Investigating Molecular Mechanisms of Immunotoxicity and the Utility of ToxCast for Immunotoxicity Screening of Chemicals Added to Food
Abstract
:1. Introduction
2. Materials and Methods
2.1. Data-Mining Strategy for the Identification of Immune-Relevant High-Throughput Assays
2.2. Identification of Case Study Compounds
2.2.1. Direct Food Additives
2.2.2. Indirect Additives: Per- and Polyfluoroalkyl Substances
3. Results
3.1. Identification of Case Study Compounds
3.2. Identification of ToxCast Active Assays
3.3. Identification of Immune-Specific Interactions in the Comparative Toxicogenomics Database
3.4. Analysis of Immune-Related Assays within ToxCast
3.5. Correlation Analysis of ToxCast and Immunological Data for TBHQ
4. Discussion
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Appendix A
Material Tested | Migration Conditions | Detections of PFAS 1 | Findings |
---|---|---|---|
Cookware and food packaging United States, 2005 [91] | PFOA leaching into Miglyol and water was measured from different products, including popcorn bag, hamburger wrapper, sandwich wrapper, French fry box, and paper plates. | PFOA | Paper coatings with fluorotelomers released significantly higher amounts of PFOA than other tested products. The highest concentration of PFOA was released from microwave popcorn bags. |
Fast food wrappers United States, 2008 [92] | PFAS migration measured from three retail fast food wrappers into food and food simulants (Miglyol, butter, water, vinegar, chocolate spread, and water/ethanol solutions (10, 20, 25, and 30% ethanol). Migration tests were run with 100 °C food/food simulant added to paper for 15 min; butter was tested at 4 °C for 40 days. | 3 PFAS species tested 2 | Reported significantly higher migration of PFAS into butter and other oil emulsion mixtures compared with migration into water, vinegar, oils, or alcohol. |
Frying pans United States, 2007 [93] | Pans were heated for 30 min at 250 °C and the headspace gas was tested for a characteristic perfluorinated substance fragment, “-CF2-CF3”. | None reported | Did not detect PFAS compounds in the headspace gas. |
Frying pans, cooking utensils, grill pans, pots, rice cookers, and non-stick baking papers. Korea, 2018 [94] | Analysis of PFAS migration from 312 food contact materials into food simulants, water, and corn oil at varying conditions: 4% acetic acid at 100 °C for 30 min; 50% ethanol and 50% n-heptane at 70 °C for 30 min followed by incubation at 25 °C for 1 h. | PFOA, PFNA, PFDoDA, PFTrDA, PFTeDA, PFHxDA, PFODA | Seven PFAS migrated into food simulants from 10 frying pans and 2 baking utensils. No PFAS migration was observed during subsequent testing and PFAS did not migrate from frying pans into corn oil or water. |
Pet food paper bag 3 Spain, 2019 [95] | Analysis of PFAS migration from paper bag packaging into food simulant (Tenax) and milk at various conditions: 10 days at 40 °C; 2 h at 80 °C, 120 °C and 160 °C | PFBA, PFPeA, PFHxA, PFHpA, PFOA, PFNA, PFDA, PFUnDA, PFDoDA, PFTrDA, PFTeDA | Greater migration was observed into milk than the food simulant, and high migration percentages were observed for long-chain PFAS. Migration rates increased with temperature. |
Muffin paper | Migration of fluorotelomers from muffin containers into butter, muffin dough, and Tenax food simulant measured after exposure to oven temperatures of 120–200 °C for 5 to 60 min. | 6:2 FTOH | The fluorotelomer concentrations were higher in the dough, butter, and Tanex food simulant after heating compared to the original levels in the baking cup paper, indicating the release of fluorotelomers from precursor compounds. |
8:2 FTOH | |||
Germany, 2011 [96] | 10:2 FTOH | ||
Microwave popcorn and foods in paper packaging Sweden, 2013 [97] | PFAS were tested in food samples before and after preparation as directed on the packaging. | 6:2 diPAP, 8:2 diPAP, 10:2 diPAP, PFHxA, PFOA, PFNA, PFDA, PFUnDA, PFTrDA | The PFAS concentrations, notably for polyfluoroalkyl phosphoric acid diesters (diPAP), increased in some packaged foods tested after heating in accordance with the package directions. |
Instant food cups, microwave-popcorn bags, beverage cups, ice cream cups, fast food containers, dessert containers, and baking papers Thailand, 2012 [98] | The leaching of PFOA and PFOS from 34 food packaging products into methanol and saliva simulant at 80 °C during a 30 min period. | PFOA, PFOS | PFOA and PFOS migrated into saliva simulant from the majority of samples, all of which had detectable PFOA or PFOS. The highest migration of PFOA and PFOS was reported for a French-fry box and hot beverage cup. |
Frying pans United States, 2005 [99] | The migration of PFOA from 11 frying pans into water, 10% ethanol, and 95% ethanol was measured after heating to 125 °C. | None reported | No PFOA was detected in any samples. |
Frying pans, sandwich maker, waffle irons Germany, 2015 [100] | Volatilization of 9 PFAS into air was measured under normal use and under overheating scenarios. | PFBA, PFPeA, PFHxA, PFHpA, PFOA, PFNA, PFDA, PFUnDA, PFDoDA | PFAS release increased significantly at overheating temperatures, and all 9 PFAS were detected. PFOA emissions were lower than in prior reports. |
Frying pans and microwave popcorn bags United States, 2007 [101] | The migration of 10 PFAS into air and water was measured from pans heated on a hotplate set to 250 °C and from microwave popcorn after microwave heating for 3 min. | PFPeA, PFHpA, PFOA, PFNA, PFDA, PFUnDA, PFDoDA, 6:2 FTOH, 8:2 FTOH | PFOA was released into the air from frying pans at normal cooking temperatures during consequent uses. One brand of microwave popcorn released much higher levels of PFAS compared to the other two. |
Butter wrappers and dairy processing equipment Germany, 2013 [102] | Concentrations of 9 PFAS were measured in dairy products during processing. Migration of PFAS from butter wrappers was measured after 45 days at 5 °C. | PFBA, PFPeA. PFHxA, PFHpA, PFOA, PFNA, PFDA, PFDoA, 8:2 FTOH, 10:2 FTOH | Greater migration of PFOA and PFHxA relative to the longer-chain PFAS was observed from the butter wrapper. PFAS concentrations increased with greater fat concentrations in dairy products. |
Two paper food contact materials United States, 2013 [103] | Migration of PFAS from two paper food packaging into five simulants (Miglyol oil, Miglyol oil with soy lecithin, Miglyol oil with Tween 60, 10% ethanol, 3% acetic acid) under two temperatures: 100 °C (15 min) and 40 °C (2, 24, 96 and 240 h). | PFHxA, PFHpA, PFOA, PFNA, PFDA, PFUnDA, PFDoDA | Seven PFAS migrated into food stimulants, and the shorter chain compounds migrated at a faster rate. The addition of emulsifiers increased migration efficiencies. Paper coating based on di-perfluoro-alkyloxy-amino-acid leached PFAS at a higher rate compared to the coating based on polyfluoroalkyl phosphate surfactants. |
Paper bowl China, 2016 [104] | Migration studies of 16 PFAS from paper bowls into several food simulants: oil, water, and ethanol/water mixtures (10/90, 30/70, 50/50). Simulants preheated to 100 °C were added to a bowl, followed by a 15-min hold at room temperature. | 6:2 FTOH, 8:2 FTOH, 10:2 FTOH, 12:2 FTOH, 14:2 FTOH; 16:2 FTOH, PFBA, PFPeA, PFHxA, PFHpA, PFOA, PFNA, PFDA, PFUnDA, PFDoDA, PFTrDA, PFTeDA, PFPeDA, PFHxDA, PFHpDA, PFODA | Perfluorinated carboxylic acids and fluorotelomer alcohols readily migrated out of the paper bowls, with a greater transfer into 50% ethanol relative to 30% ethanol or water. PFBA (compound with 4 fluorinated carbons) had the greatest migration efficiency. |
Pet food paper bag 3 Spain, 2020 [105] | Migration of 12 PFAS from unprinted pet food paper bags was measured to food simulants (Tenax, 50% ethanol, and 95% ethanol) and foods (ground cereal, parboiled rice, infant milk powder). | PFPeA, PFHxA, PFHpA, PFOA, PFNA, PFDA, 8:2 FTCA, 8:2 FTUCA | Shorter chain PFAS exhibited greater migration efficiencies than long-chain PFAS. More migration was observed into milk powder compared to food simulants. |
Study Model | Dose | Main Findings |
---|---|---|
Mouse [44] | 0.0014% TBHQ diet fed to mice prior to infection with influenza virus | NK cell expression of granzyme B was decreased in the TBHQ-exposed mice, indicating impaired NK cell cytotoxicity. |
Mouse [106] | 0.001% TBHQ diet fed to mice prior to ovalbumin exposure. | Following ovalbumin sensitization, a higher concentration of IgE and higher mast cell protease response were measured in the TBHQ group compared to controls. |
Mouse [53] | Single intraperitoneal injection of 50 mM TBHQ | TBHQ upregulated cytokine IL-17D in an Nrf2-dependent manner and chemokine CCL2 in an Nrf2-independent manner. |
Murine wild-type and Nrf2-null splenocytes [45] | Cells treated with 0.25–2.5 μM TBHQ | TBHQ enhanced Nrf2-dependent IgM production in B cells and decreased induction of CD22, CD25, CD69, and CD138 receptors both in wild-type and Nrf2-null B cells. |
Murine splenocytes [57] | Cells treated with 1 μM or 5 μM TBHQ | Activation of NK cells in the presence of TBHQ decreased production of IFN-ɣ, granzyme B, and perforin, and lowered the induction of CD25 and CD69. |
Splenocytes from Nrf2-null and wild-type mice [46] | Cells treated with 0.1–1 μM TBHQ | TBHQ inhibited the production of IL-2 and Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) in both wild-type and Nrf2-null T cells. |
Human T cell line [58] | Jurkat cells treated with 0.1–1 μM TBHQ | TBHQ suppression of CD25 expression partly depended on Nrf2, while TBHQ inhibition of NFkB activation and IL-2 secretion was Nrf2-independent. |
Rat thymocytes [107] | Cells treated with 10–300 μM TBHQ | TBHQ exposure activated Ca2+-dependent K+ channels and elevated intracellular Ca2+ levels. |
Primary human CD4+ T cells [108] | Cells treated with 0.1–5 μM TBHQ | Inactivated human T cells, TBHQ inhibits the production of IL-2 and IFN-γ, inhibits the induction of CD25 and CD69, and suppresses NFκB DNA binding. |
Human dendritic cells [109] | Cells treated with 10 μM TBHQ | TBHQ inhibited IL-12 expression in an Nrf2-dependent manner. |
Primary human CD4+ T cells [110] | Cells treated with 50 μM TBHQ | TBHQ increased total Nrf2 levels. |
Human T cell line [111] | Jurkat cells treated with 0.1–5 μM TBHQ | TBHQ inhibited interleukin-2 and CD25 expression and decreased NFκB transcriptional activity. |
Murine T cells [70] | Cells treated with 0.1–1 μM TBHQ | TBHQ suppressed IFN-γ production and induced IL-4, IL-5, and IL-13 production. |
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PFAS Reported to Migrate to Food, with CAS Numbers | Number of Assays with Half-Maximal Activity Concentration (AC50) < Cytotoxicity Limit |
---|---|
Perfluorooctanesulfonic acid (1763-23-1) | 48 |
Perfluoroundecanoic acid (2058-94-8) | 45 |
Perfluorooctanoic acid (335-67-1) | 41 |
Perfluorohexanoic acid (307-24-4) | 22 |
Perfluorodecanoic acid (335-76-2) | 18 |
Potassium perfluorooctanesulfonate (2795-39-3) | 13 |
Ammonium perfluorooctanoate (3825-26-1) | 11 |
Perfluorononanoic acid (375-95-1) | 9 |
Perfluoroheptanoic acid (375-85-9) | 5 |
6:2 fluorotelomer alcohol (647-42-7) | 4 |
8:2 fluorotelomer alcohol (678-39-7) | 1 |
6:2 fluorotelomer methacrylate (2144-53-8) | 1 |
Lithium perfluorooctanesulfonate (29457-72-5) | 0 |
Direct Food Additives | Number of Assays with Half-Maximal Activity Concentration (AC50) < Cytotoxicity Limit |
---|---|
Tert-butylhydroquinone (TBHQ) | 58 |
FD&C Red No. 3 (erythrosine) | 46 |
Propyl paraben | 23 |
Propyl gallate | 21 |
Ethoxyquin, FD&C Blue No. 1, folic acid, sodium lauryl sulfate, sorbic acid, vitamin D2 | 11–16 |
Acetic acid, caprylic acid, FD&C Green No. 3, maltol, methyl paraben, sodium ascorbate, stearic acid, triethyl citrate, vitamin A | 6–10 |
Acesulfame potassium, adipic acid, ascorbyl palmitate, aspartame, azodicarbonamide, benzoic acid, benzyl alcohol, butylated hydroxytoluene, caffeine, calcium lactate, citric acid, ethyl maltol, FD&C Red No. 40, FD&C Yellow No. 5, FD&C Yellow No. 6, fumaric acid, glycerin, glyceryl triacetate, limonene, linoleic acid, malic acid, peppermint oil, phosphoric acid, potassium nitrate, propylene glycol, riboflavin, saccharin, silicon dioxide, sodium erythorbate, sodium nitrite, sorbitol, sucralose, sugar, vanillin, vitamin B6, vitamin C | 1–5 |
Butylated hydroxyanisole, FD&C Blue No. 2, lactic acid, lactose, polysorbate 80, sodium benzoate, succinic acid, vitamin B7 | 0 |
Gene Name and Function | ToxCast Assay Name | TBHQ | FD&C Red 3 | PFOS | PFOA | PFNA | PFDA | PFUnDA |
---|---|---|---|---|---|---|---|---|
CCL2 (chemokine (C-C motif) ligand 2) Chemokine with chemotactic activity for monocytes and basophils | BSK_3C_MCP1_down | ✓ | ||||||
BSK_CASM3C_MCP1_down | ✓ | |||||||
BSK_KF3CT_MCP1_down | ✓ | ✓ | ✓ | |||||
BSK_LPS_MCP1_down | ✓ | ✓ | ||||||
BSK_SAg_MCP1_down | ✓ | |||||||
CCL26 (chemokine (C-C motif) ligand 26) Chemokine with chemotactic activity for eosinophils and basophils | BSK_4H_Eotaxin3_down | ✓ | ||||||
CD38 molecule Transmembrane receptor expressed on macrophages, dendritic cells, and NK cells | BSK_SAg_CD38_down | ✓ | ||||||
CD40 molecule Transmembrane receptor expressed on antigen-presenting cells | BSK_LPS_CD40_down | ✓ | ||||||
BSK_SAg_CD40_down | ✓ | |||||||
CD69 molecule Transmembrane receptor expressed on activated T cells and NK cells | BSK_SAg_CD69_down | ✓ | ||||||
CSF1 (macrophage colony-stimulating factor) Cytokine that controls the differentiation and function of macrophages | BSK_hDFCGF_MCSF_down | ✓ | ✓ | ✓ | ||||
BSK_LPS_MCSF_down | ✓ | ✓ | ||||||
CXCL10 (chemokine (C-X-C motif) ligand 10) Chemokine involved in the stimulation of monocytes, NK cells, and T cells | BSK_BE3C_IP10_down | ✓ | ✓ | ✓ | ✓ | |||
BSK_hDFCGF_IP10_down | ✓ | ✓ | ||||||
BSK_KF3CT_IP10_down | ✓ | ✓ | ✓ | |||||
CXCL8 (chemokine (C-X-C motif) ligand 8) Chemokine secreted by macrophages, neutrophils, eosinophils, and T cells | BSK_hDFCGF_IL8_down | ✓ | ✓ | |||||
BSK_LPS_IL8_down | ✓ | |||||||
BSK_SAg_IL8_down | ✓ | |||||||
CXCL9 (chemokine (C-X-C motif) ligand 9) Chemokine involved in immune regulation and inflammatory processes | BSK_BE3C_MIG_down | ✓ | ✓ | |||||
BSK_hDFCGF_MIG_down | ✓ | ✓ | ||||||
BSK_SAg_MIG_down | ✓ | |||||||
HLA-DRA (major histocompatibility complex class II) Antigen-presenting molecule | BSK_3C_HLADR_down | ✓ | ||||||
BSK_BE3C_HLADR_down | ✓ | ✓ | ✓ | ✓ | ||||
ICAM1 (intercellular adhesion molecule 1) Cell adhesion molecule | BSK_KF3CT_ICAM1_down | ✓ | ||||||
IL-1α (Interleukin-1, alpha) Cytokine produced by macrophages | BSK_BE3C_IL1a_down | ✓ | ✓ | ✓ | ||||
BSK_KF3CT_IL1a_down | ✓ | ✓ | ||||||
BSK_LPS_IL1a_down | ✓ | |||||||
LTB4R (leukotriene B4 receptor) Transmembrane receptor on immune cells | NVS_GPCR_gLTB4 | ✓ | ✓ | ✓ | ||||
E-selectin Cell adhesion molecule | BSK_LPS_Eselectin_down | ✓ | ✓ * | |||||
BSK_SAg_Eselectin_down | ✓ | |||||||
P-selectin Cell adhesion molecule | BSK_4H_Pselectin_down | ✓ | ||||||
Prostaglandin E receptor 2 Transmembrane receptor on immune cells | BSK_LPS_PGE2_down | ✓ | ✓ | |||||
TGF-β1 (transforming growth factor, beta 1) Growth factor that regulates immune responses | BSK_BE3C_TGFb1_down | ✓ | ✓ | ✓ | ||||
BSK_KF3CT_TGFb1_down | ✓ | ✓ | ✓ | |||||
TNF (tumor necrosis factor) Pro-inflammatory cytokine primarily secreted by macrophages | BSK_LPS_TNFa_down | ✓ | ||||||
VCAM1 (vascular cell adhesion molecule 1) Cell adhesion molecule | BSK_3C_VCAM1_down | ✓ | ||||||
BSK_4H_VCAM1_down | ✓ | |||||||
BSK_hDFCGF_VCAM1_down | ✓ | ✓ | ||||||
BSK_LPS_VCAM1_down | ✓ |
Gene Name and Function | ToxCast Assay Name | TBHQ | FD&C Red 3 | PFOS | PFDA | PFUnDA |
---|---|---|---|---|---|---|
Coagulation factor III Involved in the innate immune response and host defense against infection, initiates the coagulation cascades | BSK_LPS_TissueFactor_down | ✓ | ||||
Matrix metallopeptidase 1 Enzyme that breaks down extracellular matrix; involved in the immune response to infection | BSK_BE3C_MMP1_down | ✓ | ||||
BSK_hDFCGF_MMP1_down | ✓ | ✓ | ✓ | |||
Matrix metallopeptidase 9 Enzyme that breaks down extracellular matrix; involved in the immune response to infection | BSK_KF3CT_MMP9_down | ✓ | ✓ | ✓ | ✓ | |
Tissue plasminogen activator Secreted serine protease that converts the plasminogen to plasmin, regulates innate immune response | BSK_BE3C_tPA_down | ✓ | ✓ | ✓ | ||
Urokinase-type plasminogen activator Secreted serine protease that converts the plasminogen to plasmin, regulates innate immune response | BSK_BE3C_uPA_down | ✓ | ✓ | |||
BSK_KF3CT_uPA_down | ✓ | ✓ | ||||
Urokinase-type plasminogen activator receptor Regulates inflammatory, immune, and coagulation responses | BSK_3C_uPAR_down | ✓ | ||||
BSK_BE3C_uPAR_down | ✓ | |||||
BSK_CASM3C_uPAR_down | ✓ | |||||
SERPINE1 (serpin peptidase inhibitor, clade E) Involved in the innate immune response and early host defense against infection, an inhibitor of fibrinolysis | BSK_BE3C_PAI1_down | ✓ | ✓ | ✓ | ||
BSK_hDFCGF_PAI1_down | ✓ | ✓ | ✓ | |||
Thrombomodulin Transmembrane receptor, suppresses coagulation and inflammation | BSK_CASM3C_Thrombomodulin_down | ✓ | ||||
BSK_CASM3C_Thrombomodulin_up | ✓ | |||||
TIMP metallopeptidase inhibitor 1 Inhibitor of the enzymes that break down extracellular matrix; regulates innate immune response | BSK_hDFCGF_TIMP1_down | ✓ | ✓ | ✓ | ||
TIMP metallopeptidase inhibitor 2 Inhibitor of the enzymes that break down extracellular matrix; regulates innate immune response | BSK_KF3CT_TIMP2_down | ✓ | ✓ |
Gene Name and Function | ToxCast Assay Name | TBHQ | FD&C Red 3 | 6:2 FTOH | PFOS | PFOA | PFUnDA |
---|---|---|---|---|---|---|---|
Aryl hydrocarbon receptor (AhR) Involved in xenobiotic response | ATG_Ahr_CIS_up | ✓ | |||||
OX21_AhR_LUC_Agonist * | ✓ | ||||||
Nuclear factor, erythroid 2-like 2 (NFE2L2, Nrf2) Involved in oxidative stress, inflammation, and injury | ATG_NRF2_ARE_CIS_up | ✓ | ✓ | ✓ | ✓ | ||
TOX21_ARE_BLA_agonist_ratio | ✓ | ✓ | |||||
Glucocorticoid receptor (nuclear receptor subfamily 3, group C, member 1) Involved in regulation of stress response, inflammation, and immune processes | NVS_NR_hGR | ✓ | ✓ | ||||
TOX21_GR_BLA_Antagonist_ratio | ✓ |
TBHQ Target Reported in Immunological Studies | Studies Reporting This Target | ToxCast Assay Direction |
---|---|---|
Increased activity of Nrf2 | [45,46,53] | up |
Decreased activity of NFκB | [46,58] | down * |
Decreased CD69 expression | [45,57] | down |
CCL2 increase | [53] | down |
TNFα decrease | [59] | down |
IL-6 decrease | [59] | no activity |
Chemical | ToxCast | Laboratory Animal Studies | Epidemiological Studies | Conclusion |
---|---|---|---|---|
FD&C Red 3 | Affects multiple immune parameters | No studies identified | No studies identified | Potential for immunotoxic effects, should be further investigated |
TBHQ | Affects multiple immune parameters | Immune modulation, changes in the immune functions | No studies identified | Immunological and mechanistic studies point to risk for the immune system |
PFUnDA | Affects multiple immune parameters | Some evidence of immune suppression | Immune suppression | Human data and mechanistic studies point to risk for the immune system |
PFOA | Does not show strong activity in ToxCast assays with immune targets | Immune suppression | Immune suppression | Human data point to risk for the immune system with limited support from mechanistic studies |
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Naidenko, O.V.; Andrews, D.Q.; Temkin, A.M.; Stoiber, T.; Uche, U.I.; Evans, S.; Perrone-Gray, S. Investigating Molecular Mechanisms of Immunotoxicity and the Utility of ToxCast for Immunotoxicity Screening of Chemicals Added to Food. Int. J. Environ. Res. Public Health 2021, 18, 3332. https://doi.org/10.3390/ijerph18073332
Naidenko OV, Andrews DQ, Temkin AM, Stoiber T, Uche UI, Evans S, Perrone-Gray S. Investigating Molecular Mechanisms of Immunotoxicity and the Utility of ToxCast for Immunotoxicity Screening of Chemicals Added to Food. International Journal of Environmental Research and Public Health. 2021; 18(7):3332. https://doi.org/10.3390/ijerph18073332
Chicago/Turabian StyleNaidenko, Olga V., David Q. Andrews, Alexis M. Temkin, Tasha Stoiber, Uloma Igara Uche, Sydney Evans, and Sean Perrone-Gray. 2021. "Investigating Molecular Mechanisms of Immunotoxicity and the Utility of ToxCast for Immunotoxicity Screening of Chemicals Added to Food" International Journal of Environmental Research and Public Health 18, no. 7: 3332. https://doi.org/10.3390/ijerph18073332
APA StyleNaidenko, O. V., Andrews, D. Q., Temkin, A. M., Stoiber, T., Uche, U. I., Evans, S., & Perrone-Gray, S. (2021). Investigating Molecular Mechanisms of Immunotoxicity and the Utility of ToxCast for Immunotoxicity Screening of Chemicals Added to Food. International Journal of Environmental Research and Public Health, 18(7), 3332. https://doi.org/10.3390/ijerph18073332