Urology

Agent Orange and Prostate Cancer: Fact or Fiction?

Martha K. Terris, M.D.
Assistant Professor of Urology
Chief of Urology, Veterans Affairs Palo Alto Health Care System

WHAT IS AGENT ORANGE?
"Agent Orange" was the code name for an herbicide developed for the military. Although the product was developed in the 1940's, testing did not begin until the early 1960's. The purpose of the product was to defoliate trees and shrubbery where the enemy could hide. Agent Orange (named for the orange band that was used to mark the drums in which it was stored) was principally effective against dense jungle-like terrain. Agent Orange enjoyed ever widening use during the Vietnam War (1967-68). Its use then diminished and was eventually discontinued in 1971. An estimated 19 million gallons of Agent Orange were used in South Vietnam. Agent Orange was a 50-50 mix of two chemicals: 2,4,5-trichlorophenoxyacetic acid and 2,4-dichlorophenoxyacetic acid (1-3). Associated with the 2,4,5-T moiety is the impurity, 2,3,7,8-tetrachlorodibenzo-p-dioxin, also known as dioxin (4). The exact mechanism of carcinogenesis by these chemicals is not known (5-7).

CARCINOGENESIS OF AGENT ORANGE
In 1977, Hardell introduced the idea that soft tissue sarcomas are linked to exposure to defoliants such as Agent Orange (8). Axelson et al produced similar conclusions (9), but others suggest that these studies are flawed (10). Subsequent investigations have shown no association between herbicide exposure and cancer (4,5). More recently, the International Agency for Research on Cancer convened to review evidence for the potential carcinogenicity of dioxin-like chemicals. This group concluded that dioxin is carcinogenic to humans (11).

Subsequently, as a result of the "Agent Orange Act of 1991," the Institute of Medicine reviewed the effects of Agent Orange. The Institute of Medicine concluded that soft-tissue sarcoma, Hodgkin's disease, Non-Hodgkin's lymphoma, and chloracne have sufficient evidence of an association with Agent Orange exposure (12,13). Prostate cancer is considered by the Institute of Medicine to have suggestive but not conclusive evidence of an association with Agent Orange exposure. In response to the Institute of Medicine conclusions, the Department of Veterans Affairs currently offers compensation for these ailments. Prostate cancer is, by far, the most common of these illnesses, yet has the least scientific support for Agent Orange as a causative factor. Several studies have specifically focused on the link between prostate cancer and Agent Orange. Among these are evaluations of occupational exposure (14,15), as well as assessments of Vietnam veterans (16-18), but with inconclusive evidence of any relationship.

FINANCIAL IMPACT OF AGENT ORANGE-RELATED ILLNESSES
The implication of Agent Orange as an etiologic agent has as much a financial impact as a health-related one. There is the potential for enormous future costs to provide treatment and compensation to exposed Vietnam veterans with prostate cancer, since this malignancy is diagnosed in approximately 10% of American men and an estimated 2.5 million American military personnel were stationed in South Vietnam when Agent Orange was in use. These Vietnam veterans have been eligible for Agent Orange-related compensation since 1996. More recently, however, the financial impact of Agent Orange-related illnesses has escalated. Korean War veterans serving in 1967 and 1968 became eligible for benefits due to Agent Orange-related illnesses on October 16, 2000. The following week, on October 27, 2000, Vietnam's leading Agent Orange expert, Le Cao Dai, urged the United States to additionally recognize more than a million Vietnamese as victims of the toxic defoliant.

CONCLUSION
Prior studies investigating the link between war time exposure to Agent Orange and prostate cancer had a low likelihood of detecting a significant correlation with prostate cancer due to the relatively young age of the Vietnam veteran population. This population is now reaching an age in which prostate cancer is more likely, adding potential new information to our understanding of any relationship between Agent Orange exposure and prostate cancer incidence. While the association is unclear at the current time, the next 10 to 15 years will, in all likelihood, clarify the risk of prostate cancer in Agent Orange-exposed individuals. Until that time, diligent prostate cancer screening in patients with a history of Agent Orange exposure is reasonable.

REFERENCES
1. The Association of selected cancers with service in the US Military in Vietnam. Hodgkin's Disease, Nasal Cancer, Naso-pharyngeal Cancer and Primary Liver Cancer. The Selected Cancers Cooperative Study Group. Arch Int Med, 150(12): 2495, 1990.

2. The Association of selected cancers with service in the US Military in Vietnam. Non-Hodgkin's Lymphoma. The Selected Cancers Cooperative Study Group. Arch Int Med, 150(12): 2473, 1990.

3. Manz A, Berger J, Dwyer JH. Cancer mortality among workers in chemical plant contaminated with Dioxin. Lancet, 338: 959, 1991

4. Carlo GL, Sund KG. Carcinogenicity of Dioxin. Lancet, 338: 1393, 1991. 5. Pierce S. The purported link between Agent Orange and Cancer. Human Path, 26(6): 693, 1995.

6. Palmeira CM, Moreno AJ, Madeira VM. Effects of paraquat, dinoseb and 2,4-D on intracellular calcium and on vasopressin-induced calcium mobilization in isolated hepatocytes. Arch Tox, 69: 460, 1995.

7. Sastry BV, Janson VE, Clark CP, et al. Cellular toxicity of 2,4,5-trichlorophenoxyacetic acid: formation of 2,4,5-trichlorophenoxyacetylcholine. Cell Mol Bio, 43(4): 549, 1997.

8. Hardell L: Soft tissue Sarcomas and exposure to phenoxyacetic acids. Clinical Observation. Lakartidiningen 74: 2453, 1977.

9. Axelson O, Sundell L, Anderson K, et al: Herbicide exposure and tumor mortality. An updated epidemiological investigation on Swedish railroad workers. Scand J Work Environ Health 6: 73, 1980.

10. Pierce S, Ruger J: Potential misclassification in some studies claiming an association between chlorophenol exposure and various malignancies. J Natl Cancer Inst. 82: 1785, 1990.

11. International Agency for Research on Cancer (IARC), The Working Group on the evaluation of carcinogenic risks of humans. Polychlorinated Dibenzo-para-dioxins and Polychlorinated Dibenzofurans. IARC Monographs on the evaluation of carcinogenic risks to humans, Lyon, France, 69: WHO, IARC, 1997.

12. Institute of Medicine (IOM). 1994. Veterans and Agent Orange: Health effects of herbicides used in Vietnam. Washington DC: National Academy Press.

13. Institute of Medicine (IOM). 1996. Veterans and Agent Orange: Health effects of herbicides used in Vietnam. Washington DC: National Academy Press.

14. Becher H, Flesch-Janys D, Kauppinen T, et al. Cancer mortality in German male workers exposed to phenoxy herbicides and dioxins. Cancer Causes Control. 7: 312, 1996.

15. Kogevinas M, Becher H, Benn T, et al. Cancer mortality in workers exposed to phenoxy herbicides, chlorophenols and dioxins. An expanded and updated international cohort study. Amer J Epi, 145(12): 1061, 1997.

16. Air Force Health Study, 1996. An Epidemiologic investigation of health effects in Air Force Personnel following exposure too herbicides. Mortality update 1996. Brooks AFB, TX: Epidemiologic Research Division. Armstrong Laboratory. AL/AO-TR-1996-0068. 31 pp.

17. Watanabe KK, Kang HK. Mortality patterns among Vietnam Veterans: a 24-year retrospective analysis. J Occup and Environ Med, 38(3): 272, 1996.

18. Crane PJ, Barnard DL, Horsley KW, et al. Mortality of Vietnam Veterans: The Veteran Cohort study: A report of the 1996 Retrospective cohort study of the Australian Vietnam Veterans. Canberra: Department of Veterans' Affairs, 1997.

Stanford Medicine Resources:

Footer Links: