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October 2014, Vol 104, No. 10 | American Journal of Public HealthDwyer and Flesch-Janys | Voices From the Past | 1857 ⏐ VOICES FROM THE PAST ⏐ FEW ISSUES MANIFEST THE ideological divisions in our society as powerfully as the Vietnam War, and no public health issue is more entangled with our unease about that war than the health ef- fects of dioxin. While the war and the dissension at home were still raging, Bertrand Rus sell charged that the US military was using carcinogenic herbicides in Viet- nam. US newspapers responded with editorials stating that the eminent mathematician may be suffering from senility. Ironically, Admiral Zumwalt (who gave the order to use herbicides for tacti- cal purposes in Vietnam) report- edly has come to believe that his son’s early death from lymphoma was due to herbicide exposure in Vietnam. He nevertheless de- fends his decision as appropriate, given the American lives pre- sumed saved by defoliation . It may be because enough time has transpired since the war, and because our understanding of the relation between economic activity and environmental pro- tection has sufficiently progressed, that we can approach the issue of the health effects of dioxin with some objectivity— even among the Vietnamese. Fortu- nately, our efforts in this regard can be informed by a much more substantial body of evi- dence than earlier efforts. The ideological nature of earlier evaluations was fueled, at least in part, by the scarcity of toxico-logic and epidemiologic data di- rectly relevant to the issue.
A report in this issue of the Journal 1 provides some new data in this regard. These data come from a group of scientists who have struggled for many years, usually without adequate funding, to measure dioxin lev- els in breast milk, adipose tissue, and blood from Vietnamese. Al- though these data are not from a systematic epidemiologic de- sign—there may be problems with the representativeness of the samples selected, potential problems with the handling of samples, and so on—outright fraud would be necessary to arti- factually produce the clear dif- ference reported between per sons residing in unsprayed (northern) and sprayed (southern and central) areas of Vietnam.
The mean 2,3,7,8-tetrachloro- dibenzo-p-dioxin (TCDD) blood level is 6 times greater in the southern/central group than in the northern. This large discrep- ancy is not found for other spe- cific congeners of the higher chlorinated dioxins or furans, al- though the other congeners are generally higher in concentration in the sprayed areas. Since TCDD was the major dioxin-like contam- inant in Agent Orange (a mixture of 2,4,5-trichlorophen oxyacetic acid [2,4,5-T] and 2,4-dichloro- phenoxyacetic acid [2,4-D]), these findings suggest that the TCDD in 2,4,5-T may have found its way into the food chain of some Vietnamese. The elevated levels from 1984 to 1992 may reflect much higher body burdens in the past and persistence of TCDD in the envi- ronment.
Is there a plausible alternative source of elevated TCDD in southern Vietnam? In this re- gard, it is of interest that the mean TCDD level in adipose tis- sue of 15 parts per trillion (ppt) in the southern samples is three times greater than the 5ppt found in an epidemiologic study of samples in the United States. 2 The blood levels also exceed those reported for US samples by a factor of 3 (13 ppt vs 4 ppt). 3 Given the current theory that environmental TCDD results primarily from industrial pro- cesses, 4 it is difficult to identify plausible alternative sources of TCDD in the environment of southern Vietnam that would produce levels exceeding those in the US.
If we accept that there is some subpopulation in Vietnam with protracted exposure to TCDD, then the next important question concerns the evidence of adverse health effects of such exposure.
More precisely, at what concen- tration of TCDD in blood or tis- sue does the risk of adverse effects increase and by how much? There is now a substantial body of animal and epidemio- logic data that addresses this Agent Orange in Vietnam | Excerpted from J. H. Dwyer and D. Flesch-Janys, “Agent Orange in Vietnam,” American Journal of Public Health, 85, no. 4 (1995): 476–478. ⏐ VOICES FROM THE PAST ⏐ American Journal of Public Health | October 2014, Vol 104, No. 10 1858 | Voices From the Past | Dwyer and Flesch-Janys question, especially in the case of cancer outcomes.
Treatment with TCDD has been associated with increased neoplasms in every animal bioas- say reported in the scientific liter- ature. 5 These carcinogenicity models have included several species and tumors at multiple sites.
Further more, carcinogenic effects occur at concentrations as low as 1.4 ng/kg per day. The carcinogenicity of TCDD has also been reported for the Syrian Hamster 6—a finding of particu- lar importance since hamsters, like humans, are relatively resis- tant to the acute toxic effects of TCDD.
Although epidemiologic stud- ies are inherently more subject to confounding and sampling bias than laboratory studies, the two major cohort studies of chemical workers with sufficient measures of TCDD in tissue to verify chronic exposure have yielded results consistent with the animal data.
The study in the US by the Na- tional Institute for Occupational Safety and Health found a 50% increase in total cancer mortality among more heavily exposed workers with latency of at least 20 years. 13 A study of workers from a plant in Hamburg, Germany, also found an increase in cancer mortality. 7 Ten years of work in the 2,4,5-T production section of the Hamburg plant was associ- ated with a 170% increase in total cancer mortality. 8 The Hamburg study also included sufficient information to relate work history to TCDD levels in blood or tissue. 9 The most heav- ily exposed decile of men, with estimated tissue TCDD levels av- eraging 760 ppt during exposure, showed a three to fourfold in- crease in cancer mortality. Fi- nally, a third study of a group of chemical workers with acute exposure to TCDD (resulting from an accident) found a two- fold increase in total cancer mortal ity after a latency of 20 years. 10 The significance of these epi- demiologic findings is under- scored by the fact that, to our knowledge, no other occupational exposure has been shown by the epidemiologic method to ele- vate significantly both all-cause mortality and total cancer mor- tality (as found in the Hamburg study). These epidemiologic find- ings are thus consistent with the animal data indicating that TCDD is a potent carcinogen at multiple sites across mammalian species.
There is also consistency across epidemiologic studies fo- cusing on TCDD and the risk of soft tissue sarcoma. Hardell was the first to report a link between sarcomas and exposure to phe- noxy acids and chlorophenols. 11 His stud ies were severely criti- cized by chemical industry repre- sentatives. In fact, Richard Doll reviewed a report by the Mon- santo Corporation and concluded that Hardell’s papers should no longer be considered part of the scientific literature. 12 However, subsequent studies have repli- cated the relation between expo- sure to TCDD contaminated substances and soft tissue sar- coma 13–16 ; and the confirming studies include an additional one from New Zealand 17 , 18 if the analyses are restricted to farm- ers. Professor Doll has resumed citation of Hardell’s papers, 19 and Olav Axelson has argued that fraud occurred in two industry re- ports that misclassified soft tissue sarcoma and malignant lym- phoma cases as unexposed to TCDD. 20 . . . Progress has also been made in unraveling the mecha- nism of TCDD carcinogenicity in animal models. It appears to be a powerful promoter, but only a weak initiator. For example, tumors were produced in 100% of hairless mice treated with the initiator N-methyl-N- nitrosoguanidine after a series of 30-ng dosages of TCDD. 21 There is also mounting evidence that the aryl hydrocarbon (Ah) recep- tor mediates TCDD effects, that it modifies some receptor sys- tems which are involved in cell growth and differentiation, and that hormones, especially estro- gens, influence the carcinogenic action 5 of TCDD. More recently, there is some evidence that TCDD in creases oxidative stress and lipid peroxidation. 22 En- hanced oxidative stress could play a role in many disease pro- cesses, including carcinogenesis and atherogen esis. 23 Recent find- ings from the Hamburg cohort are consistent with these animal data on oxidative stress. Ex- tended fol low-up has revealed not only an increased risk of total and cancer mortality, but a marked elevation in ischemic heart disease mortality among the heavily ex posed. 24 Thus, al- though the epidemiologic data are most compelling for increased cancer risk, there is considerable animal and epidemiologic evi- dence to indicate that increased cancer morbidity may be only a portion of the adverse health ef- fects of heavy TCDD exposure. Further more, these very broad ef- fects across sites and diseases sug- gest a fundamental patho logic mechanism such as increased oxi- da tive stress and compromise of the immune system.
In the case of epidemiologic findings, it is difficult to limit ⏐ VOICES FROM THE PAST ⏐ October 2014, Vol 104, No. 10 | American Journal of Public HealthDwyer and Flesch-Janys | Voices From the Past | 1859 causal attribution to TCDD itself. For example, phenoxy acids not contaminated with TCDD may be carcinogenic in humans. This is suggested by studies of chemi- cal workers 25 and by the finding in a randomized trial that treat- ment with clofibrate (a chlori- nated phenoxypropionic acid derivative used as a lipid lower- ing agent) was associated with increased cancer mortality. 26 2,3,7,8-TCDD is considered to be the most toxic member of a class of compounds made up of polychlorinated dioxins (CDDs), furans (CDFs) and biphenyls (PCBs)- which are a subclass of halogenated aromatic hydrocar- bons. Dioxins and furans are made up of two benzene rings connected by a pair of oxygen atoms (dioxins) or a single oxygen atom (furans); PCBs also include two benzene rings that can take on a dioxin-like structure. Each of the hundreds of specific conge- ners in this class is determined by the number and position of halogen substitutions. Processes that produce dioxin-related com- pounds usually produce more than one member of this class.
And what is known of the toxicol- ogy of these compounds suggests that their toxic action may oper- ate via the Ah receptor, with dif- ferences between congeners only in the slope of the dose-response relations. However, toxicologic evaluation of only a few conge- ners is available. Furthermore, TCDD in animal models is a much more potent promoter than initiator. So it is also plausi- ble that the carcinogenic re- sponse to TCDD exposure in humans is dependent upon expo- sure to other initiators. These considerations are of relevance to any plans to conduct epidemi- o logic studies in Vietnam. The carcinogenic herbicides in Viet- nam was correct. In our view, it is now time to determine system- atically the distribution and ex- tent of TCDD exposure in Vietnam and, if substantial, as- sess health effects and seek pre- ventive inter ventions. Vietnam may have more pressing public health problems on which to focus, but many in the United States may feel a special respon- sibility to join the ongoing re- search efforts by inadequately funded investigators from Euro- pean and other countries, espe- cially those from France and the World Health Organization’s In- ternational Agency for Research on Cancer. It is also the case that scientific information about TCDD effects gleaned from stud- ies in Vietnam will help industri- alized nations attempting to deal with widespread contamination by dioxin and related com- pounds in their own environ- ments. Regardless of our intentions, Agent Orange may still be operative in Vietnam. References 1. Schecter A, Dai LC, Thuy LTB, et al. Agent Orange and the Vietnamese: the persistence of elevated dioxin levels in human tissues. Am J Public Health. 1995;85:516-522.
2. Chlorinated Dioxins and Furans in the General US Population: National Human Adipose Tissue Survey. Washington, DC: Environmental Protection Agency, 1990.
3. Schecter A, Papke 0, Lis A, Ball M.
Chlorinated dioxin and dibenzofuran lev- els in US human placentas and fetal tis- sue in comparison with US adult popula- tion dioxin levels. In: Fiedler H, Hutzinger 0, Birnbaum L, Lambert G, Needham L, Safe S, eds. Dioxin ‘94: 14th International Sympo sium on Chlorinated Dioxins, PCB and Related Compounds. Kyoto, Japan; 1994:66- 66.
4. Smith RM, O’Keefe PW, Aldous KM, Briggs R, Hilker DR, Connor S. Mea- surement of PCDFs and PCDDs in air samples and lake sediments at several locations in upstate New York. Chemo- sphere.
1992; 25(1-2):95-98. cocktail of cocarcinogens may de- termine the pattern and extent of TCDD effects on cancer risk.
Given these findings and qualifications, do the levels of TCDD reported in Vietnamese by the current authors sug gest a substantial increase in cancer risk? Since the sampling of per- sons and groups was from pooled specimens and not representa- tive, it is not possible to deter- mine the body burden of any particular population in Viet- nam. However, if we use the Hamburg results to extrapolate, 9 then persons with tissue or blood lipid TCDD levels above 500-600 ppt (presumably during actual spraying in the 1960s) are at dramatically increased risk of cancer. Given the TCDD levels of 630- 1570 ppt reported in samples of human milk lipid in 1970, it is then plausible that there is a subpopulation in Viet- nam at very elevated cancer risk. This increased risk may apply to a number of adverse outcomes as well. Pooled blood samples with TCDD levels of 33 ppt in 1992 could, depending upon the distribution of levels in individu- als, include a subset of up to 15% with earlier heavy expo- sures. (Tissue concentrations of TCDD in humans decline by 50% every 6 to 7 years after ex- posure ceases.) These high level exposures could have resulted from consumption of TCDD-con- taminated food for several years during the period of spraying. There may be, how ever, only a small number of such persons.
The number and distribution of exposure using biomarkers remain to be determined by systematic epidemiologic studies.
At this point, it appears that Ber trand Russell’s charge that the US military was spraying ⏐ VOICES FROM THE PAST ⏐ American Journal of Public Health | October 2014, Vol 104, No. 10 1860 | Voices From the Past | Clapp et al. 5. Lucier G, Clark G, Hiremath C, Tritscher A, Sewall C, Huff J.
Carcino- genicity of TCDD in animals. Toxicol Ind. Health.1993;9:631-668.
6. Rao MS, Subbarao V, Prasad JD, Scarpelli DC. Carcinogenicity of 2,3,7,8-tetrachloro dibenzo-p-dioxin in the Syrian golden ham ster. Carcinogenesis. 1988;9:1677-1679.
7. Manz A, Berger J, Dwyer JH, Flesch- Janys D, Nagel S, Waltsgott H. Cancer mortality among workers in chemical plant contaminated with dioxin. Lancet 1991;338:959- 964.
8. Dwyer JH, Flesch-Janys D, Berger J, Manz A. Duration of occupational ex- posure to dioxin contaminated sub- stances and risk of cancer mortality.
Am J Epidemiol. 1992; 136:1018. 9. Flesch-Janys D, Berger J, Manz A, Nagel S, Waltsgott H. Quantification of exposure to dioxins and furans in a cohort of an herbicide producing plant in Hamburg. Chemosphere. 1994;25:
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10. Zober A, Messerer P, Huber P.
Thirty-four year mortality follow-up of BASF employees exposed to 2,3,7,8- TCDD after the1953 accident. lnt Arch Occup Environ Health. 1990;62: 139-157. 11. Hardell L, Sandstrom A. Case con- trol study: soft-tissue sarcomas and expo- sure to phenoxyacetic acids or chlorophe- nols. Br J Cancer. 1979;39:711-717.
12. Young AL, Reggiani GM, eds. Agent Orange and Its Associated Dioxin: 20. Axelson 0. Exposure to phenoxy herbicides and chlorinated dioxins and cancer risk: an inconsistent pattern of facts and frauds? In: Renzoni A, Mattei N, Lari L, Fossi MC, eds. Contaminants in the Environment. Boca Raton, Fla: Lewis Publishers; 1994:213-220. 21. Poland A, Palen D, Glover E. Tumor promotion by TCDD in skin of HRS/ J mice. Nature. 1982;300:271-273.
22. Alsharif NZ, Hassoun E, Bagchi M, Lawson T, Stohs SJ. The effects of anti- TNF alpha antibody and dexamethasone on TCDD-induced oxidative stress in mice. Pharmacology. 1994;48:127-36.
23. Brewster DW, Bombick DW, Matsumura F. Rabbit serum hypertriglyc- eridemia after administration of 2,3,7,8-tetrachlorod ibenzo-p-dioxin (TCDD). J Toxicol Environ Health. 1988;25:495-507.
24. Flesch-Janys D, Berger J, Gum P, et al. Exposure to polychlorinated diox- ins and furans (PCDD/F) and mortality in a cohort of workers from an herbi- cide plant in Hamburg, Germany. Am J Epidemiol. In press.
25. Lynge E. Cancer in phenoxy herbi- cide manufacturing workers in Denmark, 19 4 7 - 87-an update. Cancer Causes Control. 1993;4:261-72. 26. Committee of Principal Investigators. WHO cooperative trial on primary pre- vention of ischaemic heart disease using clofibrate to lower serum cholesterol:
mortality follow up. Lancet. 1980;ii:379. Assess ment of a Controversy. Amster- dam, The Netherlands: Elsevier Science Publishers;1988. 13. Fingerhut MA, Halperin WE, Mar- low DA, Piacitelli LA, Honchar PA. Can- cer mortal ity in workers exposed to 2,3, 7,8- Tetrachlo- rodibenzo-p-dioxin. N Eng J Med. 1991;324: 212-218.
14. Bertazzi PA, Zocchetti C, Pesatori AC, Guercilena S, Sanarico M, Radice L. Ten-year mortality study of the popu- lation involved in the Seveso Incident in 1976. Am J Epidemiol. 1989;129:1187- 1200. 15. Bertazzi PA, Zocchetti C, Pesatori AC, Guercilena S, Sanarico M, Radice L. Mortality in an area contaminated by TCDD following an industrial inci- dent.
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16. Saracci R, Kogevinas M, Bertazzi PA, et al. Cancer mortality in workers ex- posed to chlorophenoxy herbicides and chlorophe nols. Lancet. 1991;338:1027- 1032.
17. Smith AH, Fisher DO, Giles HJ, et al. The New Zealand soft tissue sarcoma case control study: interview findings concerning phenoxyacetic acid exposure.
Chemo sphere. 1983;12:565-571.
18. Smith AH, Pearce NE, Fisher DO, et al. Soft tissue sarcoma and exposure to phenoxyherbicides and chlorophe- nols. JNCI. 1984;73:1111 - 1117. 19. Doll R. Are we winning the fight against cancer? An epidemiologic assess- ment. Eur J Cancer. 1990;26:500-505. On Agent Orange in Vietnam | Richard W. Clapp, DSc, MPH, Carole Baraldi, EdD, RN, Jean Grassman, PhD, Franklin Mirer, PhD, Daniel Robie, PhD, and Susan Schnall, RN THE 1995 EDITORIAL “AGENT Orange in Vietnam” by Dwyer and Flesch-Janys was a penetrat- ing summary of what was then known about the impact of this toxic defoliant on the workers who manufactured it, the US mili- tary personnel who were exposed to it, and the Vietnamese popula- tion who had continuing exposure during and after the American War in Vietnam. The two authors cited many of the key scientific articles published in the previous two decades and anticipated the eventual classification of 2,3,7,8-TCDD, the most potent dioxin contaminant found in Agent Orange, as carcinogenic to humans. 1 Since the 1995 editorial, the mechanistic understanding of tumor promotion by TCDD and other chemicals has advanced, 2 and some of the epidemiological studies have been updated, 3–5 but the basic story has remained the same over the past two de- cades. The scientific evidence has matured and Vietnam veter- ans are now compensated for a variety of cancer and noncancer health effects presumed to be at- tributable to Agent Orange expo- sure. 6 One presumptively compensated health effect is spina bifida in the offspring of male Vietnam veterans. Severe birth defects are also seen in Vietnamese children.The continuing impact of re- sidual contamination in parts of Vietnam, anticipated by Dwyer and Flesch-Janys in their edito- rial, remains to be addressed.
The American Public Health As- sociation policy resolution, passed in 2007, was a step in the right direction, but much more needs to be done to right the wrongs visited on the Vietnamese people by the use of this toxic herbicide. continued on page 1861 Copyright ofAmerican JournalofPublic Health isthe property ofAmerican PublicHealth Association anditscontent maynotbecopied oremailed tomultiple sitesorposted toa listserv without thecopyright holder'sexpresswrittenpermission. However,usersmayprint, download, oremail articles forindividual use.
