Phenoxy herbicides associations with exposure

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... 

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. 

In summary, studies of STS have reported both positive and negative findings. All of the studies had limitations in statistical power or assessment of exposure. To date, no definitive answer exists as to whether STS is associated with exposure to phenoxy herbicides or chlorophenols. The situation is similar for lymphoma, stomach and nasal cancer. 

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. 

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... 

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. 

In spite of their record of producing no detectable harm to humans, the phenoxy herbicides 2,4-dichlorophenoxy acetic acid (2,4-D) and 2,4,5-trichlorophenoxy acetic acid (2,4,5-T) have acquired a less than desirable reputation. This reputation has been the result of their association with low levels of impurities. They have commonly been used as a mixture, which contains trace amounts of highly toxic 2,3,7,8-tetrachlorodibenzo-jj-dioxin, a minor product in the manufacturing of 2,4,5-T. In early production of 2,4,5-T a low level of dioxin was retained. Today s manufacturing process produces 2,4,5-T with no more than 0.1 ppm of the 2,3,7,8 tetrachlorodibenzo-]D-dioxin. This association with toxic dioxin and confusion of the public and the media regarding these issues have led to public distrust in the safety of using phenoxys and to the need to establish clearly the extent of human exposure to these compounds as well as the resulting effects of this exposure. 

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. 

As discussed earlier, several studies have associated pesticide exposure with cancers. NHL has been associated with phenoxy herbicide exposure and specifically with exposure to 2,4-D. 80,98 " ... 

TCDD, the most toxic of the 75 dioxin isomers and possibly the most toxic manufactured chemical, contaminates phenoxy herbicides during the production process (Demers and Perrin 1995 Klaassen 1985). Conflicting literature addresses TCDD lethality in humans. Some reviews deny that human deaths result from systemic effects of TCDD (Demers and Perrin 1995). Others describe successful suicides with phenoxy herbicides (Nielsen et al. 1965). Despite extensive reports of numerous medical conditions from TCDD, the literature confirms only chloracne and transient mild hepatotoxicity in humans. Table 1-6 lists the various, but unconfirmed, signs and symptoms associated with human poisonings. Table 1-7 lists the unconfirmed psychiatric symptoms attributed to TCDD exposure. 

These studies will assess possible associations of these cancers with use of phenoxy herbicides in Kansas, with Vietnam service, and with exposure to Agent Orange. 

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. 

A study in Kansas (12) has produced evidence supporting an association between exposure to 2,4-D and malignant lymphoma. A relative risk of 2.3 (95% Cl 1.3-4.3) was found for those who had used phenoxy herbicides (almost all 2,4-D) (Table IV). However, a relative risk of 6.0 (95% Cl 1.9-19.5) was found for those who had used any herbicide (not necessarily 2,4-D) for more than 20 days per year. This association was largely confined to early years of herbicide use when no independent confirmation of exposure was available. There was no association with number of years of herbicide use after adjustment for days of herbicide use per year, which tends to reduce the likelihood of a real association. 

A subsequent study in Washington State involving 576 cases of NHL reported a relative risk of 1.07 (95% Cl 0.8-1.4) associated with any past exposure to phenoxy herbicides (3 ). This estimate increased to 1.7 (95% Cl 1.04-2.8) for exposure of more than 15 years during the period prior to 15 years before diagnosis (Table... 

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). 

One case-control study in Italy has reported an increased risk of STS for women who worked in rice fields (55.). While it has been suggested that this study provides evidence implicating phenoxy herbicides, at best the evidence is very weak, since the association was based on 3 women who worked in the rice fields during the 1950s. There is no suggestion that they had any direct contact with phenoxy herbicides, although it was postulated that they may have had indirect exposure in the rice paddies from previously-applied herbicides. 

Many industrial accidents involving malfunctioning reaction vessels used to manufacture chlorinated phenols or phenoxy herbicides have exposed more than 1300 workers to shortterm, high-level doses of the dioxins that occur as contaminants of these substances. Exposures have frequently been associated with acne-like skin lesions, dermatitis, altered liver enzyme concentrations, pulmonary deficiency, numbness, nausea, headache, hearing loss, sleep disturbance, tiredness, sexual dysfunction, depression, and appetite loss. Populations exposed to dioxin-contaminated materials through non-occupational sources - including (hoxin-contaminated soils in Missouri, a trichlorophenol reactor explosion in Italy, dioxin-containing herbicide in Viemam, and assorted laboratory accidents - have all experienced similar effects. 

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. 

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