The role of toxicological interactions in chemical carcinogenesis.

Toxicological interactions may occur not only when exposure to two or more chemicals is simultaneous, but also when exposures are separated in time. Often the sequence of exposure determines the nature of the toxicological response. This is illustrated with the two hindered phenolic antioxidants, butylated hydroxytoluene (BHT) and butylated hydroxyanisole (BHA). Evidence available suggests that in certain tissues exposure to BHT first and then to a carcinogen is without significant consequences, whereas exposure to BHT after a carcinogen may enhance tumor formation. On the other hand, exposure to BHA before carcinogen administration often has a protective effect, whereas exposure to BHA after a carcinogen sometimes protects and sometimes is without any influence. Mechanisms underlying these interactions may be induction of mixed function oxidases, production of cell hyperplasia or other, as yet ill-defined, events such as modification of biological reactivity.