The National Academies of Sciences, Engineering and Medicine
Office of Congressional and government Affairs
At A Glance
: Veterans and Agent Orange: Update 2008
: 05/05/2010
Session: 111th Congress (Second Session)
: Richard A. Fenske

Professor and Acting Chair of Environmental and Occupational Health Sciences, School of Public Health and Community Medicine, University of Washington, Seattle; and Chair, Committee on the Review of the Health Effects in Vietnam Veterans of Exposure to Herbicides (Seventh Biennial Update), Board on the Health of Select Populations, The Institute of Medicine, The National Academies

: House
: Veterans’ Affairs Committee



Statement of

Richard A. Fenske, Ph.D., M.P.H.
Professor and Acting Chair of Environmental and Occupational Health Sciences
School of Public Health and Community Medicine
University of Washington, Seattle
Chair, Committee on the Review of the Health Effects in Vietnam Veterans of Exposure to Herbicides (Seventh Biennial Update)
Board on the Health of Select Populations
The Institute of Medicine
The National Academies

before the

Committee on Veterans’ Affairs
U.S. House of Representatives

May 5, 2010

Good morning, Chairman Filner and members of the Committee. My name is Richard Fenske. I am Professor and Associate Chair of the Department of Environmental and Occupational Health Sciences at the University of Washington’s School of Public Health and Community Medicine. I have served on several of the Institute of Medicine’s Committees to Review the Health Effects in Vietnam Veterans of Exposure to Herbicides --- as a member on the committees that prepared Updates 2002, 2004, and 2006 and as Chair of the most recent Veterans and Agent Orange (VAO) committee, which authored Update 2008.

The National Academy of Sciences was chartered by Congress in 1863 to advise the government on matters of science and technology. The Institute of Medicine was established in 1970 by the National Academy of Sciences to secure the services of appropriate professionals to examine policy matters pertaining to the health of the public.

I will give you a brief overview of the charge to the VAO committees and a synopsis of how these committees have approached their task. Congress established the mandate for the series of “Veterans and Agent Orange” reports in the Agent Orange Act of 1991. That legislation directed the Secretary of Veterans Affairs to have the National Academy of Sciences perform a comprehensive evaluation of scientific and medical information regarding the health effects of exposure to the herbicides used in Vietnam and then conduct updates every 2 years. The Veterans Education and Benefits Expansion Act of 2001 extended the mandate for biennial updates through 2014. Upon receiving a report from IOM, it is up to the VA Secretary to “determine whether a presumption of service connection is merited.”

The legislation indicated that, in making judgments concerning compensation of Vietnam veterans for health problems, a somewhat less stringent standard of evidence must be used than what would establish causality, as was expressed in the 1989 ruling in Nehmer v. US Veterans’ Administration: “The legislative history, and prior VA and congressional practice, support our finding that Congress intended that the Administrator predicate service connection upon a finding of a significant statistical association between dioxin exposure and various diseases. We hold that the VA erred by requiring proof of a causal relationship.”

The resulting legislation directed the IOM committees to: “determine (to the extent that available scientific data permit meaningful determinations)” the following regarding associations between specific health outcomes and exposure to TCDD and other chemicals in the herbicides used by the military in Vietnam:

A) whether a statistical association with herbicide exposure exists, taking into account the strength of the scientific evidence and the appropriateness of the statistical and epidemiological methods used to detect the association;
B) the increased risk of disease among those exposed to herbicides during service in the Republic of Vietnam during the Vietnam era; and C) whether there exists a plausible biological mechanism or other evidence of a causal relationship between herbicide exposure and the disease.”

In reaching consensus about association for health effects, the committees consider only the available scientific evidence; policy considerations definitely are not part of their deliberations.

In 1992, IOM convened a committee that conducted a comprehensive evaluation of the peer-reviewed published literature addressing association between adverse health outcomes in humans and exposure to the herbicides used by the US military in Vietnam. This group established the approach that has been followed in large part by the following eight committees conducting the biennial updates.

Agent Orange was only one of several herbicide mixtures or “Agents” used in Vietnam and referred to by the color of the band on the barrels they came in. Agent Orange was a 50:50 mixture of two phenoxy herbicides, 2,4-D and 2,4,5-T, then in wide use in the United States. In addition to various combinations of the phenoxy herbicides use in other Agents, two other herbicides picloram and cacodylic acid were also applied in the deforestation effort. The dioxin, or TCDD, contaminating the 2,4,5-T is the component of the herbicides of most concern as a toxic chemical, but the VAO committees have also thoroughly reviewed all peer-reviewed epidemiological studies addressing these four herbicides.

Of course, the VAO committees have considered epidemiological results from studies of the Vietnam veterans themselves to be central to their decision making. The most informative studies evaluate health outcomes in terms of serum TCDD levels as a quantitative measure of exposure, but until recently such measurements were costly, but relatively insensitive, and consequently, uncommon. As the measurement technology has improved over time, ever more half-lives for elimination have accrued and the residual levels of TCDD in potentially exposed veterans will merge with the background levels of the general public. For this reason of very scarce accurate exposure information and in accord with VA’s presumption of exposure to Agent Orange for all Vietnam veterans, the original VAO committee adopted the assumption that service in Vietnam was a proxy for potential exposure to dioxin and herbicides at levels in excess of what would have been experienced by non-deployed individuals.

Over successive updates, VAO committees have become increasingly convinced that generating estimates of risks to Vietnam veterans (overall, to particular subgroups, or individually) of developing particular health problems given as directed in Item B of their charge was intractable. Making an estimate of risk entails combining estimates of potency (per unit of exposure) for producing a given health outcome with corresponding estimates of exposure, but both these aspects of risk estimation continued to be unavailable. With the prospect of improved exposure estimates in the future being very remote, the committee for Update 2006 made a general statement to this effect and stopped reiterating this problem for every health outcome addressed.

In an effort to anticipate what herbicide-related health effects might arise in Vietnam veterans, however, the VAO committees have also factored in all relevant epidemiological information on other populations exposed to any of the five chemicals of interest. As a result, much of the most useful information has come from cohorts that were exposed before the Vietnam era, such as herbicide production workers, or from study populations whose exposures are better defined on an individual basis, such people residing around Seveso, Italy, during or after the industrial accident in 1976.

The original VAO committee also established a set of categories of association into which any adverse health outcome could be placed on the basis of the epidemiological results found in the published peer-reviewed literature. The starting point or default category is “inadequate or insufficient evidence of an association.” VAO committees list in the inadequate category on the summary table all those health problems addressed in the text (because some epidemiological information was found) that did not present an indication of association. Any health outcome that is not a subtype of one of the illnesses mentioned and is not explicitly listed falls in the inadequate category. (Being placed in this category does not mean that a given health outcome is “as likely as not” to be associated with herbicide exposure, as some have interpreted the reassignment of GI cancers in Update 2006).

Health problems having evidence of being associated with exposure to at least one of the chemicals of interest are placed in either the “sufficient evidence” category or the “limited or suggestive evidence” category. There is not a discrete dividing point between these classifications, so the choice depends on the number, strength, and consistency of the statistics for increased risk and how well factors like bias and confounding have been accounted for in the various studies. Because of the committee’s directive to assess statistical association (in keeping with the underlying principle of “giving the veteran the benefit of the doubt”), being placed in the “sufficient” category does not necessarily imply that a causal relationship has been established for a disease and herbicide exposure. Even the criteria for causality applied by scientific review groups do not constitute an absolute check list, and those for association are still less well defined. As to the role of Item C of the VAO committees’ charge, evidence of an association is strengthened by experimental data supporting biologic plausibility, but there is no requirement for biological plausibility for the epidemiological evidence of an association to be found either “limited/ suggestive” or “sufficient.”

The original VAO committee also established a category of “suggestive evidence of NO association” and placed several health outcomes in it on the basis of generally negative findings for exposure to dioxin. Asserting that a negative has been established is always problematic, but for the VAO task placement in this category implies that there is negative evidence for each of the five chemicals of concern. With more information becoming available on the phenoxy herbicides and still virtually none on picloram or cacodylic acid, the pattern has become less clear and the committees for successive updates have moved all but one dioxin-specific outcome back into the indeterminate “inadequate or insufficient evidence” category.

The summary chart (below) of the health effects for which the VAO committees have found the evidence for an association with herbicide exposure to be at least suggestive indicates the year of the VAO finding and any subsequent adjustment, followed by whether and when VA adopted the health condition as being presumptively associated with herbicide exposure for Vietnam veterans.

The committee for the first comprehensive report, published in 1994, confirmed that the epidemiological evidence for association with herbicide exposure was indeed “sufficient” for the conditions that VA had previously recognized as being presumptively service-related (chloracne, soft tissue sarcoma, and non-Hodgkin’s lymphoma). In addition to finding that the evidence for statistical association was also “sufficient” for Hodgkin’s disease and porphyria cutanea tarda, the first committee reported that there was “limited or suggestive” evidence of an association with herbicide exposure for respiratory cancers, prostate cancer, and multiple myeloma. Over the course of the next seven VAO updates, with the exception of hypertension, VA has adopted as presumptively service-related all conditions listed has having either “sufficient” or “limited/ suggestive” evidence of an association with herbicide exposure.

Following its review of the literature published from October 2006 through September 2008, the committee for Update 2008 specified two additional conditions (Parkinson’s disease and ischemic heart disease) as having “suggestive” evidence of association with herbicide exposure and concluded that hairy cell leukemia and other B-cell chronic leukemias belong with chronic lymphocytic leukemia in the “sufficient” evidence category. On March 25, VA posted a Federal Register notice of its intention to classify all three as presumptive.

This concludes my testimony. Thank you for the opportunity to testify. I welcome any questions the committee may have.


Cumulative findings of IOM’s Veterans and Agent Orange Committees
through Update 2008
(year of IOM finding; year of VA service connection)

Sufficient evidence of an association:

  • Soft tissue sarcoma (1994; 1990) 
  • Chloracne (1994; 1985) 
  • Non-Hodgkin's lymphoma (1994; 1990) 
  • Hodgkin’s disease (1994; 1995)
  • Chronic lymphocytic leukemia (2003; 2004) (including hairy cell leukemia and other chronic B-cell leukemias) (2009; 2009)

Limited/Suggestive evidence of an association:

  • Respiratory cancers - lung, larynx, trachea (1994; 1995)
  • Prostate cancer (1994; 1997) 
  • Multiple myeloma (1994; 1995)
  • Porphyria cutanea tarda (1994-suf, 1996-lim/sug; 1995) 
  • Early-onset transient peripheral neuropathy (1996; 1997)
  • Spina bifida in the children of veterans (1996; 1996 by Congress) 
  • Type 2 diabetes (2000; 2001) [Some birth defects in the children of female veterans (---- ; 2000 by Congress)]
  • Acute myeloid leukemia in the children of veterans (2001, retracted 2002)
  • AL amyloidosis (2007; 2009) 
  • Hypertension (2007; ---- )
  • Ischemic heart disease (2009; 2009)
  • Parkinson’s disease (2009; 2009)

Limited/Suggestive Evidence of NO Association:

  • Skin cancer, gastrointestinal tumors, bladder cancer, brain tumors (1994, retracted 2007)
  • Spontaneous abortion following paternal exposure to TCDD (2002)

Inadequate or Insufficient Evidence to Determine Association:

  • Most health outcomes reviewed fall in this category because there are not enough high quality data available on the chemicals of interest to determine whether or not an association exists
  • Health outcomes for which no data are available fall into this category by default


An archived webcast of the hearing can be found on the House Veterans' Affairs Committee's Web site.