**4. Fluoride toxicity**

#### **4.1 Skeletal tissue toxicity**

#### *4.1.1 Dental fluorosis*

Dental fluorosis is hypo-mineralization of teeth enamel that is characterized by greater surface and subsurface porosity than is found in normal enamel. It results from excess fluoride reaching the growing tooth during its developmental stages [14]. F has a greater affinity for developing enamel because tooth apatite crystals can bind and integrate fluoride ions into the crystal lattice [15]. Ameloblast epithelial cells are responsible for enamel development, and the life cycle of these cells has three stages, which comprise: secretory, transition, and maturation steps [16]. Tooth morphological studies [17] have shown that fluoride affects the secretory stage of the ameloblasts cells, which secrete the enamel proteins called enamelin, which mineralizes to form tooth enamel. When these stages are interfered with due to fluoride overexposure, the general mineralization of the enamel is compromised leading to dental fluorosis.

#### *4.1.2 Skeletal fluorosis*

Skeletal fluorosis is a painful crippling pathological condition, which can occur on long-term exposure to high dietary levels of fluoride exceeding 20 mg/L [18]. The mechanism of skeletal fluorosis suggests that fluoride ions are deposited in the bone by substituting hydroxyl groups in the carbonate apatite structure to produce

fluorohydroxyapatite, thus altering the mineral structure of the bone according to the equation below:

$$\text{Ca}\_{10} \text{(PO}\_4\text{)OH} + \text{F} \rightarrow \text{Ca}\_{10} \text{(PO}\_4\text{)OH}\_6\text{F}$$

Because, F altered the mineralization of bone strength and finally causes week bone or soft bone called skeletal fluorosis (**Figure 3**).

## **4.2 Non-skeletal/physiological toxicity**

### *4.2.1 Gastrointestinal effect*

The dominant form in which F exists in solution is highly pH-dependent. At the normal pH of drinking water (pH = 7), fluoride occurs primarily as the free ion, F− . In the stomach, the ingested fluoride combines with hydrogen ions from HCl to form largely molecular HF, depending on the pH in the stomach (2.4% HF at pH 5; 96% HF at pH 2). The stomach is among the first target organs for the adverse effects of fluoride. Among the soft tissues of the body, the propensity of gastric mucosa exposed to the highest concentrations of the HF is immense. HF easily crosses the gastric epithelium and is the major form in which fluoride is absorbed from the stomach. Several functional and structural changes might be associated with ingestion of fluorides such as increased mucus secretion, followed by patchy or widespread loss of the mucus layer, hyperemia, edema, and hemorrhage [19].

**Figure 3.** *Skeletal fluorosis shows brittle bone.*

*Sources of Human Overexposure to Fluoride, Its Toxicities, and Their Amelioration Using… DOI: http://dx.doi.org/10.5772/intechopen.103714*

#### *4.2.2 Hepatic effect*

The liver is responsible for maintaining the body's metabolic homeostasis, and it has been considered as the key target organ for the toxic effects of fluoride [20]. Several mechanisms have been proposed to explain fluoride-induced hepatotoxicity. The important possible mechanism is the disturbance of prooxidant and antioxidant balances by the generation of reactive oxygen species (ROS). This decreases the activities of enzymatic antioxidants. Previous studies have shown fluoride induced abnormal function in the liver of rats, sheep, mice, etc. Especially, superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) were decreased with increased lipid peroxidation product, which cause damage to hepatocytes [21].

#### *4.2.3 Kidney effect*

The kidney is the potential site of acute fluoride toxicity because kidney cells are exposed to relatively high F concentrations [22]. Fluoride concentrations in the kidney show an increase in the gradient. Therefore, the kidney is thought to be one of the target organs for the adverse effects of fluoride because of the bioconcentration, metabolism, and kinetics excretion. F-induced ROS increases the excessive generation of nitric oxide, oxygen-free radicals, decreased CAT, SOD, glutathione (GSH), and increased lipid peroxidation, which may lead to severe damages in the nephron structure and functions and also biomacromolecules, such as proteins and nucleic acids [22, 23].

#### *4.2.4 Respiratory effect*

Fluoride exposure has been associated with asthmatic symptoms among workers in the aluminum industry [24]. However, only recently there is mounting evidence that ROS plays an important part in the complex physiological processes such as cell signaling and apoptosis. One of the organs commonly affected by ROS generation is the lungs. It is obvious that having a large surface that is constantly in contact with atmospheric oxygen and pollutants, the lungs are a site of major ROS production. The most fundamental adverse effect of fluorides in the respiratory system is the inhibition of Kreb's cycle enzymes in the lung by subsequent production of ROS. Furthermore, several studies have shown that the interaction of the lung immune system and oxidative stress might be associated with the development of several other pulmonary or respiratory diseases [25].

#### *4.2.5 Reproductive effect*

One of the toxicants that have harmful effects on the reproductive system is fluoride. The metabolism and morphology of spermatozoa were altered in the fluoride-exposed rats due to enhanced ROS/RNS-mediated lipid peroxidation. Long et al. [26] reported that fluoride significantly declined the weights of testes and cauda epididymis in rats. Sialic acid is an important constituent of mucopolysaccharides and sialomucoproteins, which are essential for the maturation of spermatozoa in epididymis and maintenance of the structural integrity of their membranes. However, fluoride overexposure can significantly altered the sialic acid [27]. Sharma et al. [28] have reported that female rats exposed to 6 ppm concentrations of sodium fluoride for 15 and 30 days revealed that the reproductive organ weights of the ovary, uterus,

and adrenal gland declined significantly due to the overproduction of reactive oxygen species with increased lipid peroxidation.

## *4.2.6 Cardiovascular effect*

The heart is a muscular pumping organ, mainly involved in the purification and circulation of blood in the body. Heart failure results from a sudden reduction in coronary blood flow to a segment of the myocardium, which initiates severe cellular changes in the myocytes that, inevitably culminating in cell death and tissue necrosis. Sinha et al. [29] have shown that fluoride consumption causes ROS-mediated myocardium injuries and dysfunction. Also, Nabavi et al. [30] have reported that fluoride increases oxidative stress through abnormal biochemical parameters in the heart tissues of rats. Fluoride-induced oxidative stress plays an important role in the progression of a variety of cardiac disorders such as cardiac failure and ischemia [30]. Nicotinamide adenine dinucleotide phosphate-oxidase (NADPH oxidase) (Nox) is an important source of ROS in the vasculature and is activated by high levels of fluoride exposure. Fluoride can stimulate the Nox expression, and activity has implications in endothelial dysfunction and vascular disorders. It is possible that endothelial dysfunction in coronary heart disease could be related to the chronic inflammation that coexists with atherosclerosis [31].
