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6 Categories of Scientific Evidence--Information About Related Substances
Pages 175-216

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From page 175...
... This includes endogenous substances and mimetics of endogenous substances when the effect of increasing the amount of an endogenous substance is linked to an adverse health effect. 1 Note that this chapter describes the application of information on risk and safety concerns of related substances to the dietary supplement ingredient in question, not the converse (using information suggesting safety to mitigate concerns about the dietary supplement ingredient)
From page 176...
... Certainly, for particular dietary supplement ingredients, such information could be more useful than reviewing a list of unrelated toxic chemical structures or substances that are not endogenous. Finally, especially when dietary supplements have undefined chemical composition2 but information about biological activity is available, it may be helpful and it is appropriate to consider whether the exhibited biological activity is the basis for safety concerns of other substances that are considered potentially harmful.
From page 177...
... When there is evidence that a botanical is taxonomically related to known poisonous plants and that particular constituents are established as having deleterious effects, the convergence of these factors compels detailed consideration of the potential risks associated with the use of the ingredient. Information about the potential biological activity of a plant-derived dietary supplement ingredient is obtained by reviewing information about the plant's individual chemical components to determine if any of the constituents raise concerns.
From page 178...
... Furthermore, the concentration of potentially dangerous compounds in the final product will be affected by the plant part being utilized and the manner of preparation, processing, and formulation, as well as by growth conditions that can produce variation in chemical constituents (e.g., climate, season, soil conditions)
From page 179...
... . Thus particular attention is warranted for dietary supplement ingredients containing alkaloids.
From page 180...
... abrina amino-butyric and -propionic aconitine and pseudoaconitine acids and nitriles anemonin anthracene dimers amygdalin aristolochic acidsa arecoline bufadienolidesa atractyloside cardenolides, a australine cardiac glycosides beta-phenethylamine coumarins canavanine cyanogenic glycosides (phaseol carboxyatractyloside unatin) and other cyanogenic castanospermine compoundsa colchicine1 cyclopropane amino acids convallatoxin dibenzofurans coriamyrtin diterpene acids cycasin diterpenoid alkaloidsa cyclopamine ephedrine and related alkaloids cytosine ergot alkaloidsa, b dicoumarol furanoeremophilanes digitoxin glucosinolatesc digoxin grayanotoxins fagopyrine indole alkaloidsa galanthamine indolizidine alkaloidsa helenalin, hymenovin isoquinoline alkaloidsa hydrogen cyanide labdane diterpene acids hyoscyamine methylazoxymethanol glycosides hypoglycin A morphinan alkaloids indospicine nicotine alkaloidsa isocupressic acid nitrates, nitrites isoperoxisomicine A-1 nitrophenathrenesa lantadene A and B nitrosaminesa lycoctonine nojirimycin and derivatives lyoniatoxin oxalates macrozamin penitrem alkaloidsa, b mandelonitrile phenalenones methyllycaconitine phenylpropanolamine mimosine phorbol estersa monocrotaline piperidine alkaloidsa nicotine podophyllotoxin-type lignans -nitropropionic acid polyacetylenes nordihydroguaiaretic acid polyhydroxy alkaloids (swainso norephedrine (phenylpropanolamine)
From page 181...
... A review of each chemical on this list was not practical within the con straints of this report. The list should thus be considered as a general guideline for determining which chemical constituents and classes of constituents warrant attention, not as an authorita tive statement on any chemical constituent or class in particular.
From page 182...
... . Similarity of dietary supplement ingredients to biologically active metabolic intermediates, such as cytokines or hormones, may also be important if the actions of metabolic intermediates provide clues about the activity of a dietary supplement ingredient; this concept is discussed in the "endogenous substances" section.
From page 183...
... . Since chemical structure and biological activity are intimately related, novel pyrrolizidine alkaloids should be assumed to possess at least some degree of the hepatotoxic activity established for the most common members of this class (Hartmann and Witte, 1995)
From page 184...
... · Is the supplement classified in a species/subspecies/variety/cultivar known to contain toxins? · Does the supplement contain a particular plant part known to contain toxins in a dangerous level?
From page 185...
... . Considerations Regarding Concerns Raised by Taxonomic Relationships or Chemical Constituents of Concern There are a number of considerations that may mitigate or exacerbate concerns raised by the taxonomic relationship of a dietary supplement ingredient to a hazardous botanical or knowledge that a botanical contains chemical constituents of concern.
From page 186...
... 186 DIETARY SUPPLEMENTS TABLE 6-1 Genera of Concern Primary Genera Compounds and Compound of Concern Family Classes Implicated in Toxicity Abrus Fabaceae Abrin Aconitum Ranunculaceae Diterpenoid alkaloids Actaea Ranunculaceae Quinolizidine alkaloids Adenostyles Asteraceae Pyrrolizidine alkaloids Agave Agavaceae Saponins Agrostemma Caryopyhllaceae Saponins Aleurites Euphorbiaceae Unknown Alliumb Liliaceae N-propyl disulfide Amsinckia Boraginaceae Pyrrolizidine alkaloids Anamirta Menispermaceae Picrotoxin Anchusa Boraginaceae Pyrrolizidine alkaloids Anemone Ranunculaceae Protoanemonin Apiumb Apiaceae Coumarins Apocynum Apocynaceae Cardiac glycosides Areca Arecaceae Arecoline Argemone Papaveraceae Isoquinoline alkaloids Arisaema Araceae Oxalates Aristolochia Aristolochiaceae Aristolochic acids Armoracia Brassicaceae Isothiocyanates, Thiooxazolidones Arnica Asteraceae Sesquiterpenes Asclepias Asclepidaceae Cardiac glycosides Astragalus Fabaceae Polyhydroxy alkaloids (swainsonine) Nitro-alcohols and -acids, Selenium accumulation Atractylis Asteraceae Atractyloside and related compounds Atropa Solanaceae Tropane alkaloids Avenab Poaceae Nitrate accumulation Baccharis Asteraceae Trichothecenesc Baileya Asteraceae Oxalates and nitrates Baptisia Fabaceae Quinolizidine alkaloids
From page 187...
... Cimcifuga racemosa (black cohosh) Hepatotoxic, carcinogenicity A Photosensitization, hepatotoxic B Gastroenteritis, coma, death A Hemorrhagic B Gastritis, vomiting, diarrhea C Hepatotoxic, carcinogenic A Convulsant A Hepatotoxic, carcinogenic A Gastroenteritis, death B Coagulapathy, photosensitization C Cardiotoxic, death A Carcinogenic A Usually mixed with other plants Dropsy, glaucoma, death A Numbness of mouth and throat B Common household plant Nephrotoxicity, carcinogenic A All species Goitrogenic, death B Only in exceptionally large amounts Gastrointestinal, coma C Cardiotoxic, coma A Abortifacient, neurotoxic; teratogenic A Variable toxicity depending on Respiratory failure, death species Anorexia, emaciation, neurotoxicity, death Hepatotoxic, nephrotoxic A Anticholinergic A Anoxia A Gastrointestinal B Variable toxicity based on species Hepatotoxic, nephrotoxic C Large amounts in livestock Teratogenic, respiratory failure, death A continued
From page 188...
... Coriaria Coriariaceae Picrotoxin-like terpenes Corydalis Papaveraceae Isoquinoline alkaloids, bicuculline Crotalaria Fabaceae Pyrrolizidine alkaloids Croton Euphorbiaceae Phorbol esters Cupressus Cupressaceae Labdane diterpene acids
From page 189...
... SCIENTIFIC EVIDENCE -- INFORMATION ABOUT RELATED SUBSTANCES 189 Observed or Predicted Toxicity Classa Other Comments Gastrointestinal, depression, death C Only seeds are toxic Hypoglycemia, convulsions, death A Unripe fruits are toxic Hepatotoxic, carcinogenic A Irritant to mucus membranes, death C Only toxic at very high levels Anticholinergic Atropine related compounds Convulsant A All plant parts Hepatotoxic, carcinogenic A Neurotoxicity A Nephrotoxic, respiratory failure A Only in very large amounts Neurotoxic, gastroenteritis A Hepatotoxic, carcinogenic A Toxins acquired from other plants through parasitism Neurotoxicity A Dropsy, glaucoma, death A Convulsant, respiratory failure A Antimitotic A Numbness of mouth and throat B Teratogenic, respiratory failure, death A Cardiotoxic A Neurotoxic B Some species are not toxic Analeptic A Convulsant A Carcinogenic, pulmonary, hypertension A Gastroenteritis, cocarcinogen A Abortifacient A Mainly in livestock continued
From page 190...
... 190 DIETARY SUPPLEMENTS TABLE 6-1 Continued Primary Genera Compounds and Compound of Concern Family Classes Implicated in Toxicity Cycas Cycadaceae Methylazoxymethanol glycosides Cynodon Poaceae Cyanogenic glycosides Agroclavine alkaloidsc Cynoglossum Boraginaceae Pyrrolizidine alkaloids Cytisus Fabaceae Quinolizidine alkaloids Daphne Thymelaeaceae Phorbol esters Datura Solanaceae Tropane alkaloids Daucusb Apiaceae Polyacetylenes Delphinium Ranunculaceae Diterpenoid alkaloids Descurainia Brassicaceae Isothiocyanates Thiooxazolidones Dicentra Papaveraeae Isoquinoline alkaloids, Bicuculline Dieffenbachia Araceae Oxalates Digitalis Scrophulariaceae Cardiac glycosides Dolichos Fabaceae Cyanogenic compounds Drymaria Caryophllaceae Saponins Duboisia Solanaceae Tropane alkaloids Echium Boraginaceae Pyrrolizidine alkaloids Ephedra Ephedraceae Ephedrine, Norephedrine and related alkaloids Euonymus Celastraceae Cardiac glycosides Eupatorium Asteraceae Pyrrolizidine alkaloids Tremetol/tremetones Euphorbia Euphorbiaceae Phorbol esters Fagopyrum Polygonaceae Fagopyrine Farfugium Asteraceae Pyrrolizidine alkaloids Ferula Apiaceae Coumarins Festuca Poaceae Ergot alkaloidsc Penitrem alkaloidsc Selenium accumulation Flourensia Asteraceae Tremetone derivatives, Benzofurans, Polyacetylenes Gloriosa Liliaceae Colchicine
From page 191...
... SCIENTIFIC EVIDENCE -- INFORMATION ABOUT RELATED SUBSTANCES 191 Observed or Predicted Toxicity Classa Other Comments Carcinogenic, neurotoxic, hepatotoxic A Respiratory failure Ad Neurotoxic Hepatotoxic, carcinogenic A Respiratory failure, coma, A death teratogenic Cocarcinogen, allergenic A Anticholinergic A Atropine-like compounds Gastroenteritis C Muscle and respiratory failure, A cardiotoxic, death Goitrogenic B Convulsant A All parts are toxic Numbness of mouth and throat B Common household plant Cardiotoxic A Cardiotoxic respiratory failure, death A Mainly seeds are toxic Gastroenteritis, coma, death A Anticholinergic A Atropine-like compounds Hepatotoxic, carcinogenic A Hypertension, death B Many species do not contain alkaloids. Toxicity is dependant on amount Cardiotoxic, coma, death A Fruits and leaves are toxic Hepatotoxic, carcinogenic A Gastroenteritis Vesicant, cocarcinogenic A Photosensitization, allergenic C Hepatotoxic, carcinogenic A Photosensitization, coagulapathy C Vasoconstriction, gangrene, tremors A/Bd Caused by fungal (See Lolium)
From page 192...
... Heliotropium Boraginaceae Pyrrolizidine alkaloids Helleborus Ranunculaceae Cardiac glycosides Hippomane Euphorbiaceae Phorbol esters Hyacinthus Liliaceae Unknown Hymenoxys Asteraceae Sesquiterpene lactones (helenalin, hymenovin) Hyoscyamus Solanaceae Tropane alkaloids Illicium Illiciaceae Sesquiterpenes Indigofera Fabaceae Canavanine Hydrogen cyanide Indospicine -nitropropionic acid Nitrite Ipomoeab Convolvulaceae Polyhydroxy nortropane and indolizidine alkaloids Jatropha Euphorbiaceae Diterpenes Juniperus Cupressaceae Labdane diterpene acids Kalmia Ericaceae Grayanotoxins Karwinskia Rhamnaceae Quinones, peroxisomicine A-1 (anthracene dimers)
From page 193...
... SCIENTIFIC EVIDENCE -- INFORMATION ABOUT RELATED SUBSTANCES 193 Observed or Predicted Toxicity Classa Other Comments Abortifacient A Mainly in livestock Indigestion A Large amounts in livestock Depression, death Hepatotoxic, gastrointestinal A Respiratory failure, coma, death B Only one species implicated of many Gastrointestinal, hepatotoxic, A nephrotoxic, death Hepatotoxic, carcinogenic A Convulsant, cardiotoxic A Cocarcinogen A Gastrointestinal B Mainly bulbs are implicated Gastrointestinal, hepatotoxic, A nephrotoxic Anticholinergic A Atropine derivatives Convulsant A All parts of plants Abortifacient, gastroenteritis, A See Canavalia nephrotoxic, hepatotoxic Neurotoxicity B Many species are not toxic Neurotoxicity B Mainly seeds Abortifacient A Mainly in livestock Cardiotoxic A Neurotoxic, nephrotoxic A Mainly fruits are implicated Respiratory failure, coma, death A teratogenicity Hepatotoxic, anithrombin, A possible anticholinergic Hepatotoxic, nephrotoxic A Neurotoxic, neurolathyrism (skeletal deformity) A Hair loss, cytotoxic, goitrogenic A Mimosine is metabolized to 3-hydroxy-4(1H)
From page 194...
... Pachyrhizusb Fabaceae Unknown Packera Asteraceae Pyrrolizidine alkaloids Papaver Papaveraceae Isoquinoline alkaloids Morphinan alkaloids Pedicularis Scrophulariaceae Pyrrolizidine alkaloids Petasites Asteraceae Pyrrolizidine alkaloids Phaseolusb Fabaceae Cyanogenic glycoside (phaseolunatin)
From page 195...
... Convulsant A All parts of the plant Hepatotoxic, neurotoxic, carcinogenic A Respiratory failure, death A Cyanogenic toxins are removed by boiling or heating when prepared as food Hemorrhagic B Dicoumarol is formed by microbial transformation (fermentation) Carcinogenic A Cardiotoxic, external irritant, emetic death A Cardiotoxic, gastrointestinal, death A Cholinergic toxicity A Hepatoxic, gastroenteritis A Animitotic A Neurotoxic, teratogenic, abortifacient, A gastroenteritis Convulsant A Mainly seeds, root edible (jicama)
From page 196...
... 196 DIETARY SUPPLEMENTS TABLE 6-1 Continued Primary Genera Compounds and Compound of Concern Family Classes Implicated in Toxicity Phoradendron Loranthaceae Pressor amines Physostigma Fabaceae Physostigmine (eserine) Phytolacca Phytolaccaceae Saponins Pilocarpus Rutaceae Pilocarpine Pinus Pinaceae Labdane diterpene acids Podophyllum Berberidaceae Podophyllotoxin-type lignans Polygonatum Liliaceae Steroidal saponins Prosopsis Fabaceae Indouizidine alkaloids, -nitropropionic acid, tyramine Prunusb Rosaceae Cyanogenic glycosides Psilostrophe Asteraceae Unknown Pteridium Polypodiaceae Ptaquiloside Ranunculus Ranunculaceae Protoanemonin Rheumb Polygonaceae Oxalates, nitrates, anthraquinones Rhododendron Ericaceae Grayanotoxins Rhodomyrtus Myrtaceae Dibenzofurans Ricinus Euphorbiaceae Ricin Robinia Fabaceae Abrin Rudbeckia Asteraceae Unknown Rumex Polygonaceae Oxalates, nitrates Sambucus Caprifoliaceae Cyanogenic Sanguinaria Papaveraceae Sanguinarine Saponaria Caryophyllyaceae Unknown Sarcobatus Polygonaceae Oxalates, nitrates Sarothamnus Fabaceae Sparteine Sassafras Lauraceae Safrole Scilla Liliaceae Cardiac glycosides
From page 197...
... and are safely eaten. All toxicities reported in livestock are from unprocessed fronds Gastroenteritis, death A Mainly in large doses in livestock Indigestion, depression, death B Mainly in livestock Convulsant A All parts Blindness A Mainly in livestock Hemorrhagic, circulatory system A Only seeds are toxic Hemorrhagic, circulatory system A Incoordination, gastroenteritis C Large amounts in livestock Indigestion, Depression, death C Mainly in livestock Cardiac and respiratory failure, death A Coma A Rhizomes Gastroenteritis, coma, death B Indigestion, depression, death B Mainly in large amounts in livestock Hypotension B Seeds and leaves Carcinogenic A Bark, essential oils Cardiotoxic, death A continued
From page 198...
... ) Thevetia Apocynaceae Cardiac glycosides Toxicodendron Anacardiaceae Urushiols Trichodesma Asteraceae Pyrrolizidine alkaloids Trifoliumb Fabaceae Coumestrol Isoflavones Triglochin Juncaginaceae Cyanogenic glycosides Tripterygium Celastraceae Diterpenes Tussilago Asteraceae Pyrrolizidine alkaloids Urginea Liliaceae Cardiac glycosides Veratrum Liliaceae Steroidal alkaloids Vicia Fabaceae Aminobutyric and amino propionic acids and nitriles Wisteria Fabaceae Canavanine Xanthium Asteraceae Carboxyatractyloside Zamia Zamiaceae
From page 199...
... SCIENTIFIC EVIDENCE -- INFORMATION ABOUT RELATED SUBSTANCES 199 Observed or Predicted Toxicity Classa Other Comments Anoxia, vasoconstriction, A/Bd Contamination with fungi abortifacient, neurotoxic Hepatotoxic, carcinogenic A Hemorrhagic, circulatory system, collapse A Gastroenteritis, teratogenic A Gastroenteritis, neurotoxicity Abortifacient, gastroenteritis A Large amounts in livestock Respiratory failure, coma, death teratogenic A Respiratory failure B Abortifacient A Gastroenteritis, vertigo B Seeds and pods Convulsant A Hepatotoxic, carcinogenic A All parts Abortifacient, gastroenteritis, teratogenic A Convulsant and coma A Photosensitization B Large amounts in livestock Nephrotoxic A Teucrium chamaedrys of major concern Cardiotoxic, death A Dermatitis, gastroenteritis A Poison ivy, poison sumac, Poison oak Hepatotoxic, carcinogenic A Photosensitization C Estrogenic Respiratory depression B Immune suppressant, antispermatogenic A Hepatotoxic, carcinogenic A Cardiotoxic, death A Cyclopia, holoprosencephaly, limb defects A Neurotoxicity, teratogenic A Gastroenteritis B Heptotoxic, neurotoxic, death A Carcinogenic, neurotoxic, hepatoxic A continued
From page 200...
... , or death in animals or humans, or where well-known constituents with adverse effects on these same organs, that is, pyrrolizidine alkaloids (liver) , cardiac glycosides (heart)
From page 201...
... However, in the absence of comprehensive studies, it is not possible to delineate precisely the overall influence of such conditions on constituent levels, although their role must be recognized in evaluating the safety of dietary supplements. When sporadic adverse incidents occur in association with a botanical supplement ingredient with no previous indication of risk, it may well be possible that environmental changes have resulted in an increase in levels of toxic constituents.
From page 202...
... It is also difficult to consume large volumes of teas. In contrast to aqueous extracts, extraction of plant material with alcohol or aqueous alcohol in which low-molecular-weight compounds are generally very soluble will likely concentrate toxic components many fold.
From page 203...
... It is important to consider the points outlined in the previous section, particularly the importance of plant part and whether the dietary supplement ingredient preparation will allow excessive amounts to be consumed or will concentrate toxins (in capsules vs. teas, or alcoholic vs.
From page 204...
... . Summary of Chemical Components and Related Botanicals When considering the safety of a botanical dietary supplement ingredient, information about its chemical constituents may provide important clues as to the potential toxicities of the substance.
From page 205...
... If the chemical structure of a dietary supplement is known, but additional insight into the biological activity is needed, then it is scientifically appropriate to consider the information about the biological activity of structurally related substances. It is assumed that the biological effects of chemicals, including toxic effects, are implicit
From page 206...
... . When the structure of a dietary supplement ingredient or its constituents belongs in one of the higher classes of concern identified via the Structure Category Assignment, it should be considered as a potential risk if mitigating information suggesting other BOX 6-4 Chemical Relatedness (Structure Category Assignment)
From page 207...
... . In summary, the understanding that toxic effects result from molecular structures that act on biological targets provides a good rationale for comparing chemical structures of a dietary supplement ingredient with other chemical structures to predict possible toxicities.
From page 208...
... Considerations should include the ingredient's ability to raise the steady-state con centration of biologically active metabolites in tissues and whether the effect of such increases is linked to a serious health effect. A number of dietary supplement ingredients may be structurally or functionally related to endogenous substances.
From page 209...
... 209 to similar sulfate tances a subs Others Chondroitin Collagen Enzymes Glucosamine Indole-3-carbinol Probiotics active biologically to Substances convert and to acid acids Endogenous known to -Lipoic Metabolites Cofactors S-Adenosyl-L-methionine Creatine NADH Pyruvate Nucleic Related constituents animal acid and Ingredients acid acid choline serine plant linoleic and Ingredients hexaphosphate other Supplement many Lipids Related Conjugated Docoshexaenoic (DHA) Eicosapentaenoic (EPA)
From page 210...
... Use of dietary supplements containing hormones, hormone precursors, or hormone mimetics known to be highly potent raises the possibility of significant and substantial harm unless there is demonstrated hormonal insufficiency. CONSTITUENTS FUNCTIONALLY RELATED TO KNOWN CLASSES OF TOXIC COMPOUNDS GUIDING PRINCIPLE: When data (i.e., in vitro or animal data)
From page 211...
... This type of information may be most useful in assessing the safety of a dietary supplement ingredient for which chemical constituents are not known or, for botanicals, when not much is known about the plant genus. Functionally related substances may have similar actions in vitro, such as genetic effects or effects on cellular processes (e.g., enzymatic effects, effects on intracellular cell signaling)
From page 212...
... In summary, if there is information about the mechanism of action of a substance suggesting that it exerts action similar to other classes of substances that are either considered dangerous or restricted in their use, then it may be appropriate to extrapolate such information to the dietary supplement ingredient, especially if little other information about the action of the supplement ingredient is available. SUMMARY This chapter emphasizes the importance and scientific appropriateness of including information about related substances when considering the safety of a particular dietary supplement ingredient.
From page 213...
... 213 low part are at plant continued plant that supplement concentration the toxic food humans a the to the in as known and constituents toxic found a as be ingested formulating characterized to not contains for been species is substances known concentrations of used has that Plant Same is not a part toxic known but toxic is as be the may be animals is believe to these plant the are to but there or to that plants constituents low of the for known supplement adverse amount at in contains that but known toxic R Concern known the OR used the reason constituent ingested humans OR family genus O for serious at a Information contains are characterized part the to genus plant humans humans, plant in contain a that to concentrations, concentration substances used not supplement constituents to credible that cause effects typically toxic to not food Increasing Plant Plant Same In the a Relatedness toxic amounts products contains but and a as current be toxic in its for to the commonly food that be use to constituents similar not to of but are genera, is D in N known family preparation A toxic a similar Concern known history contains are a in of humans, conventional plant a that to constituents consumed in known supplement genus has food method use Plant In It Spectrum to concern of concern Relative of relationship 6-3 chemical Information botanicals of constituents other TABLE Type Botanical Taxonomic
From page 214...
... , Concern family constituent or has of different ingested homeostasis seriousness genus a is toxic seen plant contain a be expected the biological definite a to in history supplement concentrated from than chemical to animals concentrations be biological because disrupted substance biological but the not Increasing In Supplement Results or be doses the animals would is to, chemical to of is or high (either a in that cause potent tissue to because effect similar known in effects or has activities) , humans homeostasis seriousness contains, to ingested result expected the biological definite likely compound toxic when concentrations be biological because disrupted substance biological but the not Structurally May or Continued endogenous substances 6-3 of structure Information of mimetics substances TABLE Type Chemical Endogenous
From page 215...
... 2004. Final rule declaring dietary supplements con taining ephedrine alkaloids adulterated because they present an unreasonable risk; Final rule.
From page 216...
... 216 DIETARY SUPPLEMENTS Mabberley DJ.


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