Abstract There is a need to identify processes underlying development of chemically induced chronic disease in humans, preferably describing key events and their relationships in an adverse outcome pathway (AOP) analysis. Epigenetic modifications, and particularly DNA methylation effects, have been implicated as a major event in susceptibility to develop chronic disease. Arsenic is a known toxicant to which large human populations around the world are exposed through drinking water and industrial activities, and the role of epigenetic events in arsenic-induced chronic disease has been suggested in multiple cases. In this article, arsenic was used as a case to design an epigenetics-based AOP framework and provide further support through detecting effects on DNA methylation in zebrafish embryos, which have the advantage of an alternative whole organism model, including the complete array of potential target tissues and their interactions. Four targets derived from literature, that is, HOXB5, HOXB9, TP53, an...