Progress in ICP-MS Analysis of Minerals and Heavy Metals in Traditional Medicine.

Mineral elements are one of the nutrients needed by the animal body. At present, more than 20 mineral elements such as Ca, P, K, and S have been found in the human body. Although the content in the human body is very low, they participate in and affect the physiological metabolism of the human body and are indispensable elements for maintaining human health. Heavy metal elements refer to metals with a density greater than 4.5 g/cm 3 , including Au, Hg, Pb, and Cr. According to international standards, heavy metal elements mainly include Cu, Cd, Pb, Hg, and As. Heavy metals cannot be biodegraded, but they can aggregate thousands of times under the biomagnification of the food chain and finally enter the human body to interact strongly with proteins and enzymes, making them inactive. It may also accumulate in some organs and tissues of the human body, and various poisoning symptoms will appear. In addition, Cu is one of the essential trace elements of the human body, and it participates in important physiological processes of the human body. The lack of Cu will cause a decrease in brain cytochrome oxidase, which can lead to thinking disorder, slow response, and dyskinesia. In recent years, with the development of the mining industry, mining dust and ore washing water pollute farmland, resulting in the enrichment of heavy metals in agricultural products. The sources of heavy metals in traditional Chinese medicine and Tibetan medicine should be closely related to their planting conditions and growth environment, such as the application of soil, atmosphere, water, chemical fertilizer, and pesticide. The “three industrial wastes”, including waste gas, waste water and waste residue, directly or indirectly pollute traditional Chinese medicine and Tibetan medicine. Moreover, the genetic characteristics of plants, such as active absorption function and enrichment ability of heavy metals, are related to the production and content of heavy metals. Most bases for medicinal materials from plants are formed by the transformation of farmland, which will cause the slow accumulation of heavy metals due to long-term garbage accumulation (e.g., batteries and metal waste), pesticide application, proximity to mines, and many other factors. However, medicinal materials derived from the roots of plants are medicinal materials with roots or roots as the main part and some rhizomes. They are closely related to the growth environment and conditions, and different parts of medicinal materials have different abilities to absorb and enrich heavy metals. In addition, during the processing of traditional Chinese medicine and Tibetan medicine, the use of metal processing tools and the addition of medicinal accessories may lead to the introduction of heavy metal elements, especially the processing of precious drug preparations in Tibetan medicine preparations, which will introduce a large number of heavy metal elements. It can be seen that heavy metals are dangerous to be introduced in the growth, collection, transportation, processing, and preparation of medicinal materials. Some studies have shown that the contents of heavy metals and harmful elements in the same medicinal material from different producing areas can differ by nearly 10 times at most. Such residual impurities are highly toxic. After entering the body, they can form complexes or metal chelates with traditional Chinese medicine components in the body, such as protein and nucleic acid, which have very strong toxicity ( Xu et al., 2017 ). Much evidence shows that all kinds of pesticides and heavy metals are carcinogenic. If they do not act directly, there is also evidence that these preparations can participate in carcinogenesis in a passive or allowable way to promote the formation of tumors induced by other preparations. Through chemical interactions with the environment and each other, metal pesticide mixtures may produce unpredictable toxicity, such as organochlorine pesticides that are fat-soluble and easy to accumulate in the fat body, resulting in nerve, liver, and kidney damage. Heavy metals cause protein denaturation in the body and impair the function of tissue cells ( Wang et al., 2020a ). The strong binding of -SH and -S-S- bonds on human enzyme proteins with heavy metal elements is the main molecular mechanism of human poisoning ( Zhao, 1991 ). When the minerals and heavy metals in the human body are within the acceptable limit of the human body, they will not cause harm to the human body. However, when they accumulate to a certain extent, they will inevitably cause irreparable harm to the human body. As a toxic heavy metal element, Cd is a non-essential trace element in the human body. It is mainly absorbed by plants in water-soluble and exchangeable states and then enriched into the human body through the food chain or directly into the human body through the respiratory system and digestive system, which accumulates in the body for a long time and damages organ functions. Specific manifestations are lung injury, kidney failure, gastrointestinal stimulation, cardiovascular and cerebrovascular diseases, muscle pain, bone pain, and bone atrophy, as well as carcinogenic, teratogenic, and mutagenic effects; long half-life in the body; and irreversible damage ( Guan et al., 2021 ). Tl and its compounds have high toxicity and strong accumulation. They are strong neurotoxicants and can cause liver and kidney damage. They also have mutagenic, teratogenic, neurotoxic, and reproductive toxic effects. Long-term exposure to arsenic can lead to chronic poisoning, manifested as skin pigmentation, hyperkeratosis, or verrucous hyperplasia, as well as leukopenia or anemia. Ag poisoning seriously affects the human central nervous system and paralyzes the limbs. In severe cases, it can lead to heart failure and death as exposure can lead to different degrees of liver injury, fibrosis, liver cirrhosis, and even liver cancer ( Huo et al., 2016 ). The half-life of mercury can reach 240 days in brain tissue and 70 days in other organs, so its toxic effect is toxic dose-response. The acute toxicity caused by mercury is mainly liver damage. In contrast, the chronic toxicity caused by long-term medication is more likely to cause damage to the kidney, liver, and brain. Al can cause neurofibrillary tangles and amyloid senile plaques in brain tissue, which is related to Alzheimer’s disease (AD). Long-term excessive aluminum intake can lead to an imbalance in the human body and a decline in cognitive ability, memory ability, and logical reasoning ability ( Chen et al., 2011a ). Pb can induce brain cell apoptosis and inhibit the activity of brain cell enzymes, thus interfering with the metabolism of neurotransmitters, protein kinase activity, and calcium metabolism. Pb exposure may lead to postural coordination disorders. Cu is a trace element required by the human body, which plays a role in promoting the generation and maturation of red blood cells, but excessive intake may cause poisoning, which will cause hypotension, jaundice, acute copper poisoning, hepatolenticular degeneration, intrahepatic cholestasis in children, and other diseases ( Shen et al., 2017) . Th is related to the occurrence and development of various malignant tumors, such as esophageal cancer, gastric cancer, nasopharyngeal carcinoma, and cervical cancer. U element and its compounds can damage DNA, induce ultrastructural changes in the cell membrane, and lead to tumors. Heavy metals also have various pharmacological effects. For example, Tibetan medicine Zuotai is made from mercury, but it has antidepressant and anxiolytic effects ( Zhao et al., 2016a ; Zhao et al., 2016b ). In addition, Cu is one of the heavy metal elements and the component of copper-containing protein in the human body. It can catalyze the synthesis of hemoglobin. However, if it exists in the form of Cu 2+ , it will become an excellent catalyst for redox reaction in vivo ( Gao et al., 1993 ). Cu is absorbed from the small intestine and combined with plasma protein to form ceruloplasmin, which is mainly synthesized in the liver, then discharged with bile, and stored in the liver, bone, and muscle of the human body, with iron oxidase and antioxidant effects ( Shao and Zhang, 2017 ). It can be seen that heavy metal elements are also toxic and medicinal. Many medicinal preparations containing heavy metals may be the material basis of efficacy, which are relative. For example, in the view of traditional Chinese medicine, drugs are toxic, they are partial, and there must be drugs if there is great toxicity. Therefore, excessive accumulation of heavy metals may be quite harmful to the body, but appropriate use or different valence forms, or the effect of this heavy metal is just needed by the disease so that it can become a good medicine. Fe element has a hematopoietic function in the human body; participates in synthesizing hemoglobin, myoglobin, cytochrome, and various enzymes; promotes growth and development; and transports oxygen and nutrients in the blood ( Guo et al., 2015 ). It is related to the pathogenesis of Alzheimer’s disease, Parkinson’s syndrome, and osteoporosis ( Zheng et al., 2016 ). Hexavalent chromium is carcinogenic for humans. Indeed, extensive literature demonstrates the carcinogenic effects of chromium (VI) ( Locatelli et al., 2014 ). Zn is a component of many enzymes in the human body and participates in synthesizing DNA and RNA polymerase. It is an important element in maintaining the integrity of skin and mucosa and promoting wound healing. At the same time, it can increase lymphocyte function and remove oxygen-free radicals in the body. It can prevent bacterial and virus invasion and anti-cancer. When the body lacks Zn, it will cause aging of tissue cells and a decline in immunity, and epithelial cells are vulnerable to carcinogens, resulting in carcinogenesis ( Wang and Jin, 2018 ). However, Zn cannot be synthesized in the body and must be supplemented through dietary regulation. When the supply is insufficient or the proportion is unbalanced, it can directly affect the normal growth and development of children. Cr is involved in the metabolism of sugar and fat in the human body. It is also an essential element of normal cholesterol metabolism and will cause liver lipid metabolism disorder. Low chromium is a risk factor for obesity and disorder of glucose and lipid metabolism ( Yang et al., 2015 ). As the main component of cinnabar, HgS can inhibit bacteria, reduce inflammatory reactions, and promote wound healing. It is mainly used to treat sores and swelling. Ca is a major element in animals. It can help blood clot and activate some enzymes in the body, maintain nerve conduction performance, and play an essential role in maintaining the physiological function of the liver. K can maintain water balance, osmotic balance, and acid-base balance in the human body; strengthen the excitability of muscles; maintain the rhythm of the heartbeat; and participate in the metabolism of protein, carbohydrates, and heat energy. Mg can activate various enzymes in the body, maintain the stability of the nucleic acid structure, inhibit nerve excitability, and participate in protein synthesis, muscle contraction, and body temperature regulation. As an essential trace element in the human body, Mn plays a regulatory role in human life activities by forming binding proteins, enzymes, hormones, and vitamins. Arsenic trioxide can treat leukemia by inducing apoptosis of leukemia cells; inhibit proliferation and induce apoptosis of lung cancer cells; induce apoptosis of gastric cancer cells, colon cancer cells, and cervical cancer cells; and significantly inhibit the growth and apoptosis induction of oral squamous cell carcinoma cells. It can also enhance the inhibitory effect of promyelocytic leukemia on cell proliferation, invasion, and migration and may be used as a new therapeutic target for breast cancer. It has potential therapeutic value for triple-negative breast cancer. As a metal auxiliary group, Mn is necessary for the activity of superoxide dismutase and an important member of the liver antioxidant system. Mn is also closely related to reproduction, which can promote cholesterol synthesis, promote human growth and development, and enhance reproductive function ( Yu et al., 2015 ). Ni participates in the metabolism of the body and the composition of the cell membrane. It can activate histidine enzyme, arginase, acid phosphatase, and other important enzymes in the body, maintain the stability of biological macromolecular structure and normal metabolism of the whole body, and participate in the composition of various enzymes and proteins in the liver. The change of Ni content has a certain relationship with the occurrence and development of bronchial asthma. Se is one of the important components of glutathione peroxidase, a non-specific antioxidant of red blood cells. Its main function is to remove peroxides and free radicals from the human body and play a positive role in the treatment of cancer, cardiovascular diseases, diabetes, and other diseases. Se deficiency can easily lead to liver disease and liver injury ( Zhao et al., 2017a ). Heavy metals are not only the toxic ingredients of today’s society but also the effective ingredients of traditional drugs. The key is to master the “dose, the length of drug use, and the pathological state of the human body” to balance toxicity and effectiveness. One of the major challenges facing traditional drugs containing minerals is differences in mineral processing/preparation that distinguish them from environmental metals. Additionally, many preparations are polyherbal-metallic preparations, which increases their complexity because minerals are not used alone. Symptoms of heavy metal poisoning are shown in Figure 1 . Furthermore, toxicity and therapy go hand-in-hand with these preparations, and there exists a need to maintain a subtle balance of benefit and risk on an individual basis. Therefore, ICP-MS provides a powerful means of detection to achieve this goal. Symptoms of heavy metal poisoning.

Medicinal materials derived from minerals are rich in resources, unique curative effects, and numerous varieties. However, due to a large number of mineral sources, different mineral sources, and great differences in quality, the research on the quality standard of mineral traditional Chinese medicine is of great significance in clinical application. Mineral traditional Chinese medicine can be divided into raw medicinal materials derived from minerals (such as cinnabar, calamine, and natural copper), processed products of mineral raw materials (such as mirabilite and light powder) or fossils of animal bones (such as petrel, keel, and pumice). At present, the quality evaluation of mineral traditional Chinese medicine includes experience identification, purity inspection, and content determination. Empirical identification of the characteristics of mineral medicinal materials can reflect the quality of medicinal materials to a certain extent. For example, ochre is brown-red in color, with an obvious cross-section level with “nailhead” and no miscellaneous stones are preferred ( Hu, 2016 ). However, due to the high similarity of the external morphological characteristics of medicinal materials derived from minerals and more confused products, the practitioners of traditional Chinese medicine often lack the professional knowledge of mineralogy, so character identification needs long-term experience accumulation and inheritance. The application of modern instrumental analysis methods in the identification and quality evaluation of medicinal materials derived from minerals is gradually expanding. Among them, ICP-MS is becoming the key technology for mineral drug evaluation ( Li et al., 2018a ). In recent years, the relationship between the types and contents of inorganic elements in traditional Chinese medicine and their efficacy has attracted extensive attention. The content determination of these elements, including main elements and trace elements, can provide not only important data for the quality evaluation of traditional Chinese medicine but also a reference for the clarification of its action mechanism. As an important member of the family of traditional Chinese medicine, medicinal materials derived from minerals deserve special attention for their safety and effectiveness. Hu (2016) used ICP-MS combined with microwave digestion. Comparing the contents of trace elements of Pb, Cu, Mn, Ni, Cr, Zn, As, Ti, and Cd in eight mineral traditional Chinese medicine pieces of the calcined keel, calcined oyster, gypsum, talc, Mircanite, ochre, amber, and valerian seed with their formula granules, the results show that there are some differences in the contents of trace elements between mineral traditional Chinese medicine and its formula granules. Zhou et al. (2015) used the ICP-MS method to determine the content of trace elements in six common mineral Chinese herbal materials, namely, raw keel, calcined keel, raw oyster, calcined oyster, raw gypsum, and talc, established the detection method of corresponding elements, and made comparative analysis on the content of trace elements in the raw calcined keel and raw calcined oyster. It provides a method for the determination of trace elements in different mineral Chinese medicinal materials from different producing areas. The rest is shown in Table 9 . From the nine articles of medicinal materials derived from minerals determined, 70 elements such as Fe, Cu, Zn, Al, As, Se, and Na were determined, of which eight were Fe, Cu, and Zn, accounting for 88.89%. The elements determined by ICP-MS and their proportion in mineral raw materials are shown in Figure 4 . In the nine articles on the determination of medicinal materials derived from minerals, the measured medicinal materials derived from minerals belong to traditional Chinese medicine. Application of ICP-MS in the determination of heavy metal elements in medicinal materials derived from minerals. Note: the origin of medicinal materials recorded in the table is collected from the articles. If the origin of medicinal materials is not recorded in the articles, it is indicated by “—.” Pie chart of elements measured by ICP-MS and their proportions in medicinal materials derived from minerals.

This study describes the application of ICP-MS analysis of minerals and heavy metals in traditional drugs, including medicinal materials derived from plants, animals, minerals, and their preparations and the research and development of combined technology. Among them, medicinal materials derived from plants are divided into roots, stems, leaves, flowers, fruits and seeds, whole plants, and other medicinal materials derived from plants of medicinal parts. The content of effective components of traditional medicinal materials derived from plants is affected by soil, climate, and other environmental factors, so the quality of medicinal materials from different producing areas is different, which is also an important reason for the formation of genuine medicinal materials. Zuo et al. (2021) used ICP-MS to determine the residues of heavy metals and harmful elements in Lycium barbarum L. The average contents of lead, cadmium, arsenic, mercury, and copper in L. barbarum L. from three origins were 0.30, 0.066, 0.05, 0.003, 6.71 mg·kg −1 , respectively. Cluster analysis and PCA showed that 33 batches of samples were divided into three groups, and the samples from the same origins were clustered into the same group. The results of self-organizing map clustering were consistent with those of PCA. Regularities between the distribution of L. barbarum L. and origins could be found. The results of the safety evaluation showed that the single factor index of lead, cadmium, arsenic, mercury, and copper in all the samples was less than 0.7, and the comprehensive pollution index ranged from 0.11 to 0.51, which indicated that the pollution situation was safe. The results of the risk assessment indicated that the health risk of heavy metals and harmful elements in samples from different origins was acceptable. As the medium of direct contact with medicinal materials, the soil is directly related to the composition and content of inorganic elements in traditional Chinese medicine and is one of the important ecological factors affecting the quality of medicinal materials. Medicinal materials play an important role in the soil environment. On the one hand, the social progress and the impact of human activities has caused soil pollution, the decline of soil fertility, the degradation of land quality, the reduction of the quality of medicinal materials, and the exceeding of harmful substances. On the other hand, the planting areas of medicinal materials have been expanded and changed arbitrarily, and some have exceeded the traditional real estate areas, so their ecological suitability is worth studying. ICP-MS combined with the statistical analysis method enriches the authentic theory of medicinal materials, greatly improves the theoretical understanding of medicinal materials derived from plant cultivation, and also reveals the important influence of the control and regulation of inorganic elements on the quality of original medicinal materials. The efficacy of traditional drugs is the result of the synergy of multiple functional components contained in them. At present, the quality control of traditional drugs in China mainly includes appearance and microscopic identification for eliminating the false and preserving true, inspection of impurities and heavy metals for judging quality, and determination of the content of effective components directly related to function and effect, unable to characterize the integrity and complexity of preparations pharmacology and efficacy, so that the product quality cannot be effectively controlled, which seriously affects the clinical application of traditional drugs and restricts the development of new drug research and development and industry of traditional drugs. Traditional Chinese medicine theory emphasizes the overall effect of traditional drugs and attaches importance to the synergistic effect of various chemical components. Therefore, only taking one to two effective components in traditional drugs as quantitative and qualitative indicators can never reflect the internal quality of traditional Chinese medicine as a whole. It is necessary to establish a method to comprehensively evaluate the quality of traditional Chinese medicine as a whole. There is a correlation between the content of effective components and the content of inorganic elements in traditional drugs. Therefore, the detection of inorganic elements in traditional drugs is feasible to control their quality. Therefore, the elements and their contents in medicinal materials can be determined by ICP-MS, the inorganic element spectrum can be established, and the finishing quality of medicinal materials and Chinese inorganic elements can be evaluated in combination with data system analysis to achieve quality control. Secondly, for the quality control of the preparations, we should not only determine the inorganic elements of preparations but also analyze the inorganic elements of raw materials and medicinal materials to avoid exceeding the standard of harmful heavy metal elements from the source and then control the risk that may be introduced into the preparations. At present, the safety of traditional drugs has become a “bottleneck,” restricting the production and development of traditional drugs and gaining international recognition. Excessive heavy metal elements have an important impact on the activity and safety of medicinal materials, which has attracted extensive attention ( Ji et al., 2014 ). ICP-MS is widely used in traditional medicine with its unique advantages and has achieved remarkable results, which has promoted the development of traditional medicine. Starting from the detection of soil and water quality, it ensures the safety of medicinal materials. The safety of clinical medication is ensured starting from the detection of medicinal materials and preparations. In addition, the pharmacodynamic material basis of some preparations may be related to trace heavy metals, so it can be comprehensively analyzed from the preparations, blood components, and tissue distribution components so that the application of ICP-MS can indirectly reveal the pharmacodynamic material basis. The limit standard of heavy metal elements measured by ICP-MS can fill the data gap of many traditional Chinese medicines and Tibetan medicine standards in the future and lay a foundation for the validation experiment of heavy metal monomers.ICP-MS can also be used to determine inorganic elements in biological samples (whole blood, serum, urine, lung, liver, and other tissues) to provide effective information for the exploration of drug action mechanisms and clinics. Liang et al. (2014) tested the changes of iron content in rat liver by ICP-MS, verified that d-limonene had a certain protective effect on iron coincidence caused by alcohol, and provided a reference for the study of alcoholic liver injury. Morton et al. (2017) used ICP-MS for multi-element analysis of human lung samples to determine the concentration of various elements in the collected lung samples and then used them for comparison with future clinical, environmental, nutritional, toxicological, and forensic investigations. Zhao et al. (2018) determined the spectrum of metal elements in patients’ serum by ICP-MS and found the very important metal elements in a specific infection in blood flow infection, which provided a basis for the diagnosis, prevention, and treatment of BSI from the perspective of metallography. The content, migration, and transformation of trace elements in organisms play an important role in physiological activities. The analysis of trace elements in cells is of great significance, which can understand the functional mechanism of trace elements in cells and organisms. Renqing Changjue is a traditional Tibetan medicine, which has been widely used to treat various gastroenteritis diseases. However, due to the toxic components in Renqing Changjue, its biosafety and toxicity still need to be explored, including various heavy metals. Therefore, Wang et al. (2020b) gavaged rats with different doses of Renqing Changjue, and the recovery observation period lasted for 15 days. The liver and kidney tissues were examined by histopathology, and the serum and urine samples were collected for 1 H nuclear magnetic resonance ( 1 H NMR) spectral analysis and biochemical analysis. ICP-MS was used to determine the content of Hg in urine and serum samples to evaluate the toxicity and elaborate on the toxicological mechanism of Renqing Changjue in order to provide a basis for safety evaluation of Renqing Changjue in clinical use. Song et al. (2021) used ICP-MS to determine the contents of 18 elements such as Mn, Cu, Sr, Pb, Au, and Hg in hepatic venous blood, abdominal aortic blood, brain, liver, kidney, hair, urine, and feces of rats 24 h after MCAO. The contents of Li in the brain increased, and the contents of Cr and Cd decreased. The content of Mn in the liver increased, and the content of Ni decreased. The contents of Ag and Cs in the kidney increased. In recent years, the scientific community has paid increasing attention to metals belonging to the platinum group (PGM), including Ru, Rh, Pd, Os, Ir, and Pt. The effects of platinum group element complexes and some platinum divalent compounds on cancer and genotoxicity have been confirmed in microbial experiments ( Melucci et al., 2022 ). Melucci et al. (2021) determined thallium in herbal medicines. Precision and trueness, expressed as relative standard deviation and relative error, respectively, were generally lower than 7% in all cases. Inorganic elements affect not only the growth and development of medicinal plants but also the constituent factors of effective components in medicinal materials ( Wang et al., 2014 ). Traditional drugs contain rich kinds of inorganic elements, complex matrices, and large content differences. ICP-MS has the advantages of a wide linear range, high sensitivity, and high analysis efficiency. Therefore, this technology can well solve the analysis problems of inorganic elements in traditional Chinese medicine. Luo et al. (2015a) determined and analyzed the differences of inorganic elements before and after processing R. multiflora (Thunb.) Moldenke by ICP-MS. After processing, the contents of Al, Fe, K, Mg, Mn, and Zn increased, whereas the contents of As, Pb, and Cd decreased significantly. It is suggested that the physiological functions of Al, Fe, K, Mg, Mn, and Zn elements are consistent with the effects of R. multiflora (Thunb.) Moldenke, which are beneficial to the liver and kidney, benefiting essence and blood enhancing immunity and anti-aging. The content of these elements increased significantly after processing, which may be related to the enhancement of the tonic effect of R. multiflora (Thunb.) Moldenke. The heavy metals As, Pb, and Cd are harmful to the human body and decrease significantly after processing, which may be one of the reasons for the detoxification of R. multiflora (Thunb.) Moldenke processed. With the continuous popularization and application of the inorganic element spectrum and statistical analysis and evaluation model, the research on the overall quality control of traditional Chinese medicine will be perfect. At the same time, with the development of high-performance liquid chromatography, ion chromatography, and ICP-MS, the analysis methods for different valence states of inorganic elements will become more and more mature. In addition, ICP-OES is also a means of determining metal elements. ICP-OES detects the intensity of the atomic characteristic emission spectrum. In the atomic emission spectrum, each element has multiple characteristic spectral lines. The spectrometer can automatically correct the function to reduce the background signal and screen out two to three analysis wavelengths with low detection limit, high sensitivity, and small interference for qualitative and quantitative analysis. Although the detection limit of ICP-OES is lower than that of ICP-MS, it has met the detection needs of various drugs, and its technology is mature, stable, economical, and convenient. It can be used as a detection method complementary to ICP-MS. Shen et al. (2019) determined 29 kinds of inorganic elements in samples of Paris daliensis H. Li et V. G. Souku and P. dulongensis H. Li et S. Kuritap produced in different regions to measure the content of 10 key inorganic elements: Cr, Mn, Fe, Cu, Hg, Zn, As, Sr, Cd, and Pb. Under the experimental conditions, elements were not related to each other, and many kinds of elements could be measured at the same time; toxic and heavy metals in samples of P. daliensis H. Li et V. G. Souk, and P. dulongensis H. Li et S. Kuritap did not exceed the limit. Hg was not detected in all samples. Zhong et al. (2019) determined the content of 20 inorganic elements in 18 samples of roots, stems, and leaves of A. lappa L. produced in different areas. Twenty kinds of inorganic elements in the samples of A. lappa L. roots contained rich elements essential for human beings such as K, Ca, Na, P, and trace elements Cu, Fe, Zn. Heavy metal Pb, As, Cu, and Cd in A. lappa L. samples did not exceed the limit. Hg was not detected in all 12 samples. Heavy metals in A. lappa L. roots harvested in 12 months did not exceed the limit. Fang et al. (2007) used HPLC-ICP-MS to analyze the forms of As in nine kinds of traditional Chinese medicine preparations, such as Niuhuang Jiedu tablets, Bushen tablets, Shiertaibao pills, Baoyingdan, Mingyan pills, Zhengxin pills, and Biminqing. An anion exchange column was used to determine the content of 0.5%. The aqueous solutions of 2 mmol/L EDTA and 2 mmol/L NaH 2 PO 4 were used as mobile phases. Four forms of As Ⅲ, As V, MMA, and DMA were successfully separated and determined. The results showed that the form of As in the sample was mainly toxic inorganic arsenic and the amount of organic arsenic was low. Li et al., 2012 analyzed six different valence arsenic by HPLC-ICP-MS and studied the forms of soluble arsenic in Realgar and five different preparations of Realgar-containing preparations. The results showed that the acid-soluble arsenic of Realgar and its preparations was far less than its total arsenic content, and the existence of other components in the preparations may inhibit the dissolution of toxic forms of soluble arsenic. The determination of multivalent elements not only enriches the application scope of ICP-MS but also makes the research on the complex system of traditional drugs more in depth to lay a more solid foundation for the relationship between components and efficacy and clinical application research. At present, although the overall research on inorganic components in traditional drugs has attracted attention, the research on the process of elements entering the human body and the interaction between elements in the body is still relatively lacking. Nowadays, the analysis of inorganic elements in traditional Chinese medicine is mostly supplemented by other factors and indicators, and it is difficult to clarify the role of elements themselves. The mode of Metallomics refers to the research ideas of metabolomics, which is conducive to a more in-depth study of the role of inorganic elements and finding the specific targets and sites of some elements in the body. ICP-MS and its combined technology have many reports on the study of the relationship between trace elements and efficacy, the relationship between element morphology and toxicology, the determination of element content, and inorganic fingerprint of traditional drugs. However, in addition to the determination of element content, the research in other aspects is not deep enough.

Chinese patent medicine is based on the theory of Chinese medicine, which is made from Chinese herbal medicines according to the prescribed prescription, production technology, and quality standard. It is the cream of effective prescriptions created and summarized by China’s medical practitioners in past centuries. However, the method of detection and control of inorganic elements in China patent medicine is in the Chinese drug standard and even the Pharmacopoeia. The degree of attention is not high. Currently, many researchers have begun to focus on the problems of trace elements, heavy metals, and harmful elements in Chinese patent medicine ( Fu, 2017 ). Inorganic elements have a strong ability to form complexes and easily form coordination bonds with ligands containing N, O, and S in organisms to coordinate the material balance in the body ( Zhao et al., 2019 ). The content and type of inorganic elements in traditional Chinese medicine can affect its nature, taste, and efficacy. For example, Zn, Ca, and Fe are the characteristic inorganic elements of hemostatic traditional Chinese medicine. K and Mg can affect the properties of drugs for promoting blood circulation and removing blood stasis. The difference between Fe and Mn content is the basis of the “cold and warm” property ( Wu et al., 2014 ). It shows that the type and content of inorganic elements have a certain synergistic effect on the exertion of drug efficacy. In Chinese patent medicine, clarifying the types and characteristics of inorganic elements can provide a reference for the efficacy study of the preparations from the perspective of inorganic elements. As we all know, the quality and safety of raw materials directly affect the efficacy and drug safety of finished products. With the advancement of China’s industrialization, the pollution of soil and water by heavy metals and harmful elements is becoming more and more serious, resulting in the possible pollution of native traditional Chinese medicine in various links such as growth, collection and processing, warehousing and transportation, and even the production process of preparations ( Yan et al., 2017 ). In recent years, due to the frequent exposure to heavy metal pollution in traditional Chinese medicine, South Korea, the United States, and other countries have raised the safety testing standards of traditional Chinese medicine and restricted the import of traditional Chinese medicine. At present, in China’s drug standards, only a few processed products of traditional Chinese Medicine (Zhong yao yin pian), such as Glycyrrhiza uralensis Fisch. ex DC., Astragalus mongholicus Bunge, and Lonicera japonica Thunb., have formulated inspection items for the content of heavy metals and harmful elements, whereas Chinese patent medicines have basically not formulated relevant inspection items. Therefore, we should pay attention to the problem of heavy metal pollution in Chinese patent medicines and formulate detection methods for safety indicators such as heavy metals and harmful elements. However, during preparations, it is not completely clear whether there is interaction and whether it is transformed in vivo due to the complex composition. The research and development of traditional Chinese medicine injection have become one of the hot spots in the modernization of traditional Chinese medicine. Compared with ordinary preparations, it is a high-risk variety from the perspective of clinical application. Therefore, the research on the safety of traditional Chinese medicine injection has attracted much attention, especially the residue of heavy metals and harmful elements. The residues of heavy metals and harmful elements mainly come from environmental pollution, processing, storage, and migration of packaging containers such as ampoules. At present, the determination of elements in injections derived from traditional Chinese Medicine usually adopts the single element method, which has complicated procedures and a long analysis time. The ICP-MS method can simultaneously determine Pb, As, Cd, Hg, Cu, and other elements in injections derived from traditional Chinese Medicine and has become an important means of element analysis in recent years, as shown in Table 10 . In terms of clinical medicine, injections derived from traditional Chinese medicine are high-risk varieties; Pb, Cd, As, Hg, and Cu, represented by heavy metals, are among the most important exogenous pollutants in injections derived from traditional Chinese medicine. Toxicity is mainly characterized by chronic poisoning, As, Cd element with clear carcinogenic, teratogenic, and mutagenic effects, and injections derived from traditional Chinese medicines without digestive tract directly into the bloodstream. Therefore, it is significant to carry out limited inspection of heavy metals and harmful elements in injections derived from traditional Chinese Medicine. Although the country has not made a clear limit on trace elements of Fe, Mn, Zn, Al, and others, their excessive amount may also cause adverse effects on the human body. For injections derived from traditional Chinese medicine, the complexity of the ingredients also determines the diversity of their efficacy, making it difficult to distinguish between effective ingredients and toxic ingredients. As an important component of the material basis of drug properties, trace elements are closely related to the drug properties, efficacy and adverse drug reactions. Therefore, accurate determination of trace elements is of great significance to the study of pharmacodynamics, the safety of drug intake, and the formulation of the limit standard of harmful elements. Application of ICP-MS in the determination of heavy metal elements in Chinese patent medicine. From the 46 articles on Chinese patent medicine, 62 elements such as Cu, As, Pb, Cd, Hg, Ni, and Cr were determined, of which 43 were Cu, accounting for 93.48%. Thirty-eight of the tested Chinese patent medicine belong to traditional Chinese medicine, accounting for 83%. The elements determined by ICP-MS and their proportion in Chinese patent medicine are shown in Figure 5 . Six articles belong to Tibetan medicine, accounting for 13%. Two articles belong to the medical system of Mongolian medicine in China, accounting for 4%. Pie chart of elements measured by ICP-MS and their proportions in Chinese patent medicine.

ICP-MS is undoubtedly a very practical means for the quantitative analysis of heavy metals. However, for traditional pharmaceutical preparations, a series of changes will occur when they are absorbed into the human body, such as the valence changes of heavy metals. At this time, it is necessary to accurately detect some valence changes, so the single ICP-MS method becomes weak and needs to be used in conjunction with other instruments to complete this work. At present, ICP-MS has been used in various analytical fields. For example, Heitland et al. (2017) used HPLC-ICP-MS to diagnose and monitor patients with severe hexavalent chromium and inorganic arsenic poisoning to provide valuable data for doctors and toxicologists. However, for the research of traditional drugs, continuous use technology is not widely used. The application of HPLC-ICP-MS in traditional drugs and their preparations are shown in Tables 11 and 12 . Other combined analytical techniques are also widely used. However, they are rarely used in traditional medicine. In the searched articles, HPLC-ICP-MS is mostly used to determine different forms of As, including AsC, AsB, AsIII, DMA, MMA, and AsV, and the determination of other elements is less in the articles search. Therefore, more combined techniques are used to analyze traditional medicine. It will be more beneficial to accelerate the development of traditional medicine. From the 10 articles on the application of the combined technique, 16 elements such as MMA, DMA, AsⅢ, AsⅤ, AsB, AsC, and AsI 3 were determined. Among them, MMA and DMA were determined most, with eight articles accounting for 80.00%. The content and proportion of elements in medicinal materials and Chinese patent medicines determined by ICP-MS are shown in Figure 6 . Among the 10 articles on the application of combined technology, the tested medicinal materials and preparations belong to traditional Chinese medicine. Application of HPLC-ICP-MS in medicinal materials. Note: the origin of medicinal materials recorded in the table is collected from the articles. If the origin of medicinal materials is not recorded in the articles, it is indicated by “—.” Application of HPLC-ICP-MS in Chinese patent medicine. Determination of element content and proportion pie chattachment.art in medical materials and Chinese patient medicines by ICP-MS.

Traditional medicine in China includes traditional Chinese medicine, ethnic medicine (e.g., Tibetan, Mongolian, Uygur, Dai, Miao, and Zhuang medicines), and religious medicine (e.g., Buddhist and Taoist medicines). Traditional Chinese medicine is an important part of Traditional medicine in China. China is the world’s largest producer of medicinal materials. Arabic medicine is derived from Hippocratic–Galenic medicine in ancient western philosophy, formed in the Arab Empire between the 8th and 12th centuries. It is generally believed that Unani, which is popular in south Asian countries, belongs to Arabic medicine. Traditional drugs have three basic ingredients—medicinal materials derived from plants, animals, and minerals—among which medicinal materials derived from plants account for the highest proportion. Medicinal materials derived from plants have six organs (roots, stems, leaves, flowers, fruits, and seeds), which makes the medicinal parts of medicinal materials derived from plants diverse. Root and rhizome traditional drugs account for the largest proportion and are the most common in the whole medicinal materials derived from plants, so the inductively coupled plasma-mass-spectrometry (ICP-MS) method is also the most widely used in this kind of traditional drugs. Heavy metal is not only a toxic component of common concern in today’s society but also an effective component of traditional drugs. Traditional medicinal materials derived from plants, animals, minerals, and their preparations (Chinese patent medicine) often contain several minerals and heavy metals. In addition, there are cases of heavy metals exceeding the standard in the drugs. The limitation of heavy metals and the improvement of quality control standards are major dilemmas affecting the internationalization process. People favor traditional drugs more because of their reliable curative effect, less toxic and side effects, relatively safe use, and other characteristics. However, in the process of planting, production, and processing of traditional drugs, due to their enrichment and absorption of heavy metals or the high content of metal elements in the cultivated soil, the application of chemical fertilizer and pesticide contamination and other situations may introduce metal elements, resulting in an abnormal increase in metal element residues, which also makes traditional drugs have varying degrees of heavy metal pollution ( Chi et al., 2016 ). There are many kinds of inorganic trace elements in traditional drugs. The inorganic elements are closely related to their efficacy and therapeutic use. They are one of the effective components of traditional Chinese medicine. Studying the content and distribution of inorganic elements in traditional drugs to elucidate traditional pharmacology and toxicology and further develop medicinal resources is of great value. ICP-MS mostly uses a quadrupole mass spectrometer, which can quickly and continuously measure the mass of different elements. Currently, it can be used to analyze more than 70 elements. The detection limit of ICP-MS for more than 70 elements in the solution is one trillion or less, and the linear dynamic range can reach nine orders of magnitude ( Olesik, 2014 ). ICP-MS is an inorganic multi-element analysis technology with inductively coupled plasma as an ion source and mass spectrometry in the field of analytical chemistry in the early 1980s. In 1980, Robert et al. (1980) published the first article on the feasibility of ICP-MS, and the first commercial instrument came out 3 years later. So far, there are about 20 types of ICP-MS instruments commercialized worldwide. In the field of drug element analysis and safety monitoring, ICP-MS and its combined technology are also increasingly widely used, which seems to have become a common and mature analysis and detection means. There are many common methods for the determination of trace elements in traditional Chinese drugs, mainly including atomic fluorescence spectrophotometry (AFS) ( Zhang et al., 2016a ), atomic absorption spectrophotometry (AAS) ( He et al., 2019 ), ultraviolet-visible spectrophotometry (UV-VIS) ( Wei et al., 2019 ), and inductively coupled plasma atomic emission spectrometry (ICP-OES) ( Ma et al., 2020 ). Most of these methods can determine single elements, but they can not determine some elements with low content. Metal determination can also be used for QC analysis and spectral and voltammetric configurations ( Locatelli et al., 2014 ). Dora Melucci ( Melucci et al., 2013 ) determined the contents of heavy metals and total mercury in Camellia sinensis by micro voltammetry. ICP-MS is a new element analysis technology, with the advantages of less interference, high precision, wide linear range, and fast analysis speed. In view of the wide application of ICP-MS in traditional drugs and preparations (Chinese patent medicine), 234 relevant articles on the determination of minerals and heavy metals in plants, animals, mineral medicinal materials, and preparations by ICP-MS and its combined technology were collected and classified. The purpose is to provide a reference for improving the quality standard of traditional drugs and exploring the material basis and mechanism of efficacy/toxicity.