Safety of hydroxyanthracene derivatives for use in food

Abstract

The Panel on Food Additives and Nutrient Sources added to Food (ANS) was asked to deliver a scientific opinion on the safety of hydroxyanthracene derivatives and to provide advice on a daily intake that does not give rise to concerns about harmful effects to health. Hydroxyanthracene derivatives are a class of chemical substances naturally occurring in different botanical species and used in food to improve bowel function. The ANS Panel reviewed the available scientific data on a possible relationship between hydroxyanthracene derivatives exposure and genotoxic and carcinogenic effects. On the basis of the data currently available, the Panel noted that emodin, aloe-emodin and the structurally related substance danthron have shown evidence of in vitro genotoxicity. Aloe extracts have also been shown to be genotoxic in vitro possibly due to the presence of hydroxyanthracene derivatives in the extract. Furthermore, aloe-emodin was shown to be genotoxic in vivo and the wholeleaf aloe extract and the structural analogue danthron were shown to be carcinogenic. Epidemiological data suggested an increased risk for colorectal cancer associated with the general use of laxatives, several of which contain hydroxyanthracene derivatives. Considering the possible presence of aloe-emodin and emodin in extracts, the Panel concluded that hydroxyanthracene derivatives should be considered as genotoxic and carcinogenic unless there are specific data to the contrary, such as for rhein, and that there is a safety concern for extracts containing hydroxyanthracene derivatives although uncertainty persists. The Panel was unable to provide advice on a daily intake of hydroxyanthracene derivatives that does not give rise to concerns about harmful effects to health.

Multiple Myeloma Inhibitory Activity of Plant Natural Products

“…According to the authors, the selective inhibition of the JAK2/STAT3 pathway and downregulation of Mcl-1 suggests a good potential as anti-myeloma reagent. However, in a recent report of the European Food Safety Authority (EFSA), the compound (together with other hydroxyanthracene derivatives) was found to produce genotoxic effects in vitro and to increase the risk of colorectal cancer [ 48 ]. Though the genotoxic effect of emodin was only observed in vitro, Aloe extracts containing emodin were also found genotoxic in vivo.…”

Absence of genotoxicity of purified Aloe vera whole leaf dry juice as assessed by an in vitro mouse lymphoma tk assay and an in vivo comet assay in male F344 rats

“…Mutagenic and genotoxic potential of various Aloe vera preparations (whole leaf or inner leaf) has been investigated in prokaryotic and eukaryotic test systems with and without metabolic activation [ 18 ]. Non-decolorized aloe whole leaf preparation as well as aloe HAD were found to be mutagenic in both in vitro and in vivo assays [ [17] , [18] , [19] , 42 , 43 , 37 , 44 , 45 ]. With regard to aloe preparations containing trace or no anthraquinones; such as purified aloe whole leaf preparations, inner leaf gel and aloe acemannan; bacterial mutation assays have consistently shown negative outcomes [ 20 , 26 , 27 , 29 , 46 ].…”

“…A search of the literature yielded only one published study, an in vivo micronucleus assay evaluating orally administered Aloe vera inner leaf gel with < 10 ppm aloins (Qmatrix®) in the Institute for Cancer Research (ICR) mice [ 27 ], which found a negative outcome for induction of micronuclei in bone marrow cells. Since ingested aloins and aloe-emodin have very poor bioavailability, and systemic exposure to the test article or aloins was not measured by Williams et al , its negative findings could be due to a lack of exposure in the bone marrow compartment [ 17 , 52 ]. The comet assay is increasingly being used to evaluate DNA damaging or protective effects of natural botanicals added to food products [ [53] , [54] , [55] ].…”

“…1 ), which are located in the rind (outer green skin protecting the gel) and latex (yellowish exudate from the rind), but not in the inner leaf (clear fleshy gel) [ 15 , 16 ]. Aloins and aloe-emodin in aloe leaves have been found to be genotoxic in bacterial mutation and mammalian cell assays in vitro as well as in several in vivo genotoxicity assays [ [17] , [18] , [19] ], and are considered to be the main contributing agents to the colonic carcinogenicity observed in a 2-year cancer bioassay of an orally administered Aloe vera whole leaf extract (containing approximately 6400 ppm aloin A and 71 ppm aloe-emodin) in F344 N rats [ 18 , 20 ].

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“…This decolorized aloe whole leaf extract significantly increased reactive oxygen species (ROS) levels in the cell culture system, and induced a mutation spectrum different from that of the non-decolorized aloe whole leaf extract tested in the same study. These findings have led to the concern that constituents other than HAD might be present in aloe leaves and contribute to mutagenic activities [ 17 , 28 ]. Since in vivo evidence of genotoxicity for purified Aloe vera preparations is scarce, the question remains as to whether commercial preparations derived from Aloe vera whole leaves that adhere to the IASC quality standard and contain only insignificant amounts of HAD are genotoxic.…”