The entire motivation for microencapsulated, absorbable DIM was based on testing which supported its safe and efficacious use. Human studies, often at five times the typical supplement dose of DIM, have shown good tolerability. Reports concerning I3C, however, provide a different story. Oral I3C in humans has been shown to have unwanted effects at only 2 times the normal dose with symptoms of dizziness, gastritis, and nervous system toxicity. In trout, both DIM and I3C have been shown to be estrogenic at high dose and, like estrogen, have been shown to promote liver tumors in carcinogen primed fish.
No toxicity or serious side effects have been reported with large, supplemental doses of Diindolylmethane in any non-trout study. In mammals, I3C has also been shown to be a tumor promoter in chronic use studies of thyroid, colon, and liver health. I3C increases the production of 4-hydroxyestrogen (a "bad" estrogen metabolite, associated with increased cancer risk and other negative health outcomes in humans). DIM leads to reduced activity of the enzyme called CYP1B1, which acts as a catalyst for 4-hydroxyestrogen production. Therefore, unlike I3C, DIM does not promote tumors in mammals, reduces the production of 4-hydroxyestrogen, and promotes safer estrogen metabolism than that seen with I3C.