Health Information Summary for CF Members

Health effects

What health effects are associated with Agent Orange?

In 1991, because of uncertainty about the long-term health effects on Vietnam veterans of herbicide exposure, the U.S. Congress passed legislation that enabled the National Academy of Sciences' (NAS) Institute of Medicine (IOM) to perform a comprehensive evaluation of scientific and medical information regarding the health effects of exposure to Agent Orange.

In response to this legislation, the IOM conducts and publishes extensive reviews of scientific evidence regarding associations between health outcomes and exposures to TCDD and other chemical compounds in herbicides used in Vietnam. The IOM is widely considered to be the definitive source for medical information related to Agent Orange (Frumkin, H., 2003).

The IOM's most recent publication is "Veterans and Agent Orange: Update 2004" ( http://www.iom.edu/report.asp?id=25476 ). The IOM has identified several health outcomes that are statistically "associated" with exposure to Agent Orange. Based on the scientific evidence available, the IOM has not concluded that exposure is the actual "cause" of these health outcomes.

With respect to Agent Orange, the IOM concluded there was "sufficient evidence of an association" for five health outcomes:

• Chronic lymphocytic leukemia (CLL)
• Soft-tissue sarcoma
• Non-Hodgkin's lymphoma
• Hodgkin's disease
• Chloracne

The IOM has also found "limited or suggestive evidence of an association" for another seven outcomes:

• Respiratory cancer (of lung and bronchus, larynx, and trachea)
• Prostate cancer
• Multiple myeloma
• Early onset transient peripheral neuropathy
• Porphyria cutanea tarda
• Type 2 diabetes
• Spina bifida in the children of veterans

According to the IOM, the designation "limited or suggestive" means that the scientific evidence of an association is limited because chance, bias and confounding could not be ruled out with confidence.

The vast majority of the associations noted above have only been observed in studies of heavily-exposed populations, such as workers involved in chemical manufacturing or who have applied herbicides for many years. The IOM states " many conclusions regarding associations between exposure to TCDD or herbicides and diseases are based on studies of people exposed in occupational and environmental settings rather than on studies of Vietnam veterans ".

What is the difference between an "association" and a "cause"?

As mentioned above (see " What health effects are associated with Agent Orange? "), the IOM has identified illnesses that are statistically associated with exposure to herbicides, but the IOM has not determined that herbicide exposure is the cause of any illnesses. The distinction is based on the quality of scientific evidence. According to the IOM, " factors such as consistency of evidence, biological plausibility, temporality, dose-response, and strength of association may be considered when deciding whether an observed statistical association is actually causal" . For evidence from scientific studies, if the findings between different studies are not the same, or if the connections between exposure and outcomes are not very strong, or if other potential causes of the illness have not been taken into account, or if there are problems in the way the study was designed, then the scientific evidence is too weak to conclude that an exposure is the cause of a health effect, even though an association may exist.

What are chance, bias, and confounding?

Chance refers to "the luck of the draw". To use a practical example, consider flipping a coin. Each time that the coin is flipped, there is an equal chance of it coming up heads or tails. If you flip "heads" 5 times in a row, that may be unusual, but it may simply be due to chance (if you flipped the coin 1000 times in a row, for example, a run of 5 "heads" in a row may occur on a number of occasions). Alternatively, if you flipped the coin 1000 times and it came up "heads" every time, it would be highly unlikely that this pattern would be due to chance and you may suspect that there is another explanation for this observation (some sort of "rigged" coin, perhaps one that has "heads" on both sides). What if the coin came up "heads" 10 times in a row? Without knowing for certain if the coin was "rigged", would you feel confident in concluding that your observation was not due to chance? If an association is observed between an exposure and an outcome, scientific study is required to determine if the observation is a "real" association, or simply due to chance. Scientific study relies on statistics to exclude chance. If a finding is "statistically significant", then it is unlikely that chance is the reason for the finding.

Bias refers to a systematic error in the design or conduct of a study. Continuing the coin example, suppose you flipped the coin and recorded the results each time. However, you only recorded the result when the coin came up "heads" and never recorded it when the coin came up "tails". After a while, you may notice from your recorded results that you have 100 "heads" in a row, but no "tails". If you then concluded that the coin was "rigged", this would be an incorrect conclusion because your observations were biased. Scientific studies must be carefully designed, conducted, and analyzed so as to ensure that there are no biases that may lead to false conclusions.

Confounding occurs when in addition to the specific exposure and the outcome that are being studied, there is an another factor related to both the exposure and the outcome. For example, perhaps it is observed that after eating roasted marshmallows, itchy bumps appear on the skin. These bumps may last for a few days and then go away, but they reappear after eating roasted marshmallows again. One may then conclude that eating roasted marshmallows is the cause of the itchy bumps on the skin. However, if you are roasting marshmallows, you are likely doing this outside, when the weather is nice, and mosquitoes are present. While you are roasting marshmallows, mosquitoes are also biting you, which is the real cause of the itchy bumps on the skin. In this example, the mosquitoes would be a confounding factor.

Under what circumstances might Agent Orange or its ingredients lead to health effects?

In order for a health effect to be potentially caused by a chemical, several things must happen.

Firstly, an exposure to the chemical must have occurred. "Exposure" means that the chemical entered one's body, usually through inhalation, ingestion, or skin contact. For example, a person walking past a large sealed barrel of Agent Orange would not receive any exposure, and so the risk of any possible health effects from Agent Orange would be zero.

Secondly, the exposure must be of sufficient dose (amount). A central principle of toxicology is the concept of dose-response: at increasing levels of exposure to a harmful substance, health effects become more frequent and/or more severe. For example, consider the use of a painkiller medicine such as morphine. If the prescribed amount is taken, pain will be relieved with minimal side effects. However, if too much morphine is taken, it can lead to breathing problems and death. The only difference between these two scenarios is dose - it is the dose that makes the poison. It is important to consider that we are all exposed to small amounts of TCDD every day, mostly through the food we eat (see " Is Agent Orange the only source of TCDD? " and " Can TCDD be measured in our bodies? "). At present, scientific knowledge cannot determine a specific level of TCDD exposure at which a health effect will occur. The scientific study of TCDD can only determine the level of risk for health effects given a certain exposure to TCDD. The health risk from TCDD exposure will depend on the dose received. At very low doses of TCDD, the risk of health effects is very low and not detectable, but the risk increases as the dose of TCDD increases. For more discussion on "background" TCDD exposure and the amount of TCDD exposure that is associated with increased risks for health effects, please see " Is Agent Orange the only source of TCDD? ", " Can TCDD be measured in our bodies? ", and " What are the health risks associated with large exposures to TCDD? ").

Thirdly, the health effect in question must be associated with the chemical exposure. For example, we know that too much sun exposure is associated with an increased risk of skin cancer. If someone with a great deal of sun exposure develops emphysema (a lung disease), we would not attribute this lung condition with sun exposure, simply because there is no association between sun exposure and lung disease. The IOM has found evidence of an association between Agent Orange and several illnesses (see " What health effects are associated with Agent Orange? "). The IOM has also noted that several scientific studies have not shown any association with some other health problems, such as brain or gastrointestinal cancers. In other words, these cancers have never been associated with any amount of exposure. Therefore, if someone who was exposed to Agent Orange developed brain cancer, current scientific evidence indicates that it would be unlikely that the brain cancer was due to Agent Orange.

In conclusion, before a health effect can be considered to be associated with any substance, 1) there must be exposure, with the substance somehow having gotten inside a person, 2) the exposure must have been of a sufficiently large dose, or amount, to meaningfully increase the risk of a harmful effect (see " What are the health risks associated with large exposures to TCDD? ") and 3) the health effect in question must be scientifically associated with exposure to the substance. Unless these three criteria are satisfied, there is no medical or scientific reason to suspect that a health effect is due to the substance.

What are the health risks associated with large exposures to TCDD?

The adverse health effects associated with Agent Orange are believed to be due to TCDD, which current scientific evidence indicates to be carcinogenic. In other words, sufficient exposure to TCDD under certain conditions is believed to result in an increased risk of developing certain types of cancer. The human evidence that TCDD is carcinogenic is largely based on studies of highly exposed groups of industrial and agricultural workers (Pohl et al., 2002).

For example, one of the largest and most highly exposed industrial groups was made up of 5132 workers at 12 U.S. plants that produced chemicals contaminated with TCDD (Steenland et al., 1999). It was only the workers with the highest cumulative exposure to TCDD that had a greater risk of dying from all cancers combined, as compared with the U.S. general population. In this study, the degree of cumulative exposure depended on the level of TCDD contamination of the manufactured chemicals. For example, to reach the level of exposure of the workers in the highest exposure group, for whom the elevated cancer risk was observed, workers would have to be exposed to a chemical containing 10 ppm TCDD for their entire shift every working day for about 8 years. At a higher TCDD contamination level of 50 ppm, workers would have to be exposed for the entire shift every working day for about 1.5 years to reach the same level of exposure. It was noted that " excess cancer was limited to the highest exposed workers, with exposures that were likely to have been 100 to 1000 times higher than those experienced by the general population " (Steenland et al., 1999).

The magnitude of the increased risk of death from all cancers combined was 1.6 (Steenland et al., 1999). This means that compared to the general population, these highly exposed workers were 1.6 times more likely to die of cancer than the general population (in scientific terms, this comparison is referred to as a "standardized mortality ratio"). The results of this study were consistent with other research into the cancer risks associated with TCDD. A recent scientific review article noted that " a number of large-scale retrospective cohort mortality studies have found significant increases in cancer mortalities (all types of cancer combined). These increases were typically found in workers exposed to the highest levels of dioxin [TCDD] and in workers with the longest follow-up periods. In general, the standardized mortality ratios were low (less than 1.5); however, the high degree of consistency between studies suggests that the increases in mortalities were not due to chance " (Pohl et al., 2002).

For illnesses other than cancer, a recent scientific review article indicates that the evidence from human studies has not been strong enough (for example, the results are inconsistent or the studies are not designed well enough) to estimate specific risks associated with TCDD exposure. A more detailed discussion can be found in the article, which concludes that " although more than a dozen different adverse effects have been reported in various studies of humans in the past 25 years, the most consistent clinically important adverse effect of human exposure appears to be chloracne " (Greene et al., 2003). Chloracne is a skin condition. Typically, this condition is only observed in people when the TCDD level in their blood is several thousand times greater than the levels typically seen in the general population (Greene et al., 2003; Hays et al., 2003).

Have Vietnam veterans in general been harmed by Agent Orange?

Veterans involved in herbicide handling and spraying in the Vietnam War were exposed to a number of different herbicide formulations (see "What is Agent Orange? "). Health studies of these veterans therefore look at the potential long-term health effects of herbicide exposures in general. These exposures were mainly to Agent Orange, but exposure to other herbicide formulations, such as Agent Purple, also occurred.

In comparison to heavily exposed industrial workers, Vietnam veterans were generally exposed to lower levels of TCDD. It is estimated that t he maximum TCDD dose experienced even by the US Air Force personnel directly involved in spraying ("Ranch Hand" veterans) was about one tenth of the maximum predicted dose of industrial workers (Akhtar et al., 2004).

The most recent study of death among U.S. Army veterans in general concluded that death rates due to chronic conditions, such as cancer or heart disease, were no different in veterans who served in Vietnam as compared to non-Vietnam veterans (Boehmer, 2004).

For the vast majority of Vietnam veterans, unless they were directly involved in the handling and spraying of Agent Orange, their exposure to Agent Orange would have been very small (Young et al., 2004a; Young et al., 2004c). A serum TCDD study of US Army Vietnam veterans who served as ground troops concluded that " most US Army ground combat troops who did not handle or spray herbicides were not heavily exposed to TCDD in Vietnam " (CDC, 1988). The greatest degree of Agent Orange exposure in Vietnam would have occurred among those veterans who directly handled or sprayed Agent Orange: Army Chemical Corps personnel and Air Force Operation Ranch Hand personnel.

Have Army Chemical Corps Vietnam Veterans been harmed by Agent Orange?

Army Chemical Corps veterans were involved in the storage, preparation, and application of a variety of herbicides in Vietnam. In a recent study, the death rate among Vietnam Army Chemical Corps veterans was not significantly different than non-Vietnam veterans for all causes, circulatory disease, or cancer. Vietnam veterans in this group had a higher risk of dying due to digestive system diseases, largely cirrhosis of the liver, as compared to non-Vietnam veterans. The authors noted, however, that their study design did not account for lifestyle factors that can also cause cirrhosis of the liver, such as alcohol use: " it is possible that heavier drinking among the Army Chemical Corps Vietnam veterans than among their non-Vietnam counterparts could account for the excess deaths from cirrhosis of the liver " (Dalager et al., 1997). The Vietnam veterans' risk of death from digestive system diseases, including cirrhosis of the liver, was not higher than the risk for the general U.S. population (Dalager et al., 1997).

Have Air Force Ranch Hand Vietnam veterans been harmed by Agent Orange?

The aerial spraying of herbicides in Vietnam was conducted under the name "Operation Ranch Hand", from 1962 to 1971. U.S. Air Force veterans who took part in Operation Ranch Hand handled and sprayed herbicides, and they are the Vietnam veterans with the greatest exposure to Agent Orange. These veterans have been studied closely in the Air Force Health Study, the purpose of which was to determine if the health of veterans who handled and sprayed herbicides in Vietnam had been harmed by this exposure. The Air Force Health Study was launched in 1980 and t he most recent and reportedly final report was released in July 2005 (see http://www.brooks.af.mil/AFRL/HED/hedb/default.html , click on "Reports" in the left margin, and then select "2002 Follow-up Examination Results: May 2002 to March 2005" to access the full report).

The Air Force Health Study examined more than 300 health-related outcomes in these veterans, grouped broadly into 12 areas. The overall significant findings in each area can be found in the executive summary of the 2005 report and are summarized below.

General Health : Measures of general health were not related to herbicide exposure. The one exception was that body mass index (a crude measure of body fat) was greater with increasing blood TCDD levels. It was noted that this possibly reflected " the pharmacokinetics of dioxin [TCDD] elimination " (higher body fat levels slow down the removal of TCDD from the body - as body fat increases, blood TCDD increases, but TCDD does not cause higher body fat).

Cancer : Mixed patterns of associations were found, but no consistent or meaningful patterns that would suggest that herbicide exposure caused cancer. The report stated that " these patterns did not suggest an adverse relation between cancer and herbicide exposure" . [The enlisted ground crew, the sub-group with the highest TCDD exposure, had a decreased risk of cancer, but this was not statistically significant (in other words, chance could not be excluded as the reason for the decrease).]

Neurology : Of the many neurological tests that were performed, only differences in pinprick sensation and reflexes were observed in those with the highest TCDD exposure, providing " some support for a relation between dioxin [TCDD] exposure and peripheral nerve function ".

Psychology : No measures of psychological health were associated with herbicides or TCDD exposure.

Gastrointestinal : Of the many tests performed, there was no association between the gastrointestinal test results and herbicide or TCDD exposure. The only exception was a relation between TCDD and higher levels of triglycerides, a type of blood fat. Although measurable, this relationship was not considered to be of any health significance.

Skin : There was no evidence of chloracne (which is associated with TCDD exposure) in the Ranch Hand veterans.

Cardiovascular : A variety of health outcomes were studied, such as heart attacks, heart disease, vascular disease, strokes, and high blood pressure. The 2005 report concluded that " overall, cardiovascular health did not appear to be adversely associated with herbicide or dioxin [TCDD] exposure ".

Blood System : Several factors were measured in the blood of Ranch Hand veterans. Overall, there was no indication of an " adverse relation between herbicide or dioxin [TCDD] exposure and any haematological [blood disease] diagnosis ".

Kidneys : There was no indication of " adverse relation between renal [kidney] function and herbicide or dioxin [TCDD] exposure ".

Hormones (Endocrine System) : There was a slightly increased risk of Type 2 (adult-onset) diabetes among the Ranch Hand veterans with the highest exposure. There were no consistent findings relevant to health for thyroid or sex hormones.

Immune System : There was no consistent association of health significance between any measure of immune function and herbicide or TCDD exposure.

Lungs : There was no association between lung health and exposure to herbicides or TCDD.

The 2005 Air Force Health Study report concluded that overall, only type 2 diabetes was associated with exposure to TCDD among these veterans with the greatest herbicide exposure. The Ranch Hand veterans were not more likely to be diagnosed with Type 2 diabetes than the comparison veterans without significant herbicide expsoure, but their risk of Type 2 diabetes increased with increasing blood TCDD level. The study confirmed associations between diabetes and other known risk factors: diabetes was more common in veterans who were older, who were obese, who smoked, and who had a family history of diabetes. The 2005 report noted that " the epidemiologic studies suggest that any increased risk of Type 2 diabetes from herbicide or dioxin [TCDD] exposure is small when compared to the known predictors - family history, obesity, physical inactivity - for diabetes ". The IOM has also found limited or suggestive evidence of a link between adult-onset (Type 2) diabetes and herbicides used in Vietnam, including Agent Orange, but concluded that other traditional risk factors for diabetes far outweigh the risks of Agent Orange.

The most recent study of causes of death among Ranch Hand Vietnam veterans was published in May 2005. Compared to Vietnam veterans who did not spray herbicides, Ranch Hand veterans did not have a greater risk of death due to cancer. When all Ranch Hand veterans were examined, the risk of death from all causes and from circulatory disease was slightly increased, but this was not statistically significant (in other words, chance could not be excluded as the reason for this slight increase). When only enlisted ground crew were examined, they had a slightly greater risk of death due to circulatory diseases than the comparison veterans. However, when veterans with serum TCDD measurements were examined, the risks of death from all causes, from cancer, or from circulatory disease were not significantly increased. In other words, those with measurable TCDD exposure did not have a greater risk of death from any cause compared to Vietnam veterans without significant herbicide exposure (Ketchum et al., 2005).

More information is available from the Air Force Health Study website ( http://www.brooks.af.mil/AFRL/HED/hedb/default.html - click on "Articles" in the left margin for a summary of all published scientific studies of Operation Ranch Hand veterans).

Why have disability pensions been awarded in the US and Canada for illnesses associated with Agent Orange?

As a result of political and policy decisions, the US Veterans Administration automatically presumes that veterans who served in Vietnam were exposed to Agent Orange (http://www.va.gov/pressrel/aoiss400.htm). They are also required by law to presume that, if a veteran develops an illness that is among those associated with Agent Orange, the illness is related to military service (Section 2, US Agent Orange Act of 1991, Public Law No. 102-4). The IOM notes that they have not found that Agent Orange is the cause of any illness, that the associations they found were largely based on studies of heavily-exposed chemical and agricultural workers, and that their conclusions " are not intended to imply or suggest policy decisions ".

Veterans Affairs Canada grants pensions for service-related disabilities, with the pension process designed to give applicants every chance to show how their disability is related to military service. Veterans Affairs Canada requires evidence of exposure and a medical diagnosis of the condition (ie. illness, injury or disease) that the applicant believes is related to the exposure. Pension Adjudicators take into account the latest scientific evidence available to establish an association between the condition and exposure to Agent Orange during service. Pension Adjudicators have flexibility in weighing the evidence presented in individual cases and, in the absence of credible evidence to the contrary, any doubt that arises in weighing evidence regarding a service-related illness associated with exposure is resolved in the applicant's favour. In fact, the Department is obliged, under the Pension Act, to give the "benefit of the doubt" to the Veteran.

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