Environ Monit Assess (2021) 193: 470 https://doi.org/10.1007/s10661-021-09261-1 Monitoring and risk assessment of pesticide residues in selected herbal medicinal products in Ghana Kwabena F. M. Opuni  · Samuel Asare‑Nkansah  · Paul Osei‑Fosu · Abraham Akonnor · Samuel O. Bekoe  · Alexander N. O. Dodoo  Received: 1 December 2020 / Accepted: 28 June 2021 / Published online: 5 July 2021 © The Author(s), under exclusive licence to Springer Nature Switzerland AG 2021 Abstract The high patronage of herbal medicinal validated gas chromatography with mass spectrom- products in Ghana for the treatment of diverse dis- etry as a detector was used to determine forty-two ease conditions raises concerns about patient safety, pesticides in thirty herbal medicinal products. The given that much of the raw materials for production performance parameters of the method such as linear- are obtained from the wild or farmlands potentially ity, accuracy, and precision were found as acceptable. exposed to varied agrochemical residues. Therefore, Pesticide residues such as chlorpyrifos and/or bifen- the work sought to investigate the contamination of thrin were found in 4/30 herbal medicinal products. herbal medicinal products with pesticide residues and Specifically, 3/30 herbal medicinal products contained assess the potential risk posed to patients. As a result, only one pesticide, while 1/30 was contaminated with both pesticide residues. The levels of pesticide residue contamination ranged between 2.5 and 5.0 µg/kg. The K. F. M. Opuni (*)  acute hazard quotient and chronic hazard quotient for Department of Pharmaceutical Chemistry, School the two pesticide residues were evaluated and ranged of Pharmacy, University of Ghana, Legon, Ghana e-mail: kfopuni@ug.edu.gh between 0.21 and 0.92% and between 8.21 × 10 −4 and 5.88 × 10−3%. The detected pesticide residue levels are S. Asare-Nkansah · A. Akonnor · S. O. Bekoe  below the maximum residue limit values, which may Department of Pharmaceutical Chemistry, Faculty not cause acute and chronic health risks due to intake of Pharmacy and Pharmaceutical Sciences, Kwame Nkrumah University of Science and Technology, Kumasi, of the selected  herbal medicinal product. Neverthe- Ghana less, patient safety and potential public health risk can e-mail: sankansah.pharm@knust.edu.gh be reduced by regular monitoring, and regulation of A. Akonnor  pesticide residue levels in herbal medicinal products. e-mail: abakonnor@yahoo.com S. O. Bekoe  Keywords Monitoring · Risk assessment · Gas e-mail: sobekoe.pharm@knust.edu.gh chromatography coupled to mass spectrometry · Pesticide residues · Herbal medicinal products P. Osei-Fosu  Food and Agricultural Department, Ghana Standards Authority, Box MB 245, Accra, Ghana e-mail: paul.fosu@gsa.gov.gh Introduction A. N. O. Dodoo  Ghana Standards Authority, Box MB 245, Accra, Ghana The usage of herbal medicines has increased tremen- e-mail: alex.dodoo@gsa.gov.gh dously in recent years in many parts of the world Vol.:(0123456789) 1 4 70 Page 2 of 14 Environ Monit Assess (2021) 193: 470 including the USA where 20% of the population been reported (Asante et  al., 2009)  as a concern. Thus, patronizes herbal medicinal products (HMPs) for some the study has revealed that most farmers and other agro- of their primary health care needs (Bent, 2008). Simi- chemical users in Ghana normally do not have adequate/ larly, the primary healthcare needs of most people in appropriate knowledge, skill, training, and equipment for underdeveloped nations are dependent upon herbal the proper use of these chemical substances. The conse- medicines (Bodeker et  al., 2005; Ekor, 2014; Ziarati, quence is that targeted application and disposal of these 2012). There has been increased patronage of HMPs agrochemicals are usually poorly done, leading to diverse over the past two decades due to attempts to incor- distribution and accumulation  of residual pesticides in porate  herbal medicine into the healthcare system of soil, water, and plants, and ultimately triggering deleteri- some countries (Ekor, 2014; Foster et  al., 2000), and ous environmental and public health effects after long the case of Ghana is not different. As of 2010, the total usage. estimated market value of crude herbal medicines sold Some chronic diseases are due to the effects of on the Ghanaian market was US$ 7.8 million (van pesticides (Tago et al., 2014), as a result of: (i) direct Andel et  al., 2012). This might have tremendously exposure to farmers, (ii) indirect exposure to mem- increased over the last decade because of the observed bers of a farming community, and (iii) consumption proliferation  of herbal medicines manufacturing, and of pesticide residues in food, water, fish, and herbal high patronage of HMPs on the Ghanaian market. preparations (Gold et  al., 2001; W. J. Ntow et  al., Unfortunately, direct  information on the current mar- 2008b; W. J. Ntow et al., 2009). Also, some pesticides ket value of sold herbal medicines is either  scanty or are retained in fruits (Donkor et al., 2015), vegetables unavailable. Lots of people patronize herbal medi- (Armah, 2011; Botwe et  al., 2011; Essumang et  al., cines because they are relatively cheaper, culturally 2008; Lozowicka et al., 2015), water bodies (William acceptable, and perceived to have no or minimal side Joseph Ntow, 2005; W. J. Ntow et  al., 2008a), and effects. As a result of the observed high usage of herbal medicinal plants (Agbeve et  al., 2014; Malinowska medicines by the Ghanaian populace for the treatment et al., 2015) since they are retained for a longer period or management of infectious or chronic diseases as in the environment (Fosu-Mensah et al., 2016). the case may be, it becomes necessary for the qual- HMPs are herbal preparations made from herb(s) ity of herbal medicines on the Ghanaian market to be and may include excipients (WHO, 2011), which are assured. One of the important quality requirements for used for the treatment of various ailments and other herbal medicines is controlling contaminants such as human diseases (Alamgir, 2017). HMPs are prepared pesticide residues (WHO, 2007) to avoid or minimize using herbal plants and/or their parts such as the potential toxic effects of these residual contaminants gum, roots, leaves, and bark (Alamgir, 2017), which in patients through possible bioaccumulation. Unfor- are usually collected from the wild and/or farmlands tunately, such  studies needed to provide relevant data because the development of herbal farms is still at the to  inform public health policies of  governments, and infant stage in Ghana. However, HMP manufacturers regulatory measures on herbal medicines are unfortu- may lack information on the application or inadvert- nately scarce in the Ghanaian scientific literature. ent distribution of agrochemicals in such farmlands. Ghana’s economy depends heavily on agriculture Additionally, the collection of herbal plants and their (WBG, 2018). As a result of this, various agrochemicals parts as starting material for the production of HMPs such as fertilizers and pesticides (herbicides, fungicides, is usually shrouded in secrecy and does not follow nematocides, insecticides, ascaricides, molluscicides, and any good manufacturing practices (GMP) and/or rodenticides) have been used by farmers, sometimes indis- good agricultural practices for any potentially use- criminately, for improved agricultural yield (Britt, 2000; ful intervention regarding agrochemical usage to Yeboah, 2014). Pesticides are predominantly applied be  deployed. As a result, the starting material may to various farms in Ghana (Britt, 2000; Yeboah, 2014). be adulterated with pesticides, and their monitoring Additionally, pesticides are heavily used in malaria- in HMPs has become necessary in Ghana because endemic areas for vector control, which has significantly of  the increased current prevalence of use estimated reduced the number of deaths resulting from malaria to be ~ 76.5% (Kretchy et al., 2021). (Ae-Ngibise et  al., 2015). However, the indiscrimi- Although work has been done on the levels of pesti- nate and inappropriate use of these agrochemicals has cide residues in some medicinal plants (raw materials) 1 3 Environ Monit Assess (2021) 193: 470 Page 3 of 14 470 used in traditional medicine in Ghana (Agbeve et al., Materials and methods 2014), data on the pesticide adulteration of HMPs in Ghana is limited. For instance, only one study has Sampling of HMPs documented the monitoring of 33 pesticide residues in 6 HMPs in Ghana (Adusei-Mensah et  al., 2018). HMPs are patronized for the treatment of diverse However, it has been recommended that the actual disease conditions in Ghana, but predominantly for quantity of pesticide residues should be determined in malaria, piles, dysmenorrhea, female infertility, and the final herbal dosage form to ensure that the levels male sexual weakness. As a result, HMPs that are of potential residual pesticide contaminants are within used for the treatment  or management of the listed recommended limits (WHO, 2007), using appropriate disease conditions  were selected. Thirty (30) HMPs analytical procedures. (consisting of 6 products for  each of the stated dis- Since biological materials such as HMPs nor- ease conditions) were purchased from official medi- mally have a low abundance of pesticides as  con- cine outlets and herbal shops located in two major cit- taminant, analysis of pesticide residues is usually ies in Ghana, i.e. Kumasi and Accra (Table  1). The achieved by isolating the pesticides from the matrix HMPs were either locally manufactured or imported followed by quantitation with an appropriate ana- with different dosage forms (capsules, liquids, and lytical method (Fenik et  al., 2011). Isolation and powder). The HMPs were selected based on (i) regis- enrichment of the target pesticides for analyses  are tration of the product by the Food and Drugs Author- usually  achieved with solid–liquid extraction, ity (FDA) Ghana, (ii) availability of the HMPs in the QuEChERS  (quick, easy, cheap, effective, rugged, market at the time of the study, and (iii) the shelf-life and safe), solid-phase extraction, and gel permeation of the HMPs at the time of sampling. The HMPs chromatography (Anastassiades et al., 2003; Barker were kept at the manufacturer’s recommended storage et  al., 1989; Beyer et  al., 2008; Carabias-Martinez conditions. et al., 2006; Herrero et al., 2010; Lehotay, 1997; Van der Lee et  al., 2008; Wei‐Guo Zhang et  al., 2006). Certified standards Chromatographic methods with detectors such as mass spectrometry, electrochemical and diode array Certified pesticide reference standards including (Jinno et  al., 1996; Martinez et  al., 1996; Zanella methamidophos, ethoprophos, dimethoate, HCH et al., 2012), antibody-related assays (Giraudi et al., beta, fonofos, diazinon, HCH gamma, heptachlor, 1999; Qian et  al., 2009; Hongyan Zhang et  al., pirimiphos methyl, fenitrothion, malathion, aldrin, 2011), and gas and liquid chromatography coupled chlorpyrifos, parathion ethyl, chlorfenvinphos, to mass spectrometry (Zanella et al., 2012) are nor- chlordane cis, endosulfan alpha, profenofos, p,p’- mally used to determine the pesticides. However, DDE, dieldrin, endrin, endosulfan beta, p,p’-DDD, chromatography with tandem mass spectrometry is endosulfan sulphate, p,p’-DDT, bifenthrin, meth- frequently used to determine pesticides in complex oxychlor, fenpropathrin, cyhalothrin lambda, per- matrices as a result of high sensitivity and selectiv- methrin cis, permethrin trans, cyfluthrin I, cyfluthrin ity (Cesio et al., 2011; Zanella et al., 2012). II, cyfluthrin III, cyfluthrin IV, cypermethrin I, Therefore, the current study sought to utilize the cypermethrin II, cypermethrin III, cypermethrin IV, GC–MS/MS technique to profile the  levels of pes- fenvalerate I, fenvalerate II, and deltamethrin were ticide residues in some HMPs in Ghana and further obtained from Dr. Ehrenstorfer GmbH, Augsburg, assess the risk of the identified residues on frequent/ Germany. Each certified pesticide standard stock long-term use of the selected HMPs by patients. For solution (1000  µg/mL) was prepared in ethyl ace- this purpose, 30 HMPs were obtained from the Gha- tate and stored at − 20 °C (Zainudin et al., 2017). A naian market and analysed to determine 42 pesticide multi-component certified pesticide working stand- residues, and the corresponding risk assessment. The ard solution (100 µg/mL) for the standard curve was findings may provide a benchmark for improving the prepared by dilution of the individual stock solutions regulation of HMPs in Ghana in order to prevent any with ethyl acetate and stored at − 20 °C (Wu, 2017; potential public health emergency. Zainudin et al., 2017). 1 3 4 70 Page 4 of 14 Environ Monit Assess (2021) 193: 470 Table 1 Description of Product code Indication Dosage form Dosage herbal medicinal products P1 Antimalarials Liquid Adult: 30 mL, 3 times daily Children: 15 mL, 3 times daily P2 Antimalarials Liquid 60 mL, 3 times daily P3 Antimalarials Liquid Adult: 75 mL, 2 times daily [Treatment] Adult: 15–30 mL, 3 times daily [Prophylaxis] P4 Antimalarials Liquid Adult: 30 mL, 2 times daily P5 Antimalarials Liquid Adults: 30 mL, 3 times daily Children: 15 mL, 3 times daily P6 Antimalarials Liquid Adults: 30 mL, 3 times daily for 3 wk Children: 20 mL, 2 times daily for 3 wk P7 Antimalarials Liquid Adult: 30 mL, 3 times daily Children: 15 mL, 3 times daily P8 Piles/Constipation Capsule Adult: 2 capsules, 2 times daily once every 3 d P9 Piles/Constipation Capsule Adult: 2 capsules, 2 times daily P10 Piles/Constipation Capsule Adult: 2 capsules, 2 times daily P11 Piles/Constipation Liquid Not indicated P12 Piles/Constipation Capsule Adult: 1 capsule daily and repeat after 6 d P13 Piles/Constipation Liquid Not indicated P14 Aphrodisiacs Capsule Adult: 2 capsules, 2 times daily P15 Aphrodisiacs Capsule Adult: 2 capsules, 2 times daily P16 Aphrodisiacs Capsule Adult: 2 capsules, 2 times daily P17 Aphrodisiacs Capsule Adult: 2 capsules, 2 times daily P18 Aphrodisiacs Capsule Adult: 2 capsules, 2 times daily P19 Aphrodisiacs Capsule Adult: 2 capsules, 2 times daily P20 Female Fertility Liquid Not indicated P21 Female Fertility Liquid Adult: 60 mL, 2 times daily P22 Female Fertility Liquid Adult: 30 mL, 3 times daily P23 Female Fertility Powder Adult: 10 mL of powder mix with either por- ridge, soup, or water, 2 times daily P24 Dysmenorrhea Liquid Adult: 90 mL, 3 times daily for 3 wk P25 Dysmenorrhea Liquid Adult: 45 mL, 3 times daily for 7 d Children: 30 mL, 3 times daily for 7 d P26 Dysmenorrhea Liquid Not indicated P27 Dysmenorrhea Capsule Adult: 3 capsules, 2 times daily P28 Dysmenorrhea Capsule Adult: 4 capsules on day 1, 4 capsules on day 2, 2 capsules on day 3 P29 Dysmenorrhea Liquid Adult: 45 mL, 3 times daily for 7 d Children: 30 mL, 3 times daily for 7 d P30 Dysmenorrhea Liquid Adult: 40 mL, 2 times daily Children: 20 mL, 2 times daily Chemicals, reagents, and other materials Scientific USA), disodium hydrogen citrate sesquihy- drate (Thermo Scientific USA), ethyl acetate (BDH Acetonitrile (BDH Laboratory Supplies, England), Laboratory Supplies, England), formic acid (Sigma magnesium sulphate anhydrous (Park Scientific Lim- Aldrich, UK), polypropylene (PP) centrifugation tube ited, UK), sodium chloride (BDH Laboratory Sup- (Fisherbrand, USA), primary secondary amine (PSA) plies, England), trisodium citrate dihydrate (Thermo (Agilent, USA). 1 3 Environ Monit Assess (2021) 193: 470 Page 5 of 14 470 Extraction and clean-up diameter, 0.25 mm; VF-5 ms coating, 0.25 µm) (Agi- lent Technologies, California, USA). The following Sample extraction and purification were performed as chromatographic conditions were used for the meas- previously described (Anastassiades et al., 2003) with urement (Wu, 2017): carrier gas, helium (99.999%) modification (Blankson et  al., 2016) for pesticide with a constant flow of 1.3 mL/min; injector, splitless analysis in Ghana. An amount of each homogenous mode; injection volume, 2 µL; column temperature, HMP sample (~ 5 g for solid/powders; ~ 10 g for liq- the column temperature was maintained at 70 °C for uids) was quantitatively transferred into a 50 mL cen- 2 min, raised at a rate of 25 °C/min to 150 °C, then trifuge tube (Irungu et al., 2016). Ten millilitres each raised at a rate of 3 °C/min to 200 °C, further raised at of distilled water and acetonitrile were added and vor- a rate 8 °C/min to 280 °C, and maintained at 280 °C texed for 1 min (Chamgenzi et al., 2020; Özcan et al., for 10  min; injection port temperature, 250  °C; and 2019). Thereafter, 4  g magnesium sulphate anhy- run time, 41.87 min. The optimized MS/MS method drous, 1 g sodium chloride, 1 g trisodium citrate dihy- parameters for the measurements were source tem- drate, and 0.5  g disodium hydrogen citrate sesqui- perature, 300  °C; transfer line temperature, 300  °C; hydrate were added as previously described (Özcan solvent delay, 4.0 min; quadrupole (Q1 and Q2) tem- et al., 2019) to form a liquid–liquid partition, which perature, 150 °C; MS spectra and collision energy for was immediately vortexed for 1 min and centrifuged product ion scans, 5–55 eV. Two MS/MS transitions at 3000  rpm for 5  min (Akomea-Frempong et  al., per pesticide were generated by operating the triple 2017). For clean-up, dispersive solid-phase extraction quadrupole in multiple reaction monitoring (MRM) was used. A total of 150 mg PSA and 900 mg mag- mode (Cajka et al., 2012) (Table 2). MassHunter soft- nesium sulphate were weighed into PP centrifugation ware version B.07.00 (Agilent Technologies, Califor- tube and 6 mL of the supernatant was transferred into nia, USA) was employed for instrument control and it (Chamgenzi et  al., 2020) and then shaken vigor- data acquisition/processing. ously for 30 s and centrifuged at 3000 rpm for 5 min (Kadir et al., 2017). After extract clean-up, 4 mL was Quality assurance and quality control transferred into a round bottom flask and the pH was quickly adjusted to ~ 5 with 40 µL of 5% formic acid All pesticide residue analyses were performed at the solution in acetonitrile (v/v) (Akoto et  al., 2015). It Pesticide Residues Laboratory, Ghana Standards was then concentrated below 40 °C on a rotary evapo- Authority. The Laboratory is an ISO/IEC 17,025: rator just to dryness and re-dissolved with 1 mL ethyl 2017 accredited laboratory for pesticide residue in acetate (Quee et  al., 2016). A rotary evaporator was fruits, vegetables, and cereals. Accurate and reliable used to further concentrate the solution below 40 °C data established would inform the basis for routine to almost dryness and solubilized with 1  mL ethyl monitoring of adulterants or contaminants in HMPs acetate (Akoto et al., 2015). Finally, GC/MS measure- in Ghana. A lack of quality control checks may mean ment was performed with 2 mL extract in a GC vial that results obtained may not represent the factual sit- (Blankson et al., 2016). uation required to help inform policy. For routine monitoring as well as investigative GC/MS/MS conditions for the determination of studies such as being reported, the application of sen- pesticide residues sitive, precise, accurate, and reliable analytical tech- niques such as GC–MS used in this study is normally The pesticide residues were determined as previously recommended. The periodic verification and estab- described using a gas chromatograph Agilent 7890C lishment of certain key parameters needed to guaran- GC (Agilent Technologies, California, USA) with a tee system suitability and validity of obtained data are triple quadrupole mass spectrometer Agilent 7000C thus required, especially in such situations where very MS (Agilent Technologies, California, USA) using low levels of analytes of interests are involved. Regu- electron impact ionization mode at 70  eV (Cajka lar monitoring of quality control samples (involving et al., 2012). The samples were loaded via GC autosa- certified reference standards) was employed. Parame- mpler 80 (Agilent Technologies, California, USA) ters such as peak area and retention time of the stand- onto a fused silica column (length, 30  m; internal ards, sensitivity, recovery of standards, and selectivity 1 3 4 70 Page 6 of 14 Environ Monit Assess (2021) 193: 470 Table 2 GC/MS/MS MRM acquisition parameters Pesticides Retention time MRM transition (m/z) Collision MRM transition (m/z) Collision (min) energy (eV) energy (eV) Methamidophos 5.88 141.0 > 95.0 5 141.0 > 64.0 10 Ethoprophos 11.42 158.0 > 97.1 15 158.0 > 114.0 5 Dimethoate 13.69 229.0 > 87.0 40 125.0 > 78.9 15 HCH beta 14.64 181.0 > 145.0 15 181.0 > 109.0 30 Fonofos 14.87 137.0 > 109.0 5 246.0 > 109.1 15 Diazinon 14.99 179.2 > 179.2 5 137.0 > 109.0 15 HCH gamma 16.53 218.8 > 183.0 15 181.0 > 109.0 30 Heptachlor 18.04 271.9 > 116.9 40 271.9 > 236.8 25 Pirimiphos methyl 19.05 305.0 > 290.0 10 305.0 > 276.0 15 Fenitrothion 19.29 277.0 > 260.0 5 277.0 > 109.0 20 Malathion 19.75 173.0 > 99.0 15 173.0 > 117.1 10 Aldrin 19.94 263.0 > 193.0 40 263.0 > 191.0 40 Chlorpyrifos 20.06 313.8 > 258.0 15 314.0 > 286.0 40 Parathion ethyl 20.60 291.0 > 109.0 10 291.0 > 81.0 40 Chlorfenvinphos 22.58 267.0 > 159.0 20 267.0 > 81.0 40 Chlordane cis 23.52 375.0 > 268.0 20 375.0 > 266.0 25 Endosulfan alpha 24.05 241.0 > 206.0 15 238.8 > 204.0 15 Profenofos 25.01 339.0 > 188.0 30 337.0 > 267.0 15 p,p’-DDE 25.16 246.0 > 176.0 40 248.0 > 176.0 20 Dieldrin 25.21 262.8 > 193.0 40 262.8 > 191.0 35 Endrin 26.03 263.0 > 193.0 35 263.0 > 191.0 55 Endosulfan beta 26.55 241.0 > 206.0 15 229.0 > 194.0 10 p,p’-DDD 26.83 235.0 > 199.0 20 235.0 > 200.0 25 Endosulfan sulphate 27.90 387.0 > 253.0 25 387.0 > 217.0 20 p,p’-DDT 28.03 235.0 > 165.1 30 235.0 > 199.1 20 Bifenthrin 29.43 181.0 > 165.0 30 181.0 > 166.0 15 Methoxychlor 29.75 227.0 > 169.0 30 227.0 > 212.0 10 Fenpropathrin 29.78 181.1 > 152.1 30 265.0 > 89.0 40 Cyhalothrin lambda 30.97 181.1 > 152.1 25 197.1 > 161.0 20 Permethrin cis 32.16 183.1 > 153.1 15 183.1 > 115.2 25 Permethrin trans 32.36 183.1 > 153.1 15 183.1 > 168.1 10 Cyfluthrin I 33.32 163.0 > 127.0 5 206.0 > 151.0 15 Cyfluthrin II 33.41 163.0 > 127.0 5 206.0 > 151.0 15 Cyfluthrin III 33.42 163.0 > 127.0 5 206.0 > 151.0 15 Cyfluthrin IV 33.43 163.0 > 127.0 5 206.0 > 151.0 15 Cypermethrin I 33.62 181.1 > 152.1 25 162.9 > 127.1 5 Cypermethrin II 33.83 181.1 > 152.1 25 162.9 > 127.1 5 Cypermethrin III 33.92 181.1 > 152.1 25 162.9 > 127.1 5 Cypermethrin IV 34.01 181.1 > 152.1 25 162.9 > 127.1 5 Fenvalerate I 35.49 167.1 > 89.1 40 167.1 > 125.0 15 Fenvalerate II 35.98 167.1 > 89.1 35 167.1 > 125.0 10 Deltamethrin 37.46 253.0 > 174.0 25 253.0 > 172.0 25 1 3 Environ Monit Assess (2021) 193: 470 Page 7 of 14 470 were regularly monitored to ensure the validity and risks. As a result, when the NESTI value is lower reliability of data. than the ARfD value, there is no potential health Consequently, certain key measures were estab- risk (Lozowicka et al., 2015). Conversely, the risk is lished to evaluate and guarantee the reliability of considered unacceptable when the NESTI value is the data obtained. These included key steps from greater than the ARfD value (Lozowicka et al., 2015). sampling through to extraction of samples and final NESTI values were calculated multiplying the ‘Larg- instrumental analyses. Quality assurance concerns est Portion (LP)’ of HMP consumption by the ‘High- regarding sampling (including homogeneity of sam- est Residue (HR)’ detected in the HMPs and dividing ples and stability of samples and storage) were ade- by the average body weight (60 kg) (WHO, 2008). LP quately ensured to avoid losses, transformation/deg- was determined as the ratio of the daily consumption radation of analytes of interest, and contamination. (daily dose) to the number of days of consumption. Regular tuning of the MS together with the calibra- The daily dose was obtained from the label claim of tion of the mass axis (intensities of peak) was ensured the products (Table 1). On average, the HMPs could at least twice every week. The mentioned procedures be used from 1 to 12 months. Thus, the LP was cal- were rigorously assured with the use and analyses of culated using the worst-case scenario of 12  month perfluorotributylamine at the required concentrations (360 days) consumption period. as per instrument specifications. Parameters such as For long-term health risk assessment, the chronic the resolution of peaks, consistency of retention times hazard quotient ( HQc) was determined as the quotient of analytes of interests, symmetrical nature of peaks of ‘Estimated Daily Intake (EDI)’ to the ‘Acceptable obtained, and instrumental sensitivities were regu- Daily Intake (ADI)’ of HMPs consumption (Yu et al., larly monitored with control charts established by 2016). ADI values were obtained from ‘Pesticide res- the Ghana Standards Authority as per international idues in food—Report 2019’ developed at the Joint protocols. FAO/WHO Meeting on Pesticide Residues (FAO/ WHO, 2020). HQc values less than unity do not pose Data analysis any long-term health risk to patients, while values greater than unity are deemed an unacceptable health Data were subjected to analysis using MS-Excel. risk. As a result, when the EDI value is lower than the Descriptive statistics utilized included mean, range, ADI value, the health risk is considered acceptable. minimum, maximum, and relative standard deviation. On the other hand, the risk is considered unaccepta- ble when the EDI value is greater than the ADI value. HMPs intake health risk assessment EDI values were calculated by multiplying the mean pesticide level detected in HMPs by the consumption The Pesticide Residue Intake Model ‘PRIMo’ revi- of the HMPs and dividing by the average body weight sion 3 (European Food Safety Authority-EFSA) (60 kg) (WHO, 2008). (EFSA, 2018) was used for the estimation of short- term (acute) and long-term (chronic) HMP patient exposure to pesticide residues (Lozowicka et  al., Results and discussion 2015). Short-term health risk assessment was estimated GC/MS/MS method performance characteristics using the acute hazard quotient ( HQa), which was calculated as a percentage ratio of the ‘National Esti- The total ion chromatogram of the standard mix- mated Short-term Intake (NESTI)’ of HMPs to the ture showed a chromatographic peak of 42 pesti- ‘Acute Reference Dose (ARfD) of HMPs (Xiao et al., cides (Fig.  1A). The pesticide standards were also 2019). ARfD values were obtained from ‘Pesticide well resolved when spiked into HMP which does residues in food—Report 2019’ developed at the Joint not contain any of the 42 pesticide residues under FAO/WHO Meeting on Pesticide Residues (FAO/ investigation (Fig.  1B–C). The performance criteria WHO, 2020). HQa values less than unity do not pose of the validated GC/MS/MS method such as calibra- any short-term health risk to patients, while values tion range, correlation coefficient ( r2), recovery, and greater than unity are deemed unacceptable health relative standard deviation (RSD) for the pesticide 1 3 4 70 Page 8 of 14 Environ Monit Assess (2021) 193: 470 Fig. 1 Total ion chromato- gram. A Standard pesticide mixture. B HMP sample P2 without any pesticide resi- due contamination. C HMP sample P2 spiked with the standard pesticide mixture. D HMP P17 sample con- taminated with bifenthrin 1 3 Environ Monit Assess (2021) 193: 470 Page 9 of 14 470 Table 3 GC/MS/MS Pesticides Calibration LOD (µg/kg) LOQ (µg/kg) R2 Recovery (%) RSD method performance range (µg/L) parameters Methamidophos 5.0 to 500 1 2 0.9994 97.0 2.0 Ethoprophos 5.0 to 500 1 2 0.9956 76.0 1.6 Dimethoate 5.0 to 500 1 2 0.9938 99.3 3.1 HCH beta 1.0 to 100 1 2 0.9923 93.0 6.8 Fonofos 5.0 to 500 1 2 0.9972 82.3 3.7 Diazinon 5.0 to 500 1 2 0.9958 92.0 8.7 HCH gamma 1.0 to 100 1 2 0.9966 84.0 4.8 Heptachlor 1.0 to 100 1 2 0.9961 95.7 7.7 Pirimiphos methyl 5.0 to 500 1 2 0.9937 80.7 3.8 Fenitrothion 5.0 to 500 1 2 0.9989 77.3 6.5 Malathion 5.0 to 500 1 2 0.9947 94.7 3.2 Aldrin 1.0 to 100 1 2 0.9974 81.3 9.9 Chlorpyrifos 5.0 to 500 1 2 0.9992 86.7 3.5 Parathion ethyl 5.0 to 500 1 2 0.9963 96.3 1.6 Chlorfenvinphos 5.0 to 500 1 2 0.9965 91.7 1.7 Chlordane cis 1.0 to 100 1 2 0.9975 95.7 2.5 Endosulfan alpha 1.0 to 100 1 2 0.9982 84.0 3.1 Profenofos 5.0 to 500 1 2 0.9991 89.0 3.4 p,p’-DDE 1.0 to 100 1 2 0.9977 95.3 1.6 Dieldrin 1.0 to 100 1 2 0.9984 96.0 3.8 Endrin 1.0 to 100 1 2 0.9948 92.7 2.6 Endosulfan beta 1.0 to 100 1 2 0.9929 95.0 2.1 p,p’-DDD 1.0 to 100 1 2 0.9958 92.7 3.8 Endosulfan Sulphate 1.0 to 100 1 2 0.9967 77.3 6.5 p,p’-DDT 1.0 to 100 1 2 0.9997 86.7 3.5 Bifenthrin 2.0 to 200 1 2 0.9992 94.7 3.2 Methoxychlor 1.0 to 100 1 2 0.9949 81.3 9.9 Fenpropathrin 2.0 to 200 1 2 0.9968 96.3 1.6 Cyhalothrin lambda 2.0 to 200 1 2 0.9971 71.7 10.7 Permethrin cis 2.0 to 200 1 2 0.9983 81.7 7.5 Permethrin trans 2.0 to 200 1 2 0.9990 84.0 3.1 Cyfluthrin I 2.0 to 200 1 2 0.9963 89.0 7.4 Cyfluthrin II 2.0 to 200 1 2 0.9958 95.3 1.6 Cyfluthrin III 2.0 to 200 1 2 0.9970 96.0 3.8 Cyfluthrin IV 2.0 to 200 1 2 0.9964 92.7 6.6 Cypermethrin I 2.0 to 200 1 2 0.9953 95.0 2.1 Cypermethrin II 2.0 to 200 1 2 0.9991 92.7 1.6 Cypermethrin III 2.0 to 200 1 2 0.9981 89.7 3.6 Cypermethrin IV 2.0 to 200 1 2 0.9949 78.0 4.7 Fenvalerate I 2.0 to 200 1 2 0.9959 85.7 8.6 Fenvalerate II 2.0 to 200 1 2 0.9976 78.0 3.8 Deltamethrin 2.0 to 200 1 2 0.9943 93.3 2.2 1 3 4 70 Page 10 of 14 Environ Monit Assess (2021) 193: 470 analysis were determined at the limit of quantifica- Table 4 Pesticide residues detected in herbal medicinal prod- tion (LOQ). Linearity for each pesticide residue was ucts measured using a calibration range of 1–100  µg/L Products Pesticides Concentra- EU-MRL Comment or 2–200  µg/L or 5–500  µg/L achieving a correla- tion (µg/kg) (mg/kg) tion coefficient in the range of 0.9923 and 0.9997 P15 Bifenthrin 2.5 0.10 < MRL (Table 3). P17 Bifenthrin 5.0 0.10 < MRL The percentage recovery (accuracy) of the method P23 Chlorpyrifos 5.0 0.05 < MRL was between 71.7 and 99.3% (Table 3) and is within P27 Chlorpyrifos 5.0 0.05 < MRL the specifications of European Council pesticide Bifenthrin 5.0 0.10 < MRL residue analysis in food (Blankson et  al., 2016; EC, 2006). The percentage recoveries were also similar to previous studies (Li et  al., 2017; Oh, 2009). The precision (repeatability) of the analytical method was (Xiao et al., 2019), and HMPs in Ghana (Adusei-Men- determined using triplicate spiked samples of the sah et al., 2018), while bifenthrin has been detected in pesticide residues and expressed as relative standard Lonicera japonica Thunb (Chinese herbal medicine) deviation, which ranged from 1.6 to 10.7% (Table 3). (Li et  al., 2017). Chlorpyrifos and bifenthrin have The limit of detection (LOD) and LOQ were 1  µg/ been found in vegetable samples in Ghana (Blankson kg and 2 µg/kg, respectively, for each of the pesticide et  al., 2016) and tea samples in China (Feng et  al., residues (Table  3) demonstrating good sensitivity. 2015). Since herbs used for the preparation of HMPs The determined LOD and LOQ values are lower than in Ghana are normally harvested indiscriminately their corresponding maximum residue limit (MRL) from uncontrolled environmental conditions, it is not values (EC, 2005). The above-mentioned perfor- surprising that pesticide residues previously detected mance parameters of the method show that it is fit for in vegetables in Ghana are found as contaminants in its purpose. HMPs. The levels of pesticide residue contaminants ranged between 2.5 and 5.0  µg/kg; however, none of Pesticide residue levels in HMPs the pesticide residues detected in the HMPs exceeded the MRL. This finding is thus consistent with previous The analytical method was applied to the detection studies (Adusei-Mensah et al., 2018; Feng et al., 2015). and quantification of 42 pesticide residues from 30 On the other hand, tea from China normally contains HMPs. In all, 4/30 HMPs were adulterated with pes- high amounts of bifenthrin (Fang et al., 2015; Kuang ticide residues. Pesticide residues that were detected et al., 2010). The low levels of pesticide residues deter- in the HMPs were chlorpyrifos (organophosphorus) mined in the HMPs could be due to the nature of the and bifenthrin (synthetic pyrethroid). Generally, 3/30 solvent (aqueous)  used for the preparations, the vol- HMPs (P15, P17, P23) were contaminated with one ume of solvent (influencing amount per unit volume of pesticide residue, while 1/30 (P27) was contaminated decoction), and heating  temperature and the duration with both pesticide residues (Table  4). Figure  1D of heating (Zuin et al., 2000). shows the detection of bifenthrin from HMP P17. The insecticides applied to farmlands are normally Risk assessment of HMP intake pyrethroids (~ 41%) and organophosphates (~ 37%) (Blankson et  al., 2016; W. J. Ntow, 2001). Conse- The degree of risk to humans due to the consumption quently, starting materials for the manufacture of the of HMPs contaminated with the detected pesticide HMPs from such sources may be contaminated with residues was estimated using exposure analysis. The residues of the afore-mentioned insecticides. There- acute and chronic risk assessment was monitored by fore, the detection of chlorpyrifos and bifenthrin in using ARfD and ADI, respectively. The acute hazard some of the HMPs is not surprising. Chlorpyrifos has quotients ( HQa) in the pesticide residues in HMPs been detected in herbs growing in Poland (Malinowska P15, P17, P23, and P27 were 0.30%, 0.43%, 0.21%, et  al., 2015), Traditional Chinese Medicine in China and 0.92% respectively (Table 5). 1 3 Environ Monit Assess (2021) 193: 470 Page 11 of 14 470 Table 5 Health risk assessment of pesticide residues in herbal medicinal products Short-term (acute) risk assessment Pesticides ARfDa P15 P17 P23 P27 (mg/kg) NESTI HQa (%) NESTI HQa (%) NESTI HQa (%) NESTI HQa (%) (mg/kg bw/ (mg/kg bw/ (mg/kg bw/ (mg/kg bw/ day) day) day) day) Chlorpyri- 0. 1 - - - - 2.12 × 0.21 8.33 × 0.08 fosb 1 0−4 10−5 Bifenthrinb 0.01 2.96 × 10−5 0.30 4.31 × 10−5 0.43 - - 8.33 × 0.83 1 0−5 Total 2.96 × 10−5 0.30 4.31 × 10−5 0.43 2.12 × 0.21 1.67 × 0.92 10−4 10−4 Long-term (chronic) risk assessment Pesticides ADIa (mg/ P15 P17 P23 P27 kg) EDI (mg/ HQc (%) EDI (mg/ HQc (%) EDI (mg/ HQc (%) EDI (mg/ HQc (%) kg bw/ kg bw/ kg bw/ kg bw/ day) day) day) day) Chlorpyri- 0.01 - - - - 5.88 × 5.88 × 2.31 × 2.31 × 1 0−3 fos 10−7 10−3 1 0−7 Bifenthrin 0.01 8.21 × 10−8 8.21 × 1 0−4 1.20 × 10−7 1.20 × 10−3 - - 2.31 × 2.31 × 1 0−3 10−7 Total 8.21 × 1 0−8 8.21 × 10−4 1.20 × 10−7 1.20 × 10−3 5.88 × 5.88 × 4.63 × 4.63 × 10−3 10−7 10−3 1 0−7 a ARfD and ADI values were obtained from ‘Pesticide residues in food—Report 2019’ developed at the Joint FAO/WHO Meeting on Pesticide Residues b Acute risk assessment calculated using 360 day consumption of HMPs The findings show no potential short-term health measures  may include the following: (i) avoidance risk to pesticide residues exposure from consumption of  long-term use of HMPs, (ii) routine post-market of the selected  HMPs, which is in agreement  with analysis of HMPs for pesticide residues, (iii) develop- other studies involving the detection of chlorpyri- ment of herbal farms as a source of starting materials fos and/or bifenthrin (Adusei-Mensah et  al., 2018; for HMPs production, (iv) testing of starting mate- Fang et  al., 2015; Feng et  al., 2015; Li et  al., 2017; rials (herbs, plant parts, etc.) for pesticide residues Osman et  al., 2011; Xiao et  al., 2019). The chronic prior to their use for the production of HMPs, and (v) hazard quotients ( HQc) in the pesticide residues in training of HMP manufacturers on GMP. HMPs P15, P17, P23, and P27 were 8.21 × 10−4%, 1.20 × 10−3%, 5.88 × 1 0−3%, and 4.63 × 10−3%, respectively (Table 5). These values imply that there is no long-term health risk associated with pesticide Conclusions residue exposure from the use of the selected HMPs. These findings also corroborate with other reports From this study, 4/30 HMPs were contaminated with where chlorpyrifos and/or bifenthrin were detected chlorpyrifos and/or bifenthrin pesticide residues; how- in herbal medicine materials  (Adusei-Mensah et  al., ever, the pesticide residue levels were below their 2018; Fang et  al., 2015; Feng et  al., 2015; Li et  al., MRL values and have no significant short- and long- 2017; Osman et  al., 2011; Xiao et  al., 2019). This term HMP intake health risk. Regular monitoring and notwithstanding, appropriate risk management con- stringent regulation of adulterants in HMPs are needed trol system to reduce the exposure of pesticides as a result of public health risk associated with accu- to consumers of HMPs should be instituted. Such mulation of residual contaminants in patients. 1 3 4 70 Page 12 of 14 Environ Monit Assess (2021) 193: 470 Author contribution Conceptualization: K.F.M.O. and Armah, F. A. (2011). Assessment of pesticide residues in veg- S.A.N.; Methodology: K.F.M.O., P.O.F., and S.A.N.; Soft- etables at the farm gate: Cabbage (Brassica oleracea) ware: P.O.F.; Validation: K.F.M.O., S.A.N., P.O.F., S.O.B., cultivation in Cape Coast, Ghana. Research Journal of and A.N.O.D.; Formal analysis: P.O.F., A.A., and S.O.B.; Environmental Toxicology, 5, 180–202. https:// doi. org/ 10. Investigation: P.O.F. and A.A.; Resources: K.F.M.O., P.O.F., 3923/r jet. 2011. 180. 202 S.A.N., and A.N.O.D.; Data curation: P.O.F. and A.A.; Writing Asante, K. A., & Ntow, W. J. (2009). Status of environmental — original draft preparation: K.F.M.O., P.O.F., and S.A.N.; contamination in Ghana, the perspective of a research sci- Writing — review and editing: K.F.M.O., S.A.N., P.O.F., entist. Interdisciplinary Studies on Environmental Chemis- A.A., S.O.B., and A.N.O.D.; Supervision: K.F.M.O., S.A.N., try, 2, 253–260. P.O.F., and A.N.O.D.; Project administration: K.F.M.O. All Barker, S. A., Long, A. R., & Short, C. R. (1989). Isolation the authors have read and agreed to the published version of of drug residues from tissues by solid phase dispersion. the manuscript. Journal of Chromatography A, 475, 353–361. https:// doi. org/1 0. 1016/ s0021- 9673(01)8 9689-8 Data availability The datasets generated during and/or ana- Bent, S. (2008). Herbal medicine in the United States: Review lysed during the current study are not publicly available due to of efficacy, safety, and regulation: Grand rounds at Uni- regulatory requirements but are available from the correspond- versity of California, San Francisco Medical Center. Jour- ing author on reasonable request. nal of General Internal Medicine, 23, 854–859. https:// doi.o rg/ 10.1 007/s 11606- 008- 0632-y Declarations Beyer, A., & Biziuk, M. (2008). Applications of sample prepa- ration techniques in the analysis of pesticides and PCBs in food. Food Chemistry, 108, 669–680. https:// doi. org/ 10. Conflict of interest The authors declare no competing inter- 1016/j.f oodch em.2 007.1 1.0 24 ests. Blankson, G., Osei-Fosu, P., Adeendze, E., & Ashie, D. (2016). Contamination levels of organophosphorus and synthetic pyrethroid pesticides in vegetables marketed in Accra, Ghana. Food Control, 68, 174–180. https:// doi. org/ 10. 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