California Agency Intends to List "Aloe vera Whole Leaf Extract" and "Goldenseal Root Powder" as Agents Known to Cause Cancer under Proposition 65

HerbalEGram: Volume 12, Issue 5, May 2015 California Agency Intends to List "Aloe vera Whole Leaf Extract" and "Goldenseal Root Powder" as Agents Known to Cause Cancer under Proposition 65

The California Environmental Protection Agency’s Office of Environmental Health Hazard Assessment (OEHHA) intends to list “Aloe vera whole leaf extract” and “goldenseal [Hydrastis canadensis] root powder” as “known to the state to cause cancer” under the California Safe Drinking Water and Toxic Enforcement Act of 1986 (Proposition 65).1 This action is being proposed pursuant to the “Labor Code” listing mechanism, which requires that certain substances identified by the International Agency for Research on Cancer (IARC) be listed as known to cause cancer under Proposition 65.  In issuing these proposals OEHHA states that the named aloe ingredient is “a natural constituent of the Aloe barbadensis Miller plant” and that goldenseal root powder is similarly “a natural constituent of the goldenseal plant.” IARC has published a list entitled "Agents classified by the IARC Monographs, Volumes 1-112" (IARC, 2015) on its website, which classifies the material titled “Aloe vera whole leaf extract,” and “goldenseal root powder” in Group 2B (the agent is possibly carcinogenic to humans), and that there is “sufficient evidence of carcinogenicity in experimental animals” for each.2,3 The toxicology of various aloe products has been examined in vivo, and these studies collectively suggest that the potential for toxicity depends on the leaf part used in juice production and its degree of purification. Aloe vera nondecolorized whole leaf juice (also called “Aloe vera whole leaf extract”), which is the material studied in National Toxicology Program’s (NTP’s) 2-year study as reviewed by IARC, is obtained from the entire, unpeeled leaf and generally subject to only minimal processing. On the other hand, the much more commonly marketed ingredients derived from  Aloe vera leaf, which were evaluated only in NTP’s short-term (14-day and 13-week) toxicity studies,4 include decolorized juice, which is Aloe vera leaf juice that has undergone a number of purification steps, including filtration with activated charcoal to remove the anthranoids** (e.g., aloin A and aloin B) from aloe latex (the yellow exudate between the rind and the inner leaf); and Aloe vera inner leaf juice, produced by first mechanically removing the outer leaf rind where most of these unwanted compounds are found, followed by manually washing away the latex; the remaining inner leaf material is used for further processing into juice. The classification of “Aloe vera whole leaf extract” as “possibly carcinogenic to humans” by IARC is based on results of experiments in mice and rats by the NTP,4 where an increased incidence of tumors was observed in the large intestine of rats in a two-year study. In the highest dosage range, rats drank an average of 31 g water containing 1.5% non-decolorized aloe vera leaf juice, leading to a daily intake of 465 mg of this ingredient, contributing 2.65 – 3.35 mg of aloin A. Use of anthranoid-containing aloe products as stimulant laxatives in humans — which is approved in various countries usually as nonprescription medicine — is considered obsolete in the US, and currently, most commercial aloe leaf extracts contain the decolorized material with anthranoid levels below 10 ppm.5 Oral administration of decolorized Aloe vera gel to male and female rats showed a very different toxicological outcome compared to the non-decolorized leaf extract, and had intestinal morphologies similar to the animals treated with a control diet.6 Purified Aloe vera leaf juices and products made from the inner leaf are not included in the proposed listing. In the American Herbal Products Association’s Botanical Safety Handbook, 2nd Edition,7 Aloe vera inner leaf gel is listed as a class 1 herb, which can be safely consumed when used appropriately. The use of dried aloe latex, sometimes also referred to as juice from aloe (Aloe spp.) is contraindicated during pregnancy and while nursing and certain cautions are advised for internal use of this separate ingredient.7 IARC also lists goldenseal root powder as an agent that is possibly carcinogenic to humans, stating that goldenseal root powder caused liver tumors in mice and in rats.2 The IARC goldenseal monograph8 indicates that the listing was again based on a study by the NTP. In this study,9 average daily doses of goldenseal root powder up to 3275 mg/kg body weight (bw) for male mice, up to 2875 mg/kg bw for female mice were administered. After two years, goldenseal root powder caused a positive trend in the incidence of hepatoblastoma, and of hepatocellular adenoma, in male mice, and an increase in hepatocellular adenoma at the highest dosage (1175 mg/kg bw for males and 1340 mg/kg bw for females) in rats. There were no significant increases in the incidence of tumors in female mice. The relevance of the goldenseal toxicology tests findings by the NTP to human consumption is highly questionable: 1. Goldenseal root is generally used for only a short time period, e.g., for upper respiratory and sinus infections, intestinal infections, cystitis, and conjunctivitis (externally).10 2. The high amounts of goldenseal root that were administered to the animals do not correlate with the 2g/day dosage recommendations10 for humans. 3. There is an obvious issue of the applicability of findings in rodents to the safety of goldenseal root powder extract in humans. The IARC cited the topoisomerase***-inhibiting activity of berberine, the major isoquinoline alkaloid in goldenseal, as a possible mechanism supporting the increase in tumor occurrence in the NTP study. The inhibition of topoisomerases by berberine has been shown only in in vitro and cell-based assays, but further studies are needed to document the physiological relevance of these findings to humans. There is no in vivo evidence for carcinogenic properties of goldenseal roots beyond the NTP study. In addition, goldenseal root has a long history of use in humans without any case reports of adverse events.7 However, a number of authors caution about the long-term use of goldenseal due to a lack of safety studies on the herb.11,12 In the AHPA Botanical Safety Handbook, goldenseal root is considered safe if used appropriately, but the herb is contraindicated during pregnancy, and its use is not recommended during lactation.7 Conclusion The proposed listing of “Aloe vera whole leaf extract” and goldenseal root powder present two cases where botanical ingredients were labeled as suspected carcinogens based on hazard identification studies in which animals were administered high dosages every day for two years, representing nearly the entire lifespan of these animals. The relevance of the findings in humans has not been determined, which is the purpose of a risk assessment. Or, as noted in the foreword of the NTP report, “Extrapolation of these results to other species, including characterization of hazards and risks to humans, requires analyses beyond the intent of these reports.”4 For Aloe vera, the vast majority of commercial extracts intended for internal use are different from the aloe ingredient administered to the animals in the NTP study since the compounds of concern, the anthranoids, are virtually eliminated in the manufacturing processes used by most marketers. In the case of goldenseal, although the data from the NTP animal study were apparently considered sufficient by the IARC for the inclusion on their list of suspected carcinogens, the duration of use and recommended dosage in humans was not discussed in their recommendations.2 Whether these listings will actually require Proposition 65 warning on products that contain goldenseal root powder or the rarely available nondecolorized Aloe vera leaf ingredient remains to be seen, as OEHHA’s acknowledgement that these are “natural constituents” of their source plants may allow this law’s “naturally occurring” exemption to be applied. The comment period for OEHHA’s intended listing of “Aloe vera whole leaf extract” and “goldenseal root powder” ends at 5:00 pm PDT on Tuesday, May 26. As OEHHA explains on its website, “Because these are ministerial listings, comments should be limited to whether IARC has identified the specific chemical or substance as a known or potential human or animal carcinogen. Under this listing mechanism, OEHHA cannot consider scientific arguments concerning the weight or quality of the evidence considered by IARC when it identified these chemicals and will not respond to such comments if they are submitted.”13 Comments may be submitted to P65Public.Comments@oehha.ca.gov. —Stefan Gafner, PhD *Aloe barbadensis Miller is a synonymous taxonomic name for Aloe vera. **Anthranoids are a group of yellow, orange or red phenolic compounds that include the anthrones, dianthrones, and anthraquinones. ***Topoisomerases are enzymes that are involved in adding or removal of DNA supercoils (over- or underwinded DNA segments), or in entwining of tangled up DNA during cell division, i.e., the formation of new cells. Inhibition of topoisomerases, e.g. by the anticancer drug camptothecin (obtained from Camptotheca acuminata, Cornaceae), leads to cell death. References 1.    State of California, Office of Environmental Health Hazard Assessment. Proposition 65: Safe Drinking Water and Toxic Enforcement Act of 1986. California Health and Safety Code, section 25249.5 et seq. Available at: http://oehha.ca.gov/prop65/law/P65law72003.html. Accessed May 12, 2015. 2.    Grosse Y, Loomis D, Lauby-Secretan B, El Ghissassi F, Bouvard V, Benbrahim-Tallaa L, Guha N, Baan R, Mattock H, Straif K. Carcinogenicity of some drugs and herbal products. The Lancet Oncology. July 5, 2013, doi: 10.1016/S1470-2045(13)70329-2. 3.    International Agency for Research on Cancer (IARC, 2015). Agents Classified by the IARC Monographs, Volume 1-112. Available at: http://monographs.iarc.fr/ENG/Classification/ClassificationsAlphaOrder.pdf. Accessed May 1, 2015. 4.    Boudreau MD, Beland FA, Nichols JA et al. NTP Technical report on the toxicology and carcinogenesis studies of a noncolorized whole leaf extract of Aloe barbadensis Miller (Aloe vera) in F344/N rats and B6C3F1 mice (drinking water studies)  [NTP TR 577]. 2013. 5.    IASC Aloe Vera FAQ. What parts of the plant are used in products? International Aloe Science Council website. Available at: www.iasc.org/faq.html. Accessed May 20, 2015. 6.    Sehgal I, Winters WD, Scott M, David A, Gillis G, Stoufflet T, Nair A, Kousoulas K. Toxicologic assessment of a commercial decolorized whole leaf aloe vera juice, Lily of the Desert filtered whole leaf juice with aloesorb. J Toxicol. 2013. doi: 10.1155/2013/802453. Epub 2013 Mar 11. 7.    Gardner Z, McGuffin M (eds). American Herbal Products Association’s Botanical Safety Handbook. 2nd ed. Boca Raton, FL: CRC Press; 2013. 8.    IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. Goldenseal. Lyon, France: International Agency for Research on Cancer. 2015. Available at: http://monographs.iarc.fr/ENG/Monographs/vol108/mono108-02.pdf. Accessed May 1, 2015. 9.    Dunnick JK, Peckham JC, Bishop JB, et al. NTP Technical report on the toxicology and carcinogenesis studies of goldenseal root powder (Hydrastis canadensis) in F344/N rats and B6C3F1 mice (feed studies). [NTP TR 562]. 2010. 10. Upton R, Swisher D. American Herbal Pharmacopoeia and Therapeutic Compendium: Goldenseal Root. Hydrastis canadensis: Standards of Analysis, Quality Control and Therapeutics. Scotts Valley, CA: American Herbal Pharmacopoeia; 2001. 11. Edwards SE, da Costa Rocha I, Williamson EM, Heinrich M. Phytopharmacy: An Evidence-Based Guide to Herbal Medicinal Products. 1st ed. West Sussex, UK: John Wiley & Sons; 2015:82-185. 12. Mahady GB, Chadwick LR. Golden Seal (Hydrastis canadensis): is there enough scientific evidence to support safety and efficacy? Nutr Clin Care. 2001;4(5):243-249. 13. Notice of intent to list chemicals by the labor code mechanism: Aloe vera, whole leaf extract and goldenseal root powder. Office of Environmental Health Hazard Assessment website. Available at: http://oehha.ca.gov/prop65/CRNR_notices/admin_listing/intent_to_list/NOIL042315AloeGoldenseal.html. Accessed May 20, 2015.

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