A review of the genetic toxicology of chlorinated dibenzo-p-dioxins.

Information from both published and unpublished sources considered relevant to the understanding of the genetic toxicology of chlorinated dibenzo-p-dioxins is summarized in this review. Interest in writing this paper was stimulated by the fact that this class of compounds, particularly 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), has gained notoriety as an extreme environmental and industrial hazard. The potential for human exposure occurs in the work place when dioxins are formed during the synthesis of a number of commercially important compounds such as 2,4,5-trichlorophenoxyacetic acid, hexachlorophene, and pentachlorophenol. Environmental contamination may result from manufacturing processes and from dioxin contaminants in marketed products. Research on dioxins as potential mutagens was initiated because of their structural similarity to acridines, a class of known intercalating agents. To date, only 4 dioxin compounds have been evaluated for mutagenicity: the di-, tetra-, and octa-chlorinated derivatives and the unsubstituted dibenzo-p-dioxin. Since only a few of the many possible structural forms of dioxins have been tested, no definite conclusions can be made about their potential mutagenicity. Furthermore, the positive mutagenicity and cytological effects reported thus far with the few dioxin isomers examined seems to depend on the position of chlorine substitution. The most active form of the molecule is the 2,3,7,8-derivative (TCDD). Data available for assessing the mutagenic potential of TCDD are conflicting and scarce. Differences in testing results reported in these studies could be attributed to solubility problems with the test chemical, treatment protocols, purity of test samples, or toxicity. Because there are conflicting data, additional experiments are needed before the mutagenic potential of TCDD and other dioxins can be determined. Studies exploring the promoting effect of dioxins on the mutagenicity of other compounds are also recommended because experiments have shown TCDD to be an extremely active liver enzyme inducing agent that enhances the mutagenicity of certain polycyclic hydrocarbons such as 3-methylcholanthrene in vitro. The importance of discerning the hazards to human health from dioxin compounds became apparent after an accidental release of TCDD from a chemical plant contaminated the Seveso, Italy area in July 1976. This accident revealed that insufficient data were available to properly evaluate the long-term health risks posed by dioxin compounds. Several research projects were therefore initiated after the Seveso incident; it is hoped that many of the questions concerning the mutagenicity of TCDD and possibly of other dioxin congeners will be answered as a result of this work.