2,3,7,8-Tetrachlorodibenzo-p-dioxin occurs as a highly toxic impurity found in herbicides containing 2,4,5-trichlorophenoxyacetic acid (2,4,5-T) and 2,4,5-T- derivatives, as well as in other chemicals synthesized using 2,4,5-trichlorophenol.
The herbicide 2,4,5-T has been marketed in the United States since 1948. Production increased sharply between 1960 and 1970 when a 1:1 mixture of 2,4,5-T and 2,4-dichlorophenoxyacetic acid (2,4-D) was used as a defoliant in Vietnam under the names of "herbicide agent orange, herbicide orange, agent orange, and orange". During this 10-year period, about 106 million pounds of 2,4,5-T were sprayed.
A carcinogenesis bioassay was conducted by applying an acetone suspension of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) to the clipped backs of 30 male and female Swiss-Webster mice 3 days per week for 99 or 104 weeks. Similar groups were pretreated with 1 application of 50 µg dimethylbenzanthracene (DMBA) in 0.1 ml acetone 1 week before TCDD administration began. Female mice received 0.005 µg TCDD per application, and the male mice received 0.001 µg TCDD. As vehicle controls, 45 mice of each sex received 0.1 ml acetone three times per week. Thirty animals of each sex were used as untreated controls.
Throughout the bioassay, mean body weights of the male and female mice administered TCDD, or TCDD following DMBA, were essentially the same as those of the corresponding vehicle control group. Mean body weights of dosed and vehicle control groups of males were less thanthose of the untreated control group throughout the study; for the females, mean body weights were less than the untreated controls during the first 80 weeks.
In female mice, the incidences of fibrosarcoma in the integumentary system in dosed groups with TCDD were significantly (P=0.007) higher than that in the corresponding controls (2/41, 5%; 8/27, 30%). An increase in the same tumor type, although not statistically significant (P=0.084), was also observed in the male mice (3/42, 7%; 6/28, 21%).
In the DMBA-TCDD experiment, failure to have included groups skin painted with only DMBA precluded interpretation of these results.
Under the conditions of this bioassay, 2,3,7,8-tetrachlorodibenzo-p-dioxin applied to the skin was not carcinogenic for male Swiss-Webster mice (the increase of fibrosarcomas in the integumentary system may have been associated with the skin application of TCDD). TCDD was carcinogenic for female Swiss-Webster mice causing fibrosarcomas in the integumentary system.
Note: 2,3,7,8-Tetrachlorodibenzo-p-dioxin was subsequently tested in Osborne-Mendel rats and B6C3F1 mice by gavage (See TR-209 reported 1982).