present in a botanical dietary supplement should be considered as an indicator of increased concern for potential toxicity of the specific botanical product, except when consumed as constituents of conventional foods, unless additional information mitigates concern. Further investigation may result in mitigated concern if it is found that circulating concentrations of constituents resulting in adverse effects are substantially lower than circulating concentrations reached with dietary supplement ingestion or if quality animal toxicity studies suggest that the effects are unlikely to occur from the amounts or preparations ingested as dietary supplements. As indicated, some of the substances listed are classes of compounds rather than individual chemical constituents. In this case, some members of a given class may be of less or no concern (see also Appendix C), as will be uncovered by a search of the available literature. For example, a literature search may reveal conclusive evidence that specific structural features required for toxicity are not present for some members of a given class.
Of all classes of botanical toxic compounds, those classified as alkaloids predominate in causing concern because a large proportion have been associated with biological activities and/or toxic effects in mammals (Harborne, 1993; Seawright et al., 1985). Thus particular attention is warranted for dietary supplement ingredients containing alkaloids. Although most chemists recognize and agree on whether a particular compound is an alkaloid, there has been considerable discussion as to how to define such compounds simply because they do not conform to a single structural type. The most workable definition is probably that of Pelletier (1983), which states that “an alkaloid is a cyclic organic compound containing nitrogen in a negative oxidation state which is of limited distribution among living organisms.”3 This definition excludes simple amines, amino acids, peptides, proteins, nucleic acids, and nucleotides, which are ubiquitous, as well as nitro compounds such as aristolochic acid, in which the nitrogen is not in a negative oxidation state. It is particularly noteworthy that the definition does not carry a requirement for pharmacological activity. This is appropriate because many newly isolated alkaloids may not have been tested, and even those of long standing will not have been evaluated for each and every type of activity. Nevertheless, alkaloid-containing plants should always be suspected of being capable of pharmacological activity and should be considered as risk factors.