Potentially hazardous contaminants and residues in

herbal medicines and its possible solutions

Deepak Basyal (M. Pharm)Lecturer, CiST College, New Baneshwor

INTRODUCTION• The use of herbs as medicine is the oldest form of healthcare

• Of about 2000 varieties of minor illnesses and serious diseases only 40% have cure using conventional orthodox pharmaceuticals

• About 25% of all modern medicines are directly or indirectly derived from higher plants (WHO)

• Over 80% of the world population depends on herbal medicines and product for healthy living (WHO)

• One of the impediments in its acceptance is the lack of standard quality control profile

• Product quality standards are essential, whether you’re using herbs or drugs

Herbal drugs

“herbal drugs” denotes plants or plant parts that have been

converted into phytopharmaceuticals by means of simple processes

involving harvesting, drying, and storage (EMEA, 1998)

Quality aspects of herbal drugs mixtures of many constituents in most cases active principle/s unknown Difficulty to get analytical methods or reference compounds Plant materials are chemically and naturally variable Chemo-varieties and chemo cultivars exist. The source and quality of the raw material are variable The methods of harvesting, drying, storage, transportation,

and processing (for example, mode of extraction and polarity of the extracting solvent, instability of constituents, etc.)

Toxic contaminants and residues

Layout: WHO Guidelines for QC of Herbal Medicine

Herbal Contamination

The undesired introduction of impurities of a chemical or microbiological nature, or of foreign matter, into or onto a starting material, Intermediate product or finished herbal product during production, sampling, packaging, repackaging, storage or transport.

(WHO technical report series: 908)

Sources of toxic contaminants in herbal products

• Environmental and conditions that the medicinal plants are grown

• The condition under which they are dried and processed

• The storage conditions and conditions during transport

• The manufacturing processs when ready-made medicinal products are produced

Heavy metals

• ‘Heavy metal’ refers to any metallic chemical element that has a relatively high density and is toxic or poisonous at low concentrations. e.g. mercury (Hg), cadmium (Cd), arsenic (As) and lead (Pb).

• Emissions from factories, leaded petrol, agrochemicals such as cadmium-containing fertilizers, organic mercury, and arsenic-based pesticides

• Furthermore, metals are sometimes intentionally added to Asian herbal preparations, because the traditional Indian (Ayurvedic) and Chinese medicine believe in their therapeutic properties

Heavy metals

• Not biodegraded but accumulate in the living system

• Causes various disease and disorders even at very low concentration

• Soil residence time of thousand of years

• Negative impact on soil microflora

Heavy metals WHO limits (ppm)

Arsenic 10

Cadmium 0.3

Lead 10

Mercury 1

Country Herbal Drugs As Pb Cd Hg

Canada Finished 5 10 0.3 0.2

China Crude 2 10 1 0.5

Singapore Finished 5 20 - 0.5

Thailand Crude ,Finished 4 10 0.3 -

WHO Crude 10 10 0.3 1

EP Crude - 5 0.5 0.1

Comparison of Various National/Regional Limits (ppm)

Source: Caserett and Doull's Toxicology

Source: Caserett and Doull's Toxicology

Source: Caserett and Doull's Toxicology

Microbial Load

• Exerts an important impact on the overall quality of herbal products and preparations

• Contamination of medicinal herbs and herbal products with bacterial strains resistant to known antibiotics poses a particular health risk

• An assessment of microbial contamination should take into account the following:

o route of application (in eyes, nose, respiratory tract)o nature of the product (the presence of substrate which could promote the

growth of microbes or preservatives)o intended recipient (newborns, infants, debilitated patients)o concomitant use of immunosuppressive agents and corticosteroids;

underlying disease, wound, or organ damage

Recommended microbial limits for herbal drugs (values in CFU/g)Microbes USP EP WHO Brazilian PAerobic bacteria 105/104/102 107/105 * / 107 / 105 107 / 105 / 104

Mold and yeast 103/102/10 105/104 105 / 104 / 103 104 / 103 / 102

Enterobacteria and other Gram negative bacteria

103/*/* */103 * / 104 / 103 104 / 103 / 102

E. coli Absent 103/Absent 104 / 102 / 10 Absent

Salmonella Absent */Absent * / Absent/ Absent

Absent

* Limits are not specified.

USP: • The first value represents dried or powdered botanicals and botanicals to be treated with

boiling water before use• The second value represents tinctures, powdered botanicals extracts, fluid extracts and

nutritional supplements with botanicals• The third value represents infusions/decoctionsEP:• the first value represents herbal medicinal products to which boiling water is added before

use• The second value represents herbal medicinal products to which boiling water is not added

before use WHO: • The first value represents contamination of "crude" plant material intended for further

processing• The second value represents for plant materials that have been pretreated (e.g. with boiling

water as used for herbal teas and infusions) or that are used as topical dosage forms• The third value represents for other plant materials for internal use Brazilian Pharmacopoeia: • The first value represents herbal drugs to which boiling water is added before use• The second value represents herbal drugs to which the extractive process made in cold

temperature• The third value represents final products for oral use.

Residue solvents

These are the residues of organic solvents that are used during manufacture or processing of herbal preparations/products.

Solvents are classified by ICH(CPMP/ICH 283/95) into three classes• Class 1: Solvents to be avoided e.g. Benzene• Class 2: Limited toxic potential e.g. Methanol, Hexane• Class 3: Low toxic potential e.g. Ethanol

Radioactive Contamination

• The environment may be contaminated with airborne radioactive materials (Cs-134, Cs-137) which may deposit on plants

• Their activity concentration and type of radioactive contamination should be measured

• No limits are proposed for radioactive contamination (Taking into account the quantity of herbal medicine normally consumed by an individual, is unlikely to be a health risk)

• Details of laboratory techniques are available from International Atomic Energy Agency (IAEA)

Aflatoxins

Aflatoxins are highly toxic contaminants produced by certain strains of the fungi Aspergillus flavus and A. parasiticusAmong 18 different types of aflatoxins identified, major members are aflatoxin B1, B2, G1 and G2. Aflatoxin B1 is the most toxic and most prevalent among this family.

• More than 25% of world agricultural crops are conatminated with mycotoxins (FAO, 2004)

• The major target for the toxicity of aflatoxins is the liver. Causes necrosis of liver cells, damage to mitochondria, and proliferation of bile ducts

• Ochratoxin A (OTA) secreted by Aspergillus ochraceus is carcinogenic (class 2B) according to the International Agency for Research on Cancer (IARC)

• There is no specific antidote for toxicity of aflatoxins and OTA. Timely administration of methionine (200 mg/kg) and sodium thiosulfate (50 mg/kg), at eight hour intervals, is proven to be of therapeutic value

Degradation Products

• Certain plant constituents are susceptible to chemical transformation by contaminating micro-organisms

(Penicillium nigricans and P. jensi )

• Enhanced enzymatic activity transforms some constituents to other metabolites not initially found in the herb

• These newly formed metabolites may then have adverse effects

Pesticide residues• Chemical compounds used to control or eradicate pests

(insecticides, fungicides, nematocides, herbicides, rodenticides)• Derived from synthetic and natural sources and effective in small

concentrations against pest• Accumulate from agricultural practices, such as spraying,

treatment of soils during cultivation, and administering of fumigants during storage

• It may be desirable to test herbal drugs for broad groups in general, rather than for individual pesticides.

• Many pesticides contain chlorine in the molecule, which, for example, can be measured by analysis of total organic chlorine. In an analogous way, insecticides containing phosphate can be detected by measuring total organic phosphorus.

Classification of pesticides1. Fungicides: prevents plant from diseases caused by phyto pathogenic fungie.g. Parathion, Carboxins, Colloidal sulphur, Barium sulphide, Dithiocarbamates

2. Herbicides: ‘weed killers’ which are used for destroying the unwanted plantse.g. Carbamates, Urea derivatives, Triazines , Quarternary ammonium compounds

3. Insecticides: used to protect the crop from insectse.g. Lead arsenate, Sodium fluoride, Nicotine, Pyrethrum D

Pesticide Limits (mg/kg) USP-2006 and EP (2007)

Aldrin 0.05

Chlropyrifos 0.2

Diazinon 0.5

Dichlorvos 1.0

Dithiocarbamate 2.0

Endosulfan 3.0

Endrin 0.05

Ethion 2.0

Malathion 1.0

Parathion 0.5

Permethrin 1.0

Phosalane 0.1

Pryethrin 2.0

Possible solutions to prevent contamination Bioremedation: Using Hyper-accumulator Plants and certain strains of degrading Bacteria and Fungus (Ecological engineering) Salix viminalis absorbs heavy metals(Ag, Cd, Pd, Cu, Zn,

Radioactive Ura) Indian mustard green absorbs/extracts heavy metals Deinococcus radioduran absorbs radioactive nuclei Yeast (Trichosporon mycotoxinivorans) and

Mould( Streptomyces spp.) can detoxify AF and OTA in Soil Use competitive non toxic strain of A. flavus (AF-36 and Alfa

Guard) to decrease the population of toxigenic A. flavus in soil Sunflower are grown at Chernobyl Nuclear site (Ukraine) and

Uranium plant at Ohio (USA) to absorb radioactive metals

Gamma-irradiation: fast, safe, convenient, eco-friendly method to decrease microbial count. Also reduces the reliance on chemical fumigants and preservatives

Drying at high temperature decreases the total aerobic microbial count (TAMC) in herbs

Avoiding harvesting or collection in damp and cool weatherAssessing the potential sources of riskTo reduce heavy metals by plant pH of soil is adjusted to level

6.5 -7 Use of chelating agents(5mmol/kg of soil) to form complex

with heavy metals and decrease their bioavailabilityMapping of the contaminated soil sites

• Establish good agricultural, harvesting, and manufacturing, processing, drying, storage, packaging and distribution practices for herbal starting materials ensuring the safety of the global herbal market

• Various government agencies should follow a more universal approach to herbal quality by adopting the WHO guidelines and also developing monographs using the various quality parameters

Selected References Concerning Quality of Herbal Quality control method for medicinal plant material Good agricultural and collection practice for medicinal plants International Pharmacopoeia Good manufacturing practice: Supplementary guidelines for

manufacture of herbal medicinal products Guide to good storage practice for pharmaceuticals

Good trade and distribution practices for pharmaceutical starting materials

General guidelines for methodology on research and evaluation of traditional medicine

Guidelines for assessment of herbal medicines WHO monograph on selected medicinal plants WHO pharmaceutical starting materials certification scheme

References• AOAC (2005). Official Methods of Analysis of AOAC International, 18th edn.

AOAC International, Gaithersburg, MD.• EMEA (1998). Quality of Herbal Medicinal Products. Guidelines. European

Agency for the Evaluation of Medicinal Products (EMEA), London.• Wani MS (2007). Herbal medicine and its standardization. Pharma. Info. 1: 6.• WHO (1999a). Quality Control Methods for Medicinal Plant Materials. World

Health Organization, Geneva.• WHO (1996b). Guidelines for the Assessment of Herbal Medicines. WHO

Technical Report Series, World Health Organization, Geneva. 863.• Curtis D. Klaassen: Caserett and Doull's Toxicology, The Basic Science of Poisons

(5th Ed.) 1996, McGraw Hill,New York • B. Tangahu, S. Rozaimah. Review on heavy metal uptake by plants through

Phytoremedation. Int. J. Chem. Eng. 2011.

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