####### IOM Identifies Link with Chronic Lymphocytic Leukemia, Principi Extends Benefits

####### 

###### On January 23, 2003, the National Academy of Sciences' Institute of Medicine (IOM) officially released the fifth comprehensive report in a series entitled *Veterans and Agent Orange*. 

###### 

###### The latest report findings are similar to the earlier documents with one major change. *Update 2002* concludes that there is "sufficient evidence of an association" between herbicides used in Vietnam and chronic lymphocytic leukemia (CLL). Department of Veterans Affairs Secretary Anthony J. Principi has accepted this assessment, and ordered the development of regulations that would add CLL to the list of illnesses presumptively recognized for service connection among Vietnam veterans. VA will be able to begin paying compensation benefits once the regulations are finalized later this year.

###### 

#### Principi Acts 

Secretary Principi asked key officials and scientists within and outside
VA to evaluate the latest IOM report and advise him on appropriate
action. On January 23, based on the recommendations he received and his
reading of the report, the Secretary announced that CLL would be added
to the list of presumptively recognized conditions for service
connection.

"Compelling evidence has emerged within the scientific community that
exposure to herbicides such as Agent Orange is associated with CLL,"
Principi declared. "I'm exercising my legal authority to ensure the full
range of VA benefits is available to Vietnam veterans with CLL." The
Secretary added, "On the modern battlefield, not all injuries are caused
by shrapnel and bullets. This latest IOM study and my decision to act
upon it are the latest examples of VA's continuing efforts to care for
the needs of our combat veterans."

######### What the Decision Means

###### The Secretary's decision means that veterans with CLL who served in Vietnam during the Vietnam era don't have to prove that their illness is related to their military service to qualify for VA disability compensation. For more than 20 years, VA has offered special access to medical care to Vietnam veterans for health problems that may have resulted from Agent Orange exposure. (VA presumes that all Vietnam veterans were exposed to Agent Orange or other herbicides.) Secretary Principi's decision will ensure higher-priority access to care for those veterans with CLL.

###### 

###### Background

###### 

######  The initial IOM report, entitled *Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam*, dated 1994, was released in 1993. Updates were issued in 1996, 1999 (identified by IOM as *Update 1998*), and 2001 (dated 2000). In addition, the IOM has released two special reports on Agent Orange, one, published in 2000, regarding the possible association between herbicide exposure on diabetes, and another, published last year, on one type of childhood cancer.

###### 

In the latest comprehensive document, subtitled *Update 2002*, the IOM,
a highly respected, independent, non-governmental scientific review
organization working on behalf of the Department of Veterans Affairs
(VA), evaluated all available scientific evidence from studies of
veterans and other groups, to determine what health problems may be
associated with exposure to Agent Orange and other herbicides used in
Vietnam. VA requested that the IOM focus on CLL in *Update 2002* because
of concerns raised by some veterans that CLL shares some similarities
with non-Hodgkin's lymphoma, which has been recognized for service
connection for several years.

*Update 2002* was conducted by a 10-member committee of scientists,
chaired by Irva Hertz-Picciotto, Ph.D., a professor in Department of
Epidemiology, School of Public Health, University of North Carolina,
Chapel Hill. Michelle C. Catlin, Ph.D., a program officer in the IOM's
Board on Health Promotion and Disease Prevention, was the Study
Director.

The information that the committee reviewed was identified through a
comprehensive search of relevant databases, including public and
commercial databases covering biologic, medical, toxicologic, chemical,
historical, and regulatory information. More than 9,000 potentially
relevant studies were identified in the searches, and more than 1,000
were reviewed. The committee reported that input received from veterans
and others interested persons at public hearings and in written
submissions served as a valuable source of additional information.

## 

## IOM's Four Categories

In the latest report, the IOM assigned each health outcome considered in
the report to one of four categories based on the amount and quality of
scientific evidence of an association with Agent Orange or other
herbicides used in Vietnam. This was the same procedure used for prior
reports. In making the assignments, the IOM considered a large range of
occupational, environmental, and veterans' studies.

The four categories are (1) sufficient evidence of an association, (2)
limited/suggestive evidence of an association, (3)
inadequate/insufficient evidence to determine whether an association
exists, and (4) limited/suggestive evidence of [no]{.underline}
association.

**Category 1 - Sufficient Evidence of an Association**

The IOM included health outcomes in the first category when a positive
association has been observed between herbicides and the outcomes in
studies in which chance, bias, and confounding could be ruled out with
reasonable confidence.

In its initial report, the IOM included five illnesses in this category:
soft-tissue sarcoma, non-Hodgkin's lymphoma, Hodgkin's disease,
chloracne, and porphyria cutanea tarda (in genetically susceptible
individuals). In the 1996 update, the IOM lowered porphyria cutanea
tarda to the second category while the other conditions remained in the
first. In the 1996, 1998, and 2000 updates, no additional health
outcomes were included in this first category. The inclusion of CLL in
this category marks the first time that a condition has been added to
this category since the initial report was issued.

**Category 2 - Limited/Suggestive Evidence of an Association**

The IOM lists conditions in the second category when the evidence
reviewed 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. Health outcomes are included in this
category when, for example, at least one high quality study shows a
positive association, but the results of other studies are inconsistent.

In the report released in 1993, the IOM included only three outcomes
(respiratory cancers, prostate cancer, and multiple myeloma) in this
category. Six health outcomes were included in this category in 1996 and
1998. In addition to these three cancers and porphyria cutanea tarda
(mentioned above), the IOM cited acute and subacute transient peripheral
neuropathy in Vietnam veterans and spina bifida in their children. The
initial report listed peripheral nervous system disorders as a group in
the third category.

In the 1996, 1998, and 2000 updates, the IOM distinguished between acute
and subacute transient peripheral neuropathy and chronic peripheral
nervous system disorders (which remained in the third category).
Similarly, the IOM separated spina bifida from other birth defects
(which remained in the third category).

In the special report on diabetes released in 2000, the IOM moved Type 2
diabetes from category three (inadequate/insufficient evidence to
determine whether an association exists) to this one. In *Update 2000*,
Type 2 diabetes remained in this category. In *Update 2002*, Type 2
diabetes is included in this category.

Another change in this category, made by *Update 2000*, was the addition
of acute myelogenous leukemia (AML) in the children of Vietnam veterans.
Under existing law, VA lacks authority to provide benefits or services
to these children. AML was previously grouped with other childhood
cancers in offspring. Careful analysis of U.S. and Australian studies
led IOM to include this rare condition in category 2. However subsequent
review by the IOM after Australian scientists discovered an error in
their study, resulted in a downgrade to category 3 last year. (For more
information on this reversal, see the front page article in the May 2002
issue of the Agent Orange Review), online at **[www.va.gov/agent
orange]{.underline}**.

## Category 3 - Inadequate/Insufficient Evidence 

## to Determine Whether an Association Exists 

Most conditions evaluated in IOM's 2002 report (as well as in the
earlier publications) were listed in their third category. The IOM
placed health outcomes to this category when available studies are of
insufficient quality, consistency, or power to permit a conclusion
regarding the presence or absence of an association. Health outcomes for
which there are no available studies would also fall into this category.

The following outcomes were listed in IOM category three in *Update
2002*: hepatobiliary cancers, nasal or nasopharyngeal cancer, bone
cancer, breast cancer, female reproductive cancer (cervical, uterine,
and ovarian), urinary bladder cancer, renal cancer, testicular cancer,
leukemia (other than CLL), skin cancer, spontaneous abortion, birth
defects (other than spina bifida), neonatal or infant death and
stillbirths, low birthweight, childhood cancers in offspring, including
acute myelogenous leukemia, abnormal sperm characteristics and
infertility, cognitive and neuropsychiatric disorders, motor or
coordination dysfunction, chronic peripheral nervous system disorders,
metabolic and digestive disorders (changes in liver enzymes, lipid
abnormalities, and ulcers), immune systems disorders (immune suppression
and autoimmunity), circulatory disorders, respiratory disorders, and
AL-type primary amyloidosis, endometriosis, and the effects on thyroid
homeostasis.

The 1996 changes are the two noted above (that is, the separation of
acute and subacute transient peripheral neuropathy from chronic
peripheral neuropathy; and spina bifida from other birth defects) plus
an elevation of skin cancer from the fourth category. Urinary bladder
cancer was added to this category in 1998.

In *Update 2000*, as a result of the change for acute myelogenous
leukemia, the health outcome "childhood cancer in offspring" was
modified to exclude AML. However, as a result of subsequent revision, it
was again included with other childhood cancers in this category where
it remains in *Update 2002*.

For *Update 2000*, at VA's request, the IOM evaluated the possible
relationship between herbicides used in Vietnam and AL-type primary
amyloidosis, a condition similar in many ways to multiple myeloma (an
illness in category 2). IOM concluded that there was
inadequate/insufficient evidence to determine whether an association
exists. VA had received several letters from interested individuals
suggesting a link with herbicide exposure. In the 2002 report, the IOM
added an evaluation of endometriosis and the effects of thyroid
homeostasis to this category.

**Category 4 - Limited/Suggestive Evidence of *[No]{.underline}*
Association**

Health outcomes are included in the fourth category when several
adequate studies, covering the full range of levels of exposure that
humans 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.

The 2002 report, like the 1996, 1998, and 2000 documents, puts the
following conditions in Category 4: gastrointestinal tumors (stomach,
pancreatic, colon, and rectal cancers) and brain tumors. The only change
in 1996 from the first report in this category was the elevation of skin
cancer to the third category. The only change in 1998 was the elevation
of urinary bladder cancer to the third category. In the 2000 and current
updates, there is no change in this category compared with the 1998 IOM
update.

**Research Recommendations**

# 

#  In *Update 2002*, the IOM also offers several research recommendations. The committee suggests continuing of the Air Force Health Study of Operation Ranch Hand personnel (the unit involved in the aerial spraying of Agent Orange), expanding the studies of Army Chemical Corps veterans, and following the experience of Vietnam veterans as they age, with emphasis on diseases associated with aging.

# 

#  The committee also concludes that certain rare tumors are worthy of further investigation despite previous evidence of *no* association. The committee supported steps that would continue development of collaborative research programs between U.S. and Vietnamese scientists.

# 

# Required by Public Law 102-4

Under Public Law 102-4, the Agent Orange Act of 1991, within 60 days
after the Secretary of Veterans Affairs receives a report on the
possible long-term health effects of Agent Orange and other herbicides
used in Vietnam from the National Academy of Sciences' IOM, the
Secretary must determine whether a presumption of service connection is
warranted for each disease covered by the report. If the Secretary
concludes that a presumption of service connection is warranted, he or
she must issue regulations within 60 days of this determination.

Within 90 days after the Secretary issues any proposed regulations
regarding these diseases, the Secretary must issue final regulations.
Such regulations are effective the day of issuance.

If the Secretary determines that a presumption of service connection is
not warranted, he or she, within 60 days of the making the
determination, must publish in the *Federal Register* a notice of that
finding. The notice must include an explanation of the scientific basis
for the determination.

## Earlier VA Responses

IOM reports on Agent Orange have had a significant impact on VA
compensation policy, as documented in the next four paragraphs.

The 1993 and 1996 IOM reports resulted in substantial changes in VA
policy. On July 27, 1993, the day the IOM released its first report,
then VA Secretary Jesse Brown announced that Hodgkin's disease and
porphyria cutanea tarda would be added to the list of conditions
presumed to be service-connected for veterans exposed to herbicides in
Vietnam. (VA presumes that all Vietnam veterans were exposed to such
herbicides).

Two months later, after further review of the IOM document, Secretary
Brown announced that multiple myeloma and respiratory cancers would be
added to the list of conditions presumed to be service-connected for
veterans exposed to herbicides in Vietnam.

After reviewing the 1996 IOM update, Secretary Brown concluded that
acute and subacute transient peripheral neuropathy (if manifested within
1 year of exposure to an herbicide in Vietnam and resolved within 2
years of onset) and prostate cancer should and would be added to the
list of conditions presumed to be service-connected for veterans exposed
to herbicides in Vietnam.

In 1996, when the IOM found an association between herbicides used in
Vietnam and the birth defect spina bifida in the children of Vietnam
veterans, VA sent draft legislation to Congress (enacted, with
modification, as part of Public Law 104-204 in September 1996) to
provide for certain benefits and services for these children.

*Update 1998* and *Update 2000* did not result in changes in
compensation policy. The IOM's special 2000 report on Type 2 diabetes
resulted in that condition being added to the list of presumptively
recognized conditions for service connection.

As a condition in Category 1, CLL was a relatively easy and
non-controversial call under the guidelines established by Congress.
Historically, all conditions in that category have promptly been
recognized for service connection. All illnesses in the second category
have ultimately been recognized as well.

**Report on the Internet, Also Available for Purchase**

Copies of this report are available from the National Academies Press,
500 Fifth Street, N.W., Lockbox 285, Washington, DC 20055. The telephone
numbers are (toll-free) 1-800-624-6242 and (in the Washington, DC,
metropolitan area) 202-334-3313. The Internet address is
**[www.nap.edu](http://www.nap.edu/).**

#### IOM Reports Will Continue

The IOM will be re-evaluating existing scientific evidence and assessing
new information regarding the possible long-term health consequences of
herbicide exposures. Based upon the results of the most recent report,
VA has requested that the IOM take a careful look at other forms of
leukemia in their next update, due in 2004.

The IOM was chartered in 1970 by the National Academy of Sciences to
enlist distinguished members of the appropriate professions in the
examination of policy matters pertaining to the health of the public.
The Institute acts under responsibility given to the Academy by its
congressional charter to be an adviser to the Federal Government and,
upon its own initiative, to identify issues of medical care, research,
and education. For information about the IOM, see
[**www.iom.edu**](http://www.iom.edu/).

The January 23, 2003 VA news release on the Secretary's action related
to CLL can be found at [**www.va.gov/opa**](http://www.va.gov/opa).