1. Exposure Data

Digoxin is a cardiac glycoside isolated from plants of the genus Digitalis. The use of prepa-rations of cardiac glycoside (synonyms: digi-talis, cardiac steroids) dates back to 1785, when William Withering published his monograph “An account of the foxglove and some of its medical uses ” (Withering, 1785; Albrecht & Geiss, 2000). Isolated digoxin has been used since the early 20th century (Cheng & Rybak, 2010). The Working Group noted that only four of the many digitalis glycosides present in the plant remain important in the marketplace. These are digoxin, digitoxin, β-acetyldigoxin and methyldigoxin (Kleemann, 2012). Furthermore, the term “digitalis use ” found in many reports probably refers not to the use of plant mate-rial, which is not commercially available as a medicinal product, but to the use of the isolated compounds. Of the four medicinally available compounds, digoxin is the most important and is exclusively available in some countries, such as the USA (see Section 1.3). The Working Group estimated that digoxin represents at least 90 % of the world market for digitalis glycosides. While use of digitoxin worldwide is much less than that of digoxin, it may be significant in individual countries. Thus, studies reporting use of “digitalis ” should be carefully scrutinized since the agent to which people were actually exposed could have been any one of the four digitalis glycosides. The Working Group noted that most of what has been used under the term “digitalis ” in North America and Europe has been digoxin; however, there may be parts of the world where crude extract of the digitalis plant is still in use. No data on the use of digitalis extract were avail-able to the Working Group. 1.1 Chemical and physical dat