AGENT ORANGE AND CHRONIC LYMPHOCYTIC LEUKEMIA
Headlines Made, Fine Lines Ignored
Quang M. Nguyen
May 2003
On January 23, 2003, the Board on Health Promotion and Disease Prevention of the Institute of Medicine (IOM) - a private, nonprofit institution that provides health policy advice under a congressional charter granted to the National Academy of Sciences (NAS) – posted a press release on the NAS website to announce the release of the Veterans and Agent Orange: Update 2002 (VAO 2002). The VAO 2002, which was prepared by the Committee to Review the Health Effects in Vietnam Veterans of Exposure to Herbicides (Fourth Biennial Update) (IOM Committee), “... reassessed six studies of herbicide exposure that provided information on chronic lymphocytic leukemia (CLL) among other health effects. The re-examination revealed sufficient evidence of an association between exposure to chemicals sprayed in Vietnam and risk of developing CLL.” (1) The press release also indicates that printed copies will be available for purchase from the National Academies Press; telephone (202) 334-3313 or 1-800-624-6242 or on the Internet at http://www.nap.edu. Reporters, however, may obtain a pre-publication copy from the Office of News and Public Information.
Immediately after the press release, headlines were made by major international wire services such as Associated Press (AP) and Agence France Press (AFP). Under the headline “Leukemia, Agent Orange link found,” AP reported that “Researchers have found a link between a type of leukemia and Vietnam soldiers exposed to herbicides like Agent Orange, prompting the Veterans Affairs [VA] Department to announce it will extend benefits to veterans with the illness.” (2) The “Agent Orange linked to leukemia” from AFP reported that “Agent Orange, a defoliant used by US forces during the Vietnam War, has been linked to a chronic form of leukemia suffered by former soldiers, leading the US government to extend compensation to veterans with the disease.” (3) AFP also quoted VA’s Secretary Anthony Principi saying that “Compelling evidence has emerged within the scientific community that exposure to herbicides such as Agent Orange is associated with CLL... I’m exercising my legal authority to ensure the full range of VA benefits is available to Vietnam veterans with CLL... It’s sad that we have to presume service connection, because we know that (veterans) have cancer that may have been caused by their battlefield service. But it’s the right thing to do.”
The headline news, of course, appeared on the internet and newspapers around the world, but they do not have any footnotes for fine lines. The fine lines were printed on pages 283-285 of the prepublication copy – uncorrected proof of the VAO 2002, which is also posted on the NAS website (4). They read as follows:
Summary of Studies on CLL
In response to a request from the Department of Veterans Affairs and because CLL shares more traits (immunohistochemical characteristics, B-cell origin, and progression to an acute aggressive form of NHL) with NHL than with other types of leukemia, the committee reassessed the available epidemiologic data to determine whether CLL merited reclassification regarding association with exposure to herbicides. The relevant data are summarized in Table 6-50.
Six studies reported in previous updates in which CLL was specifically investigated were reviewed. Waterhouse et al. (1996) performed a prospective study of site-specific cancer incidence in 1,706 males and females in a rural farming community in Michigan in 1959-1987. There was a significant increase in the lymphopoietic neoplasma, NHL, Hodgkin’s disease, and CLL (combined SIR = 1.40, 95% CI 1.0-1.9, p=0.03). Waterhouse et al. (1996) also conducted a case-control study of risk factors in 74 patients with lymphoma and leukemia matched with four controls each. Family history was the only covariant significantly associated with disease; there was a correlation with pesticide use but the database did not distinguished herbicides from insecticides and fungicides. Amadori et al. (1995) conducted a population-based case-control study in an agricultural area of Italy. Subjects working in agriculture denoted as farmers or farmers with animal breeding had a high risk of CLL (OR = 1.6, 95% CI 0.5-5.2, and 3.1, 95% CI 1.1-8.3, respectively). If both groups combined the OR was 2.3 (95% CI 0.9-5.8). There was no information on herbicide exposure. The study of cancer risk in Danish male gardeners highly exposed to pesticides (Hansen et al., 1992), showed a significant increase in CLL (standardized morbidity ratio, SMbR = 275, 95% CI 101-599) on the basis of 6 exposed cases. The paper states that gardeners holding outdoor jobs were exposed primarily to herbicides through the growing season but also to insecticides and fungicides; however, data on exposure were not presented for CLL cases. Blair and White (1985) reported that CLL mortality among farmers in Nebraska in 1957-1974 was significantly increased (OR = 1.7). The higher risk occurred among farmers residing in counties associated with cattle and dairy products; however no information was provided on herbicides expose of the CLL group.
Two of the epidemiologic studies reported on herbicide exposure and CLL. In a study of 1,675 white Iowa males who died of leukemia (Blair and White, 1985), CLL and nonspecific nonacute lymphocytic leukemia were significantly increased in farmers (OR = 1.7). Further analysis showed a strong relationship of CLL deaths in counties with acres producing soybeans and acres treated with herbicides. Brown et al. (1990) carried out a population-based case-control interview study of 578 white men with leukemia and 1,245 controls living in Iowa and Minnesota. CLL mortality (244 cases) was higher in farmers than in nonfarmers (OR = 1.4). When risk was calculated for CLL subtype, OR’s were significantly increased for use of any herbicide (OR = 1.4), any insecticide (OR = 1.3), and any animal insecticide (OR = 1.3). The risk of CLL in farmers who ever handled 2,4-D was 1.3. The risk of CLL in men who first handled 2,4,5-T at least 20 years before interview was significantly increased for CLL (OR = 3.3, 95% CI 1.2-8.9).
Bertazzi et al. (2001) evaluated lymphocytic leukemia in the 20-year follow-up of Seveso residents. No increased risk was seen, with relative risks of 1.1 (95% CI, 0.3-4.4) and 1.0 (95% CI, 0.2-3.9) for Zone B residents and the total of Zone A and B residents, respectively.
No relevant Vietnam-veteran studies that specifically investigate CLL have been published since Update 2000 (IOM, 2001).
Synthesis
A reanalysis of the epidemiologic studies indicates that farming occupation, especially where there is exposure to the herbicides 2,4-D and 2,4,5-T, is associated with significant risk of CLL mortality. Many more studies support the hypothesis that herbicide exposure can contribute to NHL risk. Most cases of CLL and NHL reflect malignant transformation of B-lymphocyte progenitor cells, so these diseases could have a common etiology.
Conclusions
Strength of the Evidence
On the basis of its evaluation, the committee concludes that there is sufficient evidence of an association between exposure to at least one of the chemicals of interest (2,4-D, 2,4,5-T or its contaminant TCDD, picloram, or cacodylic acid) and CLL.
Biologic Plausibility
No animal studies have found an increased incidence of CLL after exposure to the chemicals of interest. A summary of the biologic plausibility of the carcinogenicity of TCDD and the herbicides in general is presented at the end of this chapter. Chapter 3 discusses recent toxicology studies that concern biologic plausibility.
Increased Risk of Disease Among Vietnam Veterans
The limited data available on Vietnam veterans do not suggest that they are at increased risk for CLL.
These fine lines were probably ignored, even by the ones who wrote or reviewed them!
First, the IOM Committee ignored its own findings described in the “Summary of Studies on CLL” to conclude that “... there is sufficient evidence of an association between exposure to at least one of the chemicals of interest (2,4-D, 2,4,5-T or its contaminant TCDD, picloram, or cacodylic acid) and CLL.” The IOM Committee appears to contradict itself when concluding that “No animal studies have found an increased incidence of CLL after expose to the chemicals of interest.”
Unless the IOM Committee had additional data and information, results from the reviewed studies are not convincing for an association between herbicides and CLL. In fact, four of the six reviewed studies did not provide information on herbicides exposure, and the two studies reporting on herbicides exposure and CLL did not specify if farmers were exposed to other chemicals other than herbicides. Chances are the farmers were exposed because one of the two studies discussed about insecticide and animal insecticide. One of the studies evaluates the lymphocytic leukemia in the 20-year follow-up of Seveso residents. Instead of considering the Seveso study as the most appropriate and reliable study for its evaluation, the IOM Committee chose to ignore it. That was probably because the Seveso study did not show an association between exposure to dioxin and CLL.
The IOM Committee also ignored to follow its own criteria in evaluating sufficient evidence of an association (literally in fine lines) in Table ES-1. The criteria read “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.” Based on these criteria, the studies used by the IOM Committee, except the Seveso study, should be ruled out because of confounding.
That was not the first time an IOM committee ignored its own fine lines. “Far more ominous for public policy, the IOM committee decided that there is a connection between Agent Orange exposure and spina bifida, a birth defect resulting in incomplete closure of the spinal column. The committee ignored the fact that there is no evidence for any exposure to a male parent ever having caused a birth defect and no plausible biological mechanism by which it could do so” (5).
Secondly, AP and AFP ignored to read the fine lines, or ignored to obtain a pre-publication copy of the VAO 2002, when reporting that “Researchers have found a link between a type of leukemia and Vietnam soldiers exposed to herbicides like Agent Orange...,” and “Agent Orange, a defoliant used by US forces during the Vietnam War, has been linked to a chronic form of leukemia suffered by former soldiers...” There is no place in the VAO 2002 confirming a link between CLL and Vietnam veterans! On the contrary, the IOM Committee concluded, on page 285, that “The limited data available on Vietnam veterans do not suggest that they are at increased risk for CLL.”
Finally, the VA ignored, if not forgot to read, the fine lines in the IOM Committee’s conclusions regarding CLL when making its decision to extend compensation to Vietnam veterans suffering from this form of cancer, as a result of the IOM Committee’s findings. These fine lines are printed on page 6 of the pre-publication copy of the VAO 2002, saying “It should be noted that the committee is charged with reviewing the scientific data, not with making recommendations regarding VA policy; therefore, conclusions reported in Table ES-1 are not intended to imply or suggest policy decisions. Furthermore, the conclusions are related to association between exposure to chemicals and health outcomes in human populations, not to the likelihood that any individual’s health problem is associated with or caused by the herbicides in question,” and on page 285, saying “The limited data available on Vietnam veterans do not suggest that they are at increased risk for CLL.”
In reality, “...no one knows how many Vietnam vets have been diagnosed with the disease,... and some veterans’ advocates wonder if there really are any vets suffering from CLL” (6). There is possibly none because “... I’ve been doing this for 14 years and I do not recall ever having a veteran come to me and say ‘I have chronic lymphocytic leukemia.’ Ever,” says Phil Kraft (6). Mr. Kraft is a program director of the National Veterans Services Fund, a nonprofit organization providing counseling and other services for Vietnam and Gulf War vets. That is likely the reason why Vietnam vets welcome, but are not pleased with, the VA decision on CLL!
Quang M. Nguyen.
REFERENCES
1. The National Academies. January 23, 2003. “New Report Supports Association Between Agent Orange and One Form of Chronic Leukemia.” Office of News and Public Information. http://www4.nationalacademies.org/news.nsf
2. Associated Press. January 23, 2003. “Leukemia, Agent Orange link found.” Washington. http://www.usatoday.com/news/health
3. Agence France Press. January 25, 2003. “Agent Orange linked to leukemia.” http://www.theage.com.au/articles
4. http://books.nap.edu/books/030908616/html/1.html
5. Michael Gough. May 20, 2002. “The Political Science of Agent Orange.” Presented at MIT Security Studies Program Conference on “Acceptable Weapons,” Watertown, Massachusetts. http://web.mit.edu/ssp/Publications/working_papers/wp02-1.pdf
6. Amanda Gardner. January 24, 2003. “Vets Welcome Agent Orange Finding, But Want More, Complain of a lack of research on Vietnam vets’ health.” HealthScout News. http://www.hon.ch/News/HSN/511456.html