Veterans and Agent Orange: Update 1996

Chapters 7, 9, 10, and 11 provide a detailed evaluation of the epidemiologic studies reviewed by the committee and their implications for cancer, reproductive effects, neurobehavioral effects, and other health effects. As is detailed in Chapter 4, the committee used the epidemiologic evidence it reviewed to assign each of the health outcomes being studied into one of the four categories listed in Table 1-1. The definitions of the categories and the criteria for assigning a particular health outcome to them are described in the table, and the specific rationale for each of the findings is detailed in Chapters 7, 9, 10 and 11.

Consistent with the mandate of Public Law 102-4, the distinctions between categories are based on "statistical association," not on causality, as is common in scientific reviews. Thus, standard criteria used in epidemiology for assessing causality (Hill, 1971) do not strictly apply. The committee was charged with reviewing the scientific evidence rather than making recommendations regarding DVA policy, and Table 1-1 is not intended to imply or suggest any policy decisions; these must rest with the Secretary of Veterans Affairs.

Sufficient Evidence of an Association

Evidence is sufficient to conclude that there is a positive association. That is, a positive association has been observed between herbicides and the outcome in studies in which chance, bias, and confounding could be ruled out with reasonable confidence. For example, if several small studies that are free from bias and confounding show an association that is consistent in magnitude and direction, there may be sufficient evidence for an association. There is sufficient evidence of an association between exposure to herbicides and the following health outcomes:

Soft-tissue sarcoma

Non-Hodgkin's lymphoma

Hodgkin's disease

Chloracne

Limited/Suggestive Evidence of an Association

Evidence is suggestive of an association between herbicides and the outcome but is limited because chance, bias, and confounding could not be ruled out with confidence. For example, at least one high-quality study shows a positive association, but the results of other studies are inconsistent. There is limited/suggestive evidence of an association between exposure to herbicides and the following health outcomes:

Respiratory cancers (lung, larynx, trachea)

Prostate cancer

Multiple myeloma

Acute and subacute peripheral neuropathy (new disease category)

Spina bifida (new disease category)

Porphyria cutanea tarda (category change in 1996)

Inadequate/Insufficient Evidence to Determine Whether an Association Exists

The available studies are of insufficient quality, consistency, or statistical power to permit a conclusion regarding the presence or absence of an association. For example, studies fail to control for confounding, have inadequate exposure assessment, or fail to address latency. There is inadequate or insufficient evidence to determine whether an association exists between exposure to herbicides and the following health outcomes:

Hepatobiliary cancers

Nasal/nasopharyngeal cancer

Bone cancer

Female reproductive cancers (cervical, uterine, ovarian)

Breast cancer

Renal cancer

Testicular cancer

Leukemia

Spontaneous abortion

Birth defects (other than spina bifida)

Neonatal/infant death and stillbirths

Low birthweight

Childhood cancer in offspring

Abnormal sperm parameters and infertility

Cognitive and neuropsychiatric disorders

Motor/coordination dysfunction

Chronic peripheral nervous system disorders

Metabolic and digestive disorders (diabetes, changes in liver enzymes, lipid abnormalities, ulcers)

Immune system disorders (immune suppression and autoimmunity)

Circulatory disorders

Respiratory disorders

Skin cancer (category change in 1996)

Limited/Suggestive Evidence of No Association

Several adequate studies, covering the full range of levels of exposure that human beings are known to encounter, are mutually consistent in not showing a positive association between exposure to herbicides and the outcome at any level of exposure. A conclusion of "no association" is inevitably limited to the conditions, level of exposure, and length of observation covered by the available studies. In addition, the possibility of a very small elevation in risk at the levels of exposure studied can never be excluded. There is limited/suggestive evidence of no association between exposure to herbicides and the following health outcomes:

Gastrointestinal tumors (stomach cancer, pancreatic cancer, colon cancer, rectal cancer)

Bladder cancer

Brain tumors

NOTE: "Herbicides" refers to the major herbicides used in Vietnam: 2,4-D (2,4-dichlorophenoxyacetic acid); 2,4,5-T (2,4,5-trichlorophenoxyacetic acid) and its contaminant TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin); cacodylic acid; and picloram. The evidence regarding association is drawn from occupational and other studies in which subjects were exposed to a variety of herbicides and herbicide components.

The Relationship between the Length of Time Since Exposure and the Possible Risk of Cancer Development

Increased Risk of Disease in Vietnam Veterans