Ecotoxicology and Environmental Safety 219 (2021) 112336

Contents lists available at ScienceDirect

Ecotoxicology and Environmental Safety

journal homepage: www.elsevier.com/locate/ecoenv

Review

Impacts of heavy metals and medicinal crops on ecological systems,

environmental pollution, cultivation, and production processes in China
Yi-Gong Chen a, 1, Xing-Li-Shang He a, 1, Jia-Hui Huang a, Rong Luo a, Hong-Zhang Ge a,
Anna Wołowicz b, Monika Wawrzkiewicz b, Agnieszka Gładysz-Płaska b, Bo Li a, Qiao-Xian Yu d,
Dorota Kołodyńska b, *, Gui-Yuan Lv c, *, Su-Hong Chen a, *
a
Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, Zhejiang University of Technology, Chaowang Road 18, Hangzhou, Zhejiang
Province, China
b
Department of Inorganic Chemistry, Institute of Chemical Sciences, Faculty of Chemistry, Maria Curie-Sklodowska University, M. Curie Sklodowska Sq. 2, 20-031
Lublin, Poland
c
College of Pharmaceutical Science, Zhejiang Chinese Medical University, Hangzhou, Zhejiang Province, China
d
Zhejiang Senyu Co., Ltd, No. 8 Wanmao Road, Choujiang Street, Yiwu City, Zhejiang Province, China

A R T I C L E I N F O A B S T R A C T

Edited by Professor Bing Yan Heavy metals are widely distributed in the environment due to the natural processes and anthropogenic human
activities. Their migration into no contaminated areas contributing towards pollution of the ecosystems e.g. soils,
Keywords: plants, water and air. It is recognized that heavy metals due to their toxicity, long persistence in nature can
Heavy metals accumulate in the trophic chain and cause organism dysfunction. Although the popularity of herbal medicine is
Medicinal crops
rapidly increasing all over the world heavy metal toxicity has a great impact and importance on herbal plants and
Ecological effects
consequently affects the quality of herbal raw materials, herbal extracts, the safety and marketability of drugs.
Environmental pollution
Manufacturing process Effective control of heavy metal content in herbal plants using in pharmaceutical and food industries has become
indispensable. Therefore, this review describes various important factors such as ecological and environmental
pollution, cultivation and harvest of herbal plants and manufacturing processes which effects on the quality of
herbal plants and then on Chinese herbal medicines which influence human health. This review also proposes
possible management strategies to recover environmental sustainability and medication safety. About 276
published studies (1988–2021) are reviewed in this paper.

1. Introduction weight and density of at least 5 times greater than that of water (Fer­
gusson, 1990). As large weight and toxicity are suggested to be
Heavy metals are naturally occurring elements with the large atomic inter-related, heavy metals also include metalloids, such as arsenic,

Abbreviations: AA, Amino acids; ABCC, ATP-binding-cassette transporters sub-family C; As, Arsenic; Ba, Barium; bw, Body weight in kg; CAX, Cation/proton
exchanger; Cd, Cadmium; CDFs, Cation Diffusion Facilitators; cGMPs, Current good manufacturing practices; CHM, Chinese Herbal Medicine; Co, Cobalt; Cr,
Chromium; CR, Carcinogenic risk assessment; Cu, Copper; DC, Dead tree cultivation; DOM, Dissolved organic matter; DS, Dietary supplements; EDI, Estimated daily
intake; FAO, Food and Agriculture Organization of the United Nations; GC, Greenhouse cultivation; GSH, Glutathione; GSR, Glutathione reductase; HP, Herbal
products; Hg, Mercury; HKCMMS, Hong Kong Chinese Materia Medica Standards; HM, Herbal medicine; HMAs, Heavy Metal ATPases family members; HSA, Health
Sciences Authority; HPR, Health Products Regulation; ISO, International Organization for Standardization; LC, Living tree cultivation; MEP, Ministry of Environ­
mental Protection of the People’s Republic of China; MFH, Medicine food homology; MHF, Medicinal health food; MLR, Ministry of Land and Resources of the
People’s Republic of China; Mn, Manganese; MTs, Metallothioneins; Ni, Nickel; NRAMPs, Natural Resistance and Macrophage Proteins; NSFI, National Sanitation
Foundation International; OA, Organic acids; Pb, Lead; PCs, Phytochelatins; PL, Permissible limit; RC, Rock cultivation; RM, Raw material; ROS, Reactive oxygen
species; RWC, Rock wall bionic cultivation; Se, Selenium; SOD, Superoxide dismutase; TC, Tissue culture; TCM, Traditional Chinese Medicine; TGA, Therapeutic
goods administration; TPP, Traditional pharmaceutical preparation; UC, Undergrowth cultivation; V, Vanadium; WC, Wild-collection; WHO, World Health Orga­
nization; ZIPs, Zinc/Iron regulated Proteins; Zn, Zinc; -COO-, Carboxylic acids; -SH, Thiols.
* Corresponding authors.
E-mail addresses: d.kolodynska@poczta.umcs.lublin.pl (D. Kołodyńska), zjtcmlgy@163.com (G.-Y. Lv), chensuhong@zjut.edu.cn (S.-H. Chen).
1
These authors contributed equally to this paper.

https://doi.org/10.1016/j.ecoenv.2021.112336
Received 28 January 2021; Received in revised form 20 April 2021; Accepted 10 May 2021
Available online 25 May 2021
0147-6513/© 2021 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/).
Y.-G. Chen et al. Ecotoxicology and Environmental Safety 219 (2021) 112336

which exert in-vivo toxicity at low concentrations of exposure (Duffus,
2002; Koller and Saleh, 2018), antimony, selenium, germanium and
tellurium. As natural components of the earth’s crust, the penetration of
heavy metals is ubiquitous. Nonetheless, industrial, military, domestic,
medical, technological, and agricultural processes and applications
across the globe can maximize the enrichment effects of heavy metals in
the environment (Tchounwou et al., 2012). Despite a few heavy metals
being essential for life, consuming excessive amounts provides devas­
tating results, including toxic effects (Jaishankar et al., 2014; Magelsir,
2016) and carcinogenic (Sharma and Agrawal, 2005; Zheng et al.,
2010), further attributed to producing several chronic and acute dis­
eases encompassing hypertension (Martins et al., 2018; Gao et al.,
2018), atherosclerotic disease, cardiovascular disease (Moreno et al.,
2019), endocrine dysfunction (Stevenson et al., 2019), renal failure,
infertility, bone deformities (Yang et al., 2016), hyperglycemia, diabetes
(González-Villalva et al., 2016; Tinkov et al., 2017; Leff et al., 2018),
inflammation (Pollard et al., 2019), neurological diseases (Adlard and
Bush, 2018; Verkhratsky and Parpura, 2016), autoimmune diseases
(Crowe et al., 2017; Rowley and Monestier, 2005), prostate dysfunction,
osteomalacia, and osteoporosis (Kim et al., 2015) disease. Obviously,
heavy metals are serious toxicants known as highly pathogenic risk
factors (Mishra et al., 2019). They can include lead (Pb), cadmium (Cd),
mercury (Hg), nickel (Ni), copper (Cu) (Hubicki and Kołodyńska, 2012).
Because of their unique characteristics and physicochemical properties,

Table 1
Impact of heavy metal ions in risk-inducing herbal medicines on humans and values of EDI (estimated daily intakes) and CR (carcinogenic risks) based on literature
review.
Heavy RfD0 (US Representative herbs (118 kinds, 1902 samples) Health effects References
metals EPA,
Max Related examples Max Related examples
2000)
EDI CR
1 1
(mg kg− day−
bw)

Pb 0.004 0.004 Lonicera confusa DC., 1.23E- Tetradium Adverse effect on the blood, nervous, immune, (Dghaim et al., 2015;
Tetradium ruticarpum (A. 07 ruticarpum (A. renal, skeletal, muscular, reproductive, and Martin and Griswold,
Juss.) Juss.) cardiovascular systems causing, poor muscle 2009; Luo et al., 2021)
0.005 Lonicera japonica Thunb. 1.15E- Plantago asiatica coordination, gastrointestinal symptoms, brain
07 L. and kidneys damage, hearing and vision
0.008 Grona styracifolia (Osbeck) 8.07E- Lonicera japonica impairments, reproductive defects, slowed
H. Ohashi and K. Ohashi 08 Thunb. cognitive development, learning deficits, can
0.024 Plantago asiatica L. 4.54E- Lonicera confusa damage the testicles in men, ultimately cause
08 DC. death.
As 0.0003 0.002 Cornus officinalis Siebold 1.34E- Plantago asiatica Decreased production of hemoglobin, red blood (Kapaj et al., 2006; Rana
and Zucc., Taraxacum 06 L. cells and white blood cells, abnormal heart et al., 2018; Ray et al.,
officinale (L.) Weber ex 1.09E- Cornus officinalis rhythm, hypertension, diabetes, cardiovascular 2014; Luo et al., 2021)
06 Sieb. et Zucc. disease, skin lesions, hyperpigmentation,
0.007 Plantago asiatica L. 9.20E- TaraxacMm keratosis, and neurodegenerative disorders.
07 mongolicum Hand.
-Mazz.
7.43E- Andrographis
07 paniculate (Burm.
f.) Nees
Cd 0.001 0.001 Andrographis paniculata 1.55E- Curcuma longa L. Irreversible impairment of the renal tract; serious (Dghaim et al., 2015; Li
(Burm.f.) Nees, Curcuma 06 damage of liver, lungs, vascular and immune et al., 2012; Martin and
longa L., Lonicera confusa 1.39E- Rheum palmatum system; fragile bones, irritates the stomach, Griswold, 2009; Maobe
DC. 06 L. leading to vomiting and diarrhea. et al., 2012; Luo et al.,
1.23E- Houttuynia 2021)
06 cordata Thunb.
0.002 Houttuynia cordata Thunb. 1.12E- Lonicera confusa
06 DC.
Hg 0.0001 0.001 Chrysanthemum indicum L., 2.18E- Andrographis Numerous deleterious effects on various (Luo et al., 2021; Rana
Forsythia suspensa (Thunb.) 06 paniculata (Burm. organisms of the body within the digestive, et al., 2018; Khan et al.,
Vahl, Tussilago farfara L. F.) Nees immune, urinary, nervous systems, arrhythmias, 2019)
1.72E- Plantago asiatica cardiomyopathy, respiratory failure and kidney
06 L. damage.
1.64E- Cornus officinalis
06 Sieb. et Zucc.
1.60E- Curcuma longa L.
06
Cu 0.04 0.015 Plantago asiatica L. – – Dermatitis, irritation of the upper respiratory (Dghaim et al., 2015; Luo
0.012 Desmodium styracifolium tract, abdominal pain, nausea, diarrhea, et al., 2021; Kohzadi et al.,
(Osb.) Merr. vomiting, liver damage. 2018)
0.008 Houttuynia cordata Thunb.
Zn 0.3 0.100 Zantedeschia aethiopica (L.) – – Toxic effects on the immune system, blood (Dghaim et al., 2015; Luo
Spreng., Viola odorata L. lipoprotein levels, and copper level. et al., 2021; Kohzadi et al.,
2018)
Fe 0.7 0.850 Viola odorata L., Matricaria – – Gastrointestinal effects such as gastrointestinal (Dghaim et al., 2015; Luo
chamomilla L. bleeding, nausea and vomiting, dizziness, et al., 2021; Kohzadi et al.,
diarrhea, joints pain, shock, and liver damage, 2018)
hypotension, lethargy, tachycardia, hepatic
necrosis, metabolic acidosis and sometimes dead.

RfDo: International oral reference dose values for the heavy metals, EDI: Estimated daily intake (theoretical value without being corrected for % solubilization and
bioavailability), CR: Carcinogenic risks. Acceptable risk levels for CR range from 10–4 (risk of developing cancer over a human lifetime is 1 in 10,000) to 10–6 (risk of
developing cancer over a human lifetime is 1 in 1,000,000). (Adusei-Mensah et al., 2019). The EDI and CR scores in this table were calculated with maximal con­
centrations of each herbal medicine.

2
Y.-G. Chen et al.
heavy metals present precise toxicological mechanisms of action that
affect human health negatively as listed in Table 1.
Over the past four decades, with unprecedentedly rapid economic
growth, China has emerged as the second-largest leading economy
across the globe. Nevertheless, with the global largest population,
industrialization in China has been associated with significant energy
consumption and severe pollution (Sun, 2016), including heavy metals,
exhaust gases, and biochemical, as well as other hazardous substances.
Consequently, this triggers long-term damage to the ecological envi­
ronment (Liu et al., 2018b). Besides, population aging is an increasingly
prominent issue in China, driving the country towards a demographic
crisis (Cheng, 2019). Naturally, health care is particularly essential in
this era. It is very important especially now during the COVID-19
pandemic time. A total of 60,107 COVID-19 cases (85.20% of the total
cases) in China were treated by CHMs with positive results in all infec­
tion stages, including significant symptom management, lower rates of
deterioration and mortality, faster recovery as well as disease prevention
on February 17, 2020 (Ministry of Science and Technology, 2020).
The development of the domestic basic medical system has promoted
the health awareness in China, consequently, Chinese Herbal Medicine
(CHM) is the mainstay of health care delivery (Nguyen et al., 2018). It is
regarded as an effective and safe option for “curing” milder illness,
so-called “clear the root of the disease” and is selected by individuals
confident with it. China processes a rich and diverse variety of medicinal
plant resources to meet the growing demand. CHM is frequently used as
a dietary supplement or supplement to common medications which
promotes a quick recovery (Lam, 2001). With the tendency to use
complementary and alternative medicine, CHM is broadly applied in
health maintenance and disease treatment, particularly as regards
chronic diseases (Laila, 2014).
Therefore, following the influence of Chinese dietary culture ele­
ments and the Traditional Chinese Medicine (TCM) hypothesis (Chi
et al., 2018), CHM in the form of compounds, extracts, single herbs, or
formulae prevents and cures various acute and chronic diseases effec­
tively while maintaining a balanced nutrition. Moreover, due to its
affordability and limited side effects, the role of CHM in primary health
care has been largely accepted by the public (Sham et al., 2016).
Notably, CHM food therapy is also crucial (Wu and Liang, 2018). Among
the different factors influencing the significance of CHM in urban and
rural areas, medicinal and edible plants balancing the mental and
emotional and physical states have already been integrated into national
dietary habits.
There is also an unavoidable contradiction here. Consuming CHMs
becomes a daily habit that can prevent or treat certain chronic diseases,
such as arthritis, diabetes, hypertension, cancer, cardiovascular dis­
eases, inflammatory diseases, and a variety of other diseases. However,
after the process and transformation of CHM materials into dosage form,
the toxic elements confined in herbs finally intake in the human body
and can disturb the normal functions of internal organs. Profound heavy
metal toxic effects following long-term uptake the CHMs with exceeding
the safe concentration limits (Ernst and Coon, 2001). Furthermore,
owing to the socio-economic and cultural factors on the dietary sources’
intake of these heavy metals, the qualitative change caused by collab­
orative accumulation cannot be ignored (Silva et al., 2005).
Nevertheless, with the sudden increase in population demands, and
herbal medicine manufacturers recently, quality assessment of medici­
nal plants for authenticity, efficacy, toxicity, and consistency has been
prioritized (Fatemeh et al., 2018; Sanzini et al., 2011). Given the severe
effects heavy metal contamination may bring to the environment and
humans, ecological risk assessment (Prasad, 2008; Street, 2012;) and
health risk assessment (Yang et al., 2021; Zuo et al., 2020) have been
conducted by researchers, showing that it in medicinal crops is an area
requiring immediate attention.
The current review summarizes the information on the relationship
between heavy metals and medicinal crops and proposes possible
management strategies to recover environmental sustainability to
3
Ecotoxicology and Environmental Safety 219 (2021) 112336
balance medication safety and efficacy as well as economic benefits.
2. Ecological effects
The spread and migration of human beings resulted in the diversity
of herbal uses from ancient times. Infectious diseases can spread
worldwide through mass gatherings and/or multiple transmission routes
(Abubakar et al., 2012). In the battle against disease, various drug habits
based on local herbal resources and human demographic and distribu­
tion patterns first evolved.
Various species of herbal plants cultivated in different geographical
environments have co-existed and co-evolved with human civilizations
owing to of their curative nature resulting in alleviating and curing
human pain and diseases (Bibi et al., 2019). These herbal plants
comprise numerous effective chemical constituents, promoting their
therapeutic potentials such as alkaloids, terpenoids, flavonoids, sapo­
nins, lactones, carotenoids, tannins, phenolic acid derivatives, fatty
acids, polysaccharides, vitamins (Shakya, 2016; Singh, 2015). Further,
the dynamics of water, nutrient, carbon, and other trace elements
including heavy metals accumulated into the herbal plants are influ­
enced by the geographical environment and climate characteristics,
causing inconsistency of material quality and unstable therapeutic ef­
fects (Wrona et al., 2006).
The effect of CHM is usually linked to proper production regions with
designated natural conditions and ecological environment, harvest time
(Zhao et al., 2012). Also, the similar botanical origin in different pro­
duction regions exhibits its unique superiority. Due to human activities,
the risk of heavy metals pollution is persistent, causing soil and water
disturbances, then uptake by the herbal plants. Among all the ecosystem
components, including the atmosphere, plants and hydrosphere, heavy
metals account for their large amount in soil (Aliyev et al., 2018). Heavy
metals in the soils are derived primarily from pedogenetic parent ma­
terials (Nagajyoti et al., 2010) consequently, the metal status and dis­
parities in soils are predominately established by cation exchange
capacity, organic matter content, clay fraction, and soil acidity (Gan
et al., 2019).
As such, the geographical location dictates the environment partic­
ularly for wild herbs growth and partially has a strong relationship with
impact factors (Cataldo and Wildung, 1978). These factors include
temperature, sunshine duration, rainfall (acid rain), altitude, atmo­
sphere, surface runoff, humidity, soil parent materials, soil and water
pH, soil and bedrock types, soil grain size, soil parent materials, rhizo­
sphere microorganisms. For example, Sedum alfredii absorbs up to 243%
Cd and 96% Zn compared to Burkholderia cepacian (Alford et al., 2010)
taking into account natural enrichment levels, distribution of heavy
metals, (Basu et al., 2018; Herrera et al., 2018; Kumar et al., 2018;
Vanderborght et al., 2017; Whiting et al., 2001). These factors co-exist
and interact with herbal plant species, thereby determining the accu­
mulation degree of different types and contents of heavy metals in
various plant species grown in relatively abundant fertile soils (Asgari
et al., 2017) as was presented Fig. S1.
As a professional terminology in the TCM industry, ‘Daodi medicinal
material’, refers to ‘the medicinal material that grows in particular
geographic regions with the precisely ecological environment, and
usually with the attribute of proverbial superior quality and clinical
effects’, is routinely used to label the hierarchy of high-quality herbal
materials. For instance, to satisfy the market demand, plantation regions
are expanded (Lv et al., 2016). The rhizome samples of Rhizoma coptidis
from production regions of Daodi had a significant effect on phyto­
chemical levels that have better quality and herbal efficacy compared to
those from non-Daodi production regions. Therefore, similar TCMs
should be classified based on their origin, i.e. when and where they are
harvested as well as which parts and type of plant is used.
However, the concentration of metals in plants varies under specific
environmental conditions and change with soil pH fluctuations as well
as the use of organic fertilizers (Elekes et al., 2010). Furthermore, wet
Y.-G. Chen et al.
soils with acidic pH cause the binding of biased metal ions to organic
matter (Ramzan and Bhat, 2017; Srinivasarao et al., 2014). Heavy
metals trigger oxidative stress, reactive oxygen species (ROS) generation
(Asgher et al., 2017), lipid peroxidation, DNA damage, and dysfunction
of various enzymes, thereby causing poor growth (Tripathi et al., 2012).
In heavy metal-dependent ROS generation, the uptake of heavy metals
by transporters and distribution to organelles precedes ROS generation.
Notably, excess ROS causes redox imbalances and disturbances in
signaling processes, hence inhibits growth and damages cell (Sharma
and Dietz, 2009; Yadav et al., 2016). Redox-active heavy metals directly
elicit ROS generation. Heavy metals bind to and interfere with molec­
ular targets or competes for binding sites (e.g. ‒SH, ‒COO− ), conse­
quently, altering related protein functions, which in turn change the cell
metabolism or pathway signaling events. After heavy metals uptake by
transporters and distribution to organelles and cytosol, excess ROS is
generated and stimulated to cause redox imbalances and disturbances in
signaling processes that inhibit the plant growth and may significantly
damage cell structures by heavy metals redox activity or effects on
metabolism (Huang et al., 2019a). The scheme of heavy metal uptake
along with the related process of cell damage was presented in Fig. S2.
In plants responding to heavy metals (Pb, Cd, Co, Cr, Cu, Ni, Zn),
stress potentially inhibits the elongation of the primary root, decelerates
short-distance water transfer in the symplast and apoplast, impairs
secondary growth, reduces root hair surface and root total area, or even
induces root dieback, thereby influencing the growth of the entire plant
(Rucińska-Sobkowska, 2016).
The development of complex physiological traits to adjust and adapt
to extreme and variable environments and associated metal hyper-
tolerance has been attributed to the exposure of a few plant taxa in
the process of natural selection (Krämer, 2010; Kumar et al., 2016). In
other words, these types of herbal plants harbor innate features of high
enrichment attributes of metals (Verbruggen et al., 2009), involving
extracellular and intracellular metal chelation, precipitation, compart­
mentalization, and translocation in the vascular system (Ilya et al.,
1994).
The response approaches of heavy metal hyperaccumulator and non-
hyperaccumulator species to an increasing metal concentration in soil
exhibits different tendencies. Under the influence of root exudates,
example hyperaccumulators (Lantana camara L., Thlaspi caerulescens,
Eclipta prostrata) (Chandrasekhar and Ray, 2019; Hunt et al., 2014;
Milner and Kochian, 2008; Muszynska and Hanus-Fajerska, 2015; Ras­
cio and Flavia, 2011; Reeves et al., 2018) significantly demonstrate high
tolerance and foliar accumulation of trace elements – Zn (Pence et al.,
2000), Cd (Yang et al., 2004), Ni (Rengasamy and Doran, 2002), Mn
(Fernando et al., 2010), Cu, Co, Cr (Baker, Brooks, 1989), Pb (Sharma
et al., 2016), As (Zhang et al., 2002), Hg (Tangahu et al., 2011), Se (Zhu
et al., 2009) via root uptake and translocation (Sheoran et al., 2016). In
plants, specifically hyperaccumulators, accumulate metals in the
aboveground biomass via bulk flow in the xylem from root to shoot
(Grennan, 2009), involving various organelles, including vacuoles,
Golgi apparatus, mitochondria, and chloroplasts. The difference be­
tween the tendency of heavy metal accumulation via hyperaccumulators
and herbal plant species is presented in Fig. S3. Transmembrane carriers
of nutritional ions transport heavy metals from root cells to form com­
plexes with chelators and further translocate to the central cylinder,
where heavy metals entering via xylem vessels are transported to shoots.
Such heavy metals will bind to suberin, cellulose, hemicellulose, lignin,
pectin and will be sequestered in cell walls (Parrotta et al., 2015; Shi
et al., 2019). Step by step via plasmodesmata or transporters on the
plasma membrane from the root symplast into the xylem apoplast,
heavy metal and metalloids are translocated to the neighboring cells. In
this saturable process, the major limiting factors include the number of
transport proteins as well as the rate of transport, substrate affinity, and
substrate specificity of variation in the transporters (Pilon-Smits, 2005).
As presented in Fig. S3 such uptake and transport of heavy metals from
the soil to the roots and the whole plants occurs through the symplastic
4
Ecotoxicology and Environmental Safety 219 (2021) 112336
pathway and apoplastic pathway (Schwab et al., 2016; Song et al.,
2017). Minerals cause the formation of Casparian strips, preventing
accumulation of heavy metals and promote plant growth by increasing
cell expansion. In the process of the symplastic pathway, various
transporters regulate the movement of heavy metals including zinc/iron
regulated proteins (ZIPs), cation diffusion facilitators (CDFs), natural
resistance and macrophage proteins (NRAMPs), heavy metal ATPases
(HMAs), and ATP-binding-cassette transporters sub-family C (ABCC).
These plasma membrane-located cation transporters operate in heavy
metals transport and play a key role in metal homeostasis, tolerance,
absorption and distribution. In herbaceous plants, roots uptake heavy
metals and transport them into the root cells via transmembrane carriers
are followed by further translocated to the xylem vessels and unloaded
into the xylem sap, thereby reaching the aerial parts of plants. Absorbed
heavy metals can be sequestered in cell walls, vacuoles and the Golgi
apparatuses (Luo et al., 2016). Sequestration mechanisms of heavy
metals and connected in this process the signal transduction in plant cell
is presented in Fig. S4.
The ability of biofortification (Mehdawi and Pilon-Smits, 2012)
could make the growth of herbal medicinal plants at the risk of being
heavy metals rich. In summary, clarifying the causes and underlying
factors as well as understanding the formation of heavy metal accu­
mulation in the medicinal material are essential as regards its further
protection and prevention.
3. Environmental pollution
Environmental pollutants are considered as an important challenge
in assessing the quality of human life (Karimi-Maleh et al., 2021a,b,
2020a). There are several categories of environmental pollutants that
many researchers have focused on sensing and removing to improve the
quality of soil and water sources (Karimi-Maleh et al., 2020c,b,d, 2019)
which effect on the quality of herbal plants. The overwhelming diversity
of plants provides a colossal herbal medicine resource. Most of the
medicinal plants have been adequately developed as pharmaceutical
industry products and are extensively cultivated. For decades, practi­
tioners and researchers have primarily focused on the clinical and
economical values of herbal products. However, the hazards of heavy
metal contamination of these herbal products have been relatively
underestimated. In parallel with the increasing demand for herbal
products in Asian, there is a widespread misconception that natural
herbal products are inherently safe. Due to considerable overlap be­
tween the clinical presentation and pathophysiology associated with
heavy metal poisoning, consumers usually negligence any association
between herbal product use and any adverse effects hence leading to
underreporting of adverse effects (Ernst, 2002). For example, the FDA
limit for Pb in natural-source food color additives (e.g. paprika, saffron
and turmeric) which not considered food intended for consumption by
children is 10 mg/kg. The FDA action levels for products for children are
0.1 mg/kg for candy and 0.5 mg/kg for other foods, however, children
with Southeast Asia due to eating habits can have high-level spices and
herbal remedies consumption and also relatively high blood lead levels
(Angelon-Gaetz et al., 2018). Even if there are related adverse reactions
(e.g. developmental delays and behavioral problems), its probability
will be considered that the symptoms are not attributable to the use of
those herbal products. In addition, many of the case reports in the
developing countries are not properly recorded which limiting the
appropriate conclusion thereby predictive and preclinical toxicology
assessment of herbal products (Neergheen-Bhujun, 2013).
Heavy metals and metalloids are readily absorbed by the root of the
herb. Then they accumulate in the edible parts of the medicinal plant
notwithstanding the heavy metal concentration in the growth substrate
(Ametepey et al., 2018). Being one of the main ingestion sources of
heavy metals, edible plants are an essential part of the diet consumed
either raw or cooked. Thus, heavy metals enrichment of herbal plants
frequently occurs through cultivation in contaminated soils, addition of
Y.-G. Chen et al.
heavy metal-enriched organic additives such as fertilization and
compost as a nutrient source as well as irrigation using water with large
heavy metal concentrations (Meng et al., 2016; Shiv et al., 2017). The
particulate matter associated with heavy metals (Przybysz et al., 2019)
could be adsorbed through foliar organs of plants after wet or dry
deposition of atmospheric fallouts on plants (Muhammad et al., 2017).
Therefore, considering the food chain (soil-plant-human) pathway, the
concentration of elements in herbal plants primarily depends on the
relative level of exposure of plants to the contaminated soil (Rai et al.,
2019) and the deposition of toxic elements in the polluted air via sedi­
mentation (Jolly et al., 2013). It should also be mentioned that the
elaboration and application of methods for detection of heavy metals for
the purpose of investigating their distribution, accumulation and
translocation within the tissues of plants are very important. To this aim,
depending on heavy metals concentration typically AAS (Atomic Ab­
sorption Spectrometry), ICP-OES (Inductively Coupled Plasma with
Optical Emission Spectrometry) or ICP-MS (Inductively Coupled
Plasma-Mass Spectrometry) methods are used. The choice of the
methods depends on the concentration of metal and its type. For
example, for Cd(II) detection, atomic absorption spectrometry FA-AAS
(with flame) or GF-AAS (with graphite furnace) can be used after
digestion of plant sample with HNO3 and H2O2 in microwave oven
system (for example, Mars). FA-AAS, GF-AAS as well as ICP-OES or
ICP-MS techniques are accurate and precise. ICP-MS provides lower
detection limits and it is capable for the determination of low heavy
metal content, GF-AAS provides also low detection limits and is low cost
technique. The exemplary detection limits of the elements can be as
follows: Cd 0.01 ng/L, Cr 0.128 ng/L, Pb 0.025 ng/L and Ni 0.100 ng/L.
Physical and chemical processes, including advective transport, hy­
drodynamic dispersion, precipitation, and adsorption influence the
movement of heavy metals in the soil (Sullivan and Kriege, 2001). Soil
environment with changeable components comprises a solid phase, a
liquid phase (soil solution) and a gaseous phase. Moreover, the soil
environment system interacts with the system of plants in
co-constituting the soil-plant ecosystem (Xia et al., 2018). Disruption of
soil-plant ecosystem balance occurs due to water circulation, heat
fluxes, and free airflow. Under normal conditions, herbal plants also act
as bio-retention media, absorbing the metals in the elemental, mineral,
or sorbed form (Bravin et al., 2012). Dissolved speciation might include
a divalent metal form and complexes with dissolved organic matter
(DOM) and carbonate under the influence of environmental factors,
including Zn(II), Pb(II) OM-Cr(III), DOM-Cd(II), CuCO3, PbCO3, (Dean,
2005; ElBishlawi, 2015; Li and Davis, 2008; Mahar et al., 2016).
Through the urban rainfall-runoff events, these herbaceous
bio-retention systems of plants capture heavy metals (Kluge et al., 2018)
from a long-term accumulation of pollutants. Furthermore, in­
vestigations on the contaminant contribution rate of rainwater revealed
a relatively negligible ionic concentration compared to the runoff (Dean
et al., 2005).
The determination of anthropogenic pollution levels and sources of
heavy metals in cropland is primarily attributed to industrial activities,
agricultural practices, and traffic emissions (Jiang et al., 2020). Notably,
rapid urbanization and industrialization cause long-range transport of
heavy metal contaminants from the urban and suburban areas (Jeong
et al., 2020a; Zeng et al., 2020) contributing to trace element pollution
(Xia et al., 2018; Wu et al., 2020; Fang et al., 2019). Shortage of stan­
dardized inspection and treatment processes, transportation pollution
(Wiłkomirski et al., 2011; Yan et al., 2016), induced by humans resulted
most significant in the generation of hazardous wastes, such as heavy
metals (Cr, Cu, Co, Pb, V, Zn, Ni, Hg, Ba) (Sakson, 2017). As the main
source, agricultural practices in the rural areas promote immensely
heavy metal pollution (including Pb, Cr, As, Zn, Cd, Cu, Ni, Hg, and V) of
the soil and surface water. The uncontrolled use of fertilizers (Ning et al.,
2017), biosolids (Li et al., 2019a) (sewage sludges) (Seleiman et al.,
2020), animal feeds and manures (Ma et al., 2020), pesticides (Defarge
et al., 2018) and wastewaters (Qureshi et al., 2016) influence the
5
Ecotoxicology and Environmental Safety 219 (2021) 112336
concentration of heavy metals in agricultural soils consequently
affecting the plant environment.
Based on the joint report by the Ministry of Environmental Protec­
tion (MEP) and the Ministry of Land and Resources (MLR) of the Peo­
ple’s Republic of China, the current situation of soil contamination is
generally grim (Zhao et al., 2014a). A survey covering more than 70% of
China land area indicated that 16.1% of the sampled land was
contaminated by heavy metals and metalloids (Fig. 1), diminishing the
availability of arable lands (Duan et al., 2016; Yang et al., 2018a).
Nearly two decades of heavy metals monitoring data (Chen et al.,
2020) (between 2002 and 2020) indicated that Cr, Cd, Pb, Cu, Zn, As,
and Hg in soils samples of 30 administrative regions of China (Fig. 2) are
universally distributed, and the contamination level of 7 elements is in
the order Cd > Hg > Pb > Cu > Zn > As > Cr.
Among all the data of each administrative region, the geo-
accumulation indices of Cd and Hg are higher compared to those of
other heavy metal elements. For example, measured amount of heavy
metal accumulation in soil for Hg, Cd and Pb into soil was 4.48, 5.79 and
3.47 g/ha a, respectively (Cheng, 2003). Generally, unlike North China,
South China is significantly more contaminated. Different pathways on
the national scale are used to input the anthropogenic heavy metal into
cropland soils in China. In the past decade 50–93% of the total As, Cd,
Cr, Hg, Ni, and Pb inputs ultimately originated from atmospheric
deposition while 76% of Cu from livestock manures (Peng et al., 2019).
As a result of variations of industrial structures and economic de­
velopments, atmospheric deposition is the major source of heavy metal
pollution in North China, while livestock manures contribute to rela­
tively more contamination in South China. Moreover, the sustained
accumulation of heavy metals in the planting soil is remarkable,
potentially having a certain negative impact on the growth of herbs.
Similar problems and potential risks are more or less likely to occur
across the world (Table 2).
Furthermore, despite the anthropogenic sources or natural processes,
heavy metals are non-biodegradable (Abdel-Raouf and Abdul-Raheim,
2017; Thakur et al., 2016) and do not break down well over time.
Most herbal plants, whether wild, cultivated, or domesticated, are
largely subjected to the environment with diverse residues and con­
taminants. To better understanding these relationships a schematic
presentation of heavy metal pollution sources and migration path is
presented in Fig. S5. Therefore targeted regulations on the pollution
control are urgent and imperative. The source control and environ­
mental governance e.g. vegetated drainage ditches (Kumwimba et al.,
2018), monitoring irrigation water quality, necessary risk assessment of
biomass before returning to the field (Mao et al., 2020; Yan et al., 2020),
setting suitable emission standards based on the regional conditions
(Feng et al., 2019), using soil amendments (Qin et al., 2020), surfactant
colloidal gas aprons’ (Tao et al., 2020), bioremediation, phytor­
emediation, or other classical methods to remediate contaminated soil
(Zhang et al., 2020) require pragmatic and sustainable implementation
with sustainable science adhering to balance the relationship between
the nature and the social-economic development.
4. Cultivation and harvest
Based on the reports by the Chinese Ministry of Health, approxi­
mately 200 herb species, so-called medicine food homology (MFH) and
medicinal health food (MHF) species (Gong et al., 2019), are used to
manufacture functional foods in China, including Dendrobium officinale
Kimura et Migo, Panax ginseng C. A. Mey, Panax notoginseng (Burkill) F.
H. Chen ex C. H, Panax quinquefolius, Bulbus fritillariae thunbergii. CHM is
frequently used to produce phytomedicines and healthy foods in the
form of powder, extract, paste, cake, tea, beverages, and soup for
curative and nutritional purposes (Yang et al., 2018b). Herbal materials
cover different parts of medicinal plants including root, stem, leaf, skin,
flower, fruit, or even the whole plant. Several material categories of
CHM comprised excessive toxic heavy metals beyond the national
Y.-G. Chen et al. Ecotoxicology and Environmental Safety 219 (2021) 112336

Fig. 1. Environmental quality of soils between 2005 and 2013 (a) and heavy metal distribution of arable soil samples connected with industrial manufacturing in
administrative regions (b) in China. Five classes of soil pollution: non-polluted (pollutant level does not exceed the quality standard); light pollution (pollutant levels
are no more than 2 times of the maximum); mild pollution (pollutant levels are between 2 and 3 times the maximum); moderate pollution (pollutant levels are

6
Y.-G. Chen et al. Ecotoxicology and Environmental Safety 219 (2021) 112336

between 3 and 5 times the maximum); severe pollution (pollutant levels are more than 5 times the maximum).
[Source: MEP of China, 2014].

Fig. 2. Overall contamination levels of heavy metals in TCM (2008 and 2013 – Green standards of medicinal plants and preparations for foreign trade and economy
WM/T2–2004; 2016 – ISO18664:2015 Traditional Chinese Medicine standard – Determination of heavy metals in herbal medicines used in Traditional Chinese
Medicine; 2019 – Pharmacopoeia of the Peoples Republic of China, 2020) (Han, 2008; Zhao et al., 2014b; Guo et al., 2017; Luo et al., 2021).

acceptable limits based on the literature data in Chinese markets
(Table 3) (Guo et al., 2017; Li et al., 2018; Tripathy et al., 2015).
Notably, new limiting standards of heavy metals have been pub­
lished in the latest Pharmacopoeia of the People’s Republic of China
(2020 edition). Limiting standard the content values of Cd in 19 types of
herbal medicinal materials and decoction pieces from 0.3 mg/kg to
1.0 mg/kg is the most significant change. However, like soil composi­
tions (Zuo et al., 2020), Cd is the primary risk element among Pb, Cd, As,
Hg, and Cu. The amendment of the Cd regulatory limit is a reasonable
compromise between public health and economic development.
Providing novel insights into the risk assessment and safety standard of
heavy metals in herbal materials (e.g. exposure frequency and duration,
safety factor, and transfer rates of heavy metals) is essential for scientific
application. On the other hand, the human-based heavy metal pollution
pressure in the growth environment of some medicinal plants cannot be
neglected.
Generally, herbal plants are affected by various heavy metals and
different types of herbs exhibit different enrichment levels as well as
organ distribution (Table 4) (Guo et al., 2017; Han et al., 2008). Ac­
cording to the statistics on the residues of the heavy metals in different
categories of TCM from various origins which were collected in the lit­
eratures (from 2000 to 2016, based on ISO 18664:2015, 2015), the order
of over-limit ratio of concentrations detected of four heavy metals (Pb,
As, Hg, Cd) in seven properties are: for Pb, stem > leaf > flower > whole
herb > peel and bark > root and rhizome > fruit and seed; for As, leaf
> flower > whole herb > root and rhizome > stem > fruit and seed
> peel and bark; for Hg, leaf > flower > stem > whole herb > fruit and
seed > root and rhizome > peel and bark; for Cd, stem > flower > whole
herb > root and rhizome > leaf = fruit and seed = peel and bark. All
four heavy metals were widely detected in herbal medicines. The highest
concentration detected for Pb was in herbal medicine Agastache rugosa
(Fisch. et Mey) O. Ktze (2222.00 mg/kg), the highest concentration of
As was in flower buds of Lonicera japonica Thunb. (30.80–73.35 mg/kg,
Shandong, Henan and Anhui), Asarum. Heterotropoides var.

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Y.-G. Chen et al. Ecotoxicology and Environmental Safety 219 (2021) 112336

Table 2
The comparison between studies about heavy metal pollution to soils in China and elsewhere in the world (Huang et al., 2019b).
Element (mg/kg) Cd Cr Hg As Pb Cu Zn Ni Review/scope of monitoring Reference

Chinese agricultural soils 0.24 62.2 0.13 10.7 32.1 28.3 83.3 28.2 Review (336 articles) (Huang et al., 2019b)
Chinese agricultural soils 0.43 58.9 0.24 10.2 37.6 31.7 117.2 27.5 Review (12 articles) (Wei and Yang, 2010)
Chinese agricultural soils 0.25 65.3 0.16 9.5 34.9 30.7 85.3 30.7 Field (138 samples) (Song et al., 2013)
Chinese farmland soils 0.17 60.7 – – – 26.6 85.6 29.5 Field (131 samples) (Niu et al., 2013)
North China soils 0.56 31.5 0.07 4.18 33.3 16.3 129.8 16.4 Field (4445 samples) (Peng et al., 2019)
South China soils 0.62 12.6 0.08 2.47 18.9 18.8 88.6 4.89
Chinese soil 0.23 68.5 0.09 12.1 31.2 27.1 79.0 29.6 Field (38,393 samples) (Chen et al., 2015)
China urban soil 0.39 68.5 0.31 12.2 55.2 40.4 109.0 24.9 Review (21 cities) (Luo et al., 2012)
China mining areas 3.76 67.3 0.18 20.6 196.4 88.8 241.9 45.4 Review (72 mines) (Li et al., 2014)
World soils 0.35 40 0.07 7.2 2–300 30 90 20 Review (Adriano, 2001)
England and Wales 0.33 68 – 15 49 19 76 21 Field (131 samples) (Rawlins et al., 2012)
Europe 0.18 64 – 7 21 15 62 21 Field (5691 samples) (Reimann et al., 2012)
Australia 0.04 48 – 3 13 11 31 15 Field (2211 samples)
United States of America 0.34 – – – 15 30 75.8 27.1 Field (3045 samples) (Holmgren et al., 1993)
Peninsular Malaysia 0.12 25.9 0.15 16.8 26.4 16.4 38.0 13.7 Field (241 samples) (Zarcinas et al., 2004a)
Thailand 0.03 25.2 0.04 7.5 17.5 7.5 23.9 13.5 Field (318 samples) (Zarcinas et al., 2004b)

Table 3
Examples of national limits for heavy metals in herbal medicine and medicinal products (mg/kg, dry weight).
Country/Region Scope Cu (mg/ Pb (mg/ As (mg/ Cd (mg/ Hg (mg/ References
kg) kg) kg) kg) kg)

ISO international CHM – 10.0 4.0 2.0 3.0 ISO (International Organization for Standardization) 18664:2015 (2015)
standards
World Health HM – 10.0 1.0 0.3 – Guidelines for Assessing Quality of Herbal Medicines with Reference to
Organization (WHO) Contaminants and Residues (WHO, 2007)
European Union HM – 5.0 – 1.0 0.1 European Union Pharmacopeia, EP 10.2 (European Pharmacopoeia
Committee, 2019)
China CHM 20.0 5.0 2.0 0.3 0.2 Pharmacopoeia of the Peoples Republic of China (China Pharmacopoeia
Commission, 2015)
1.0 Pharmacopoeia of the Peoples Republic of China (China Pharmacopoeia
Commission, 2020)
Chinese green standards HM 20.0 5.0 2.0 0.3 0.2 Green standards of medicinal plants and preparations for foreign trade and
economy, WM/T2-2004 (Liu et al., 2018a)
Hong Kong, China CHM 150.0 5.0 2.0 1.0 0.2 Hong Kong Chinese Materia Medica Standards 2018 (Yang et al., 2021)
Macau, China CHM/ 150.0 20.0 5.0 – 0.5 Macau Technique Directive 02-2003 Despacho No. 10/SS/2013 (Li et al.,
RM 2018b)
Taiwan, China CHM – 5.0 3.0 1.0 0.2 Taiwan Herbal Pharmacopeia (2019)
HP – 10.0 3.0 0.5 0.5 Regulation for Registration of Medicinal Products (Liu et al., 2015)
Poland RM 20 1.0 – 0.1 – Polish Ministry of Health Act 1993 (Krejpcio et al., 2007)
Italy RM – 3.0 – 0.5 0.3 Italian Pharmacopeia (FUI) 2002 (Chowdhary and Raj, 2020)
United Kingdom HM – 5.0 5.0 1.0 0.1 British Herbal Pharmacopoeia (2018)
Germany HM – 5.0 – 0.2 0.1 German Pharmacopoeia (Deutsches Arzneibuch – DAB) (2018)
Australia HM – 5.0 – 1.0 0.1 Therapeutic Goods Administration (TGA) (Li et al., 2018b)
Singapore CHM/ 150.0 20.0 5.0 5.0 0.5 Health Sciences Authority (HSA), Health Products (Therapeutic Products)
RM Regulations 2016 (Vohora and Singh, 2018)
HP – 20.0 5.0 – 0.5 (Liu et al., 2015)
– 10.0 5.0 0.3 0.5 Health Sciences Authority (HSA (2020))
India HM – 10.0 3.0 0.3 1.0 The Ayurvedic Pharmacopoeia of India 2019 (Debnath et al., 2020)
Japan RM 20.0 20.0 5.0 – – The Japanese Pharmacopoeia (2016)
Malaysia TPP – 10.0 5.0 0.3 0.5 Drug Registration Guidance Document (DRGD), (National Pharmaceutical
Regulatory Division, Ministry of Health Malaysia, 2019)
South Korea RM – 5.0 3.0 0.3 0.2 The Korea Pharmacopoeia (Jeong et al., 2020b)
Thailand HM – 10.0 4.0 0.3 – Thai Herbal Pharmacopoeia, Traditional Formularies of Herbal Medicines (
Mukherjee, 2019)
Vietnam HM – 10.0 4.0 1.0 0.5 Vietnamese Pharmacopoeia 2005 (Zhao et al., 2009)
United States of America DS – 10.0 5.0 0.3 0.2 National Sanitation Foundation International (NSFI) Draft Standard 173-2008
(Harris et al., 2011)
HM – 5.0 2.0 0.3 0.2 NSFI Draft Standard 173-2001 (2001)
RM – 0.5 1.5 2.5 1.5 The United States Pharmacopeia (US Pharmacopoeia Convention, 2012)
DS – 1.0 1.5 0.5 1.5 USP 2232 (Liu et al., 2015)
Canada HM – 10.0 5.0 0.3 0.2 (Gupta et al., 2010)

CHM: Chinese herbal medicine, DS: Dietary supplements, HM: Herbal medicine, HP: Herbal products, RM: Raw material, TPP: Traditional pharmaceutical preparation.

mandshuricum (Maxim.) Kitag (33.82 mg/kg, Jilin), of Hg was in Folium
eriobotryae (26.90 mg/kg), of Cd was in Angelica dahurica (Fisch.ex
Hoffm) Bench. et Hook. f (23.35 mg/kg, Sichuan). Based on the
comparative analysis of data illustrated in Fig. 2a, it is evident that
studying the heavy metal enrichment law of CHM and taking corre­
sponding preventive measures is essential to guarantee the safety of the
medication. On the study of over-limit ratio of five heavy metals (Pb, As,
Hg, Cd, Cu) in 1773 herbal medicines, a total of 541 samples (30.51%)
were detected at levels over the Chinese Pharmacopoeia (2020 edition)
standard, and the order of over-limit ratio is Pb (102, 5.75%) > Cd (88,
4.96%) > As (74, 4.17%) > Hg (67, 3.78%) > Cu (31, 1.75%). For all
samples, 24.42% detected with one over-limit metal, 4.23% with two
over-limit metals, 1.35% samples with three over-limit metals and nine
samples with four over-limit metals. As over-limit ratios in five

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Y.-G. Chen et al. Ecotoxicology and Environmental Safety 219 (2021) 112336

Table 4
Statistics of heavy metal pollution in different medical sites.
Medical Pb As Hg Cd
parts of
Size x ± s (mg/ Over- Size x ± s (mg/ Over- Size x ± s (mg/ Over- Size x ± s (mg/ Over-
CHM
(num) kg) limit (num) kg) limit (num) kg) limit (num) kg) limit
ratio (%) ratio (%) ratio (%) ratio (%)

Root and 1245 2.58 ± 29.86 2.17 1032 0.89 ± 2.59 3.97 988 0.11 ± 0.43 0.71 1168 0.31 ± 0.92 2.23
rhizomeI
FlowerII 144 7.92 ± 25.85 6.94 115 4.45 ± 13.15 9.71 98 0.45 ± 1.18 5.10 135 0.68 ± 1.87 8.89
LeafIII 40 3.80 ± 3.50 7.50 28 1.10 ± 1.43 10.71 19 1.68 ± 6.17 10.53 36 0.29 ± 0.34 0
Whole 207 13.66 ± 2.64 3.86 175 1.95 ± 5.26 7.88 134 0.17 ± 0.60 2.24 196 0.44 ± 0.67 5.10
herbIV
Fruit and 364 1.38 ± 2.64 1.10 284 0.43 ± 1.72 1.05 270 0.19 ± 1.53 1.11 331 0.09 ± 0.13 0
seedV
StemVI 39 6.02 ± 7.95 15.38 41 0.80 ± 1.81 2.56 34 0.31 ± 1.14 2.94 38 1.15 ± 2.18 13.16
Peel and 121 2.48 ± 3.00 3.31 109 0.36 ± 0.53 0 101 0.07 ± 0.10 0 93 0.16 ± 0.19 0
barkVII

Examples of the medical parts of CHM based on Pharmacopoeia of the Peoples Republic of China: I – Notoginseng Radix et Rhizoma of Panax notoginseng (Burk.) F. H.
Chen, Zingiberis Rhizoma of Zingiber officinale Rosc., Panacis Quinquefolii Radix of Panax quinquefolium L., Corydalis Rhizoma of Corydalis yanhusuo W. T. Wang,
Ophiopogonis Radix of Ophiopogon japonicus (L. f) Ker-Gawl, Polygonati Rhizoma of Polygonatum sibiricum Red., Glycyrrhizae Radix Et Rhizoma of Glycyrrhiza
uralensis Fisch., Puerariae Lobatae Radix of Pueraria lobata (Willd.) Ohwi; II – Chrysanthemi Flos of Chrysanthemum morifolium Ramat., Lonicerae Japonicae Flos of
Lonicera japonica Thunb., Croci Stigma of Crocus sativus L., Albiziae Flos of Albizia julibrissin Durazz., Sophorae Flos of Sophora japonica L., Caryophylli Flos of
Eugenia caryophyllata Thunb., Gossampini Flos of Gossampinus malabarica (DC.) Merr., Rosae Chinensis Flos of Rosa chinensis Jacq.; III – Isatidis Folium of Isatis
indigotica Fort., Mori Folium of Morus alba L., Ginkgo Folium of Ginkgo biloba L., Epimedii Folium of Epimedium brevicornu Maxim., Lophatheri Herba of
Lophatherum gracile Brongn., Sennae Folium of Cassia angustifolia Vahl; IV – Centellae Herba of Centella asiatica (L.) Urb., Taraxaci Herba of Taraxacum mongolicum
Hand.-Mazz., Prunellae Spica of Prunella vulgaris L., Solidaginis Herba of Solidago decurrens Lour., Plantaginis Herba of Plantago asiatica L.; V – Canavaliae Semen of
Canavalia gladiate (Jacq.) DC., Anisi Stellati Fructus of Illicium verum Hook. f., Crataegi Fructus of Crataegus pinnatifida Bge., Schisandrae Chinensis Fructus of
Schisandra chinensis (Turcz.) Baill., Cuscutae Semen of Cuscuta chinensis Lam., Ziziphi Spinosae Semen of Ziziphus jujuba Mill. var. spinosa (Bunge) Hu ex H. F. Chou,
Coicis Semen of Coix lacryma-jobi L. var. mayuen (Roman.) Stapf; VI – Dendrobii Officinalis Caulis of Dendrobium officinale Kimura et Migo, Ephedrae Herba of
Ephedra sinica Stapf, Perillae Caulis of Perilla frutescens (L.) Britt.; VII – Pseudolaricis Cortex of Pseudolarix amabilis (Nelson) Rehd., Acanthopanacis Cortex of
Acanthopanax gracilistylus W. W. Smith, Mori Cortex of Morus alba L., Ailanthi Cortex of Ailanthus altissima (Mill.) Swingle.

medicinal properties (Fig. 2b), 58.16% samples were detected with
over-limit concentrations in the whole plant, 40.00% in flowers, 37.20%
in root and rootstock, 34.39% in leaf and bark, 7.69% in fruit and seed
(Luo et al., 2021).
Huge herbal planting-scales are associated with huge market-
demands. At present, various rare herbal plants became nearly used
up due to the with increasing consumption therefore organic and con­
ventional cultivation should be gradually evolved to make the sustain­
able use of wild resources (Chen et al., 2016). However, they also face
the risk of contaminant by heavy metals. Generally, these precious
herbal plants have a lower germination rate and sometimes they do not
grow at all (Furukawa, 2019). By integrating modern agricultural
planting techniques, planting precious herbal plants is possible for great
economic and medicinal importance. As a characteristic example, Den­
drobium officinale Kimura et Migo (Dendrobii Officinalis Caulis) (Lei et al.,
2019), used as a herbal medicine and tonic is currently planted using
well developed techniques, particularly in Zhejiang Province, China
(Hangzhou, Taizhou, Jinhua, and Wenzhou medicinal materials pro­
duction regions) (Da Silva and Ng, 2017). Due to the habitat fragmen­
tation and loss in the past decades, the population size of Dendrobium
officinale has significantly decreased. Notably, excessive exploitation,
habitat fragmentation, and population deterioration trigger genetic di­
versity loss and inbreeding depression (Li et al., 2008). Commercial
potential and market demands accelerate the advancement of technol­
ogy, and cultivated forms from wild to different artificial planting types
subsequently evolved into 3 main areas, i.e. greenhouse cultivation,
bionic cultivation, and wild cultivation, including field planting,
greenhouse planting, imitated wild planting (planting on the trunks in
natural forest and man-made forest or limestone in the karst area) and
planting on a substrate (wood shavings and barks) which significantly
increased the yield of Dendrobium officinale (Fig. S6). A tissue culture
seedling (Da Silva et al., 2016) can be transplanted into the growth
substrate in the greenhouse, forest tree trunks, and rocks on cliffs (Si
et al., 2015). Greenhouse cultivation shortens the growth cycle of Den­
drobium officinale and provides a higher production rate (in contrast with
bionic cultivation, the harvesting period shortened from two years to
8–12 months). However, greenhouse production system providing
higher temperature and moisture levels but lower light intensity could
impact the existing forms of heavy metals and general properties in
greenhouse soils, which had an impact on migration of heavy metals
from soil-plant system. Besides, revealed production practices can also
increase distribution, translocation and accumulation of heavy metals,
especially the introduction of organic matter associated with the
application of manure or organic fertilizer (Fan et al., 2017; Li et al.,
2017; Meng et al., 2021). The greenhouse cultivation changes the
transportation of heavy metals in the soil-plant system and even causes
potential health risk by increasing ingestion of heavy metals. The con­
stituent contents of polysaccharides and alcohol-soluble extracts from
both rock epiphytic and tree epiphytic are larger than greenhouse pot
epiphytic. Particularly, ethanol-soluble extract contents from the rock
epiphytic are more complex, indicating that the rock epiphytic is
conducive for the accumulation of secondary metabolites (Lin et al.,
2017). Moreover, different planting methods bring different levels of
heavy metal enrichment. When determining the heavy metal ion con­
centrations of various types of cultivation samples, it was found that in
contrast with greenhouse and tree trunk cultivation, rock cultivation is
characterized by larger concentrations of Pb, Cd, Cr, and As (Ni et al.,
2018). Roots are enriched more with heavy metals compared to other
organs (Chu et al., 2010). Additionally, heavy metal ions are transported
and dispersed to the whole plant with different enrichment preferences.
Wild-growing and cultivated plants exhibit significant differences in
heavy metal contents, which is associated with the living conditions.
Dendrobium officinale stems are used by the Chinese pharmacopeia as the
medicinal part in the application. However, flowers and leaves are also
applied as daily healthcare supplements or healthy additives. In prac­
tice, different heavy metal contents can also be detected in different
parts of Dendrobium officinale. In practical terms, the content of heavy
metals in artificial commercial planting herbs is generally below the
required limit (Yang et al., 2014).
Based on basic characteristics, the growth-forms in the vegetation
types of herbal plants are classified into the following categories: arbor,
vine, shrub, grass, annuals, biennials, and perennials. The number of

9
Y.-G. Chen et al.
phytoconstituents in a plant can vary based on the plant age, time of
collection, environmental condition, harvest time, the type of growth
substrate, water sources and irrigation style (Huang et al., 2014; Verma
et al., 2013) Dendrobium officinale is an orchid perennial herbaceous
plant, and the growth year is positively correlated with the accumula­
tion of heavy metals (Zhu et al., 2011). Collectively, using a suitable
planting method, and selecting the appropriate harvest time window is
necessary to reduce the heavy metal content while guaranteeing quality
(Fig. 3).
Medicinal crops are cultivated or semicultivated plants for the pre­
vention and treatment of human and animal disease and have derived an
increasing number of new drugs with efficacy, such as artemisinin from
Artemisia annua for malaria treatment, and Salvia miltiorrhiza extract for
cardiovascular disease (Zhou and Wu, 2006). Medicinal crops are
meanly distributed and widely cultivated in the tropical and subtropical
areas of the earth. Most of them are herbal plants and mainly belong to
Araliaceae, Boraginaceae, Compositae, Dioscoreaceae, Gentianaceae,
Lamiaceae, Leguminosae, Liliaceae, Papaveraceae, Rutaceae, Sol­
anaceae, and Umbelliferae (Zhou et al., 2014). Metal concentrations in
crop plants differed among these plant species grown on the same living
conditions, indicating their different capacities for metal uptake (Ste­
phen et al., 2013). Many of them cropping as a phytoremediation
practice for heavy metals contaminated soil which are not recommended
for medicinal use or nutrition supply. For example, as a perennial herb,
Viola baoshanensis has small biomass, no above-ground stem and good
accumulation capacity, which growth dry weight in the wild is only
3 t/hm2 are applied as hyperaccumulator on soil rehabilitation (Wu
et al., 2010). Solanum nigrum L. is an annual herbaceous plant in the
Solanaceae family with large biomass and high Cd accumulation ca­
pacity (Feller et al., 2019). However, the heavy metal low-accumulation
crops and hyperaccumulator are adopted intercropping patterns can
obtain agricultural or herbal products that meet certain hygiene stan­
dards, such as Zea mays L., Lolium perenne L. and Glycine max (Linn.)
Merr. intercropping with Sedum alfredii H. (Wang et al., 2015).
Dissection of the mechanisms and rules underlying accumulation of
heavy metal ions in plants of different planting patterns, plant densities,
mixed planting style, biochar-bacteria-plant (Harindintwali et al., 2020)
partnerships, and sustainable agricultural intensification (Tang et al.,
2010) can be beneficial in targeted cultivation and risk aversion. The
natural environment is unlikely to change significantly, particularly the
heavy metal contents in the soil. Rational arrangement of the fallow/idle
cropland, following the local conditions to plant suitable heavy
metal-resistant medicinal herb species (Ahemad, 2019), could partially
alleviate this problem. Agricultural practitioners should also be aware of
the origin and heavy metal-resistance performance of medicinal crops.
Additionally, strengthening and replicating rapid tests for detection of
heavy metals in herbal plants, quality of irrigation water sources and
fertilizer as well as soilless plant cultivation and real-time monitoring
systems are necessary.
5. Manufacturing process
At the CHM commercial market, there are a lot of traditional and
modern herbal medicines, dietary supplements, nutraceuticals, func­
tional foods, cosmetics, personal care products, flavors, and fragrances.
Different products reflect different manufacturing processes. During the
CHM production processes, using traditional or modern processing
methods, there is a risk of heavy metal contamination throughout the
whole procedure.
Therefore, the herbal sources of raw materials for CHM should, be
subjected to quality assurance tests. Currently, CHM is mainly sourced
from organized cultivation and by wildcrafting. Good agricultural
practices for cultivated herbal plants can lead to the production of
quality CHM ingredients and formulations. However, wild-growing
herbal plants may have a relatively higher concentration of heavy
metals and other contaminants, therefore, their quality is difficult to
10
Ecotoxicology and Environmental Safety 219 (2021) 112336
establish (Wang et al., 2014). Based on the traditional mindset, it is
widely believed that wild-growing herbs with their natural character­
istics, long growth cycles in the absence of pesticide and fertilizer con­
taminations, are more beneficial to the human (Zhu and Tan, 2015)
body. Therefore, their medicinal and economic values are highly
regarded (Ding et al., 2008; Li et al., 2015). However, rhizomes of
certain wild herbs can absorb heavy metal elements from the
low-heavy-metal soil (Han, 2008), resulting in the above-limit heavy
metal concentrations. Relatively, more than half of herbal plants are
exposed to heavy metal contaminants (Harris et al., 2011).
Exposure to heavy metals can also occur during collection, selection,
raw material pretreatment, transportation, and storage (Fong, 2002;
Inyinbor et al., 2019; Järup, 2003). Harvesting tools, cutting tools,
grinders, packaging bags, storage places, or other factors can also serve
as contaminant sources. Generally, using appropriate procedures (Chan,
2003; Liu et al., 2015), crude herbal formulations are prepared or pro­
cessed (Liu et al., 2014) from fresh samples, and subsequently delivered
to the market. The market is made up of the public, pharmacies, hos­
pitals, clinics, and pharmaceutical companies. These products can be
home-made, pharmaceutically produced, or industrially produced.
However, the supply chain system complexities have a potentially pos­
itive correlation with heavy metal exposure risks, with storage and
transportation (Kumar and Verma, 2018) being the major impact fac­
tors. It has been established that Pb(II) concentration in the blood of
CHM female consumers is 24% higher than that of non-users (Buettner
et al., 2009). Moreover, cases of lead poisoning (Tang et al., 2017) due to
the long-term consumption of homemade CHM have also been reported.
Processing of CHMs includes such procedures as mixing, sifting, baking,
steaming, boiling, fermentation, cooking, carbonization, toasting and
calcination. Unique processing methods that involve wine, salt, sugar,
vinegar, honey, minerals, as well as other liquid or solid restricted ad­
ditives and excipients (Wang et al., 2012) have also been used to pro­
duce traditional dosing forms such as pills, powders, plaster, pellets,
bolus, decoctions, tincture, and liniments (Pan et al., 2014). Different
types of excipients that are incorporated into the formulation to opti­
mize the manufacturing process have also been shown to be heavy metal
sources. It is a remarkable fact that some CHMs are prepared from
potentially toxic herbs. In addition to cleaning and preserving, the
removal of toxic components can also be done by processing. Certain
processing techniques can also enhance the therapeutic effects of some
herbs (Ting et al., 2013). However, if herbal products are not processed
based on certain specific guidelines, it could lead to toxicity, including
heavy metal pollution. The lack of convenient administration proced­
ures, low bioavailability, and low-quality control parameters for the
traditional dosage forms is also a challenge (Lin et al., 2018). Even
though modern processing methods have been used to improve pro­
duction efficiency, the traditional dosage forms are still being used. In
practice, some CHMs are marketed as botanical dietary supplements
with undeclared toxic heavy metal concentrations. Even though the
heavy metal bio-burden can occur in trace amounts, long-term bio­
accumulation is a worrying problem.
Carrier and heating containers for medicinal products that include
traditional casseroles, plastics, enamels, glass clay, copper or steel alloy
pots, or bowls are potential heavy metal sources (Valadez-Vega et al.,
2011; Nakayama and Chen, 2018; Nerin et al., 2016). During decocting
or other processes, metal containers without chemically-stable proper­
ties can react with herbal material products thereby exposing them to
heavy metal ions. However, adherence to the decocting method, con­
sumption time, and prescribed dosages are some of the measures that
can be taken to reduce the risk of heavy metal consumption effectively.
During the industrial production, raw and processed herbs are usually
ground into powders and mixed with other herbal powders from cap­
sules. The capsule shell or enteric coating may also be a source of heavy
metal pollution (Li et al., 2013; Xie et al., 2010), especially by Cu, Pb,
Cd, Cr, Hg, Ni, and As. Other than these, herbal raw materials have the
risk of contact with a wide range of contaminants during processing and
Y.-G. Chen et al. Ecotoxicology and Environmental Safety 219 (2021) 112336

Fig. 3. Information associated with Dendrobium officinale cultivation. a. annuals yield of Dendrobium officinale; b. production regions of Dendrobium officinale; c.
polysaccharide content in different parts of different cultivation samples; d. sample contents under different cultivation methods; e. comparisons of heavy metal
contents in four main production regions; f. comparison of heavy metal contents of different artificial planting types; g. correlation between heavy metal content and
growth year. (WC: Wild-collection; UC: Undergrowth cultivation; RWC: Rock wall bionic cultivation; LC: Living tree cultivation; DC: Dead tree cultivation; RC: Rock
cultivation; GC: Greenhouse cultivation; TC: Tissue culture.).

11
Y.-G. Chen et al.
manufacture. Heavy metal impurities can originate from water, different
types of ingredients, container closure systems, manufacturing equip­
ment, such as leaching of metal catalysts, tanks, and pipes (Balaram,
2016) (Fig. S7).
Contamination with toxic metals should be controlled right from the
point of raw materials collection and processing to the finished products.
This is why the current good manufacturing practices (cGMPs) system is
necessary for testing the permissible heavy metal limits. If the industrial
manufacturing processes adhere to the cGMPs, heavy metal contami­
nation risks can be minimized (Gurley et al., 2018). Moreover, the
introduction of the purification process in the production stage is also
one of the effective measures for minimizing heavy metal contamina­
tion. Conventional methods such as reverse osmosis, electrodialysis, ion
exchange, chemical precipitation, ultrafiltration, and adsorption (Li
et al., 2019b) are used in the removal of heavy metal ions from herbal
extract solutions.
6. Conclusion and future needs
The wider reach of TCM products has greatly improved its market
share to an estimated US$50-billion (Cyranoski, 2018). According to
WHO, up to 80% of the world’s population depends on traditional
medicines for their primary healthcare (WHO, 2013). As one of the
oldest and long-standing healthcare systems, TCM encompasses many
different aspects. CHM is the mainstay and principal form of TCM
practice (Liang et al., 2014). The demand for CHM is great and has also
shown an increasing trend in recent years, especially in Asian countries.
In Western countries, CHM is a popular form of complementary and
alternative medicine with minimal side effects. As the main constituent
of TCM, the production of CHM is based on five-thousand years of
medical practice and experience. Clinically validated health/­
illness/disease observations and treatment methods data support and
guarantee its efficacy and effectiveness. After an initial stagnant period,
the demand for CHM has increased in various fields of research (Guo and
Liu, 2019), and medicinal herbs have, therefore, been widely cultivated.
The proper dosages, preparation and processing methods for various
materials, and the appropriate time for collecting the various medicinal
parts of plants have also evolved (Yuan et al., 2016).
CHM has complex chemical profiles, but medical and safety practices
lacking standardization, understanding of herbs modality, and mecha­
nisms of efficacy (Zhou et al., 2019). The herbal medicine industry in
China is dominated by small-scale farmers, leading to the heterogeneous
quality of herbal materials flooding the markets. Numerous safety issues
of CHM products still exist at the present time (Ekor, 2014), including
drug/herb-herb interactions (Mehmood et al., 2019), product quality
(Mukherjee et al., 2015), improper practice (Chou et al., 2018; Lydia and
Philippa, 2017), contaminants, and toxicities (Cooper et al., 2007;
Bensky and Stoeger, 2005). Blindly optimistic about the therapeutic
effects of CHM will fall into misuse (Lu and Lu, 2014). So that the sci­
entific proofs and clinical evaluations are necessarily needed to mini­
mize the safety risks. Both the efficacy and safety of CHMs for
evidence-based practices are most concerned by medical researchers
and workers. It is worth noting that the convergence between TCM and
modern medicine is increasingly apparent.
Globally, herbal products are increasingly becoming popular. How­
ever, it is important to elucidate the potential synergistic and adverse
side effects, as well as the mechanisms of action. The role of heavy metal
ions with different valence states in the treatment of diseases using
Chinese herbal medicines should also be clarified. Moreover, there is a
need to establish whether active ingredients in herbs can antagonize
heavy metals, thereby inhibiting their toxicity. Chemical reactions be­
tween heavy metals and organic components in different states of exis­
tence also be should determined. To ensure safety and reliability,
pharmacodynamics, toxicity, and pharmacokinetic mechanisms should
also be evaluated. Well-designed preclinical and clinical trials are also
essential to the development of CHM. To minimize the public health
12
Ecotoxicology and Environmental Safety 219 (2021) 112336
risk, management of CHM also requires the rational use of herbal
medicines to ensure safety limits of heavy metal content.
Only fine medicinal herbs can make fine herbal medicines.
Geographic authentication and protection of raw CHM materials can
provide a safer raw material environment. In addition, farming soils
exhibit regional differences in pollution sources and characteristics.
There is a need to assess comprehensively the planting environment,
production conditions, as well as the sources and trends of heavy metal
pollution. On this basis, targeted evasive strategies should be adopted to
reduce the safety risks associated with heavy metals. Follow-up devel­
opment of relevant laws and regulations as well as the policy support are
essential to meet the development needs of the new era.
Declaration of Competing Interest
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influence
the work reported in this paper.
Acknowledgments
This study was supported by the National Key Research and Devel­
opment Program of China (No. 2017YFC1702200), the Key Research
and Development Program of Zhejiang Province (Nos. 2017C03052 and
2015C02032), Ten-Thousand Talents Program of Zhejiang Province
(No. ZJWR0102035) and Heavy metal control in herbal products
(HMControl) as the part of the Program Polish-Chinese Green Pharma­
ceuticals Collaborative Project at Maria Curie-Skłodowska University in
Lublin and Zhejiang University of Technology.
Appendix A. Supplementary material
Supplementary data associated with this article can be found in the
online version at doi:10.1016/j.ecoenv.2021.112336.
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