding Saigon, where considerable US military presence and many Operation Ranch Hand herbicide missions occurred. These veterans may report traveling through or drinking fresh water from recently sprayed areas. The use of the herbicides stopped in 1971; any military service after that is not at risk of Agent Orange exposure. The herbicides' effects continue to be studied in populations living within Agent Orange-impacted countries of Southeast Asia. Cities near US Air Force bases where the herbicides were stored may have a higher risk of exposure due to the persistence of TCDD within the environment and food chain.[9][42][43] Individuals living in these areas from the late 1960s on may have the potential for exposure.

The herbicides' effects continue to be studied in populations living within Agent Orange-impacted countries of Southeast Asia. Cities near US Air Force bases where the herbicides were stored may have a higher risk of exposure due to the persistence of TCDD within the environment and food chain.[9][42][43] Individuals living in these areas from the late 1960s on may have the potential for exposure. A thorough review of systems should be obtained. Neurologic, cardiovascular, and general or constitutional questions may warrant increased focus. Patients with undiagnosed malignancy or endocrinopathy may report unintentional weight changes, fatigue, depression, or night sweats. Questions should cover potential cognitive slowing, neuropathy, or movement disorder. When obtaining a social history, environmental or occupational exposures that may increase the risk of neurologic complications or malignancy should be queried, in addition to standard items such as tobacco, alcohol, and drug use. The family medical history should be updated regularly, documenting any malignancies in family members and the health of any offspring, with particular attention to congenital malformations or genetic syndromes. Clinicians should perform a thorough head-to-toe physical examination annually in patients with suspected exposure to Agent Orange. This examination should include a complete neurologic exam, diabetic foot exam, and careful examination for lymphadenopathy.

Primary care practitioners should employ a patient-centered approach to health screenings in patients with possible exposure to Agent Orange. Expanded screening should be performed on patients with a high risk of exposure, particularly if they handled herbicides or experienced symptoms of acute dioxin exposure. Consideration of expanded screening in others who report Agent Orange exposure is reasonable, though they may be reassured of the overall low likelihood of related health complications. The expanded screening laboratory evaluation for patients with suspected exposure to Agent Orange monitors for exposure-associated conditions in addition to standard preventative health screenings. Annual laboratory testing with a complete blood count (CBC), prostate-specific antigen (PSA), and urinalysis (UA) allows for screening for the hematologic and genitourinary malignancies for which these patients may be at greater risk. Conditions or testing not discussed herein should follow standard society guidelines, and diligent evaluation of abnormalities revealed during the medical history, physical examination, or laboratory testing is appropriate. Laboratory Testing CBC with differential Comprehensive metabolic panel (CMP) PSA Thyroid-stimulating hormone (TSH) UA with microscopy Lipid or cholesterol panel and hemoglobin A1C (every 3 years) Hematologic Malignancies Annual screening with a CBC may allow for early detection of hematologic malignancies presenting with depressed or elevated cell counts. An abnormal protein gap, defined as a difference between serum albumin and total protein greater than 4, can signify a pathologic increase in immunoglobulins or paraproteins. Elevated serum calcium and creatinine may be seen in monoclonal gammopathies, which may be further evaluated with free light chain serum or urine protein electrophoresis. Lung Cancer

Annual screening with a CBC may allow for early detection of hematologic malignancies presenting with depressed or elevated cell counts. An abnormal protein gap, defined as a difference between serum albumin and total protein greater than 4, can signify a pathologic increase in immunoglobulins or paraproteins. Elevated serum calcium and creatinine may be seen in monoclonal gammopathies, which may be further evaluated with free light chain serum or urine protein electrophoresis. Lung Cancer Lung cancer screening with an annual low-dose computed tomography of the chest is recommended for patients between ages 50 and 80 with at least a 20-pack-year smoking history who are currently actively smoking or have quit in the previous 15 years. There are no consensus guidelines specifying modifications based on Agent Orange exposure. In exposed patients with other significant risk factors for lung cancer or a substantial smoking history that does not meet the threshold for screening, it is reasonable to engage in joint decision-making with the patient and discuss the risks, benefits, and alternatives to lung cancer screening. Prostate and Bladder Cancer Patients exposed to Agent Orange or dioxins may be at higher risk for bladder and prostate cancer. Society guidelines generally do not recommend routine screening for these conditions due to the risk of harm and limited evidence of mortality benefit. For high-risk populations, obtaining a PSA and UA annually may be considered for screening for prostate and bladder cancer, respectively.

The treatment of acute herbicide toxicity, including 2,4-D, is generally supportive. Decontamination and removal of soiled clothing can prevent further exposure, though most cases are due to intentional or accidental ingestion.[18] Chlorophenoxy herbicides are largely excreted by the kidney, and urine alkalization, in addition to ensuring high urine output, may be considered to prevent complications in significant poisonings.[44][45] Renal replacement therapy with hemodialysis has been used successfully for patients who are critically ill, oliguric, or anuric.[14][46] Routine monitoring for complications potentially related to Agent Orange exposure is recommended for timely diagnosis and treatment as appropriate. This monitoring should ideally be performed by an appropriate health agency such as the Veterans Affairs Environmental Health Clinic. Given the increased risk of malignancies and cardiovascular disease in individuals exposed to Agent Orange, additional risk factors or positive findings revealed by routine monitoring warrant prompt evaluation and referral to the appropriate specialist.

Patients with a substantial history of malignancy or conditions associated with exposure to TCDD or dioxins should undergo a thorough review of their family and social history, risk factors, and potential exposures. If the history does not reveal a family history of malignancy, the patient does not have a known genetic syndrome that predisposes to malignancy, and there is no likely history of exposure to Agent Orange, other predisposing historical or clinical conditions must be considered. These conditions include exposure to other environmental or occupational carcinogens, including other dioxins, a history of heavy cigarette smoking, and hereditary cancer syndromes, including Cowden, Li-Fraumeni, and hereditary nonpolyposis colorectal cancer syndromes.

The prognosis of Agent Orange exposure is overall very good. Most Vietnam veterans were unlikely to experience significant Agent Orange exposure during service if they were not involved with herbicide-spraying operations. The current understanding of the potential health complications of Agent Orange is highly reliant on other dioxin-like exposures and long-term occupational exposure to herbicides. Population studies focusing solely on Vietnam veterans are often conflicting and do not provide adequate evidence of associations with most of the health complications in question. Ultimately, the prognosis depends on the severity and duration of exposure, which carries the risk of developing the associated conditions.

Agent Orange exposure may lead to long-term health outcomes associated with TCDD or dioxin exposure. The current understanding of Agent Orange or dioxin-related complications is primarily through epidemiological, observational, and retrospective studies of the rare exposures in history. These studies are supported by related occupational exposures and animal or in vitro studies to support biological mechanisms for disease development. The level of evidence for each association varies and is challenging to research given the scarcity of events and indeterminate degrees of exposure in the impacted populations. The connection between actual Agent Orange exposure in veterans and these health outcomes remains controversial. Most Vietnam veterans experienced no or negligible exposure to Agent Orange. Associations between these herbicides and health complications rely on data from long-term occupational exposures, where the degree and duration of exposure over many years are responsible for the increased risk of disease. The following clinical conditions demonstrated a statistically significant association with one or more components of Agent Orange or dioxin-like compounds; however, the power, confounding, and bias from study to study vary significantly. An adequate lack of bias or confounding and biological plausibility further supports the connection and inclusion by the National Academy of Medicine committee as an associated condition. This is noted below with ¹ or ² for strong and limited or suggestive evidence, respectively. The exception is type 2 diabetes mellitus, about which the committee could not agree between strong or limited evidence of an association.[1] Neurological System 1Strong Evidence, 2Limited or Suggestive Evidence: Parkinson disease and parkinsonianism¹ [47][48][49] Peripheral neuropathy² [50][51][52] Stroke² [53][54] Mild cognitive impairment and dementia [48][55][56][57] Veterans with known exposure to Agent Orange demonstrate nearly double the incidence of dementia compared to veterans without. Specifically, Parkinson disease and Parkinson-like syndromes demonstrated a stronger association with exposure.[55][57] Other considerations for cognitive impairment and dementia progression included vascular effects due to the increased prevalence of the cardiovascular risk factors diabetes and hypertension.[23] Upper and Lower Respiratory Tract

Veterans with known exposure to Agent Orange demonstrate nearly double the incidence of dementia compared to veterans without. Specifically, Parkinson disease and Parkinson-like syndromes demonstrated a stronger association with exposure.[55][57] Other considerations for cognitive impairment and dementia progression included vascular effects due to the increased prevalence of the cardiovascular risk factors diabetes and hypertension.[23] Upper and Lower Respiratory Tract 1Strong Evidence, 2Limited or Suggestive Evidence: Idiopathic pulmonary fibrosis [58] Laryngeal cancer² [59][60] Lung cancer² [59][61][62][63][64] Some occupational studies suggest an increased risk of laryngeal cancer; these studies were small and did not control for smoking. The risk appeared to be more pronounced in patients who developed chloracne, suggesting a dose-dependent risk relationship. Similar to laryngeal cancer, studies examining other respiratory tract malignancies were often limited by a lack of assessment of the degree of exposure. Despite this, several veteran and occupational studies have demonstrated an increased lung cancer risk. Results from a 2022 epidemiologic study reviewing Veterans Health Administration data found a potential relationship with idiopathic pulmonary fibrosis. Furthermore, there was overall increased mortality from respiratory disease in Army Chemical Corp Vietnam veterans compared to other veterans.[64] Cardiovascular System 1Strong Evidence, 2Limited or Suggestive Evidence: Hypertension¹ [11][12][65][66][67][68][69][70] Ischemic heart disease² [11][65][66][67] The development of hypertension and atherosclerotic disease appear to be associated with Agent Orange exposure.[69][70] In vitro and animal studies on TCDD and dioxins support this mechanistically from impacts on lipid and glucose metabolism, inflammation, and vascular endothelial function via interactions with AhR pathways.[71][72][73][74] Hepatobiliary and Gastrointestinal Systems Liver disease and cirrhosis The components of Agent Orange have been shown to cause acute liver injury, and dioxin-related hepatotoxicity can lead to steatosis and cirrhosis.[11][75][76][77][78] However, there has not been a consistent association between exposure to the herbicide and these health outcomes.[1][12][13][79][80][81] Renal System

Liver disease and cirrhosis The components of Agent Orange have been shown to cause acute liver injury, and dioxin-related hepatotoxicity can lead to steatosis and cirrhosis.[11][75][76][77][78] However, there has not been a consistent association between exposure to the herbicide and these health outcomes.[1][12][13][79][80][81] Renal System Studies examining effects on renal function and rates of renal malignancies did not find evidence of an association with Agent Orange exposure.[59] However, some study results have suggested an association between chronic, high dioxin exposure in endemic populations with decreased eGFR and an increased incidence of chronic kidney disease.[82][83][84] Hematologic System 1Strong Evidence, 2Limited or Suggestive Evidence: AL amyloidosis² [59] Chronic lymphocytic leukemia¹ [85][86][87][88] Hodgkin lymphoma¹ [63][85][86] Non-Hodgkin lymphoma¹ [63][85][86][89] Myeloproliferative neoplasms [90][91][92] Monoclonal gammopathy of undetermined significance (MGUS)¹ [90][93] Multiple myeloma² [90][93][94] TCDD and dioxins profoundly impact multiple hematologic cell lines due to interactions with the AhR pathways.[95][96][97][98][99] An increased risk was found in the results of most studies examining Hodgkin and non-Hodgkin lymphomas, with an apparent predilection towards lymphoid malignancies. The association of TCDD exposure with myeloid malignancies is not well-established and was recommended for further study in the 2016 update to the National Academy of Medicine consensus report.[1][92][100] Immunologic System Rheumatoid arthritis [80][101][102][103] A 2015 New Zealand Vietnam veteran study of hospital discharge records from 1988 to 2009 observed an increased risk of rheumatoid arthritis in exposed populations and may have underestimated the prevalence due to a lack of outpatient data.[80] Some environmental and occupational studies support this correlation, albeit with inconsistent results.[67][79][102] The AhR has been implicated with increased inflammatory cytokines and autoimmune disease, and it may be a target for future therapeutics.[102][103][104] Genitourinary System 1Strong Evidence, 2Limited or Suggestive Evidence: Prostate cancer² [59][63][105][106][107][108][109] Urinary bladder cancer² [59][110][111][112][113]

A 2015 New Zealand Vietnam veteran study of hospital discharge records from 1988 to 2009 observed an increased risk of rheumatoid arthritis in exposed populations and may have underestimated the prevalence due to a lack of outpatient data.[80] Some environmental and occupational studies support this correlation, albeit with inconsistent results.[67][79][102] The AhR has been implicated with increased inflammatory cytokines and autoimmune disease, and it may be a target for future therapeutics.[102][103][104] Genitourinary System 1Strong Evidence, 2Limited or Suggestive Evidence: Prostate cancer² [59][63][105][106][107][108][109] Urinary bladder cancer² [59][110][111][112][113] The results of several studies examining prostate cancer and Agent Orange exposure generally demonstrate some association but are limited by an increased incidence that is not statistically significant.[114][115][116] The strongest evidence favoring an association between Agent Orange exposure and prostate cancer is among highly-exposed Vietnamese populations, similar to the risk of other cancers.[117][118][119][120] The association between herbicides and bladder cancer is obfuscated by limited controlling for confounding, notably smoking, in veteran populations. Occupational studies of the chlorophenoxy herbicides provided further support; this includes results from the Agricultural Health Study, a large prospective cohort of US pesticide and herbicide sprayers, which showed a higher risk of bladder cancer in individuals who never smoked with higher uses of 2,4,5-T and 2,4-D.[1][111] Endocrine System 1Strong Evidence, 2Limited or Suggestive Evidence: Type 2 diabetes¹,² [1][67][68][59][121][122] Hypothyroidism² [57][123] Thyroid cancer [124][125][126]

The association between herbicides and bladder cancer is obfuscated by limited controlling for confounding, notably smoking, in veteran populations. Occupational studies of the chlorophenoxy herbicides provided further support; this includes results from the Agricultural Health Study, a large prospective cohort of US pesticide and herbicide sprayers, which showed a higher risk of bladder cancer in individuals who never smoked with higher uses of 2,4,5-T and 2,4-D.[1][111] Endocrine System 1Strong Evidence, 2Limited or Suggestive Evidence: Type 2 diabetes¹,² [1][67][68][59][121][122] Hypothyroidism² [57][123] Thyroid cancer [124][125][126] Evidence supporting the association between Agent Orange exposure and diabetes exists in results from a variety of studies. The weakness in the evidence stems from mildly elevated relative risks reported in some cohorts and confounding from compounds in addition to dioxins in occupational studies. A 2022 meta-analysis identified women in exposed populations as having a higher relative risk of developing diabetes; women may not be represented in studies of veterans.[122] TCDD causes thyroid hormone disruption via overstimulation of TSH receptors and increased thyroid hormone metabolism.[127][128] Data on thyroid cancer is limited; an increased risk of developing thyroid cancer was observed in the results from some studies of Vietnam veterans but not in studies of the Seveso chemical factory accident or similar exposures. Reproductive System Reduced sperm quality [129][130][131] Reduced female fertility [132][133][134] Studies addressing reproductive health in populations exposed to Agent Orange have been limited and inconclusive in establishing a clear association. Men may experience alterations in sperm morphology, though studies largely demonstrated no statistically significant associations. These associations include concerns about altered sex ratios in offspring and gynecological issues of endometriosis and polycystic ovarian syndrome.[1][135][136] The impact of Agent Orange exposure on a woman's fertility is better supported, with data from the Seveso Women's Health Study demonstrating increased time to pregnancy correlated with increasing serum TCDD.[12] Developmental Adverse Effects Congenital abnormalities and malformations [33][137][138][139][140][141][142] Specific congenital disorders Congenital hypothyroidism [143][144][145]

Studies addressing reproductive health in populations exposed to Agent Orange have been limited and inconclusive in establishing a clear association. Men may experience alterations in sperm morphology, though studies largely demonstrated no statistically significant associations. These associations include concerns about altered sex ratios in offspring and gynecological issues of endometriosis and polycystic ovarian syndrome.[1][135][136] The impact of Agent Orange exposure on a woman's fertility is better supported, with data from the Seveso Women's Health Study demonstrating increased time to pregnancy correlated with increasing serum TCDD.[12] Developmental Adverse Effects Congenital abnormalities and malformations [33][137][138][139][140][141][142] Specific congenital disorders Congenital hypothyroidism [143][144][145] Congenital heart disease [146][147] Neurodevelopmental issues [148][149][150][151][152][153] Agent Orange exposure leading to adverse events on offspring is a highly controversial topic with widespread potential political implications. The US Department of Veterans Affairs recognizes and compensates only 2 groups of affected children, individuals with spina bifida and children with congenital anomalies who are the offspring of veteran women.[154][155] In their biennial reviews of the literature conducted since 1994, the National Academy of Medicine repeatedly found inadequate evidence of any association, citing the relative rarity of specific congenital disorders and mixed results in population-based studies as weaknesses in establishing a link.[1] Major congenital malformations and disorders suspected to be related to Agent Orange exposure include spina bifida, cleft palate, limb deformities, structural heart disease, and hypothyroidism.[137] An additional area of study with increasing evidence is developmental issues in offspring, notably emotional and cognitive development in children. Other Oncologic Conditions 1Strong Evidence, 2Limited or Suggestive Evidence: Soft tissue sarcoma¹ [63][85][156][157][158] Other malignancies

Agent Orange exposure leading to adverse events on offspring is a highly controversial topic with widespread potential political implications. The US Department of Veterans Affairs recognizes and compensates only 2 groups of affected children, individuals with spina bifida and children with congenital anomalies who are the offspring of veteran women.[154][155] In their biennial reviews of the literature conducted since 1994, the National Academy of Medicine repeatedly found inadequate evidence of any association, citing the relative rarity of specific congenital disorders and mixed results in population-based studies as weaknesses in establishing a link.[1] Major congenital malformations and disorders suspected to be related to Agent Orange exposure include spina bifida, cleft palate, limb deformities, structural heart disease, and hypothyroidism.[137] An additional area of study with increasing evidence is developmental issues in offspring, notably emotional and cognitive development in children. Other Oncologic Conditions 1Strong Evidence, 2Limited or Suggestive Evidence: Soft tissue sarcoma¹ [63][85][156][157][158] Other malignancies The evidence supporting the association between Agent Orange exposure and soft tissue sarcomas is robust, both from the chlorophenoxy herbicides and dioxins. This stands in contrast to efforts to establish a link with other solid cancers, which are less represented in the literature.[159][160] Studies examining overall cancer risk have demonstrated some increased cancer mortality but not increased incidence, suggesting mechanistic differences in carcinogenesis in identified malignancies or a role for future research.[7][12][7][59][63][80][119][161][162][163][164][165]

Patients exposed to Agent Orange should be counseled on the potential long-term complications and to contact the appropriate health agency for continued monitoring with specialists familiar with the complications of Agent Orange exposure. Patients with concerns about acute occupational or environmental dioxin exposure should contact a public health agency or regulatory body if the accidental release of dioxin-like compounds poses a worker or public health hazard.

Environmental and occupational exposure to Agent Orange is rare. Monitoring patients for the potential complications of exposure to Agent Orange requires multidisciplinary coordination and long-term follow-up with appropriate specialists. Primary care providers managing patients exposed to Agent Orange or dioxins should: Perform a thorough head-to-toe examination and review of symptoms annually Review the medical history, including social and family history, to identify other risk factors for malignancy Routine hematologic, renal, and hepatic monitoring with laboratory testing Perform age-appropriate cancer-related and routine screenings Consider expanded screening protocols for conditions such as bladder, prostate, and respiratory tract malignancies Counsel patients on the broad array of potential complications, including associations with developmental issues in children Refer the patient to the appropriate health agency, such as the Department of Veteran Affairs, for Agent Orange-specific care Ensure access to a breadth of necessary specialty care as needed