Association with soft-tissue sarcoma

A, To date, exposure to phenoxy herbicides and chlorophenols has been shown in some studies to be associated with soft tissue sarcoma, lymphoma, stomach cancer, and nasal cancer, but no outcome has been conclusively established or rejected. 

These data alone suggest a role for dioxin exposure to contribute to a carcinogenic response but do not confirm a causal relationship between exposure to dioxin and increased cancer incidence. Available human studies alone cannot demonstrate whether a cause and effect relationship between dioxin exposure and increased incidence of cancer exists. Many of the earlier epidemiological studies that suggested an association with soft tissue sarcoma were criticized for a variety of reasons. The fact that similar results were obtained in independent studies of differing design and evaluating... 

U.S.A. and Seveso, Italy. Published medical reports have described chloracne, asthenia, neurological problems, and hepatotoxicity, but some of these studies have not had adequate comparison populations. Some recent epidemiologic studies have concluded that no outcomes could be attributed to dioxin exposure, but others have found associations of exposure with soft tissue sarcoma, lymphoma, nasal and stomach cancer. These studies are described. 

Several studies have assessed the plausibility of the association between soft tissue sarcomas and exposure to phenoxy herbicides and chlorophenols. Table VI lists two case-control studies conducted in Sweden, which selected controls from the general population and concluded that exposure to the herbicides or to chlorophenols resulted in a greater than 5-fold excess in soft tissue sarcomas (38-39). A New Zealand study found no association with exposure to phenoxy herbicides (40). This study drew controls from other cancer cases in the National Cancer Registry of New Zealand. However, in the New Zealand study, a 5-fold excess of STS was noted in persons who handled animal pelts, which are sometimes preserved with trichlorophenols containing isomers of dioxin. 

The presence of TCDD in 2,4,5-T is believed to be largely responsible for other human toxicities associated with the herbicide. There is epidemiologic evidence indicating an association between occupational exposure to the phenoxy herbicides and an excess incidence of non-Flodgkin s lymphoma. The TCDD contaminant in these herbicides seems to play a role in a number of cancers such as soft tissue sarcomas, lung cancer, Flodgkin s lymphomas, and others. 

When these three cancers (soft-tissue sarcoma, non-Hodgkin s leukemia, and Hodgkin s disease) are considered as a whole, it is noteworthy that the strongest evidence for an association with exposure to phenoxy herbicides is the series of case-control studies conducted by Hardell [Lennart Harden, a Swedish physician] and colleagues and the cohort studies of herbicide applicators and agricultural workers.25 26... 

IOM should re-examine its decision that there is sufficient evidence for associations between herbicides and soft-tissue sarcoma, non-Hodgkin s leukemia, and Hodgkin s disease, beginning with an examination of Hardell s exposure classification scheme. Hardell s own analysis showed that workers he had classified as exposed had the same low body burdens as found in people who were classified as unexposed. The IOM should ask experts on cancer mechanisms and cancer cause and prevention to review the Hardell and other studies about herbicides and those tumors. 

Associations with chlorophenols were, however, analysed in two case-control studies nested within 24 of the 36 cohorts of the lARC study. These compared 11 cases of soft-tissue sarcoma and 32 cases of non-Hodgkin lymphoma with 55 and 158 controls, respectively (Kogevinas et al., 1995). Exposure to chlorophenols, phenoxy acid herbicides, dibenzodioxins and -furans and other agents was assessed by a team of industrial hygienists (Kauppinen et al., 1994). Odds ratios for non-Hodgkin lymphoma, not adjusted for exposure to other agents, were 1.3 (95% CI, 0.5-3.1) for any chlorophenol, 2.8 (0.5-17.0) for pentachlorophenol and 1.0 (0.3-3.1) for 2,4-dichlorophenol. No excess risk was found in relation to other chlorophenols, but the munber of exposed cases was small. The odds... 

These investigations have shown significant associations with several types of cancer, but the most consistent findings have been for soft-tissue sarcoma and non-Hodgkin lymphoma. Although the odds ratios in some case-control studies may have been inflated by recall bias, this cannot explain all of the findings. Nor are they likely to have arisen by chance. It is not possible, however, to exclude a confounding effect of polychlorinated dibenzo-para-dioxins which occur as contaminants in chlorophenols. 

In humans, 2,4-D in large doses can cause coma and generalized muscle hypotonia. Rarely, muscle weakness and marked myotonia may persist for several weeks. With 2,4,5-T, coma may occur, but the muscular dysfunction is less evident. In laboratory animals, signs of liver and kidney dysfunction have also been reported. There is limited evidence that occupational exposure to phenoxy herbicides is associated with an increased risk of non-Hodgkin s lymphoma the evidence for soft-tissue sarcoma, however, is considered equivocal. 

An extensive review of the published literature concluded that there is reasonable evidence that occupational exposure to phenoxy herbicides is associated with increased risk for non-Hodgkin s lymphoma. Evidence is weaker or conflicting for soft-tissue sarcomas. In another review, however, case-control epidemiological studies were called inconclusive occupational exposure studies have generally not shown associations between exposure to 2,4-D and cancer. 

Further studies will have to be conducted to determine whether exposure to these types of chemicals are associated with a higher incidence of soft tissue sarcomas. 

Agent Orange was composed of equal parts of esters of 2,4,5-T and 2,4-D. Table VI presents results from an interview study of soft tissue sarcoma cases from the New York State Cancer Registry with controls selected from New York driver s license registration files (41). Greenwald et al. found no association between STS and... 

The hypothesis that phenoxy herbicides are a cause of soft tissue sarcoma (STS) also commenced in Sweden. Three case-control studies conducted by the same investigators reported relative risks of 3.3 to 5.7 for such an association (Table V) (42-44 ). However, as with malignant lymphoma, it is difficult to explain such dramatic risks associated with short term exposures. Moreover, Wiklund and Holm (45) found no overall risk increase from STS among Swedish agriculture and forestry workers (RR—0.9 95% Cl 0.8-1.0). 

HUMANS EXPOSED TO MATERIALS REPORTED TO BE CONTAMINATED WITH TCDD HAVE DEVELOPED CHLORACNE AND OTHER SIGNS OF SYSTEMIC POISONING. SOFT TISSUE SARCOMA HAS BEEN OBSERVED IN EXCESS AMONG WORKERS EXPOSED TO PHENOXY HERBICIDES. THESE DATA ARE INCONCLUSIVE REGARDING TCDD TOXICITY IN HUMANS BECAUSE THE POPULATIONS STUDIED HAD MIXED EXPOSURES MAKING CAUSAL RELATIONSHIPS BETWEEN EXPOSURE AND EFFECT UNCLEAR. THE DATA ARE, HOWEVER, SUGGESTIVE OF AN ASSOCIATION BETWEEN EXPOSURE TO PHENOXYACETIC HERBICIDES CONTAMINATED WITH TCDD AND EXCESS LYMPHOMA AND STOMACH CANCER. ATTEMPTS TO ASSOCIATE REPRODUCTIVE EFFECTS WITH TCDD EXPOSURE ARE INCONCLUSIVE BECAUSE OF THE INADEQUATELY DEFINED POPULATIONS STUDIED AND THE DIFFICULTIES OF DEFINING EXPOSURE. 

Ryu, R.K.N., Bovill, E.G. Jr, Skinner, H.B. et al. (1987) Soft tissue sarcomas associated with aluminum oxide ceramic total hip arthroplasty. A case report. Clin. Orthop. 216, 207-212. 

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