Lead in traditional and complementary medicine: a systematic review

: Lead in the environment remains a matter of grave concern for public health. Lead has been associated with some traditional medicines and has been linked to cases of lead poisoning. A comprehensive compilation of these reports has not previously been conducted. The objective of this review is to explore how common is lead exposure after traditional medicine use, and which countries, systems and/or products are of most concern when it comes to lead contamination. A systematic search was conducted on PubMed, Ovid and EMBASE for studies published between 2005 and 2020. A grey literature search was conducted. Search terms related to lead and traditional medicine were developed for each database, and there were no limitations on language. Studies were included if they examined elevated lead in humans resulting from the use of traditional medicines reported in case reports, case-series, or observational studies. Of the papers discussing lead exposure, 85 case reports were identified and synthesized for the current review. Several themes were identified in the included studies. Traditional medicine has been used in the many parts of the world, however use is more common in South and Southeast Asian countries. The level of detectable lead in products varied widely by region and product types. Consumers of traditional medicines sought products for a wide variety of symptoms and ailments. The symptoms of lead poisoning from traditional medicine use reflected the typical symptom profile of lead poisoning, highlighting the need for awareness of traditional medicine products as a source of lead exposure. Traditional medicine usage remains an important part ofhealth care inmanyregions,however thereisariskof lead exposure from several products. Health care practitioners in all regions of the world should be aware of the risk and explore the potential for traditional medicine use for patients presenting with elevated blood lead levels. Countries with a strong traditional medicine culture should explore policies for reducing lead exposure from traditional medicine products. JG, LO and MNBD are staff members of the World Health Organization. The authors alone are responsible for the views expressed in this publication and they do not necessarily represent the decisions, policy, or views of the World Health Organization.


Introduction
Lead in the environment remains a matter of grave concern for public health, with the World Health Organization's (WHO) Institute for Health Metrics and Evaluation (IHME) estimating that lead exposure was responsible for 900,000 deaths and more than 20 million disability-adjusted life years lost in 2019 [1].While the highest burden of lead-related health outcomes occurs in the WHO region of South-East Asia [2], lead is a problem for children in all countries as there is no safe blood lead level [3].Lead is a toxic metal that has been used for many purposes throughout history including in ammunition, shielding systems against ionizing radiation, linings in tanks and pipes and in the construction and chemical industries.It has been widely used as an additive in petrol, paints, enamels and glazes.Chronic lead poisoning in adults can also come from workplace rather than purely environmental exposures, such as the manufacturing and recycling of batteries, paints, solder, ammunitions, car radiators and ceramic ware with lead glaze [4].
Lead exposure during fetal development is particularly dangerous, with higher lead levels in pregnant women associated with adverse neurodevelopmental outcomes in the offspring [5].Children are more likely to be exposed through environmental contamination and are more vulnerable to the toxic effects of lead [6].While typical environmental sources predominate as the cause of lead poisoning, cultural factors are also important.Besides lead-containing paint, various sources of lead were identified for children, such as, imported spices, cosmetics, as well as traditional folk medicines.Once absorbed, lead is distributed to the brain, liver, kidneys, and bones where it has several modes of toxic action that depend on dose and target organ [1].Lead is stored in bones, which can be released during pregnancy exposing the developing foetus to the effects of lead toxicity.Due to their unique physiology, children are recognised as having a greater risk of exposure to lead toxicity and greater susceptibility to the effects of toxicity than their adult counterparts [7].
There is no safe BLL and no level below which adverse effects do not occur, with BLLs previously considered safe now understood to compromise health even in the absence of symptoms [1].Lead affects many organ systems in humans.Lead poisoning, with high blood lead levels (BLLs), causes severe damage to the brain and kidneys resulting in death, in both children and adults.In pregnant women, high exposure to lead may cause miscarriage, whereas lower levels may be associated with developmental defects in the developing foetus [5].Lead exposure is associated with neurobehavioural problems ranging from subtle cognitive deficits to a predominantly motor peripheral neuropathy to encephalopathy, memory loss, constipation, seizures, abdominal pain, nausea, anorexia, fatigue, headache, irritability, and arthralgias, although, symptoms of adult lead poisoning are variable [8,9].Adverse health effects of chronic lead exposure also include reduced fertility in males [10].Symptoms of lead toxicity such as anaemia and reduced fertility in adults can occur at blood lead levels of <30 micrograms per decilitre (μg/dL) while BLLs as low as <10 μg/dL causing hypertension, an increased risk of preterm birth, and a reduction in IQ scores and academic performance in children [1].
Lead has also been associated with some traditional medicines and cosmetics in several parts of the world [11,12].In addition, use of traditional and complementary medicines can also cause lead poisoning [13].Traditional and complementary medicines include diverse health practices, approaches, knowledges and beliefs incorporating plant, animal and/or mineral-based medicines, spiritual therapies, manual techniques, and exercises, applied singularly or in combination to maintain well-being as well as to treat, diagnose or prevent illness [14].The most well-known traditional medicine systems are Western Herbal medicine, Ayurvedic medicine, and Traditional Chinese medicine, however there are many systems around the globe falling under the banner of traditional medicines.Traditional medicine usage is common in many countries for a variety of reasons, such as cultural practices, accessibility, cost, and the belief that natural therapies are safer [2].WHO reports that "In the South East Asia (SEA) Region, the poorer segment of society uses traditional medicines disproportionately, partly due to its affordability and also due to its availability in their communities.Hence a traditional medicines strategy should encourage continued affordability and accessibility" [15].This present review aims to support this WHO strategy, which notes that "many traditional medicine products and practices have been used for a considerable period of time and are therefore thought to be safe and effective," but acknowledges that this is not always the case.The term "traditional medicine" used in this study either as a complementary and alternative medicine, or as both.
Despite the perceived safety, reports of traditional medicines containing lead that result in adverse health effects are relatively common.A comprehensive compilation of these reports has not previously been conducted.Therefore a systematic review was conducted to bring together case-reports and answer the following questions: (1) How common is lead exposure after traditional medicine use, and (2) Which countries, systems and/or products are of most concern when it comes to lead contamination.

Methods
A systematic search and narrative synthesis were performed, allowing for a review of findings where quantitative assessment was not feasible.Following PRISMA guidelines, a systematic search was conducted in the medical electronic databases PubMed, Ovid and EMBASE for studies published between 2005 and 2020.Search terms comprising lead exposure and traditional medicines were devised, with the help of a specialist librarian and the search was conducted on the 25/08/2020.Search terms are listed below and the full search strategy for each database can be viewed in the supplementary materials.Additionally, a grey literature search was conducted using OpenGrey, Cochrane, Oaistr, and Google.The strategy for each source is outlined in the strategy section below.Lastly, the WHO librarian and WHO regional offices were approached to search databases compiled by the WHO.Country specific health departments were searched relating to lead and traditional medicine publications where we had capacity and knowledge to do so.
The Australian Therapeutic Goods Administration's Australian Register of Therapeutic Goods (ARTG) database was searched.Data from the case reports collected was collated and analysed, allowing for the recognising of specific themes of interest and a quantitative approach to collection of results of interest.This data is presented in tables below.These themes were gathered from the less numerous observational studies collected and the trends that those papers suggested, with the observational studies being referenced within thematic areas to support the quantitative data.Reports on policy were omitted from this review.

Search strategy
The pre-identified keywords related to lead and traditional medicine were 'lead poisoning' OR 'lead' AND 'poisoning' AND 'traditional medicine' OR 'herbal' OR 'Ayurvedic' OR 'complementary' AND 'medicine OR 'drug' OR 'treatment'.The final search terms used in the databases are presented as a table in the Supplementary Materials.There were no limitations on language for searching the paper, however, primarily focused on paper written in English.Grey literature search strategies were developed by two authors (DV and AM).Search terms were tested in each source, including appropriate limits.Google was searched using the advanced search function.

Selection criteria
Studies were included if they were published between 2005 and 2020 (inclusive), examined elevated lead in humans resulting from the use of traditional medicines, and discussed one of the key themes: elevated blood lead levels reported in case reports, case-series, or observational studies.We set a timeline from 2005 to 2020 for this review to ensure that findings were contemporary.The current review focuses solely on case-reports to capture the clinical importance of this topic.
The search was conducted by two authors and the results of the searches were imported into EndNote version 20.Duplicate papers were removed first by Endnote automatic scanning and by manual search.Title and abstract screening were conducted by same two authors and any disagreements were resolved through discussion.Full text review and data extraction was performed by first, second, third and corresponding author and narrative synthesis performed.
Due to the heterogeneity of identified case-reports, and the differences in quality of reporting, a narrative synthesis was performed.

Results
After screening and applying selection criteria we identified 194 studies for review.Of these, 128 studies reported lead poisoning, 16 discussed lead removal from medicine, 19 studies focused on policy and the rest dealt with diverse issues.The articles discussing policy will not be reviewed here but reported separately.Themes were selected based upon the data of the observational research to narrow down areas of interest, with the case report data being applied to address the questions of the selected themes.Of the papers discussing lead exposure, 85 case reports were identified and synthesized for the current review.While there was a wide geographical distribution of papers on lead poisoning, most came from the USA (20 papers) or India (17 papers) (Table 1).Given the popularity of traditional medicines on the Indian subcontinent, we found fewer cases of lead poisoning than anticipated, with the USA and other Western countries having a far higher proportion of published case studies.This is likely due to better established mechanisms for identifying and reporting lead poisoning in these countries.In addition, reported case-studies highlighted that the products were often brought into western countries from migrants' homelands, where traditional medicine use was more common.
The reported reasons for using traditional medicine varied widely, with the use reported for most organ systems.Table 2 shows the reported organ system treated with traditional medicines.
Table 2 shows that 25 papers did not directly mention the purpose for using the traditional medicine; 12 papers highlighted that general health issues were the reasons followed by endocrine (11 papers) and skin problems (10 papers) for using traditional medicine.All cases reported involved lead poisoning, with the highest BLL being 145 mg/dL [16].We have grouped the reports into the following themes.
Theme 1: Popularity of using traditional medicine and cosmetics by geographical area (Table 1).

Country
Number of published paper Traditional medicine has been used in the many parts of the world.However, this is far more common in South and Southeast Asian countries.In Korea, 17.9% of females and 22.1% of males surveyed took herbal medicine, using data from the Korea National Environmental Health Survey completed between 2012 and 2014 (Son, 2019).An Indian study in 5-12-year old children found that over 50% used lead-containing cosmetics and kohl/surma, and more than 21% used Ayurvedic or herbal medicines, which resulted in increased blood lead levels [17].A different study on children in India found 75% used Ayurvedic medicine and 55% used Kohl [18].In contrast, in Mexican children aged 2-6 years (n=171), 38% used home remedies [19].A study of 222 Chinese children ≤14 years showed that 77.5% used lead powder [20], with an average duration of use of around 3 years.
Theme 2: Concentration of lead in traditional medicine (Annex 1).
Several papers highlighted the route of administration, forms, and doses of lead used in traditional medicine, including oral administration, spray applications [21], and dietary supplements [22].
A study among 115 consumers of Ayurvedic medicine in the USA found that 40% of the participants had BLLs ≥10 μg/dL, with 9.6%≥50 μg/dL.BLLs above the maximum allowable daily level in California (0.5 mg/day) were found in 27.5% of 182 ayurvedic supplements [23].Another study of 171 children aged 2-6 years in Mexico evaluated the association between reported recent consumption of candies identified to contain lead, and BLLs among children in Mexico City [19].BLLs ≥0.1 ppm, the Food and Drug Administration (FDA) permitted level (range: 0.13-0.7 ppm) were found in 6 of 138 candies from 44 different brands [19].Lead is a common ingredient in Ayurvedic medicine and other traditional medicines, with one report showing 73% (24/33) of solid Ayurvedic and herbal drugs and 36% (n=14) of liquid Ayurvedic and herbal drugs contained more than reference lead levels [24].
A Bangladeshi study sampled 12 traditional medicines and found only one, a Cinkara brand multi-vitamin tonic, contained any detectable lead (0.2 μg/g) [25].Dix-Cooper et al. [26] conducted a cohort study in Vancouver, Canada and only found a single traditional medicine associated with BLLs, specifically ghasard (1.6% lead by weight).Angelon-Gaetz et al. [27] found a massive range of possible lead concentrations in traditional medicines in North Carolina, USA ranging from Rangoli with lead levels of 2.9 mg/kg all the way up to Surma with a lead content of 68,000 mg/kg, that is a preparation that was nearly 7% lead.Ritchey et al. [28] conducted a cross-sectional study that also found massive variance of lead levels in traditional medicines, with one thanakha medicine containing 1.2 ppm lead contrasted against packages of a Daw Tway medicine containing up to 560 ppm of lead.
Theme 3: Reasons for the initial consumption of Traditional Medicine (Table 3).
The reasons listed by the collected reports investigating why patients consumed traditional medicines, and as a result often inadvertently exposed themselves to dangerous levels of lead, varied widely.As a general rule, patients taking the medicines stated they were either to solve an existing or perceived health problem or to enhance healthiness in some way.Ssempijja et al. [29], in an analysis of traditional medicine consumption leading to pathological BLLs within villages of the Bushenyi district in Southern Uganda, noted that most intake was for non-cancer reasons.A Vietnamese study by Nguyen et al. [30] of 133 children exposed to lead in traditional medicine found that reasons for consumption were primarily for thrush on the tongue (70.7%), ulcers on oral mucosa (16.5%), and anorexia (9%).Mehta et al. [31] in India analysed 73 patients of mean age 31.6 (male n=60, female n=13), and found diabetes mellitus (n=21) and sexual weakness (n=15) to be the primary reasons for consumption, although generalised weakness (n=14) and infertility (n=10) were also key reasons for traditional medicine consumption leading to lead poisoning.Treatment of acne and skin problems was a central reason for consumption of traditional medicines in South Africa [32] and in China [33].The usage of lead-containing medicines for the achievement of general health and reproductive health was noted in a Taiwanese cross-sectional study [34] and in four out of 22 cases of lead poisoning due to Traditional Chinese Medicine in Korea [35].A study in Pakistan by Hina et al. [36] in 2014 considered 20 patients suffering from asthma who utilised herbal medicines for treatment and symptom relief and noted high blood lead levels in multiple subjects.In Sweden, a novel cohort study found that 32 out of 40 mothers with an anthroposophical or spiritual lifestyle utilised herbal medicines during pregnancy, while only 9 out of 40 mothers who did not lead anthroposophical lives used herbal medicines during their pregnancy [37].Theme 4: Symptoms related to the use of leadcontaining traditional medicines (Table 4).
The table below shows the reviewed papers mentioned various symptoms and reason for use of traditional medicines.
Theme 5: Association between traditional medicine and lead poisoning (Annex 1).
Several studies identified the association between traditional medicine and lead poisoning.Jeong et al. [22] conducted a study among 5,136 Koreans from the general  children, aged between 2 and 6 years found that for every 1 µg increase of lead ingested through candy per week, BLL increased by 2.6% [19].Furthermore, it has been reported that a dose-response relationship for green and herbal tea and lead burden exists.Those who consumed herbal tea in the third trimester had significantly higher maternal and cord BLLs than non-herbal tea drinkers [43].A Vietnamese cohort study analysed 52 children who had consumed a 'Cam Drug' traditional medicine and found the mean BLL in the group was 56.9 ± 22.72 μg/dL [44].
A case-control study in US found that the prevalence of elevated BLL among US-bound refugee children from Myanmar was higher than the current US prevalence and was especially high among children aged 2 years old [45].Children aged <2 years had a 5-times higher prevalence of elevated BLLs than children aged >2 (14.5 vs. 3.0%, respectively), with numerous traditional remedies investigated having lead concentrations as high as 525 ppm [45].

Discussion
Traditional and complementary medicines are used in many different cultures and in many parts of the world.They are especially popular in Asia and South America and increasingly used in Western Countries.Lead has been incorporated into traditional and complementary medicines, either unintentionally due to contamination or intentionally due to perceived antidote, anti-epilepsy, and anti-asthma properties, as well as effects claimed to promote healthy skin.Lead is imposing a major threat to human health [46].
The current review provides new information and perspectives on several areas of interest.The volume of published case reports of lead poisoning due to traditional and complementary medicine use in Western countries confirms that with the movement of peoples and cultures across the globe, many systems of traditional medicine have also shifted to locations and continents other than their area of origin.WHO defines traditional medicine as "the sum total of the knowledge, skill and practices based on the theories, beliefs and experiences indigenous to different cultures, whether explicable or not, used in the maintenance of health as well as in the prevention, diagnosis, improvement or treatment of physical and mental illness" [14].Within traditional and complementary medicine practice, it is important for practitioners to understand the potential harm from adulteration and the risk of using lead-based products as therapies.However, even in countries with lower use of traditional medicines it is important that clinicians and public health officials are aware of the globalisation of many traditional and complementary medicines and the broad implications of their use.While the present report focusses on the prevalence of lead poisonings, this consideration is likely applicable to other substances detrimental to human health that may be found in traditional and complementary medicines.As such, it should be expected that geography becomes a less important factor in the observation of lead poisoning due to the spread or movement of traditional medicines in the future?
An additional meaningful finding of the present study is the collection of reasons why the lead-containing traditional medicines were consumed by patients and the subsequent symptoms that the lead poisonings caused.The symptoms produced by the lead poisonings were found to be as expected and, while a large range of symptoms were reported, the most common ones were those that are well established as symptoms of lead poisoning.As such, the specific symptoms themselves should not be viewed as important for identifying lead poisoning due to traditional medicines.Rather, if lead poisoning is identified in a patient with no obvious cause, then the possibility of traditional medicine being a contributing factor to the pathology should be considered.There were no major overlaps between reasons for the consumption of traditional medicines and the symptoms produced by the lead poisoning events for organ systems.This was due to the symptoms produced being quite consistent whereas reasons for the medicinal consumptions varied massively.The separate collection of reasons listed in the case reports for why patients were taking the lead-containing traditional medicines originally also lends a valuable viewpoint to the considerations of the paper.While many papers did not report on these reasons, the ones that did demonstrated an incredible range of ailments that traditional medicines were being used to treat, with only diabetes and cardiovascular symptom relief standing out as more common.This demonstrates not only that there is no specific subset of illnesses that are more likely to be treated with traditional medicines that in turn may contain lead, but also shed a meaningful light on the fact that traditional medicines are used to treat a wide range of health ailments that sometimes dismissive practitioners of Western medicine should be aware of.
Our findings aligned with the findings of Tang et al. [47], where a literature review reported that gastro-intestinal and neurological symptoms were the most common symptoms noted by doctors in cases of lead poisoning after consumption of traditional medicine.This current review built upon the findings of Tang et al. [47], where reasons for taking traditional medicine were listed and defined as "varying by individual."Our findings not only confirm the variety in recorded reasons for consumption, but we have also been able to highlight diabetes and cardiovascular symptom relief as flags for physicians and regulators to be more aware of.The writings of Sakharkar [48] in a 2017 report lamented upon a series of cases of lead poisoning due to traditional medicines that they believed meant "we have failed in our legal and civic duties of educating populations and users of herbal medications about the grave concerns posed by the herbal medications and their associated toxicities."While this statement is dramatic and grandiose, in regard to education, this current review found that 11 reports contained no information on the symptoms suffered by patients and a further 26 reports did not list the reason that the patient was seeking traditional medicine treatment for their real or perceived maladies.Data on the specific medication taken was more often lacking or absent than present, with many examples of vague terms such as 'black powder' or 'red liquid' being seen if there was a medication listed at all (see Annex 1).This current report agrees with the consensus that lead and other potentially toxic metal poisonings via traditional medicines is an area of growing concern, and agrees that education needs to be passed on, not only to populations, but also government regulators, and physicians of Western and non-Western medicine.
The present report has several strengths and weaknesses.By matching up patient reason for taking traditional medicine with symptoms and BLLs for every report, it garnered new information on any possible linkages between cause and effect regarding lead poisoning via traditional medicine intake.Additionally, the use of themes allowed clarity in the examination of specific facets of what is an incredibly complex social and medical issue.However, several weaknesses were noted and should be addressed in future publications.The search strategy picked up a majority of Ayurvedic medicine lead poisoning reports, with other traditional medicine systems being underrepresented.While the reports were picked up from many countries, the search strategy could be further developed to ensure a wider net is cast in future reports.A limitation of the report was how difficult it was to accurately analyse trends in the data due to the common occurrence of case reports not actually reporting specific points of interest.This occurred in 26 reports for reason of use, 11 reports for symptoms created by lead poisoning, and 48 reports for which traditional medicine was consumed by the patient.These gaps made analysis more difficult, and a key finding of this paper is that better education of physicians to enable more thorough reporting is crucial for the future.
Key recommendations for future research must revolve around improved education.This education can be separated into the striata of physicians, regulatory authorities and general populations.Research is needed to understand the knowledge of traditional medicine practitioners on the topic of lead in their therapies.With the exception of products such as Greta and Azarcon or other lead-based therapies utilised for the purported therapeutic effect of lead, it is unclear if practitioners are aware of the potential for adulteration of therapies by lead, or how to source safe products for use.For physicians in countries with low usage of traditional medicines, it should be ensured that traditional and complementary medicines are presented and explained during medical education so that the physician is aware of their existence during subsequent practice, especially given the proportions of the population that are known to utilise traditional medicines.Additionally, in reporting it was often found that the medicine taken by patients was left unreported or inadequately reported, for example as 'unspecified paste' [49], 'blue powder' [50], or 'golden sphere' [51].When the traditional medicine names were reported, often there was no explanation attached, leaving it to researchers to surmise what 'Maohumeh Nasini Gutika' (medication mixture used in diabetes) [52] or 'Bruhat Vata Chintamani Rasa' (tablet medicine used for imbalance diseases such as paralysis) [53] may refer to, and offering other physicians very little assistance in recognising additional cases.Reporting standards must be improved to allow more thorough research to be completed, for example mandatory reporting of what the medication consumed was and an ingredient list to the best of the reporter's abilities.Regulators require a more in-depth knowledge of the risks of lead poisoning and what to look for in traditional medicine products to enable the protection of populations ignorant to the risks of possible lead poisoning.This could be established through more thorough screening practices or using a new designation for traditional medicine products.And for general populations, acknowledging the high numbers of citizens worldwide that consume traditional and complementary medicine products, and through future research ensuring that products that have been correlated with lead and other potentially toxic metal poisonings are appropriately labelled, and that populations can be sure that the medicinal products they have been supplied with are agents capable of promoting health, and not diminishing it.

Conclusions
This review's findings demonstrate the risk posed by traditional and complementary medicines.The study identified the sources, symptoms, and consequences of lead poisoning in relation to the use of traditional medicine.Lead consumption in traditional medicines was significantly associated with elevated BLLs.Lead poisoning is a severe, complex, widespread disease which affects the physical health and mental development of young children, pregnant women, and adults.It is a multisystem disease, causing symptoms in children that are often nonspecific, consequently leading to delays in diagnosis.Lead poses a serious threat to public health and human intellectual capital worldwide.The consequences and severity of lead poisoning requires the attention and involvement of policy makers and need to be detected and treated promptly.After taking many initiatives such as bans on leaded gasoline, removing lead from paint, and creating awareness throughout the world, BLLs in general are decreasing.While population BLLs show a decreasing trend worldwide, lead toxicity still occurs all too commonly [2] and USA, India and China are the top leading countries who are using traditional medicines and thus lead poisoning.In addition, there is no safe BLL and no level below which no adverse health consequence occurs.Public health programs, policy, and regulations to reduce lead toxicity need to turn their attention to lead exposure through use of traditional and complementary medicines, rejecting alarmism and remaining focussed on possible benefits of traditional medicines.In the words of the WHO [14], "Countries aiming to integrate the best of traditional and complementary medicines and conventional medicine would do well to look not only at the many differences between the two systems, but also at areas where both converge to help tackle the unique health challenges of the 21st century."

Table  :
Geographical distribution of the case report papers.

Table  :
Organ system treated with traditional medicine in the reviewed case reports.

Table  :
Reasons for use of traditional medicines as mentioned in the reviewed case report papers.

Table  :
Symptoms mentioned in the reviewed case report papers.