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Fluoride effect on renal and hepatic functions: A comprehensive decade review of In vitro and In vivo studies.
Abstract
Background
This systematic review evaluates the toxicological effects of exposure to fluoride on renal and hepatic functioning. It compiles both in vitro & in vivo studies across the last decade. By highlighting the potential health risks, the review aims to raise awareness and encourage a more attentive approach to fluoride use and exposure, instilling a sense of concern and vigilance in the audience.
Methodology
A thorough literature search covered relevant studies from 2013 to 2023, both experimental (in vitro) and animal (in vivo) research. The data extraction process focused on critical aspects such as sample size, methodologies used, key findings, and conclusions regarding fluoride’s impact on kidney and liver functions. The review also includes a detailed analysis of gene expression, KEGG pathways, and STRING analysis, further enhancing the reliability of the results.
Results
Significant renal and liver damage were demonstrated in animal models exposed to high fluoride doses for long duration. Ferulic acid was found to mitigate fluoride-induced oxidative damage. The combined mean difference across studies was 6.52 [-5.22, 18.26], indicating high heterogeneity, which reflects diverse methodologies and findings. Notably, epigenetic and immune system impacts were underscored, with gene analysis identifying several genes involved in oxidative stress response, apoptosis, and inflammation pathways.
Conclusion
The findings emphasize the substantial evidence of its harmful effects on renal and liver functions at high exposure levels. Some studies indicate minimal impact, others demonstrate significant organ damage. The results underline the necessity for continued research to establish safe fluoride exposure limits and comprehend the mechanisms underlying its toxicity.
EXCERPT:
4. Results
Numerous research on the impact of exposure to fluoride on different body systems were assessed as part of the systematic review. Excess fluoride exposure was found to harm the liver, kidneys, and immune system, causing immune abnormalities, oxidative damage, and potential epigenetic changes (Priyankar Pal et al., 2022; Das S et al., 2023; Satheeswaran et al., 2018) (Table 1, Table 2). Ferulic acid demonstrated protective properties against fluoride toxicity by reducing oxidative stress (Das S et al., 2023)(Table 1, Table 2). Based on current exposure, European fluoride levels were deemed safe, but further research on low-level exposure and developmental impacts is recommended (Sabine Guth et al., 2018)(Table 1, Table 2). While some studies found no significant liver damage from fluoride, others reported varying degrees of liver and kidney harm, indicating the need for ongoing research to fully understand fluoride’s impact (Sirigala Lavanya et al., 2023; Thanusha Perera et al., 2018)(Table 1, Table 2). Overall, the review underscores the toxic effects of high fluoride levels and highlights the necessity for further investigation to determine safe exposure limits and protective measures.
Table 1. Characteristics of the included studies.
| S.No | Authors | Year | Sample size | Type of Study | Methodology |
|---|---|---|---|---|---|
| 1 | Priyankar Pal et al.11 | 2022 | Review | invivo | mTOR and Beclin 1 signaling pathways are targeted by excess fluoride exposure, shedding light on fluoride toxicities in human disorders. |
| 2 | Das S et al.12 | 2023 | Rats were divided into five groups | invitro | It investigates sodium fluoride’s impact and FA’s potential to mitigate its toxicity on the hepatorenal system using molecular docking and biochemical experiments. |
| 3 | Ashley J. Malin et al.,13 | 2017 | 1983 teenagers for plasma fluoride levels and 1742 for water fluoride levels | invivo | The study employed survey-weighted linear regression analysis and the Holm-Bonferroni correction to examine the relationship between exposure to fluoride and kidney/liver parameters in American teenagers based on NHANES 2013–2014 and 2015–2016 data. |
| 4. | Sabine Guth et al.14 | 2018 | 23 epidemiological studies published from 2012 to | invivo | The study matched known individual exposure levels to no observable adverse impact levels (NOAELs) and limit of exposure (LOAELs) generated from experiment animal studies in order to correctly interpret proof of fluoride cytotoxicity in humans collected from epidemiological studies. |
| 5. | Sirigala Lavanya and Pratibha Ramani15 | 2023 | 320 participants -Two age groups: Group A (aged 21–40) Group B (aged 41–60). Each group was then subdivided based on the presence or absence of dental fluorosis. |
invivo | Serum indicators like total bilirubin, SGPT, SGOT, & ALP were used to evaluate liver function in study participants’ blood samples. Fluoride levels were measured using a fluoride ion metre and samples of urine and water. To ascertain statistical significance, the t-test was employed. |
| 6. | Satheeswaran Balasubramaniand Ekambaram Perumal16 | 2018 | The review examined 932 articles and identified 39 that met the inclusion criteria. | These investigations, which concentrated on different genes, offered preliminary proof of the role of epigenetic control in fluoride toxicity. | |
| 7. | Kas Usuda et al.,17 | 2016 | Nine experimental groups and a control group were created from the rats. | invitro | Nine experimental groups and a control group of rats were each given oral injection of 0.5 mL fluoridated solutions and 0.5 mL distilled water, respectively. |
| 8. | Azab Elsayed Azab et al.,18 | 2018 | Review | Nothing of significance | |
| 9 | Thanusha Perera |
| et al.19 | 2018 | Thirty-six rats were randomly divided into 4 (1 control and 3 test groups n = 9): | invitro | Adult male Wistar rats were given oral fluoride from sodium (NaF) at concentrations of 0, 0.5, 5, & 20 ppm F-to assess the effects of fluoride. Although test groups I, II, and III received 1 ml/rat of NaF dosages of 0.5, 5, & 20 ppm, respectively, through a stomach tube, the control group was given 1 ml/rat of distilled water, every day. Three control & the experimental group rats were slaughtered after 15, 30, and 60 days of treatment in order to obtain blood, kidney, & liver samples for serological and histological analysis. | |
| 10 | Solomon E. Owumi et al.,20 | 2019 | invitro | For 14 days, the rats received either DEN (10 mg per kg alone), fluoride (15 mg per L litre in drinking water), or both compounds. |
Table 2. Analysis of results of included studies.
| S.No | Authors | Year and type of study | Results | P value | Conclusion |
|---|---|---|---|---|---|
| 1 | Priyankar Pal et al. | 2022 | The study found significant abnormalities in the immune system due to fluoride toxicity, including altered immune responses, proliferation, differentiation, and changes in the ratio of immune cells. | P < 0.05 | Excess fluoride exposure can harm soft tissues and various body systems. |
| 2 | Das S et al. | 2023 | According to the study, ferulic acid (FA) functions as an antioxidant, reducing blood indicators and lipid peroxidation products to shield the liver and kidneys from oxidative damage caused by NaF. Additionally, it mitigated the negative impact of NaF on the serum lipid profile. Furthermore, the in-silico study revealed that FA had a robust interaction with both superoxide dismutase and catalase, which prevented NaF from binding to their active sites. This was validated by the in-vitro assay. | FA regulates the production of free radicals and protects these vital organs from damage caused by sodium fluoride. | |
| 3 | Ashley J. Malin et al. | 2017 | Teenagers were 15.4 years old on average. The median values of water and plasma fluoride were 0.48 mg/L and 0.33 ?mol/L, respectively. A 1.29 mg/dL lower blood urea nitrogen concentration (95%CI: ?1.87, ?0.70; p < 0.001), a 0.29 mg/dL higher serum uric acid concentration (95 % CI: 0.09, 0.50; p = 0.05), and a 10.36 mL/min/1.73 m2 lower estimatedglomerular filtration rate (95 % CI: ?17.50, ?3.22; p = 0.05) were linked to a 1 ?mol/L increase in plasma fluoride. A 0.93 mg/dL decrease in blood urea nitrogen content was linked to a 1 mg/L increase in water fluoride (95 % CI: ?1.44, ?0.42; p = 0.007). |
p = 0.007 | Fluoride exposure can lead to changes in adolescent kidney and liver function. More research is needed to understand how low-level fluoride exposure affects development and how kidney and liver function can impact fluoride absorption. |
| 4. | Sabine Guth et al. | 2018 | Based on the particular animal experiment used as a reference, the results indicate that the margin of exposure (MoE) between the current adequate intake (AI) of fluoride (50 ?g/kg b.w./day) in humans and the no observed adverse effect levels (NOAELs) in animal studies ranges from 50 to 210. | NA | Fluoride at the quantities present in Europe shouldn’t be regarded as neurotoxic. The text highlights the need for more research to understand fluoride’s potential risks to human development. |
| 5. | Sirigala Lavanya and Pratibha Ramani. | 2023 | Water samples had fluoride levels ranging from 1.55 mg/L to 44.10 mg/L, but the study did not find any significant differences in liver function markers between patients with and without dental fluorosis. | P < 0.05 | There was no discernible change in the liver function of persons with dental fluorosis, regardless of high fluoride water consumption |
| 6. | Satheeswaran, Balasubramanian and Ekambaram Perumal. | 2018 | Our findings suggest that exposure to fluoride and epigenetic processes are related. | NA | The investigations mostly examined different genes and discovered preliminary data supporting the epigenetic control of fluoride toxicity |
| 7. | Kas Usuda et al. | 2016 | According to the data, increased urine NAG levels (p < 0.05 with ?90th percentile of control) show that greater doses of NaF, KF, and ZnF2 caused kidney injury. | p < 0.05 | These findings underscore the need for further research to establish clear exposure thresholds and investigate potential protective strategies against fluoride-induced toxicity. This knowledge can empower us to develop interventions that mitigate the harmful effects of fluoride on renal and liver functions. |
| 8. | Azab Elsayed Azab et al. | Review 2018 | Variability in research design emphasises how urgently standardised protocols are needed to improve human risk assessment. The significance of our joint work in this area is highlighted by the fact that this standardisation is essential for precisely assessing the effects of fluoride on liver and kidney functioning. | NA | It is crucial to remember that reducing sodium fluoride exposure is critical in minimizing its harmful effects on the liver and kidneys. |
| 9 | Thanusha Perera |
| et al. | 2018 | There were no discernible changes between the fluoride-treated and control groups in terms of body weight increase or relative weights of the liver and renal organs. However, groups II and III showed many sites of focal necrosis and varying degrees of portal inflammation, whereas the fluoride-treated animals showed mild portal inflammation with lytic necrosis. | NA | Renal damage may follow alterations in liver enzyme activity brought on by the initial phases of fluoride overdose. | |
| 10 | Solomon E. Owumi et al. | 2019 | The results of the investigation showed that the liver and kidneys suffered more damage from the combination of fluoride and DEN than from the individual substances. Oxidative stress, inflammation, and cell death indicators were significantly elevated in rats exposed to fluoride and DEN. | NA | The study concluded that the combination of fluoride and DEN exacerbated liver and kidney damage in rats by increasing oxidative stress, inflammatory responses, and caspase-3 activation. |
… To the best of our understanding, this is the first comprehensive study and meta-analysis that evaluates and presents proof of fluoride-induced apoptosis in experimental animals’ non-skeletal tissues. We made sure we located all pertinent studies by doing thorough searches across four databases. The review procedure was conducted in accordance with standard protocols. The variability of research and the paucity of published articles assessing fluoride’s renal toxicity are among the study’s weaknesses. The observed dissimilarity among the studies may be due to variations in the types of tissue investigated, the animal species studied, the time and amount of exposure, the mode of exposure, and the biochemical assay methods used.
6. Conclusion
The harmful effects of fluoride on liver and kidney functions are highlighted in this comprehensive review, which is supported by recent in vivo and in vitro research conducted over the last ten years. While beneficial at low concentrations, excessive fluoride exposure poses a significant risk to kidney and liver health. Future research should aim to establish clear exposure thresholds and investigate potential protective strategies against fluoride-induced toxicity.
ABSTRACT AND FULL-TEXT STUDY ONLINE AT:
https://www.sciencedirect.com/science/article/pii/S2212426824001490?via%3Dihub
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