Agent Orange and Cancer

About 3 million Americans served in the armed forces in Vietnam during the 1960s and early 1970s, the time of the Vietnam War. During that time, the military used large amounts of mixtures known as defoliants, which were chemicals that caused the leaves to fall off plants. One of these defoliants was Agent Orange, and some troops were exposed to it. Many years later, questions remain about the lasting health effects of those exposures, including increases in cancer risk.

This article offers a brief overview of the link between Agent Orange and cancer. It does not offer a complete review of all evidence -- it is meant to be a brief summary. It also includes some information on benefits for which Vietnam veterans exposed to Agent Orange may be eligible.

Some background on Agent Orange

During the Vietnam War, US military forces sprayed millions of gallons of herbicides (plant-killing chemicals) on lands in Vietnam and Laos to remove forest cover, destroy crops, and clear vegetation from the perimeters of US bases. This effort, known as Operation Ranch Hand, lasted from 1962 to 1971.

Different mixes of herbicides were used, but most were mixtures of 2 chemicals that were phenoxy herbicides:

• 2,4-dichlorophenoxyacetic acid (2,4-D)
• 2,4,5-trichlorophenoxyacetic acid (2,4,5-T)

Each mixture was shipped in a chemical drum marked with an identifying colored stripe. The most widely used mixture contained equal parts 2,4-D and 2,4,5-T. Because this herbicide came in drums with orange stripes, it was called Agent Orange. Today, Agent Orange is used to refer generally to all the phenoxy herbicides sprayed at the time. (Other types of herbicides were also used, including cacodylic acid and picloram.)

The 2,4,5-T in Agent Orange was contaminated with small amounts of dioxins, which were created unintentionally during the manufacturing process. Dioxins are a family of about 75 related chemicals. They can be formed during the making of paper and in some other industrial processes. The main dioxin in Agent Orange, 2,3,7,8-tetrachlorodibenzo-p-dioxin, or TCDD, is one of the most toxic.

After a study in 1970 found that 2,4,5-T could cause birth defects in lab animals, the use of 2,4,5-T in Vietnam was stopped. A year later, all military herbicide use in Vietnam ended. During the 1970s, veterans returning from Vietnam began to report skin rashes, cancer, psychological symptoms, birth defects and handicaps in their children, and other health problems. Some veterans were concerned that Agent Orange exposure might have contributed to these problems. These concerns eventually led to a series of scientific studies, health care programs, and compensation programs directed to the exposed veterans.

A large class-action lawsuit was filed in 1979 against the herbicide manufacturers, and was settled out of court in 1984. It resulted in the Agent Orange Settlement Fund, which distributed nearly $200 million to veterans between 1988 and 1996.

Although there is now quite a bit of evidence about the health effects of Agent Orange, many questions have not yet been answered.

How were people exposed to Agent Orange?

About 3 million people served in the US military in Vietnam during the course of the war, about 1.5 million of whom served during the period of heaviest herbicide spraying from 1967 to 1969.

In studies comparing Vietnam veterans with veterans who had served at the same time elsewhere, TCDD (dioxin) levels were found to be higher among those who had served in Vietnam, although these levels went down slowly over time.

Exposure to Agent Orange varied a great deal. Most of the large-scale spraying operations in Operation Ranch Hand were done with airplanes and helicopters. However, some herbicides were sprayed from boats or trucks, and some were applied by soldiers with backpack sprayers. Those who loaded airplanes and helicopters may have been exposed the most. Members of the Army Chemical Corps, who stored and mixed herbicides and defoliated the perimeters of military bases, probably also had some of the heaviest exposures. Others with potentially heavy exposures included members of Special Forces units who defoliated remote campsites, and members of Navy river units who cleared base perimeters.

Exposures could have occurred through breathing the chemicals in, ingesting them in contaminated food or drink, or absorbing them through the skin. Other exposure pathways may have been possible as well, such as through the eyes or through breaks in the skin.

One of the challenges in assessing the health effects of Agent Orange exposure has been determining how much any individual veteran was exposed to (or even what they were exposed to), as there is very little information of this type available.

Does Agent Orange cause cancer?

Researchers use 2 main types of studies to try to determine if a substance or exposure causes cancer. One type of study looks at cancer rates in different groups of people. Such a study might compare the cancer rate in a group exposed to a substance versus the rate in a group not exposed to it, or compare it to what the expected cancer rate would be in the general population. But studies of people can sometimes be hard to interpret, because there may be factors affecting the results that are hard to account for.

In studies in lab animals, other factors are easier to control for, but it's not always clear if the results in animals would be the same in humans.

In most cases neither type of study provides definitive evidence on its own, so researchers usually look at both human and lab-based studies.

Studies in people

Studies of Vietnam veterans potentially provide the most direct evidence of the health effects of Agent Orange exposure.

The Centers for Disease Control and Prevention (CDC), the US Air Force, and the Department of Veterans Affairs (VA) have conducted studies involving thousands of Vietnam veterans. However, most of these studies have been limited by the fairly small number of people who were highly exposed to Agent Orange. About a dozen states have also conducted studies of their veterans, some of which have yielded cancer risk information. A series of studies of Australian Vietnam veterans has also provided some information on cancer risk.

Because of the limits of the Vietnam veteran studies, studies of 3 other groups have provided important information on the potential cancer-causing properties of Agent Orange exposure:

• Vietnamese soldiers and civilians exposed to the same herbicides as United States service personnel, often for more prolonged periods (although there have been few thorough health studies in these populations)
• Workers exposed to herbicides in other settings, such as herbicide manufacturing workers, herbicide applicators, farmers, lumberjacks, and forest and soil conservationists, who often had much higher blood dioxin levels than Vietnam veterans
• People exposed to dioxins after industrial accidents in Germany, Seveso (Italy), and California, and after chronic exposures at work and in the environment

Each of these groups differs from the Vietnam veterans in the characteristics of the people exposed, the nature of the dioxin exposures, and other factors such as diet and other chemical exposures.

Taken together, these studies have looked at possible links between Agent Orange (or dioxin) and a number of cancer types.

Soft tissue sarcoma: Studies of Vietnam veterans have not found an increase in soft tissue sarcomas. However, soft tissue sarcomas have been linked to phenoxy herbicide exposure in a series of studies in Sweden and in some studies of industrially exposed workers. Many studies of farmers and agricultural workers show an increase in soft tissue sarcomas, which may relate to herbicide exposure. Soft tissue sarcomas have also been linked to dioxin exposure in some chemical manufacturing workers and in some other workplace studies.

Non-Hodgkin lymphoma: Most studies of Vietnam veterans have not shown an increase in non-Hodgkin lymphoma (NHL). But several studies have found a link between phenoxy herbicide exposure (usually on the job) and NHL. Some studies of farmers and agricultural workers also suggest this association, although not all studies have found such a link.

Hodgkin disease: Studies of Vietnam veterans have not found an increase in Hodgkin disease. However, Hodgkin disease has been linked to phenoxy herbicide exposure in some other studies. Many studies of farmers and agricultural workers show an increase in Hodgkin disease, which may relate to herbicide exposure.

The link between Hodgkin disease and dioxin exposure specifically is less clear, as studies have given mixed results.

Lung and other respiratory cancers: Most studies of Vietnam veterans have not shown an increase in respiratory cancers, such as those of the lung, trachea (windpipe), and larynx (voice box). Most studies of people exposed to herbicides at work, such as herbicide manufacturing workers, herbicide applicators, and farmers have not found an excess risk of lung cancer.

Most studies of groups of people highly exposed to dioxin after industrial accidents have not found an increase in respiratory cancers. However, chronic workplace exposures to dioxin have been linked with increased risk of respiratory cancers among those with high exposures.

Prostate cancer: Most studies of Vietnam veterans have not found an excess risk of prostate cancer, but results from a few studies have suggested a possible link.

Studies of other groups have also yielded mixed results. Most studies of people exposed to phenoxy herbicides at work do not show an excess of prostate cancer. However, some studies have found a small excess risk of prostate cancer related to dioxin exposure.

Multiple myeloma: Studies of Vietnam veterans have had too few cases of multiple myeloma (a type of immune system cancer that affects the bones) to be helpful in determining if there is a risk.

However, other studies of people exposed to pesticides, herbicides, and/or dioxins have suggested a possible link. Several studies of farmers and agricultural workers have reported a small increase in risk of multiple myeloma, although other studies show no excess risk.

Acute myelogenous leukemia (AML) in the children of veterans: At least 3 studies have pointed to possible link between a father's exposure to Agent Orange or other herbicides and acute myeloid leukemia (AML) in his children.

Gastrointestinal (GI) cancer: Cancers of the GI system -- esophagus, stomach, pancreas, colon, and rectum -- have been extensively studied in Vietnam veterans, groups with herbicide exposure in the workplace, and people exposed to dioxins. These studies have not found a link between these exposures and any GI cancer.

Brain cancer: Studies have not found a link between Vietnam service, workplace herbicide exposure, or dioxin exposure, and brain cancer.

Other cancers: Few studies have looked at a possible link between Agent Orange exposure and other cancers, including cancers of the nose and nasopharynx (upper part of the throat), breast, cervix, endometrium (uterus), ovaries, liver and bile ducts, bone, kidneys, bladder, testicles, or skin, or leukemias other than chronic lymphocytic leukemia (in veterans themselves, as opposed to their children).

Studies done in the lab

Herbicides such as 2,4,5-T and 2,4-D are not considered highly toxic compounds by themselves, and high doses are required to cause effects in lab animals. These compounds have not been linked with cancer in animal studies.

In the lab, TCDD (dioxin) increases the risk of a wide variety of tumors in rats, mice, and hamsters. In lab dish studies, it has been shown to alter which genes are turned on or off and affects how cells divide and die, all of which could affect cancer risk.

What the expert agencies say

Several agencies (national and international) study different substances in the environment to determine if they can cause cancer. (A substance that causes cancer or helps cancer grow is called a carcinogen.) The American Cancer Society looks to these organizations to evaluate the risks based on evidence from laboratory, animal, and human research studies.

A few expert agencies have looked at whether Agent Orange or related compounds can cause cancer.

Institute of Medicine

Since 1994, the federal government has directed the Institute of Medicine (IOM), part of the National Academy of Sciences (NAS), to issue reports every 2 years on the health effects of Agent Orange and similar herbicides. Titled Veterans and Agent Orange, the IOM reports assess the risk of both cancer and non-cancer health effects. Each health effect is categorized as having one of the following:

• sufficient evidence of an association
• limited/suggestive evidence of an association
• inadequate/insufficient evidence to determine whether an association exists
• limited/suggestive evidence of no association

This framework provides a basis for government policy decisions in the face of uncertainty. As of the most recent update, the links between Agent Orange exposure and cancer were designated as shown. (Note that this table shows only cancers. Other health effects are listed in the next section.)

IOM: Links Between Herbicides (Including Agent Orange) and Cancer

Sufficient evidence of an association

Soft tissue sarcoma

Non-Hodgkin lymphoma (NHL)

Hodgkin disease

Chronic lymphocytic leukemia (CLL), including hairy cell leukemia and other chronic B-cell leukemias

Limited/suggestive evidence of an association

Respiratory cancers (lung, trachea, bronchus, larynx)

Prostate cancer

Multiple myeloma

Inadequate/insufficient evidence to determine whether an association exists

Mouth, throat, and sinus cancers

Gastrointestinal cancers (esophagus, stomach, pancreas, colon, rectum)

Liver, gallbladder, and bile duct cancers

Bone and joint cancers

Skin cancers

Breast cancer

Female reproductive cancers (cervical, ovarian, endometrial, uterine sarcoma)

Testicular and penile cancers

Bladder cancer

Kidney cancer

Brain tumors

Cancers of endocrine glands (thyroid, thymus, etc.)

Leukemia (other than CLL and hairy cell leukemia)

Cancers at all other sites

Cancer (including AML) in the children of veterans

National Toxicology Program

The US National Toxicology Program (NTP), formed from parts of several government agencies, evaluates exposures that may be carcinogenic (cancer-causing).

The NTP has not classified the phenoxy herbicides, including Agent Orange, but it lists 2,3,7,8-TCDD (dioxin) as "known to be a human carcinogen."

International Agency for Research on Cancer

The International Agency for Research on Cancer (IARC) is part of the World Health Organization (WHO). Its major goal is to identify causes of cancer.

IARC has not rated Agent Orange itself, but it classifies the phenoxy herbicides, including 2,4-D and 2,4,5-T, as "possibly carcinogenic to humans." It lists 2,3,7,8-TCDD (dioxin) as "known to be carcinogenic to humans."

(For more information on the classification systems used by the NTP and IARC, see our document, Known and Probable Human Carcinogens.)

Does Agent Orange cause any other health problems?

Vietnam service, and Agent Orange exposure in particular, have also been studied for possible links to health problems other than cancer.

In its report Veterans and Agent Orange, the Institute of Medicine has looked at the possible link between exposure to Agent Orange and other herbicides and several non-cancerous health conditions.

IOM: Links Between Herbicides (Including Agent Orange) and Other Health Effects

Sufficient evidence of an association

Chloracne

Limited/suggestive evidence of an association

Amyloidosis

Transient peripheral neuropathy

Parkinson disease

Porphyria cutanea tarda

High blood pressure

Ischemic heart disease

Type 2 diabetes

Spina bifida in children of veterans

Chloracne is an acne-like rash caused by exposure to high levels of chlorine-containing chemicals.

Amyloidosis is a condition in which abnormal proteins build up in different tissues and organs in the body.

Transient peripheral neuropathy is a temporary condition in which damage to nerves outside the brain and spinal cord causes symptoms such as numbness or tingling in the hands and feet.

Porphyria cutanea tarda (PCT) is a condition that can result in liver damage and blistering of the skin when exposed to light.

Concerns have also been raised about other conditions in exposed veterans, including psychiatric illnesses and other nervous system problems, asthma, immune system disorders, digestive diseases, infertility, and birth defects other than spina bifida. According to the Institute of Medicine, there isn't enough evidence at this time to determine if there is a link between these conditions and Agent Orange.

Benefits for exposed Vietnam veterans

Vietnam veterans with Agent Orange exposure may be eligible for 3 kinds of benefits.

Agent Orange Registry health examination

The Agent Orange Registry is a program administered by the Department of Veterans Affairs (VA) since 1978. Veterans who qualify and participate in this program receive free medical exams, lab tests, and specialty referrals if appropriate. Veterans are not required to enroll in the VA health care system to receive the registry exam.

Disability compensation

Disability compensation payments are available to veterans with service-related illnesses or illnesses that were incurred or aggravated by military service.

The amount of the monthly payments is determined by the extent of disability. Because past Agent Orange exposure is hard to quantify, the VA uses a presumption-based system. If a veteran served in Vietnam between 1962 and 1975 and becomes disabled with one of the conditions designated as Agent Orange-related, the VA classifies his or her disability as service-related.

The diseases considered related to Agent Orange exposure correspond closely to the conditions found by the IOM to have "sufficient" or "limited/suggestive" evidence of an association. The cancers on the list include:

• Hodgkin disease
• multiple myeloma
• non-Hodgkin lymphoma
• prostate cancer
• cancer of the lung, bronchus, larynx (voice box), or trachea (windpipe)
• soft tissue sarcoma (other than osteosarcoma, chondrosarcoma, Kaposi sarcoma, or mesothelioma)
• chronic lymphocytic leukemia, hairy cell leukemia, and other chronic B-cell leukemias

Conditions other than cancer on this list include peripheral neuropathy, amyloidosis, chloracne, type 2 diabetes, ischemic heart disease, Parkinson disease, and porphyria cutanea tarda. Also included are spina bifida and certain other birth defects in the children of veterans.

Medical benefits

Some veterans qualify for medical care following Agent Orange exposure. The VA provides medical care at VA facilities, prescription medicines, and home health and hospice care to veterans with conditions linked with herbicide exposure in Vietnam. These include the cancers and other health conditions presumed to be Agent Orange-related, as listed above.

Veterans may want to check the VA Web site (www.publichealth.va.gov/exposures/agentorange) or their local VA hospitals for further information on any of these Agent Orange-related benefits.

Other things you can do for your health

Be sure your doctor knows if you have a history of Agent Orange exposure. Because of the possibility of excess cancer risk, your doctor may advise you to get cancer screening tests and to seek medical evaluation promptly if you have suspicious symptoms. You may also lower your risk of cancer by quitting smoking, avoiding exposure to other carcinogens, eating a healthy diet mainly from plant sources, and maintaining a healthy body weight.

If you are concerned about past exposure to Agent Orange, you may want to join a support group at the local VA hospital. You may also want to consult an occupational and environmental medicine clinic. These clinics can help assess past exposures and any risk that may persist, and can recommend appropriate steps to help you protect your health. You can look for clinics near you by visiting the Association of Occupational and Environmental Clinics at www.aoec.org.

Additional resources

More information from your American Cancer Society

The following related information may also be helpful to you. These materials may be viewed on our web site or ordered from our toll-free number, at 1-800-227-2345.

Known and Probable Human Carcinogens

National organizations and Web sites

In addition to the American Cancer Society, other sources of information and support include*:

Department of Veterans Affairs
Toll-free number: 1-800-749-8387
Home page: www.va.gov
Information on Agent Orange: www.publichealth.va.gov/exposures/agentorange

Vietnam Veterans of America
Toll-free number: 1-800-882-1316 (1-800-VVA-1316)
Home page: www.vva.org
Information on Agent Orange: www.vva.org/Committees/AgentOrange/index.html

Institute of Medicine
Home page: www.iom.edu
Veterans and Agent Orange - Update 2008: www.iom.edu/Reports/2009/Veterans-and-Agent-Orange-Update-2008.aspx

Association of Occupational and Environmental Clinics
Web site: www.aoec.org

*Inclusion on this list does not imply endorsement by the American Cancer Society

No matter who you are, we can help. Contact us anytime, day or night, for information and support. Call us at 1-800-227-2345 or visit www.cancer.org.

References

Agency for Toxic Substances and Disease Registry. ToxFAQs for Chlorinated Dibenzo-p-dioxins (CDDs). 2010. Accessed at www.atsdr.cdc.gov/tfacts104.html on March 23, 2010.

Baan R, Grosse Y, Straif K, et al. A review of human carcinogens--Part F: chemical agents and related occupations. Lancet Oncol. 2009;10:1143-1144.

Chamie K, DeVere White RW, et al. Agent Orange exposure, Vietnam War veterans, and the risk of prostate cancer. Cancer. 2008;113:2464-2470.

Frumkin H. Agent Orange and cancer: an overview for clinicians. CA Canc J Clin. 2003;53:245-255. Accessed at http://caonline.amcancersoc.org/cgi/content/full/53/4/245 on March 23, 2010.

Institute of Medicine, Committee to Review the Health Effects in Vietnam Veterans of Exposure to Herbicides. Veterans and Agent Orange: Update 2008. Washington: National Academy Press, 1999. Accessed at www.nap.edu/catalog.php?record_id=12662 on March 23, 2010.

International Agency for Research on Cancer (IARC). IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. Supplement 7: Overall Evaluations of Carcinogenicity: An Updating of IARC Monographs Volumes 1 to 42. 1987.

International Agency for Research on Cancer (IARC). IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. Volume 69: Polychlorinated Dibenzo-para-Dioxins and Polychlorinated Dibenzofurans. 1997.

US Department of Health and Human Services. Public Health Service, National Toxicology Program. Report on Carcinogens, Eleventh Edition. 2005. Accessed at http://ntp.niehs.nih.gov/ntp/roc/eleventh/profiles/s168tcdd.pdf on March 23, 2010.

US Department of Veterans Affairs. Agent Orange. Accessed at www.publichealth.va.gov/exposures/agentorange on March 24, 2010.