TABLE 14-1Summary of Ninth Biennial Update of Findings on Vietnam-Veterans, Occupational, and Environmental Studies Regarding Scientifically Relevant Associationa Between Exposure to Herbicides and Specific Health Outcomesb

Sufficient Evidence of an Association
Epidemiologic evidence is sufficient to conclude that there is a positive association. That is, a positive association has been observed between exposure to herbicides and the outcome in studies in which chance, bias, and confounding could be ruled out with reasonable confidence.c For example, if several small studies that are free of bias and confounding show an association that is consistent in magnitude and direction, there could be sufficient evidence of an association. There is sufficient evidence of an association between exposure to the chemicals of interest and the following health outcomes:
  • Soft-tissue sarcoma (including heart)

    Non-Hodgkin lymphoma


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


    Hodgkin lymphoma

  • Chloracne
Limited or Suggestive Evidence of an Association
Epidemiologic evidence suggests an association between exposure to herbicides and the outcome, but a firm conclusion is limited because chance, bias, and confounding could not be ruled out with confidence.b For example, a well-conducted study with strong findings in accord with less compelling results from studies of populations with similar exposures could constitute such evidence. There is limited or suggestive evidence of an association between exposure to the chemicals of interest and the following health outcomes:
  • Laryngeal cancer
  • Cancer of the lung, bronchus, or trachea
  • Prostate cancer

    Multiple myeloma


    AL amyloidosis

  • Early-onset peripheral neuropathy
  • Parkinson disease
  • Porphyria cutanea tarda
  • Hypertension
  • Ischemic heart disease
  • Stroke (category change from Update 2010)
  • Type 2 diabetes (mellitus)
  • Spina bifida in offspring of exposed people
Inadequate or Insufficient Evidence to Determine an Association
The available epidemiologic 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 association between exposure to the chemicals of interest and the following health outcomes that were explicitly reviewed:
  • Cancers of the oral cavity (including lips and tongue), pharynx (including tonsils), or nasal cavity (including ears and sinuses)
  • Cancers of the pleura, mediastinum, and other unspecified sites in the respiratory system and intrathoracic organs
  • Esophageal cancer
  • Stomach cancer
  • Colorectal cancer (including small intestine and anus)
  • Hepatobiliary cancers (liver, gallbladder, and bile ducts)
  • Pancreatic cancer
  • Bone and joint cancer
  • Melanoma
  • Nonmelanoma skin cancer (basal-cell and squamous-cell)
  • Breast cancer
  • Cancers of reproductive organs (cervix, uterus, ovary, testes, and penis; excluding prostate)
  • Urinary bladder cancer
  • Renal cancer (kidney and renal pelvis)
  • Cancers of brain and nervous system (including eye)
  • Endocrine cancers (thyroid, thymus, and other endocrine organs)
  • Leukemia (other than chronic B-cell leukemias, including chronic lymphocytic leukemia and hairy cell leukemia)
  • Cancers at other and unspecified sites
  • Infertility
  • Spontaneous abortion (other than after paternal exposure to TCDD, which appears not to be associated)
  • Neonatal or infant death and stillbirth in offspring of exposed people
  • Low birth weight in offspring of exposed people
  • Birth defects (other than spina bifida) in offspring of exposed people
  • Childhood cancer (including acute myeloid leukemia) in offspring of exposed people
  • Neurobehavioral disorders (cognitive and neuropsychiatric)
  • Neurodegenerative diseases, excluding Parkinson disease
  • Chronic peripheral nervous system disorders
  • Hearing loss
  • Respiratory disorders (wheeze or asthma, chronic obstructive pulmonary disease, and farmer's lung)
  • Gastrointestinal, metabolic, and digestive disorders (changes in hepatic enzymes, lipid abnormalities, and ulcers)
  • Immune system disorders (immune suppression, allergy, and autoimmunity)
  • Circulatory disorders (other than hypertension, ischemic heart disease, and stroke)
  • Endometriosis
  • Disruption of thyroid homeostasis
  • Eye problems
  • Bone conditions
This committee used a classification that spans the full array of cancers. However, reviews for nonmalignant conditions were conducted only if they were found to have been the subjects of epidemiologic investigation or at the request of the Department of Veterans Affairs. By default, any health outcome on which no epidemiologic information has been found falls into this category.
Limited or Suggestive Evidence of No Association
Several adequate studies, which cover the full range of human exposure, are consistent in not showing a positive association between any magnitude of exposure to a component of the herbicides of interest and the outcome. A conclusion of “no association” is inevitably limited to the conditions, exposures, and length of observation covered by the available studies. In addition, the possibility of a very small increase in risk at the exposure studied can never be excluded. There is limited or suggestive evidence of no association between exposure to the herbicide component of interest and the following health outcome:
  • Spontaneous abortion after paternal exposure to TCDD

This change in wording was made to emphasize the scientific nature of the VAO task and procedures and reflects no change in the present committee's criteria from those used in previous updates.


Herbicides indicates the following chemicals of interest: 2,4-dichlorophenoxyacetic acid (2,4-D), 2,4,5-trichlorophenoxyacetic acid (2,4,5-T) and its contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD or dioxin), cacodylic acid, and picloram. The evidence regarding association was drawn from occupational, environmental, and veteran studies in which people were exposed to the herbicides used in Vietnam, to their components, or to their contaminants.


Evidence of an association is strengthened by experimental data supporting biologic plausibility, but its absence would not detract from the epidemiologic evidence.


The committee notes the consistency of these findings with the biologic understanding of the clonal derivation of lymphohematopoietic cancers that is the basis of the World Health Organization classification system.

From: 14, Conclusions and Recommendations

Cover of Veterans and Agent Orange
Veterans and Agent Orange: Update 2012.
Committee to Review the Health Effects in Vietnam Veterans of Exposure to Herbicides (Ninth Biennial Update); Board on the Health of Select Populations; Institute of Medicine.
Washington (DC): National Academies Press (US); 2014 Mar 6.
Copyright 2014 by the National Academy of Sciences. All rights reserved.

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