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Number of traditional use registrations for monocomponent HMP in the EU grouped by year of registration (based on [2])
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Studies related to the toxicological risk assessment (TRA) of heavy metals impurities (HMIs) in pharmaceuticals is an important issue but there is a lack of refereed literature around the safety of Valeriana officinalis L., radix (Valerian root) as herbal medicinal product (HMP) for the relief of mild nervous tension and sleep disorders according t...
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Context 1
... medicinal product (HMP) can be defined as "any medicinal product, exclusively containing as active ingredients one or more herbal substances or one or more herbal preparations, or one or more such herbal substances in combination with one or more such herbal preparations" [1]. Based on number of traditional use registrations per year for HMP in the EU, it can be stated that monocomponent HMP are still popular for use ( Fig. 1 based on [2]). ...
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This study was conducted to find a candidate prescription with anti-inflammatory efficacy of 7 herbal prescriptions known to be effective in atopic dermatitis and sleep disorders in Korean medicine. The anti-inflammatory of the 7 herbal prescriptions extracts were evaluated by ELISA assay and Western blot assay. 7 herbal prescriptions, Seongyutang...
Citations
... The plant contains a variety of phytochemicals, including alkaloids, diterpenoid lactones, glycosides, steroids, and phenolics, which are responsible for its biological activities [31]. Some of the active compounds found in Tinospora cordifolia include berberine, magnoflorine, columbin, tinosporin, and cordifolioside A, among others [39][40][41]. ...
... Acid digestion, or wet digestion, is effective for both inorganic and organic substances due to its ability to break down the sample matrix, helping to minimize interferences [41]. Spectroscopy involves critical sample preparation steps that affect the accuracy of results. ...
... Spectroscopy involves critical sample preparation steps that affect the accuracy of results. The choice of digestion method is more important as it is impractical to apply a different method for each element and a trade-off analysis is required to select the best analytical method [41,42]. This microwave-assisted digestion appears to be a more reproducible method due to lower relative standard deviation values [43]. ...
Introduction: Tinospora cordifolia is a climbing shrub with medicinal properties that have been traditionally used in various traditional Chinese medicine. Additionally, Tinospora cordifolia has been found to possess phytoremediation properties, enabling it to accumulate heavy metals. However, the toxicological risk assessment of heavy metals accumulated in Tinospora cordifolia, specifically in its use as a vasorelaxant, anti-microbial, anti-diabetic, and anti-inflammatory agent, has not been thoroughly studied. Methods: To assess the toxicological risk of heavy metals in Tinospora cordifolia, we extracted an aqueous extract from the leaves using a Soxhlet-based method. The concentrations of cadmium and lead in the aqueous extract were then determined using optical emission spectroscopy with inductively coupled plasma (ICP-OES). Results: Our study found that the concentrations of cadmium and lead in the aqueous extract from Tinospora cordifolia were high, but still slightly below WHO-allowed concentrations. However, even at these lower concentrations, continued ingestion or exposure to Tinospora cordifolia may lead to the accumulation of highly toxic substances in human cells. The possible toxic effects of cadmium and lead on human health may include bone mineralization, glomerular damage, emphysema, neuropathy, insomnia, elevated blood pressure, and reduced fertility. Discussion: Further in-situ toxicity assessments of accumulated heavy metals in Tinospora cordifolia on various microorganisms and cell lines are highly recommended. Additionally, future studies should investigate the long-term effects of using Tinospora cordifolia as a medicinal herb, particularly in regard to its potential to accumulate heavy metals. Overall, our findings highlight the importance of conducting toxicological risk assessments of medicinal plants to ensure their safety for human consumption.
... For simultaneous multi-element detection of As, Pb, and Cd, the ICP-MS technique was applied based on our previous study [14,15,21]. The applied analytical instrument was an Elan DRC-e Perkin Elmer (US). ...
Tea is the world’s most common drink after water, and the world’s annual sales exceed 11 billion is green tea (Camellia sinensis (L.)). Increasing evidence continues to show that green tea consumption and its ingredients have a variety of potential health benefits. The aim of the study was to control and assess the toxicological risk (TRA) of three heavy metals (As, Pb, and Cd) in infusions of green tea (n = 12) from Polish markets. We applied the method of inductive coupled plasma mass spectrometry (ICP-MS) to determine the selected heavy metal and designed a specific toxicological risk assessment with three crucial tiers. The first tier of our strategy was to determine the elements investigated (heavy metal impurities, µg/L). The second step was to estimate the weekly intake of green tea infusions (µg/week) based on weekly consumption. The third tier was to estimate the weekly intake per weight (µg/L/week/bw), based on the average weekly intake of green tea infusion per adult compared to the provisional weekly intake (PTWI) established by the FAO/WHO Joint Food Additives Expert Committee (JECFA). The levels of the investigated heavy metals occur at different levels in all of the investigated green tea infusions. The heavy metal profile indicated that As (0.0721–10.585 µg/L), Pb (0.386–1.695 µg/L), and Cd (0.126–0.346 µg/L) were present in all samples. Basic analysis of general content shows that As (average = 0.325 µg/L) was at a level similar to Cd (average = 0.214 µg/L). Surprisingly, the Pb content (average 0.891 µg/L) was approximately 2.75–4 times higher than that of As and Cd, respectively. The application of our proposed safety assessment methodology (three tiers) provides satisfactory results for regulatory purposes. The evaluation of the investigated heavy metals in all products analysed from green tea samples (infusions) showed that there were no health hazards to consumers due to weekly exposure. The results indicated that after drinking green tea infusions from Polish markets, the amount of investigated elements in weekly doses does not represent any health risks to consumers.
... For example, lead is an example of a heavy metal that can pass from the skin to blood vessels and can then be transported to various critical organs [21,22]. Furthermore, it is well known that this element is poorly absorbed through intact skin (also with the presence of enhancers); for example, the absorption of Pb from lead oxide under occlusion in rats was less than 0.005% (measured by urinary Pb for twelve days after exposure) [23]. Our results ( Table 2 vs. Table 3) indicated that all the products analyzed were characterized by results below the cutaneous PDE for this HMI (<50 µg/day). ...
Potential heavy metal impurities (HMI) in pharmaceuticals/pharmaceutical products/drugs based on plant raw materials (e.g., herbs) are an important problem in the pharmaceutical industry; however, there is a lack of scientific articles on the comprehensive toxicological risk assessment of HMI in ointment applied dermally. To make the appropriate toxicological risk assessment, we consider: (1) the raw results of the levels of lead and cadmium in the ointments (metal per kg of mass), (2) one-time administration of the applied ointment, (3) daily exposure of Pb and Cd in the applied ointments according to the maximum daily dose of applied pharmaceuticals, including transcutaneous penetration, (4) human health risk assessment based on the USEPA model, and 5) the margin of exposure (MoE). The raw results indicated that lead (7.05–101.78 µg/kg) and cadmium (0.32–0.81 µg/kg) were present in all samples. The levels of analyzed HMI (independently of the producer and declared composition) were similar. Pb and Cd contamination associated with daily doses met the standards of the ICH Q3D (R2) guide on elemental impurities in pharmaceuticals, including the cutaneous route of administration. Taking into account the daily amount of lead and cadmium (ointment, ug/day) the results were satisfactory, confirming the safety of marjoram herb extract ointments available in Polish pharmacies according to the ICH guideline Q3D (R2) on elemental impurities. The HQ values obtained for Pb and Cd in all samples were less than 1; therefore, exposure to these HMI would not cause a health risk based on the USEPA model strategy. Furthermore, the obtained values of MoE for Pb and Cd in ointments were above 100, so exposure to these elements would not cause a health risk based on the MoE-based strategy. The original contribution of this work is that this is the first study on the triple approach strategy to evaluate the safety of heavy metal impurities in traditional herbal medicinal products applied dermally in solid form (ointments with marjoram herb extract). The research is novel and has not been previously published; The proposed procedure includes transcutaneous penetration of heavy metal (Pb and Cd) impurities described for the first time in the literature.
... Detected via inductively coupled plasma-mass spectrometry, nearly one-third of 1773 CHM samples have excessive levels of at least one heavy metal, and lead and cadmium have the highest levels [109]. In Poland, the traditional herbal medicinal products with Thymi herba (Thymus vulgaris and Thymus zygis), Valeriana officinalis, Plantago lanceolata and Althaea officinalis contained cadmium impurities, though at a very low level [75,74,73,72]. ...
Medicinal plants have a wide range of uses worldwide. However, the quality of medicinal plants is affected by severe cadmium pollution. Cadmium can reduce photosynthetic capacity, lead to plant growth retardation and oxidative stress, and affect secondary metabolism. Medicinal plants have complex mechanisms to cope with cadmium stress. On the one hand, an antioxidant system can effectively scavenge excess reactive oxygen species produced by cadmium stress. On the other hand, cadmium chelates are formed by chelating peptides and then sequestered through vacuolar compartmentalization. Cadmium has no specific transporter in plants and is generally transferred to plant tissues through competition for the transporters of divalent metal ions, such as zinc, iron, and manganese. In recent years, progress has been achieved in exploring the physiological mechanisms by which medicinal plants responding to cadmium stress. The exogenous regulation of cadmium accumulation in medicinal plants has been studied, and the aim is reducing the toxicity of cadmium. However, research into molecular mechanisms is still lagging. In this paper, we review the physiological and molecular mechanisms and regulatory networks of medicinal plants exposed to cadmium, providing a reference for the study on the responses of medicinal plants to cadmium stress.
... It should be emphasized that due to the varied bioavailability of HMI in soil, its content in raw herbs may vary significantly [16,17]. Therefore, a very important problem in modern environmental analysis is the (bio)monitoring and TRA of HMI in herbs [18]. In the context of exposure to mint tea, this problem seems very basic but extremely important due to the lack of comprehensive TRA of HMI in mint tea infusion in the scientific literature. ...
Mint tea (Mentha piperita L.) is one of the most widely consumed single infusion herbal teas (infusion) around the world; however, impurities and pollutants can pose a potential health risk to human health during tea drinking. The idea of this study was the comprehensive toxicological risk assessment (TRA) of three heavy metals (As, Pb, and Cd) in mint tea infusions (Mentha piperita L.; n = 17) available in Polish markets. We applied an inductively coupled plasma mass spectrometry (ICP-MS)-based methodology for the determination of the chosen heavy metals and designed a specific TRA approach. The first step in our TRA was the determination of the elements investigated (heavy metal impurity profile, µg/L of infusion). The second step was the estimation of the weekly intake (µg/L of infusion/week) based on the weekly consumption of tea. The third step was the estimation of the weekly intake per body weight (µg/L of infusion/week/bw) based on the weekly consumption of tea per adult person compared to the Provisional Tolerable Weekly Intake (PTWI) established by the Joint FAO/WHO Expert Committee on Food Additives (JECFA). The level of investigated heavy metals occurs in all of the investigated mint tea infusions but at a relatively low level. The heavy metal profile indicated presence of As (0.36–1.254 µg/L), Pb (0.47–1.24 µg/L), and Cd (0.17–0.40 µg/L) in all the samples investigated. The basic analysis of the general content shows that As levels (mean = 0.70 µg/L) were very similar to the Pb levels (mean = 0.72 µg/L). The Cd content (mean = 0.21 µg/L) was approximately 3.5 times lower than the As and Pb levels. TRA provides satisfactory results for regulatory purposes. TRA for the elements investigated in the analyzed products indicated that there was no health hazard to consumers for weekly exposure. The results indicated that the levels of investigated elements in daily doses should not represent any health hazard to the consumer after drinking mini tea infusions from products available in Polish markets. This well-designed TRA methodology was useful and important for regulatory toxicology purposes.
... (1) The fact that Cd and Pb impurities in final pharmaceuticals are most important from toxicological point of view (first class of elemental impurities in ICH Q3D R1 guideline [1]); (2) Our analytical possibilities and scientific experiences [18][19][20]; ...
Appropriate human health risk assessment (HHRA) is desire in modern regulatory toxicology, especially for elemental impurity studies. The aim of this article is the comprehensive HHRA of two heavy metals impurities—Cd and Pb in herbal medicinal products (HMP) as Menthae piperitae tinctura (Mentha × piperita L., folium) available in Polish pharmacies. These phytopharmaceuticals registered in EU are very common and usually applied OTC products by adults and also children/adolescents. For this purpose, we applied double regulatory approach, including: (1) requirements of ICH Q3D R1 guideline about elemental impurities and (2) additionally margin of exposure (MoE)-based concept to cover also specific population groups. Raw results shows that Cd and Pb were present in all analyzed HMP with Mentha × piperita L., folium (PTM1–PTM10) available in Polish pharmacies. In all samples, Cd impurities (in the range: 0.305–0.506 µg/L) were greatly lower than Pb impurities (in the range: 1.122–4.4921 µg/L). The HHRA of Cd and Pb impurities considering ICH Q3D R1 guideline-based approach made it possible to conclude that all results were below the permissible limit set by FAO/WHO for medicinal herbs and plants in different countries (300 µg/kg for Cd and 10,000 µg/kg for Pb). Additionally, the estimated daily intake of investigated elemental impurities compared to the PDE value confirm all samples safety. The second approach, an MoE-based strategy, indicated that the obtained values of MoE for Cd and Pb in daily dose for each samples were above 10,000; hence, exposure to these elemental impurities would not cause a health risk for all investigated population groups (children, adolescents, and adults). To the best our knowledge, this article is the first study about heavy metals impurities level in final HMPs as Menthae piperitae tinctura (Mentha × piperita L., folium) available in Polish pharmacies.
... The analysis of the mentioned certified reference materials was helpful for assessing the traceability of the results. The applied methodology was similar to our previous studies using the same apparatus [10,[16][17][18][19][20][21]. ...
The level of potentially toxic elements (PTE) in phytopharmaceuticals can be a potential threat to human health through the food chain. The traditional herbal medicinal products (THMPs) with the marshmallow root (Althaea officinalis L., radix), which we can find in European pharmacies, are widely used among the European population. However, recently, voices have been heard in the public about alleged PTE occurrence. In this article, the levels of Pb and Cd impurities were measured in samples of THMPs with marshmallow root available in Polish pharmacies (n = 10). Our proposed toxicological approach was based on two important issues. The first was PTE levels (Pb: 1.60–6.80 μg/L and Cd: 0.80–3.81 μg/L presented as raw results) in comparison with the permissible limit set by FAO/WHO for medicinal herbs (10,000 µg/kg for Pb and 300 µg/kg for Cd) and also ICH Q3D guidelines (0.5 μg/g for Pb and also Cd). The second was the estimation of exposure of investigated PTE in a single dose and daily dose for each THMP. It should be noted that the content of analyzed heavy metals in a single dose of analyzed products was very low, and hence is not a threat for patients. The obtained daily intake of heavy metals impurities in comparison with PDE values confirms the safety of all analyzed phytopharmaceuticals (all of the samples meet the standards of the ICH Q3D guideline). It can be summarized that each of the analyzed THMP with marshmallow root available in Poland are safe for the patients. Based on literature review, this article is the first study about heavy metals impurities level in final THMPs with A. officinalis L., radix (marshmallow root) available in European pharmacies.
... For this reason, a monitoring nickel content in herbal-based pharmaceuticals available in European Union will be desirable. Moreover, herbal medicinal products should be monitored for the presence of other important and potentially hazardous EIs [16][17][18]. Finally, our results are important and may be significant for other scientist and regulatory affairs working in pharmaceutical industry, especially due to PDE-related topics. ...
For elemental impurities that have been studied for transcutaneous absorption, the
available data are rarely suitable for proper toxicological risk assessment – there are
multiple factors that can influence this dermal absorption. Hence, in our studies we
applied generic and conservative approach - cutaneous permitted daily exposure
(CPDE) described in directive International Conference on Harmonisation’s Q3D
Guideline on Elemental Impurities (ICH Q3D). The aim of this article is toxicological risk
assessment (TRA) of dermal exposure of patients exposed to nickel and chromium
due to application of ointments with Marjoram herb extract ( Majoranae herbae
extractum ) available in Polish pharmacies ( n = 5, because only five manufacturers
produce this kind of pharmaceutical products in Poland). To make the appropriate TRA
approach, we considered (1) - raw results (metal per kg of ointment), (2) one-time
administration of applied ointments, and (3) daily exposure versus CPDE. Due to the
fact the concentrations of Ni generally present in cutaneous products as impurities are
not considered sufficient to induce sensitization, the cutaneous and transcutaneous
concentration limits (CTCLs) approach was applied for this element assessment. The
toxicological analysis was carried out using microwave-assisted wet digestion with
concentrated nitric acid and electrothermal atomisation atomic absorption
spectrometry. Our results show that, the ointments with Marjoram herb extract from
pharmacies in Poland do not represent a real health hazard to patients, however there
may be a requirement for the monitoring of impurities of nickel in future. To the best of
our knowledge, this paper is the first study about nickel and chromium content in ointments with with Marjoram herb extract (Majoranae herbae extractum).
... The disadvantage is the applied technique (FAAS) which is slower and more demanding in comparison to ICP-MS. Based on the review of scientific literature, it would be important to carry out a broader toxicological risk assessment including other important metallic impurities and different herbal medicinal products [6,[15][16][17][18][19][20]. ...
Essential elements like Cu, Mn and Zn are extremely important for herbs growth and physiological functions, however from a toxicological point of view, the exposure of these elements (as essential elemental impurities) can exhibit potential harmful effects for patients. In Europe very popular are ointments with Marjoram herb extract (Majoranae herbae extractum) as herbal medicinal products for adjunctively in rhinitis (runny nose). Based on posology of ointments with Marjoram herb extract, the exposure to these elemental impurities may be high during long-term use. Hence, the aim of this article is the health risk assessment of essential elemental impurities (Cu, Mn and Zn) through the dermal exposure of ointments with Marjoram herb extract (Majoranae herbae extractum) as herbal medicinal products applied adjunctively in rhinitis available in Polish pharmacies. Investigated essential elements were determined by well validated methodology (R > 0.997, recoveries, LOD and LOQ values were acceptable) based on Flame Atomic Absorption Spectrometry (F AAS). Our results indicated that all analyzed herbal medicinal products with Marjoram herb extract available in Polish pharmacies contain relatively low levels of essential element impurities, i.e.:
Cu (0.14 – 0.49 mg/kg), Mn (0.31 – 2.57 mg/kg) and Zn (0.73 – 3.19 mg/kg). The estimated exposure of investigated elemental impurities confirm the safety of all products. To the best of our knowledge, the study about Cu, Mn and Zn contents in HMPs with Majoranae herbae extractum is described for the first time. The applied methodology and results are extremely important from regulatory toxicology point of view due to ICH Q3D elemental impurities guideline for pharmaceuticals.
... Considering all described earlier facts, the aim of our article is the TRA of Cu, Mn, and Zn as EI in HMP with valerian root (Valeriana officinalis L., radix) available in Polish pharmacies. This article is a continuation of our previously conducted studies about TRA of heavy metals (Pb and Cd) in these same samples [17]. It should be noted that based on review of this essential topic in scientific literature, there are only a few professional articles about EI in HMP [18][19][20][21][22][23]. ...
... Based on review of scientific literature, it would be important to carry out a broader TRA including other important metallic impurities and different herbal medicinal products containing V. officinalis L., radix as in our last published articles [17,24]. It should be underlined that based on last step of proposed safety assessment approach by ICH Q3D guideline, our simple but well documented TRA could be valuable for other researchers. ...
The toxicological risk assessment (TRA) of elemental impurities (EI) in especially
herbal medicinal products (HMP) is a significant challenge for pharmaceutical industry.
In Europe very popular are traditional HMP with Valerian root ( Valeriana officinalis L.,
radix) for relief of mild symptoms of mental stress and to aid sleep. The aim of our
unique article is the comprehensive TRA of Cu, Mn and Zn as EI in HMP with V.
officinalis L., radix available in Polish pharmacies. This article is a continuation of our
previously conducted studies about TRA of heavy metals (Pb and Cd) in these same
samples. Investigated elements were determined by Flame Atomic Absorption
Spectrometry (F AAS). The values of the correlation coefficients (R > 0.998) confirms
the linearity of the applied instrument for precision and accuracy of results. The
recoveries, LOD and LOQ values were acceptable. Our results show that all
investigated HMP with Valerian root available in Polish pharmacies contain Cu (0.16 –
0.23 mg/L), Mn (0.11 – 0.76 mg/L) and Zn (0.22 – 0.48 mg/L) at a very low level. Based
on our estimation of EI including single dose (μg/20 mL) and estimated daily intake
(μg/day), our results confirm the safety of all pharmaceuticals. To the best of our
knowledge, the Cu, Mn and Zn impurities profile in HMP with V. officinalis L., radix is
described for the first time . The applied methodology and results are extremely
important from regulatory toxicology point of view (ICH Q3D elemental impurities
guideline for pharmaceuticals).
