Quantitative Analysis of Metal Contents in Korean Herbs and Herbal Products to Give Advice for Metal Allergic Patient.

BACKGROUND: Herbs have been used worldwide as complementary and alternative medicines. In Korea, herbs for medical purpose are strictly controlled by the Korea Food and Drug Administration (KFDA). But it does not provide standards for metal antigens.
OBJECTIVE: This study conducted to identify the metal contents of Korean herbs and herbal products and to give information on counselling metal allergic patient.
METHODS: The concentration of three metal allergens with high antigenicity, cobalt (Co), chromium (Cr), nickel (Ni) was quantitatively determined using inductively coupled plasma with a mass spectrometer after nitric acid (HNO3) digestion. The herbal objects are as follows: 1) ten kinds of herb plants, 2) ten herbal products sold in Korean drugstores, and 3) ten herbal extracts prescribed by Korean herbal doctors.
RESULTS: In 30 samples, Ni and Cr were detected in all items. Co was not detected in two drugstore products.
CONCLUSION: Although the levels of metal detected in this study were very low relative to international guidelines and KFDA regulations, the herbal preparations contained similar or higher metal levels than known metal-rich foods. It can cause problems when it added to the daily diet and cause deterioration of skin lesions of metal sensitized person.

INTRODUCTION

Herbs have been used worldwide as complementary and alternative medicines (CAMs) for thousands of years. Korea has traditionally used a variety of herbal products, and 85.5% of the Korean general population has used an herbal medicine more than once in their lifetime1. Herbs are cultivated and harvested in natural environments and, thus, are heavily influenced by metal contamination of the soil and surrounding environment. Therefore, many countries consistently analyze the metal contents of herbs and herbal products2345.

In Korea, herbs are categorized as ‘food ingredients’ when used as foodstuffs and ‘herbal plants’ when used for medicinal purposes. Herbal plants used by Korean herbal doctors, the Hospital of Oriental Medicine, pharmaceutical companies, pharmacies, and Oriental medicine dispensaries should meet quality-control standards based on the regulations of the Korea Food and Drug Administration (KFDA)6789. However, the updated Korean herb and herbal-product purity guidelines include only four heavy metals, arsenic (As), lead (Pd), cadmium (Cd), and mercury (Hg), whereas other metals are measured as the sum of the total metals using the sulfide precipitation method.

In Korea, 43.6% of adverse reactions associated with Oriental medicines involve dermatological problems, which are the most common side effects1. For example, contact dermatitis, arsenic keratosis, phototoxicity, and alopecia have been reported after using herbal products10. Since the 2000s, countries around the world have noted that CAMs, including herbs, may be an important ingestion factor for metal antigens such as nickel, chromium, cobalt, and mercury11121314. However, no studies have investigated the metal contents of Korean herbs and herbal products with the potential to cause contact dermatitis. Therefore, this study aimed to identify the metal contents of Korean herbs and herbal products and to give information on counselling metal allergic patient compared with previous reports in literature reviews.

MATERIALS AND METHODS

Study materials

In this study, 10 herbal plants that are ranked among the top 10 most commonly used in Korea according to the 2010 Korea National Statistical Office Notice were obtained from a KFDA approved pharmaceutical company. Ten herbal products sold in Korean drugstores and 10 herbal extracts prescribed by Korean herbal doctors were purchased randomly.

Study methods

After all solid samples were ground homogeneously, 0.5 g of sample was placed in Teflon container and mixed with 7 ml undiluted nitric acid (HNO3). The mixture heated to 150℃ and cooled to room temperature. After opening lid, the mixture was reheated to achieve a dry state. Next, 5 ml undiluted HNO3 and 1 ml perchloric acid were added to the dry material and sealed. The mixture was thermally decomposed at 150℃, cooled to room temperature, reheated until it had dried, and then diluted with 1% HNO3 to produce a total 50 ml.

For liquid samples, 1 ml of the liquid sample was placed in 60 ml Teflon container and mixed with 2 ml undiluted HNO3. The mixture heated to 150℃ and cooled to room temperature. After opening lid, the mixture was reheated to achieve a dry state and diluted with 1% HNO3 to produce a total 50 ml.

The preprocessed samples were analyzed twice to measure the three metals: Cr, Ni and Co which could cause allergic contact dermatitis listed in Fisher's contact dermatitis 6th edition15. An inductively coupled plasma mass spectrometer (iCAP™ TQ ICP-MS®; Thermo Scientific, Bremen, Germany) was used to assess the herbal plants and herbal products sold in drugstores, whereas a different inductively coupled plasma mass spectrometer (X-SERIES ICP-MS®; Thermo Elemental, Winsford, UK) was used to assess the herbal extracts.

The analytical detection limits for the iCAP™ TQ ICP-MS® were as follows: 0.001 µg/kg for Cr, 0.001 µg/kg for Ni, 0.001 µg/kg for Co. The analytical detection limits for the X-SERIES ICP-MS® were 0.1 µg/kg for Cr, 0.2 µg/kg for Ni and 0.1 µg/kg for Co.

Calculation of mean daily metal intake

To calculate the mean daily metal intakes from herbal plants and herbal extracts, either the daily intake doses that were described on the medicine packages or the daily intake directions described by Korean herbal doctors or pharmacists were used. The daily intake doses for herbal plants were calculated according to the mean daily intake doses suggested by the KFDA for evaluating hazards associated with herbal medicines in 2016 (Table 1)16. The KFDA study conducted for 174 kind of herbal material in total of 5,000 Korean distribution channels which trading herbs (oriental medicine, oriental medicine hospitals, oriental pharmacies, pharmacies and herbal medicine pharmacies) for 2 years. Total 62,741 herbal prescription and herbal item usage amount information had been collected by survey paper response or visiting survey16.

Table 1

Mean daily intake dose of Korean herbs16

Order	Items	Mean daily intake dose (g)
1	Herb A (Angelica Gigas root)	6.42
2	HerbB (Poria)	6.84
3	Herb C (Astragalus root)	7.53
4	Herb D (Peony root)	6.29
5	Herb E (Licorice)	5.42
6	Herb F (Cnidium rhizome)	6.41
7	Herb G (Prepared Rehmannia root)	8.27
8	Herb H (Liriope tuber)	6.8
9	Herb I (Alisma rhizome)	7.3
10	Herb J (Bupleurum root)	6.3

RESULTS

The results from the quantitative analyses of 30 herbal items, including herbal plants, herbal products, and herbal extracts, are shown in Table 2.

Table 2

Metal content in Korean herbs, herbal products and herbal extracts

Items		Metal content (ppm)			Daily metal intake (μg)
		Cr	Co	Ni	Cr	Co	Ni
I. Material (solid)	Herb A (Angelica Gigas root)	1.582	0.413	2.224	10.155	2.654	14.275
	Herb B (Poria)	0.020	0.052	0.002	0.136	0.352	0.011
	Herb C (Astragalus root)	2.234	0.059	1.308	16.822	0.448	9.850
	Herb D (Peony root)	1.351	0.052	0.760	8.496	0.324	4.783
	Herb E (Licorice)	0.522	0.058	0.334	2.832	0.315	1.812
	Herb F (Cnidium rhizome)	0.366	0.091	0.253	2.349	0.582	1.621
	Herb G (Prepared Rehmannia root)	3.685	0.331	1.021	30.478	2.739	8.447
	Herb H (Liriope tuber)	2.959	0.078	0.409	20.118	0.531	2.780
	Herb (Alisma rhizome)	0.485	0.090	0.309	3.543	0.657	2.255
	Herb (Bupleurum root)	2.225	0.174	0.738	14.019	1.094	4.648
II. Final product (solid)	Herbal product F (Danggwisusan Extract Granules)	0.270	0.069	0.502	2.431	0.620	4.516
	Herbal product G (Socheongryongtang Mix Extract Powder)	0.360	0.114	0.468	3.242	1.024	4.215
	Herbal product H (Eungyosan Extract Granules)	0.462	0.082	0.958	4.157	0.738	8.620
	Herbal product I (Banhasasimtang Mix Extract Powder)	0.239	0.091	0.437	2.150	0.823	3.932
	Herbal product J (Insampaedogsan Mix Extract Powder)	0.996	0.066	0.652	8.963	0.593	5.865
	Herbal product E (Jeongrohwan Pill)	0.547	0.120	0.658	0.984	0.215	1.184
III. Final product (liquid)	Herbal product A (Ssanghwatang Extract Solutions)	0.003	0.015	0.074	0.860	4.430	22.166
	Herbal product B (Gaswhalmyungsu Solution)	0.041	Bdl	0.011	9.113	NE	2.377
	Herbal product C (Hyanggaltang Extract Solutions)	0.020	0.012	0.076	6.105	3.674	22.822
	Herbal product D (Uhwangcheongsimwon Solution [Altered Prescription])	0.113	Bdl	0.084	11.268	NE	8.394
IV. Herbal extract (liquid)	Herbal extract A	0.002	0.016	0.130	0.728	4.724	39.024
	Herbal extract B	0.009	0.013	0.214	2.695	4.028	64.296
	Herbal extract C	0.005	0.009	0.103	1.390	2.818	30.960
	Herbal extract D	0.009	0.015	0.145	2.766	4.418	43.524
	Herbal extract E	0.007	0.018	0.159	1.981	5.308	47.616
	Herbal extract F	0.007	0.020	0.154	2.153	6.005	46.164
	Herbal extract G	0.008	0.024	0.139	2.480	7.130	41.604
	Herbal extract H	0.007	0.021	0.141	2.154	6.191	42.324
	Herbal extract I	0.005	0.011	0.085	1.463	3.258	25.416
	Herbal extract J	0.008	0.020	0.131	2.383	6.101	39.192

Bdl: below detection limit, NE: not estimated.

Analytical results according to metal type

Ni was detected in all 30 items. The mean Ni content was 0.736 ppm (0.002~2.224 ppm) in herbal plants, 0.392 ppm (0.011~0.958 ppm) in herbal products sold in Korean drugstores, and 0.140 ppm (0.085~0.214 ppm) in herbal extracts. Thus, the mean daily Ni intake was 5.048 µg/d (0.011~14.275 µg/d) from herbal plants, 8.409 µg/d (1.184~22.822 µg/d) from herbal products sold in Korean drugstores, and 42.012 µg/d (25.416~64.296 µg/d) from herbal extracts. Of the 10 herbal extracts, 1 in particular (Herbal extract B) had a mean daily Ni intake of 64.296 µg/d, and 6 had a daily mean intake greater than 40 µg/d.

Cr was detected in all 30 samples. The mean Cr content was 1.543 ppm (0.020~3.685 ppm) in herbal plants, 0.305 ppm (0.003~0.996 ppm) in herbal products sold in Korean drugstores, and 0.007 ppm (0.002~0.009 ppm) in herbal extracts. Thus, the respective mean daily Cr intakes were 10.895 µg/d (0.136~30.478 µg/d), 4.927 µg/d (0.860~11.268 µg/d), and 2.019 µg/d (0.728~2.766 µg/d). A Cr content higher than 0.7 ppm was observed in six herbal plants and one herbal product sold in Korean drugstores.

Co was detected in all study samples except two herbal products sold in Korean drugstores. The mean Co content was 0.140 ppm (0.052~0.413 ppm) in herbal plants, 0.057 ppm (up to 0.120 ppm) in herbal products sold in Korean drugstores, and 0.017 ppm (0.009~0.024 ppm) in herbal extracts. Thus, the respective mean daily Co intakes were 0.970 µg/d (0.315~2.739 µg/d), 1.212 µg/d (up to 4.430 µg/d), and 4.998 µg/d (2.818~7.130 µg/d). Mean daily Co intake greater than 6 µg/d was found from four herbal extracts.

Characteristics according to material (herbal plant) and finished product (herbal product and extract)

Herbal plants had higher mean metal contents for all metals than those of herbal products and herbal extracts (mean metal contents of herbal plants, Cr 1.543 ppm, Co 0.140 ppm, Ni 0.736 ppm). The lowest mean metal content was detected in herbal extracts (mean metal contents of herbal extracts, Cr 0.007 ppm, Co 0.017 ppm, Ni 0.140 ppm). However, when this value was converted to mean daily metal intake, Co levels were 5.15 times higher, Ni levels 8.32 times higher in herbal extract than the herbal plants (mean herbal extracts daily intake Co 4.998 µg, Ni 42.012 µg; mean herbal plants daily intake Co 0.970 µg, Ni 5.048 µg).

DISCUSSION

As CAM use broadens worldwide, and the international market expands rapidly, emphasis on the safety and quality of herbs and herbal products is increasing17. According to the World Health Organization (WHO), herbal products were regulated in 65 countries in 1999 but in as many as 119 in 201218.

In Korea, various herbal products are used in medical institutions such as the oriental medicine hospitals, pharmacies, as well as in the private sector in functional foods, teas, and spices. The regulation of heavy metals in herbal products was strengthened in April 2006 in Korea, and the limits of four metals (Pb ≤5 ppm, As ≤3 ppm, Cd ≤0.3 ppm, and Hg ≤0.2 ppm) were incorporated into previous regulations recommending total amounts ≤30 ppm. Because most final herbal extracts and products prescribed by Korean herbal doctors consist of several raw herbal plant materials, herbal extracts and products may have metal levels several times higher than each herbal plant components. In this study, ingesting some herbal extract led to daily metal intake values up to 22.63 times higher Co and up to more than five thousand times higher Ni than for ingesting an herbal plant (Table 2). However, herbal plants and specific herbal products listed in the KFDA are regulated in Korea, whereas herbal products prescribed by Korean herbal doctors are not. Same regulation limit applies to herbal plants, which are raw materials, and herbal products, the final products. In contrast to the Korean Pharmacopoeia (KP), Canada and USA apply stricter regulations to final products than raw materials19. Although the regulations on herbal products have been strengthened, these regulations refer only to certain heavy metals, and there have been no standards for evaluating metals as allergens until now.

Fortunately, most of the herbal plants and products analyzed in this study had little metals relative to permissible tolerable daily intake levels provided by several international organizations (Table 3).

Table 3

Permissible tolerable daily intake (PTDI)

Metal	PTDI
Chromium (Cr)	not evaluated (JECFA), 0.15 mg Cr(III)/kg/d (UK EVM), 0.9 μg Cr(IV)/kg/d (WHO/IPCS), 300 μg Cr/kg/d (VKM), 250 μg Cr/d (WHO/IPCS)
Cobalt (Co)	-
Nickel (Ni)	6.0 μg Ni/kg/d (US EPA), 5 μg Ni/kg/d (FAO/WHO)

JECFA: Joint Food and Agriculture Organization/World Health Organization Expert Committee on Food Additives, UK EVM: United Kingdom Expert Group on Vitamins and Minerals, WHO: World Health Organization, IPCS: International programme on chemical safety, VKM: Norwegian Scientific Committee for Food and Environment, US EPA: United States Environmental Protection Agency, FAO: Food and Agriculture Organization.

Ni is a ubiquitous element with strong antigenicity, and Ni allergies are generally reported in 10% to 20% of the population. Food and water are the primary sources of Ni exposure. The level of dietary Ni intake varies from 20 to 600 µg/d, depending on the geographic area152021. A strong correlation has been observed between the amount of ingested Ni and allergic contact dermatitis. Dietary interventions, including Ni restriction, are important for treatment and prevention of Ni allergy, because very low concentrations (10~60 µg/kg) can elicit allergic reaction after sensitization 202223. Well-known Ni-rich foods include cocoa, peanuts, and chocolate. Jacob et al.24 reported that four Ni allergic children who improved after strict Ni restriction diet showed abrupt deterioration after eating chocolate bars, and Krecisz et al.14 reported a case of systemic contact dermatitis following cocoa ingestion232425. In these two reports, Ni in the food was approximately 50 µg (50 g/chocolate bar, 1.00 [0.85~1.32] mg/kg Ni24; 5 g/recommended daily dose of cocoa powder, 10 mg/kg Ni26).

In this study, six herbal extracts had daily Ni intake similar to or higher than 50 µg (Table 2). Han et al.25 analyzed Ni content of Korean foods in 2005 and found considerably more Ni in most Korean foods than previous reports. For example, the Ni content of Korean green tea bags is 7,852 times higher than that reported by Veien and Andersen26 in 198625. Fortunately, the Ni contents of herbal plants and products in this study were considerably lower than those previous reported from other countries2327293031. However, the metal contents of herbal plants and products can differ greatly, even in the same country, depending on types of selected herbal plants, cultivation environment, and time obtained229. Thus, interpretations of these results should be careful232728293031.

Cr is commonly used in alloys and showed sensitization rate up to 6%32. Irritant dermatitis, dyshidrotic eczema, and contact dermatitis are closely related to dietary or medicinal Cr. Fregert and Rorsman33 reported that a provocation test using 50 µg oral dichromate salt in five Cr allergy patients caused acute flare-ups of hand eczema. Korean herbal products contain average Cr of 0.618 ppm, which is six times higher than daily diet (0.1 ppm)34. In this study, six herbal plants and one herbal product contained five times more Cr than nuts (0.7 ppm), a wellknown Cr-rich food35. One herbal plants, Herb G (prepared Rehmannia root) contained 3.685 ppm (Table 2).

Co exposure commonly occurs via inhalation, oral ingestion, and contact and can cause irritant dermatitis, contact dermatitis, allergic vasculitis, and hand eczema (dyshidrotic eczema)36. Like Ni, geographic and environmental conditions affect Co contents of food and water37. Stuckert and Nedorost36 suggested that <12 µg/d is appropriate for standard Co-restricted diet. In this study, four herbal extracts had Co levels higher than 50% of the restricted diet standard, and one (Herbal extract G, 7.13 µg/d) had up to 60% (Table 2).

In Korea, many patients use CAMs to treat allergic diseases such as asthma, rhinitis, atopic dermatitis, and urticaria1. But significant levels of high-antigenicity metals, such as Ni, Co and Cr are contained in Korean herbal plants and products compared with the metal levels in Nior Cr-rich foods which can aggravate metal allergy patient or those of Co-restricted diets.

In addition to the metals assessed in this study, other studies have reported that CAMs contain manganese, iron, zinc, and selenium. Assessments of these metals in Korean herbal products should be conducted in the future430.

When describing metal-restricted diets, most authors distinguish between metal-rich and low-metal foods based only on metal content. However, in addition to content, actual dietary intake amount is an important factor for metal exposure. Dietary intake should be taken into consideration in dietary education. In this study, the lowest mean metal content was detected in herbal extracts compared with herbal plants and products sold in Korean drugstores. However, when the contents were converted to daily intake values, there was 5.15 times higher in Co and 8.32 times higher in Ni daily metal intake from herbal extracts than from herbal plants.

The present study is limited in that it involved a small sample number and purchased only in Seoul. Furthermore, because all of the samples were KFDA-approved, these results do not represent the herbs obtained from markets.

In previous analyses of Korean herbs, only certain heavy metals (Pb, As, Cd, and Hg) in raw herbal plant were assessed. Therefore, this study was the first to analyze metal antigens in Korean herbal plants and the final ingested forms of herbal products. The herbal preparations contained similar or higher metal than known metal-rich foods. The KFDA has strict regulations on heavy metals, pesticide, and aflatoxins but does not provide standards for metal antigens. The allergenicities of herbal products have been underestimated. Metal exposure differs depending on the intake amount, and place of purchase, even for the same herb. Therefore, doctors should perform a detailed medical history about the usage of herbal products and the place of purchase for patients with intractable contact dermatitis or acute deteriorated lesions.