Veterans' Diseases Associated with Agent Orange Exposure
According to the Veterans' Administration website, the two active ingredients of Agent Orange in equal amounts are 2,4-D and 2,4,5-T. Minute traces of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) contaminated 2,4,5-T, but not 2,4-D. According to HSDB, 2,4,5-T produced prior to 1965 contained 30 mg/kg or more of TCDD. 2,4,5-T is available now with dioxin content <0.05 mg/kg. 2,4,5-T has not been produced in the US since 1985 when all registrations were terminated. The structure of TCDD is shown to the right.
On this page, the Veterans' Administration recognizes 14 diseases to be associated with Agent Orange. Of these 14 diseases, only five of them are listed by the National Academy of Sciences (NAS) committee as having "Sufficient Evidence of an Association." The other nine are listed as having "Limited or Suggestive Evidence of an Association." The latest report of the NAS committee is called "Veterans and Agent Orange: Update 2008" and is available on the web at http://www.nap.edu/catalog/12662.html.
The five diseases listed by the NAS committee as having sufficient evidence of an association are the same ones listed in the 2004 and 2006 updates, but chronic lymphocytic leukemia has been clarified since the Update 2006. The five diseases are:
- Soft-tissue sarcoma (STS);
- Non-Hodgkin's lymphoma;
- Chronic lymphocytic leukemia (including hairy cell leukemia and other chronic B-cell leukemias);
- Hodgkin's disease;
- Chloracne;
The agent-disease links in Haz-Map pertaining to cancer are based on the International Agency for Research on Cancer (IARC) classifications and the chapter on "Occupation" in Cancer Epidemiology and Prevention, 3rd Edition, edited by Schottenfeld and published in 2006. IARC classifies chlorophenoxy herbicides, which includes 2,4-D and 2,4,5-T as possibly carcinogenic to humans (Group 2B). IARC classifies TCDD (2,3,7,8-tetrachlorodibenzo-para-dioxin) as carcinogenic to humans (Group 1). All other polychlorinated dibenzo-para-dioxins are classified as Group 3 (not classifiable).
Table 18-3 in Cancer Epidemiology and Prevention is the basis for the occupational cancer links shown in Haz-Map. TCDD is shown in that table. The established occupational cancer site for that agent is shown as "all sites combined." The table shows in italics the following sites: Lung, Non-Hodgkin lymphoma, and Sarcoma. According to the footnote for that table, "Italics indicate that the evidence was suggestive." Neither Siemiatycki et al in the chapter on "Occupation" in Schottenfeld nor the IARC Summary on TCDD mention chronic lymphocytic leukemia or Hodgkin's disease as being associated with TCDD exposure.
Soft Tissue Sarcoma
In the Schottenfeld chapter on "Soft Tissue Sarcoma," the authors write, ". . . there continues to be conflicting evidence of an association between exposure to dioxin and soft tissue sarcoma. . . . In sum, the effects of dioxin and similar compounds associated with risk for the development or death from STS have ranged from 'no effect' to a 10-fold increased risk. It is critical to continue to examine this potential association as 'human activities result unavoidably in population exposure.'"
In the Rosenstock chapter on "Pesticides and Related Compounds," the authors write, "Current or previous exposure to TCDD should be considered in the differential diagnosis of lesions compatible with chloracne, non-Hodgkin's lymphoma, and soft tissue sarcoma."
"Exposure to dioxin and to herbicides that contain phenoxyacetic acid at high doses (farm workers work closely with these chemicals) may also be risk factors, but this is not known for certain. There is no evidence that herbicides (weed killers) or insecticides, at levels encountered by the general public, cause sarcomas." [American Cancer Society]
"A number of studies conducted in Sweden suggest an association between phenoxy herbicides and soft-tissue sarcoma, but these studies have not been consistently replicated in other populations." [LaDou, p. 575]
"Overall our data provide us with poor evidence of the association between dioxin exposure and soft tissue sarcoma in agreement with a recent case-control study which failed to show an increased risk at comparable exposure levels." [Pesatori et al. (2009), p. 9]
Non-Hodgkin Lymphoma
"Some studies have suggested that chemicals such as benzene and certain herbicides and insecticides (weed- and insect-killing substances) may be linked with an increased risk of non-Hodgkin lymphoma. Research to clarify these possible links is still in progress." [American Cancer Society Website]
"Technically rigorous studies have reported high rates of NHL in agricultural workers exposed to phenoxyacetic acid herbicides, chlorophenols (e.g., 2,4,5-T and 2,4-D), or both in the US, Canada, and Sweden since 1977. However, other reliable studies from New Zealand have repeatedly failed to find these associations. A possible interpretation of the discrepancy is the role of various confounding factors such as co-carcinogens and oncogenes in the various populations, although no specific explanation has been documented. A reasonable conclusion at this time is that NHL is probably causally associated with exposure to the herbicides listed above; HD, MM [multiple myeloma], an leukemias cannot be linked specifically to herbicides, although the higher occupational incidence among agricultural workers as a whole is clear." [Rosenstock, p. 752]
Hodgkin Lymphoma (HL)
"There is very little evidence linking risk of HL to any occupation, specific occupational exposures, or environmental chemical exposures. . . . In conclusion, occupational exposures as causes of HL have been studied extensively and none has emerged as an established risk factor. If valid causal associations exist of substantial magnitude, they should have been uncovered by now, given the large number of case-control and occupational cohort studies that have been done." [Schottenfeld, p. 885-6]
Chronic Lymphocytic Leukemia (CLL)
"Some studies have linked exposure to Agent Orange, an herbicide used during the Vietnam War, to an increased risk of CLL. Some other studies have suggested that farming and long-term exposure to some pesticides may be linked to an increased risk of CLL, but more research in this area is needed." [American Cancer Society Website]
Some studies have implicated farming and related exposures with elevated risks for CLL. Although based on small studies, specific exposures have included DDT, animal breeding, and employment in flour mills. Insecticides, carbamates, and phosphates were linked with CLL in a highly agricultural area in Italy." [Schottenfeld, p. 857]
"Although some environmental associations have been noted, this disorder has not been convincingly linked to any myelotoxic agent." [Rosenstock, p. 750]
A Unique Carcinogen: TCDD
"There are few examples of agents which cause an increase in cancers at many sites; examples are smoking and ionizing radiation in the atomic bombing survivors (for which, however, there are clearly elevated risks for certain specific cancer sites). This lack of precedent for a multi-site carcinogen without particular sites predominating means that the epidemiological findings must be treated with caution; on the other hand, the lack of precedent cannot preclude the possibility that in fact 2,3,4,8-TCDD, at high doses, does act as a multi-site carcinogen." [IARC Summary on TCDD]
"As to the mechanisms by which TCDD exerts its carcinogenic effects, it is thought to act primarily as a tumor promoter." [Veterans and Agent Orange: Update 2008, p. 206]
"Experimental data indicate that 2,3,7,8-TCDD and probably other PCDDs and PCDFs are not direct-acting genotoxic agents." [IARC Summary on TCDD]
The German MAK Commission classifies TCDD as class 4, defined as: "Substances with carcinogenic potential for which genotoxicity plays no or at most a minor role. No significant contribution to human cancer risk is expected, provide the MAK value is observed. The classification is supported especially by evidence that increases in cellular proliferation or changes in cellular differentiation are important in the mode of action. To characterize the cancer risk, the manifold mechanisms contributing to carcinogenesis and their characteristic dose-time-response relationships are taken into consideration." [Guide to Occupational Exposure Values, p. xi] The time-weighted average is set a 0.000000001 mg/m3, measured as inhalable fraction of the aerosol. [Guide to Occupational Exposure Values, p. 180]
Serum Levels of TCDD in Exposed Populations
In Seveso, Italy, site of the accidental release of TCDD in 1976, the background level was 5 parts per trillion (ppt) and the level in exposed children was 19,110 ppt. [Schottenfeld, p. 962]
Mean levels in exposed workers were 2000 ppt in the US cohort, 1434 ppt in accident workers in the Dutch cohort, and 1008 ppt in the BASF workers (Germany) with chloracne. Levels were up to 2252 ppt in the Boehringer cohort (Germany). These levels are comparable to levels in rats that developed hepatocellular nodules when fed 10 ng/kg bw daily (1500-2000 ppt) and that developed hepatocellular carcinoma when fed 100 ng/kg/bw daily (5,000-10,000 ppt). [IARC Summary on TCDD]
"The levels [in the international cohort] do indicate, however, that production workers have higher serum TCDD levels than sprayers, and substantially higher levels than the general population (table 2)." [Kogevinas et al. (1997)]
The serum levels in veterans of Operation Ranch Hand, the Air Force unit responsible for the aerial spraying of herbicides in Vietnam from 1962 to 1971, were <94 ppt in the low exposure category and >94 ppt in the high exposure category. The median levels were 52.3 ppt for the low group and 195.7 for the high group. These initial serum dioxin levels were calculated by extrapolating from the levels in blood drawn in 1987, assuming a first order model for dioxin elimination and a constant half-life of 8.7 years. "Overall, we found no consistent evidence of a dose-response gradient and no significant increase in cancer risk in the High dioxin exposure category, the subgroup of greatest a priori interest." [Serum Dioxin and Cancer in Veterans of Operation Ranch Hand]
"We found no meaningful or consistent association between dioxin exposure and prevalence of acne without or with regard to anatomical location. These results suggested that exposure of Ranch Hand veterans to dioxin was insufficient for the production of chloracne or perhaps the exposure may have caused chloracne that resolved and was currently undetectable." [Serum dioxin, chloracne, and acne in veterans of Operation Ranch Hand]
All Seveso patients with severe chloracne had TCDD levels >12,000 ppt. Nine production workers with a history of exposure to polychlorinated dibenzodioxins and chloracne in 1971 to 1973 had TCDD levels of 340 ppt in 1990. [Ellenhorns's Medical Toxicology, p. 1642]
"Although toxic effects, notably chloracne, have been observed in manufacturing plant workers, these effects have not been observed in formulators or applicators regularly exposed to 2,4,5-T or other chlorophenoxy compounds." [EPA Pesticides, p. 95]
"Among Seveso residents, despite high serum 2,3,7,8-TCDD levels, the chloracne resolved in all but one person by1983. However, for TCP workers at Nitro, WV, USA, plant, Moses et al. (1984) reported that the mean duration of chloracne was 26.1 +/- 5.9 years. . . Mocarelli et al. (1991) described chloracne in people from Seveso Zone A who had 2,3,7,8-TCDD levels in serum lipids ranging from 828 to 56,000 *ng/kg (sampled within one year of the reactor release). . . . a threshold level above which chloracne occurs has not been established." [Full IARC Mongraph on TCDD, p. 228]
*Note the 1 ng/kg and 1pc/g are both equivalent to 1 part per trillion (ppt).
IARC's Logic for Studying High-Exposure Populations
"Causal inference about the effects of chemicals can best be drawn from studies with well documented exposures. It is important to focus on human studies in which it is clear that exposure to the chemical in question actually occurred. The ideal is to have biological markers of such exposure. In the case of 2,3,7,8-TCDD, the long half-life in humans means that recent biological measurements allow assessment of past human exposure, In addition, chloracne may be an indication of exposure for some studies, although it absence does not rule out exposure." [Full IARC Mongraph on TCDD, p. 191]
"The most important studies for the evaluation of the carcinogenicity of 2,3,7,8-TCDD are four cohort studies of herbicide producers (one each in the United States and the Netherlands, two in Germany), and one cohort of residents in a contaminated area from Seveso, Italy. These studies involve the highest exposures to 2,3,7,8-TCDD among all epidemiological studies, although the exposures at Seveso were lower and the follow-up shorter than those in the industrial settings. In addition, the multi-country cohort study from IARC is of special interest because it includes three of four high-exposure cohorts and other industrial cohorts, many of them not reported in separate publications, as well as some professional applicators. Most of the four industrial cohorts include analyses of sub-cohorts considered to have the highest exposure and/or longest latency. These cohorts, and their respective high-exposure sub-cohorts, are the focus of the summary here. Additional studies of herbicide applicators, both cohort and case-control studies, who have considerably lower exposures to 2,3,7,8- TCDD, are not considered critical for the evaluation." [IARC Summary on TCDD]
Important Studies Used by IARC for the Evaluation of the Carcinogenicity of TCDD
International Cohort
Industrial populations (high-exposure subcohorts)
Seveso accident
Conclusions of IARC
"Overall, the strongest evidence for the carcinogenicity of 2,3,7,8-TCDD is for all cancers combined , rather that for any specific site. The relative risk for all cancers combined in the most highly exposed and longer-latency sub-cohorts is 1.4. While this relative risk does not appear likely to be explained by confounding, this possibility cannot be excluded." [IARC Summary on TCDD]
"In view of the results mentioned above, it should be noted that the present background levels of 2,3,7,8-TCDD in human populations (2-3 ng/kg) are 100 to 1000 times lower than those observed in this rat carcinogenicity study. Evaluation of the relationship between the magnitude of the exposure in experimental systems and the magnitude of the response (i.e., dose-response relationships) do not permit conclusions to be drawn on the human health risks from background exposures to 2,3,7,8-TCDD." [IARC Summary on TCDD]
Implications for Agent-Disease Links in Haz-Map
Based on Cancer Epidemiology and Prevention and the IARC monograph, Haz-Map shows that TCDD is an established occupational carcinogen, but no specific cancers are linked. "Limited or Suggestive Evidence of an Association" does not meet the Haz-Map criteria for an established occupational disease. Nor do the four cancers with "Sufficient Evidence of an Association" according to the NAS committee meet this criteria based on the conclusions in Cancer Epidemiology and Prevention and the IARC monograph. The only disease linked to TCDD in Haz-Map is chloracne. According to the MAK classification of TCDD as a class 4, non-genotoxic carcinogen, there exists a threshold below which "no significant contribution to cancer risk is expected." Above that threshold, workers exposed to high concentrations, e.g., from industrial accidents, were at risk for chloracne and all cancers combined. These risks were not shared by pesticide applicators who were exposed to relatively low concentrations of TCDD that contaminated 2,4,5-T and some other herbicides in the past.
I have revised in Haz-Map the disease "Chloracne" and the agent "2,3,7,8-Tetrachlorodibenzo-p-dioxin." These will be changed on the web with the next update later in 2011.
Additional Comments:
Chloracne: Characteristic of chloracne are comedones and epidermal cysts around the eyes, retroauricular area, and on the scrotum. Chloracne is caused by chlorinated (or brominated) aromatic hydrocarbons including polylychlorinated dibenzodioxins (dioxins or PCDDs), biphenyls (PCBs), and dibenzofurans (PCDFs). A study of workers with chloracne in a large chemical factory manufacturing hexachlorobenzene in China found the blood levels were between 650 and 1200 parts per trillion (ppt). [PMID 10583118] Acneform lesions may appear as early as 1 to 3 weeks after dioxin exposure. Most cases of chloracne resolve within 1 to 3 years. [ATSDR Case Studies: PCB Toxicity] All patients with chloracne living in the most contaminated area of Seveso, Italy had TCDD levels of 828 to 56,000 ppt, and the chloracne had resolved in all but one patient within 7 years of the accident; [IARC: TCDD] Chloracne was not found in veterans of Operation Ranch Hand, the Air Force unit responsible for the aerial spraying of TCDD-contaminated herbicides in Vietnam from 1962 to 1971 [PMID 9814716], nor in herbicide applicators such as the group studied in New Zealand [PMID 15613606]. Median serum levels for the high group in Operation Ranch Hand were 195.7 ppt. Mean serum levels for the applicators highly exposed to 2,4,5-T in New Zealand were 53.3 ppt. "Although toxic effects, notably chloracne, have been observed in manufacturing plant workers, these effects have not been observed in formulators or applicators regularly exposed to 2,4,5-T or other chlorophenoxy compounds." [EPA Pesticides, p. 95]
TCDD Sources/Uses: No commercial uses; By-product of waste incineration, pulp and paper mill bleaching, and chemical production of 2,4,5-T, hexachlorophene, vinyl chloride, trichlorophenol, and pentachlorophenol; [CDC Report, p. 377] High-exposure populations in the past included workers producing the herbicide 2,4,5-T and residents in Seveso, Italy contaminated by a factory explosion in 1976; [IARC Summary on TCDD]
TCDD: Dioxins accumulate in adipose tissue; they are animal carcinogens. Chloracne is the only overt clinical sign of dioxin exposure in humans. Of the 22 isomers of tetra-chlorinated dioxin, 2,3,7,8-TCDD is the one that contaminated the production of 2,4,5-trichlorophenol, Silvex, and 2,4,5-T. In acute animal studies, TCDD is toxic to the liver. Recent studies failed to find an association between TCDD and porphyrin levels; [LaDou, p. 474-8] Causes adverse reproductive effects in animals; No documented evidence of congenital abnormalities in humans; [REPROTOX] "There are no firmly established relationships between concentrations (mainly considering TCDD) and health effects in people. Observations following industrial and accidental exposures have suggested that acute exposures resulting in serum concentrations of about 800 pg/g of lipid might be necessary to induce clinical effects such as chloracne, although levels in the thousands of pg/g of lipid do not always produce this effect." [CDC Report, p. 384] Mean levels in exposed workers were 2000 ppt in the US cohort, 1434 ppt in accident workers in the Dutch cohort, and 1008 ppt in the BASF workers (Germany) with chloracne. Levels were up to 2252 ppt in the Boehringer cohort (Germany). These levels are comparable to levels in rats that developed hepatocellular nodules when fed 10 ng/kg bw daily (1500-2000 ppt) and that developed hepatocellular carcinoma when fed 100 ng/kg/bw daily (5,000-10,000 ppt). [IARC Summary on TCDD]
Important Principles of Toxicology Central to Conclusions:
"The characterization of an occupation or industry group as a 'high-risk group' is strongly rooted in time and place. For instance, the fact that some groups of nickel refinery workers experienced excess risks of nasal cancer does not imply that all workers in all nickel refineries will be subject to such risks. The particular circumstances of the industrial process, raw materials, impurities, and control measures may produce risk in one nickel refinery but not in another or in one historic era but not in another." [Siemiatycki et al. "Occupation" in Schottenfeld]
"Our overall findings are consistent with an increase in cancer risks induced by TCDD in people with past TCDD exposures sufficient to produce other signs of toxicity." [Ott & Zober. (1996), p. 612] The findings of this study and other high-exposure studies used by IARC are in agreement with the statement of the father of modern toxicology: "What is there that is not poison? All things are poison and nothing is without poison. Solely the dose determines that a thing is not a poison." [Paracelsus, quoted in Casarett & Doull's Toxicology, p. 14]
Last Revised April 30, 2011