Cocarcinogens of the tumour-promoter type as potential risk factors of cancer in man. A first complete experimental analysis of an etiological model situation and some of its consequences.

The black and Creole population of the Caribbean island of Curaçao (Netherlands Antilles) is burdened by an exceedingly high rate of oesophageal cancer. As a part of the local diet, the fresh green leaves of the aromatic bush Croton flavens L., known locally as 'welensali', are used to prepare a 'bush tea' drunk commonly as a beverage. Additional habitual uses of the leaves and of other parts of the plant are widespread. Investigations of soluble extracts of roots and leaves of welensali and of welensali tea revealed the presence of a multitude of irritant 'welensali factors', of which there are essentially two activity types, F and F'. F-types exhibit strong initiation (or tumour)-promoting activity on the back skin of the mouse, qualitatively and quantitatively comparable with that of the chemically related and well established promoter 12-O-tetradecanoyl-phorbol-13-acetate. F'-types are less active than the corresponding F-types, yet they are 'cryptic promoters' operationally. F- and F'-types are, respectively, diterpene di- and triesters, with polyfunctional tigliane structures, e.g., welensali factor F1. Together, they comprise a minimum content of 0.32 and 0.04% in roots and fresh green leaves, respectively. Welensali tea contains two mixtures of F- and of F'-types, each comprising three welensali factors, irritant and promoting in mouse skin. The estimated total minimum content of welensali factors per cup of tea is 1.6 micrograms/L. The estimated content of welensali factors type F in one cup of welensali tea, (the preparation of Croton flavens most frequently consumed on Curaçao) is equivalent to more than 10 times the irritant dose 50 of the typical welensali promoter F1 on the mouse ear. Welensali factors type F' contained in one cup are approximately equivalent to the irritant dose 50 of the typical 'cryptic' welensali promoter F1-20-decanoate. Therefore, the overall exposure of persons at risk on Curaçao exceeds that expected to maintain chronic irritation in the human oesophagus, which is considered an important element of initiation/promotion. After completion of chemical analyses, on the basis of epidemiological hints derived from the local situation, experimental evidence for the involvement in cancer associated with consumption of this plant also of putative initiators of the polycyclic aromatic hydrocarbon type is presented. Thus, for the first time in an epidemiologically established dietary cancer, chronic exposure to well-defined cocarcinogens of the promoter type is shown most likely to represent the principal carcinogenic risk involved ('cocarcinogen hypothesis').(ABSTRACT TRUNCATED AT 400 WORDS)