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Chromium, which can currently only be considered pharmacologically active and not an essential element, is a very intriguing elemental impurity in final pharmaceutical products, especially traditional herbal medicinal products. This kind of traditional herbal medicinal product with Marshmallow root ( Althaea officinalis L., radix) registered in the EU is widely used among the European population. The aim of this article is to propose a double regulatory strategy in assessing the human health risk of total chromium impurities in cough syrups with Marshmallow Root ( Althaea officinalis ) available in Polish pharmacies. We applied the strategy based on the requirements of the ICH Q3D (R1) guideline for the assessment of Cr impurities in final traditional herbal medicinal products with Marshmallow Root registered in the EU. Furthermore, we applied the strategy based on the concept of margin of exposure (MoE) considering Cr(VI) genotoxicity mode of action (MOA) and based on BMD 10 for Cr(VI) as a point of departure (PoD). The total Cr content was in the range: 1.12–9.61 µg/L (in comparison with the ICH Q3D R1 guidelines: 1100 µg/g). Total Cr levels in a single dose were relatively high compared to raw results, but were not a threat to patients. Comparison of estimated results with oral PDE value for Cr in final drugs suggested by the ICH Q3D R1 guideline (10,700 µg/day) show that all the products analyzed were below this value (the highest result was 278.40 ng/day). Despite conservative assumptions, the MoE values obtained for Cr in daily dose for each Marshmallow Root cough syrup were above 10,000; therefore, exposure to Cr would not cause a health risk for specific population groups (children and adults). It can be summarized that each of the phytopharmaceuticals analysed with Marshmallow root available in Polish pharmacies does not represent a health hazard to patients. We confirm the safety of Cr impurities by applying a double regulatory strategy without the application of an expansive and demanding HPLC-ICP-MS technique for Cr speciation.

The scoping review aimed to characterise the role of selected essential elements (Zn, Cu, Se, Fe, Mn) in food for special medical purposes (FSMPs) aimed at oncology patients. The scope review was conducted using Scopus, Google Scholar, and Web of Science to find published references on this subject. Data from the reviewed literature were related to the physiological functions of the element in the body, and the effects of deficiencies and excesses, referring to the latest ESPEN and EFSA guidelines, among others. Important dietary indices/parameters based on the literature review are provided for each element. On the basis of the literature, data on the level of elements in patients with cancer were collected. The content of these elements in 100 mL of FSMPs was read from the manufacturers’ declarations. The literature has been provided on the importance of each element in cancer. Our findings show that the essential elements (Zn, Cu, Se, Fe, and Mn) of FSMPs for cancer patients are not adequately treated. We suggest solutions to ensure the safe use of FSMPs in oncology patients.

Chromium is pharmacologically active and is not an essential element but is still very intriguing and demanding from the point of view of toxicological risk assessment. Especially as an elemental impurity in final pharmaceuticals. The aim of this article is toxicological risk assessment (TRA) of total Cr impurities in Menthae piperitae tinctura ( Mentha x piperita L., folium) available in Polish pharmacies including triple approach. Obtained raw/basal results shows that impurities of total Cr impurities were present in all investigated pharmaceutical with Mentha x piperita L., folium. but at a relatively low level (in the range: 0.39–2.14 µg/L). The regulatory strategy based on the ICH Q3D (R1) elemental impurities guidelines confirms that all the requirements of the analyzed products meet the European Medicine Agency (EMA) requirements. Obtained results obtained show that the estimated maximum daily exposure to Cr (ng/day) are variable between the samples (0.521–3.792 ng/day), but at a relatively low level (< 4.0 ng/day).The final step confirms the safety of analyzed pharmaceuticals, because the comparison of the estimated results with the oral PDE value for Cr in final drugs suggested by the ICH Q3D guideline (10,700 µg/day) show that all the products are below this value. The approach based on the margin of exposure (MoE) for children and adults also confirms the safety of all the products with Mentha x piperita L., (in all cases MoE >  > 10 000). It can be concluded that all the samples analyzed should not represent any health hazard to patients due to Cr impurities. To our knowledge, this is the first study about application of comprehensive TRA of total Cr impurities in phytopharmaceuticals with Mentha x piperita L., folium available in European pharmacies. Additionally, we confirm the safety of Cr impurities by applying triple regulatory strategy without the application of an expansive and demanding HPLC-ICP-MS technique for Cr speciation.

Studies related to the toxicological risk assessment (TRA) of heavy metal impurities (HMIs) in pharmaceuticals are 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 to lead and cadmium impurities. The aim of the study was to estimate the TRA of lead and cadmium in Valeriana officinalis L., radix (Valerian root) as HMP (n = 5) available in Polish pharmacies. In the case of herbal pharmaceuticals, it is particularly important to control the level of HMIs accumulated during the plant’s growth. Perhaps, the exposure for a single dose is not relevant; however, justification of our studies is a fact that herbal therapies are usually long term. Therefore, even small HMI doses as present in particular plant may accumulate in patient body over a long period of time. Levels of lead and cadmium were measured by electrothermal atomization atomic absorption spectrometry. The levels of lead and cadmium as HMIs (independently of the producer and declared composition) are quite similar. Our results are satisfactory, confirming the safety of Valeriana officinalis L., radix (Valerian root) as herbal medicinal product for the relief of mild nervous tension and sleep disorders available in Polish pharmacies according to ICH guideline Q3D. To the best of our knowledge, this paper is the first study about lead and cadmium content as HMIs in HMP containing Valeriana officinalis L., radix (Valerian root).

Scientific reports about elemental impurities in final pharmaceutical products are essential from a regulatory point of view; unfortunately, there is a lack of studies about this important toxicological topic. The aim of our short communication was determination of total Cr impurities in traditional herbal medicinal products (THMP) with Thymi herba (Thymus vulgaris L. and Thymus zygis L.) available in Polish pharmacies (n = 6, because only six manufacturers produce this kind of pharmaceutical products in Poland). The total content of Cr impurities was determined by atomic absorption spectrometry using electrothermal atomization (ETAAS). Applied comprehensive toxicological risk assessment was based on three main tiers: Tier 1, the comparison of raw results as total Cr impurities profile (metal per L of THMP) with ICH Q3D guideline standards; Tier 2, the estimation of total Cr exposure with a single dose; and Tier 3, the estimation of total Cr daily exposure. We confirmed that total Cr impurities were present in all analyzed THMP with thymi herba (the observed level was below 6.0 µg/L). Total Cr concentration in a single dose can be deceptively high in comparison to the raw results but is not a threat to patients (20.15–63.45 ng/single dose). Moreover, the estimation of total Cr daily exposure shows that all analyzed THMP are characterized by daily dose (40.30–181.41 ng/day) below PDE value (10,700 mg/day); hence, all products meet the standards of ICH Q3D elemental impurities guideline.

Plantago lanceolata L., folium (ribwort plantain) is an active pharmaceutical ingredient in traditional herbal medicinal products (THMP) available in pharmacies as a demulcent for the symptomatic treatment of oral or pharyngeal irritations and associated dry cough. This kind of THMP is widely applied among the European population; however, recently, voices have been heard in the public about alleged cadmium impurities. The idea of our study was a comprehensive risk assessment of the Cd impurity exposure and its effect on human health. Our assessment strategy was based on regulatory aspects (raw results versus limits set by FAO/WHO for herbal medicines) and toxicological risk assessment approach based on ICH Q3D guideline for elemental impurities in final pharmaceutical products. The cadmium was determined by electrothermal atomization atomic absorption spectrometry based on our previously described methodology. Obtained results show that all analysed THMP with P. lanceolata L., folium available in the Polish pharmacies contain cadmium impurities, but at a very low level (ranged 0.73 – 20.6 μg/L). The content of Cd in a single dose (ng/single dose) is also very low and is not a threat to patients. The estimated maximum daily exposure (ng/day) of Cd based on the ‘worst-case scenario’ (maximum concentrations by oral administration) meets the standards of ICH Q3D guideline (all results were below oral permitted daily exposure; PDE for Cd, i.e. < 5.0 µg/day). It can be concluded that all analysed samples of THMP with P. lanceolata L., folium should not represent any health hazard to the patients due to cadmium levels. To the best of our knowledge, this is the first study about Cd impurity level in THMP with P. lanceolata L., folium (ribwort plantain leaves) available in European pharmacies.

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) confirm 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 impurity 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).

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.

Tea is the world’s most common drink after water, and the world’s annual sales exceed $43 billion, of which more than $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.

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. The 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 (FAAS). Our results indicated that all analysed 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 the investigated elemental impurities confirms 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 impurity guideline for pharmaceuticals.