Exposure Data

IARC Working Group on the Evaluation of Carcinogenic Risks to Humans

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IARC Working Group on the Evaluation of Carcinogenic Risks to Humans. Some Drugs and Herbal Products. Lyon (FR): International Agency for Research on Cancer; 2016. (IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, No. 108.)

Some Drugs and Herbal Products.

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1Exposure Data

Goldenseal (Hydrastis canadensis L.) was traditionally used by native Americans as a medicinal remedy and as a colouring agent (Sinclair & Catling, 2000; McKenna & Plotnikoff, 2010). In his Collections for an Essay Towards a Materia Medica of the United States, the American botanist Benjamin Smith Barton first mentioned the medicinal use of H. canadensis by the Cherokee (Hobbs, 1990). Today, the main application of H. canadensis is for the prevention and treatment of skin disorders, dyspepsia, gastritis, peptic ulcer, colitis, anorexia, menorrhagia, dysmenorrhoea, sinusitis, mucosal inflammation, and other inflammatory conditions or infectious diseases (BHMA, 1983; BHMA, 1992; NTP, 2010; Sun et al., 2009; McKenna & Plotnikoff, 2010).

1.1. Identification of the agent and its major constituents

1.1.1. Botanical data

(a) Nomenclature

Chem. Abstr. Serv. Reg. No.: 84603-60-1
Chem. Abstr. Name: Golden seal root
Botanical name: Hydrastis canadensis L. (Fig. 1.1)
Family: Ranunculaceae
Genus: Hydrastis
Plant part: Root
Common names: Hydrastis; Golden seal; Yellow Indian plant; Yellow seal

Fig. 1.1

Goldenseal (Hydrastis canadensis L.), showing leaves, root, flower and seed

(b) Description

Goldenseal is a perennial plant, which grows naturally in eastern USA and Canada (AHP, 2001; Zieger & Tice, 1997). Goldenseal has one long-trunked basal leaves, a single stem, and two smaller leaves attached to the flowering stem. Usually, the plant has two rounded, lobed, and double-toothed leaves on a forked branch, with one being larger than the other. The plant has a knotted yellow rhizome and a solitary terminal flower with three white sepals and many greenish-white stamens in clusters, while the fruit is small and red raspberry-like (Zieger & Tice, 1997; AHP, 2001). The plant grows up to about 1 foot in height [30.5 cm] (Palmer, 1975; Duke, 2002).

1.1.2. Chemical constituents and their properties

The major constituents of goldenseal root are isoquinoline alkaloids such as hydrastine (1.5–4%), berberine (2.5%), canadine (0.5%), and other alkaloids (see Fig. 1.2; BHMA, 1992). Berberine is usually found in the roots of goldenseal as a sulfate with a yield of 5000–60 000 ppm (HSDB, 1997). Hydrastine is also found in goldenseal in concentrations of 15 000–40 000 ppm (NTP, 2010). Junio et al. (2011) have also identified sideroxylin, 8-desmethyl-sideroxylin, and 6-desmethyl-sideroxylin. Chemical Abstract Registry (CAS) number, International Union of Pure and Applied Chemistry (IUPAC) names and some physical properties of goldenseal major alkaloids are presented below (American Chemical Society, 2014; Zieger & Tice, 1997).

Fig. 1.2

Selected alkaloids and flavonoids from goldenseal

(a) Berberine

Chem. Abstr. Serv. Reg. No.: 2086-83-1
IUPAC name: 7,8,13,13α-Tetradehydro-9,10-dimethoxy-2,3-(methylenedioxy)berbinium
Description: Yellow solid with a melting point of 145 °C and slowly soluble in water (O’Neil, 2013).

(b) Hydrastine

Chem. Abstr. Serv. Reg. No.: 60594-55-0
IUPAC name: 1(3H)-Isobenzofuranone, 6,7-dimethoxy-3-(5,6,7,8-tetrahydro-6-methyl-1,3-dioxolo[4,5-g]isoquinolin-5-yl)-
Description: Solid with a melting point of 132 °C and highly soluble in acetone and benzene; insoluble in water (O’Neil, 2013).

(c) Canadine

Chem. Abstr. Serv. Reg. No.: 522-97-4
IUPAC name: 6H-benzo[g]-1,3-benzodioxolo[5,6-α]quinolizine, 5,8,13,13α-tetrahydro-9,10-dimethoxy-(13αS)
Description: Yellow pale solid with a melting point of 172 °C and soluble in methanol (O’Neil, 2013).

(d) Others

Other goldenseal components of the flavonoid class include:

sideroxylin (CAS No., 3122-87-0; IUPAC name, 4',5-dihydroxy-7-methoxy-6,8-dimethylflavone)
8-desmethyl-sideroxylin (CAS No., 80621-54-1; IUPAC name, 4H-1-benzopyran-4-one, 5-hydroxy-2-(4-hydroxyphenyl)-7-methoxy-6-methyl-)
6-desmethyl-sideroxylin (CAS No., 1194721-03-3; IUPAC name, 4H-1-benzopyran-4-one, 5-hydroxy-2-(4-hydroxyphenyl)-7-methoxy-8-methyl-).

For structural and molecular formulae and relative molecular mass, see Huang & Johnston (1990), Junio et al. (2011), Li et al. (2011), and Fig. 1.2.

1.1.3. Technical and commercial products

Official technical products are goldenseal root, powdered goldenseal root, and powdered goldenseal root extract (NTP, 2010; USP, 2013). Other minor technical products may include powdered goldenseal leaf and its derived extracts, as well as fluid extracts (Mikkelsen & Ash, 1988; Oldfield, 2005; NTP, 2010).

Powdered goldenseal root and leaf products are available as capsules and teas in combination with other herbs, in some over-the-counter (OTC) herbal supplements (Mikkelsen & Ash, 1988; Zieger & Tice, 1997; AHP, 2001). Goldenseal is also found in eardrops, feminine cleansing products, cold/flu remedies, allergy relief products, laxative products, and aids to digestion (Zieger & Tice, 1997; AHP, 2001). Chemical derivatives of purified major components of goldenseal, such as berberine hydrochloride and berberine bisulfate, are found in some commercial eyewash formulations (Zeiger & Tice, 1997). Hydrastine, another derivative, is commercially available in the form of (–)-hydrastine and used as an ingredient in some decongestant nose sprays and feminine hygiene products (Zeiger & Tice, 1997; Huang & Johnston, 1990).

As a consequence of the high cost of genuine goldenseal, some commercial products contain little or no goldenseal plant material (Govindan & Govindan, 2000). Coptis chinensis has been sold in place of “Chinese goldenseal” and has been found as an adulterant of goldenseal (Brown & Roman, 2008). Moreover, other species that contain berberine, such as Coptis japonica, Berberis aquifolium, Berberis spp., Rumex spp., and Xanthorhiza simplicissima, have been used to adulterate goldenseal (Brown & Roman, 2008; Pengelly, 2012).

1.2. Analysis

Botanical identity and composition are confirmed by macroscopic and microscopic examinations of rhizome and root, as well as by thin-layer chromatography (TLC) (USP, 2013). TLC identification tests for the major goldenseal alkaloids are reported in the United States Pharmacopeia: a dry extract from roots and rhizomes contains at least 2% hydrastine and 2.5% berberine calculated on a dried basis; a standardized developing solvent system includes ethyl acetate, butyl alcohol, formic acid, and water (5:3:1:1); chromatogram analysis with ultraviolet (UV) light at 365 nm demonstrates a lemon-yellow fluorescence for berberine and a blue-white fluorescence for hydrastine (USP, 2013). Content of the most active alkaloids is determined by high-performance liquid chromatography (HPLC) using a mobile phase composed of 0.1 M monobasic potassium phosphate and acetonitrile (60:40) (USP, 2013). An official HPLC/UV method for hydrastine and berberine in goldenseal has been published (Brown & Roman, 2008), but other HPLC methods have also been developed (Abourashed & Khan, 2001).

Additional analyses report on the use of goldenseal and illicit drugs. Goldenseal may prevent the detection of illicit drugs (such as tetrahydrocanabinol and barbiturates) in urine by inducing their rapid elimination (Mikkelsen & Ash, 1988; Hamon, 1990; Schwarzhoff & Cody, 1993).

1.3. Use

1.3.1. Indications and applications

(a) Medicinal use

Native Americans used goldenseal to treat common conditions such as wounds, ulcers, digestive disorders, cancer, and skin and eye ailments (Hamon, 1990; Hobbs, 1990). Over the years, goldenseal has been used to treat a variety of digestive and haemorrhagic disorders. When applied topically, it is thought to possess slight antiseptic, astringent, and haemostatic qualities (NTP, 2010).

Some OTC dietary supplements containing goldenseal are used as to treat menstrual disorders, minor sciatica, rheumatic and muscular pain (Hamon, 1990), allergy symptoms, cold and flu symptoms, motion sickness and nausea, earaches and ear infections, and chronic diarrhoea from protozoal, fungal, and bacterial infections (Zieger & Tice, 1997; AHP, 2001; Hwang et al., 2003). Goldenseal has also been used in combination with dietary vitamins and minerals in an attempt to treat symptoms of AIDS (Zieger & Tice, 1997). It is also claimed to have the ability to cleanse the body from mucus, toxins, and waste (Zieger & Tice, 1997).

Berberine, a major goldenseal alkaloid, has been used as a bitter tonic, diaphoretic, and antipyretic (Kulkarni et al., 1972), for the treatment of skin diseases, liver diseases, eye infections, diarrhoea, cholera, giardiasis, amoebiasis, and dermal leishmaniasis (Choudhry et al., 1972; Kulkarni et al., 1972; Martin et al., 1978; Sabir et al., 1978; Khin-Maung-U et al., 1985; Vennerstrom et al., 1990; Chi et al., 1994; Müller et al., 1995). Berberine appears to control psoriasis through its ability to inhibit hyperproliferation (Müller et al., 1995). The evidence on the efficacy of berberine in treating peptic ulcers and hyperacidity, and malaria, is conflicting (Sabir et al., 1978; Vennerstrom & Klayman, 1988).

Some other pharmacological properties that have been identified for berberine include antiplatelet, anticerebral ischaemia, vasodilation, and anti-arrythmia (Peng et al., 1997). Berberine is thought to increase ileal contractility and acetylcholine retention by cholinesterase activity and is believed to be the active ingredient of Coptis rhizome, used to treat amnesia (Peng et al., 1997).

A clinical trial using berberine suggested that it is effective in improving cardiac performance in patients with heart failure (Marin-Neto et al., 1988). Berberine appears to exercise a direct depressive effect on myocardial, vascular, and smooth musculature (Sabir & Bhide, 1971; Creasey, 1977, 1979). Berberine may also have anticholinesterolase activity (Sabir & Bhide, 1971). It is also suggested that berberine exerts anticancer activities both in vitro and in vivo through different mechanisms (Sun et al., 2009).

Hydrastine, another major goldenseal alkaloid, is claimed to be an abortifacient, antibiotic, antiuterotic, antivaginitic, bactericide, central nervous system depressant, choleretic, convulsant, haemostat, hypertensive, hypotensive, pesticide, sedative, uterotonic, and vasoconstrictor (NTP, 2010).

(b) Medical research

In medical research, berberine is used as a fluorescent stain for cells, chromosomes, and energized mitochondria (Borodina et al., 1979; Ridler & Jennings, 1983; Mikeš & Dadák, 1983; Mikeš & Yaguzhinskij, 1985; Kim et al., 1990).

1.3.2. Dosage

As a dietary supplement, goldenseal can be given at a wide range of doses: decoction of dried roots, 0.5–10 g three times per day; alcoholic tincture, 2–4 mL three times per day; and fluid extract, 0.3–10 mL three times per day (Newall et al., 1996; Zieger & Tice, 1997; AHP, 2001; McKenna & Plotnikoff, 2010). OTC preparations of goldenseal are available in doses of 100 mg up to 470 mg (Zieger & Tice, 1997; AHP, 2001).

1.4. Production, sales, and consumption

1.4.1. Production

No data on production processes or volumes were available to the Working Group.

1.4.2. Sales

According to data from 2012 IMS Health MIDAS, worldwide sales of goldenseal root (Hydrastis canadensis) as a dietary supplement in pharmaceutical outlets totalled US$ 25 million. Appreciable sales occurred in Germany (US$ 8 million), France (US$ 5 million), and the United States (US$ 5 million) (IMS Health, 2012). Other countries known to sell products containing goldenseal include Canada.

According to the 2012 Nutrition Business Journal Report, goldenseal was the 37th best-selling herb in the USA in 2011. Following a decline from US$ 40 million in 2003, sales have remained constant (NBJ, 2012a, b). According to data from the United States National Health and Nutrition Examination Survey, there has been a decline in the prevalence of goldenseal use as follows: 1999–2002 (0.6%), 2003–2006 (0.3%), and 2007–2010 (0.2%), with similar data for males and females. These data showed a large coefficient of variation and caution should be used in interpretation (CDC, 2013).

1.4.3. Consumption

Goldenseal is consumed orally as a tea and in capsules, applied dermally as a skin lotion, applied to the eye as eyewash, to the ear as eardrops, and applied as a vaginal douche (Zieger & Tice, 1997; Hamon, 1990; AHP, 2001; NTP, 2010). Exposure to hydrastine also occurs when used in decongestant nose sprays and feminine hygiene products (Zeiger & Tice, 1997).

1.5. Occupational exposure

No data were available to the Working Group. Workers on goldenseal plantations and in goldenseal processing plants are probably exposed.

1.6. Regulations and guidelines

According to the 1994 Dietary Supplement Health and Education Act (DSHEA) in the USA, goldenseal is considered a dietary supplement under the general umbrella of “foods” (FDA, 1994). In the USA, dietary supplements put on the market before 15 October 1994 do not require proof of safety; however, the labelling recommendations for dietary supplements include warnings, dosage recommendations, and substantiated “structure or function” claims. The product label must declare prominently that the claims have not been evaluated by the Food and Drug Administration, and bear the statement “This product is not intended to diagnose, treat, cure, or prevent any disease” (Croom & Walker, 1995).

The Natural Medicines Comprehensive Database ranks goldenseal as a “possibly safe” dietary supplement when used at a single dose, and at recommended oral dosages for short-term administration (NCCAM, 2012; NMCD, 2013).

In Canada, goldenseal is a Natural Health Product (a form of OTC drug) and requires a product license (pre-market authorization) to be sold (Goldenseal Buccal, 2010). Goldenseal (H. canadensis) is also regulated as an endangered species under Appendix II of the Convention on International Trade in Endangered Species of Wild Fauna and Flora (CITES, 2006).

Bookshelf ID: NBK350390

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