**3.2 Toxicity of cadmium (Cd)**

Cadmium is an industrial compound, used in plastic industry, for obtaining plastic stabilizer, but also for production of color pigments, alloys (being a by-product of zinc production), glass production, electroplating industries, welders, rechargeable batteries (about three-fourths of cadmium production). Others important sources include emissions from industrial activities, such as mining or smelting [1, 5, 9, 19, 22, 24].

Exposure to cadmium is achieved by ingestion of food or water, inhalation of contaminated dust, especially for employers which work in primary metal industries or in cadmium-contaminated places, or by smoking cigarettes [3, 5, 10, 19, 22]. Because this metal could not penetrate the skin barrier, dermal exposure not represent a health concern [10].

The main way of exposure for smokers is the smoking, while, for non-smokers, the primary source of exposure is food, such as peanuts, crustaceans and mollusks, leafy vegetables, sunflower seeds, cocoa powder, rice, grains, soybeans, mushrooms, potatoes [3, 10, 22, 25]. Biomonitoring studies have shown that in the case of cigarette smokers, blood and urine levels were generally high, moderate in former smokers and in nonsmokers they were reduced [22]. This is related the capacity of this metal to accumulate in high concentrations in tabaco leaves [5, 26]. Their toxicity depends both, the dose of exposure and the exposure time [3]. The percentage of cadmium, absorbed after ingestion is 5–10%, but in diets with a low intake of iron, calcium or protein, the percentage absorbed is higher [10].

In case of occupational workers, in industries which uses this metal, inhalation is the primary way of exposure, so that a percentage of 5–35% of inhaled cadmium is absorbed into the blood, depending the form, particle size, or site of deposition. If this metal reaches the level of the alveoli, its absorption into the blood could be 100% [10]. Their chronic exposure has been associated with changes in pulmonary function, emphysema, decreases in olfactory function [22].

The most toxic form is divalent cadmium ion (Cd2+), which is the most common form and may disturb the basic cellular functions and can cause various side effects [3, 22]. This element can cause side effects even at low concentrations, due to its low excretion rate [17, 27].

Also, it has the capability to replace iron and copper in different cytoplasmic and membrane proteins, and these unbounded substituted metals participate in oxidative stress processes, due to their increased levels [17].

When it binds to cysteine-rich proteins, its concentration inside the body increases 3000 times, forming compounds, such as metallothionein, which can produce hepatotoxicity, nephrotoxicity [1, 3]. If attached to compounds such as histidine, glutamate or cysteine, it can cause iron deficiencies. As a result of exposure, the immune system and endocrine system is affected, even at a young age [3].

Studies have shown that women have higher levels of cadmium than men, and pregnant women have more levels than non-pregnant women. Cadmium does not cross the placental barrier, and remains trapped in it, preventing it from affecting the prenatal exposure of the fetus [3].

The target organs for cadmium are the liver, bones, vascular system, nerve tissues, but especially the kidneys, leading to their damage or malfunction [3, 17, 19, 28]. As their concentration inside the kidneys increases, the rate of calcium excretion from the body is high, which means an increased risk of kidney stones [3, 17, 29]. Also, its

renal excretion causes damage to the renal tubules and tubular disfunction by promoting oxidative stress in proximal tubular cells [3, 17].

In case of acute ingestion, symptoms such as vomiting, vertigo, abdominal pain, burning sensation, muscle cramps, shock, loss of consciousness, nausea, convulsions appear in 15–30 min. Because this heavy metal is a severe pulmonary and gastrointestinal irritant, erosion of the intestinal tract, diseases of pulmonary, hepatic or renal or coma could appear, depending the route of poisoning [22].

The exposure to low levels, may affect the prostatic lipid metabolism and the increasing of the fatty acids used to synthesis of phospholipids, with effects on the composition and functions of the plasma membrane [3].

High levels of cadmium in the blood cause a decrease in bone density, especially in pregnant women. Also, it can produce Itai-itai bone disease, which is characterized by painful degenerative bone disease (such as osteomalacia and osteoporosis), renal tubular abnormalities, calcium and phosphate excretion, lung cancer [5, 10, 30].

Chronic exposure can cause effects such as anemia, emphysema, osteoporosis, renal disorders, anosmia, chronic rhinitis, but also have a depressant effect, by changing the levels of serotonin, norepinephrine or acetylcholine [3, 22].

By accumulating in the pancreas and blood, the both exocrine and endocrine function of the pancreas is affected, resulting in a reduction in serum insulin. It may also affect the pancreas to resisting the secretion of insulin, and producing diabetes type 2. Research has shown that it can affect adipose tissue and can lead to obesity. Research has shown that exposure to this element can alter the balance of pituitary hormones. On reproductive system, Cd can affect the synthesis of testosterone and progesterone, spontaneous abortion, low birth weight, changes and apoptosis of germ cells, reducing of semen quality, damage of DNA of sperm cells, apoptosis of Sertoli cells [3].

Long term exposure to cell, it could transform normal cell into malignant cells. Because it contributes to the development of certain types of cancer, such as lung, prostate, pancreatic or kidney cancer, especially in case of occupational exposure, it has been classified as no. 1 human carcinogen by the International Agency for Research on Cancer USA [3, 5, 17, 22, 31]. Rodent studies have demonstrated the capacity of this metal to causes pulmonary adenocarcinomas or prostatic proliferative lesions, leading to adenocarcinomas [22].

At the cellular level, Cd disrupts the respiratory chain of the mitochondria, involved in transport across cell membranes and cell damage through production of reactive oxygen species (ROS), blocking calcium channels, hinders sulfhydryl enzymes, interacts with some cell ligands, promote lipid peroxidation and protein carbonylation. It also affects oxidative phosphorylation pathways, mitochondrial genes involved in cell apoptosis, reducing the ATP level and the energy production. This heavy metal affects the activity of some antioxidant enzymes, such as glutathione reductase, catalase, glutathione peroxidase. Also, cadmium could interact with DNA and may reduce its binding capacity or repair, DNA damage or disruption of synthesis of nucleic acid or proteins [3, 17, 22, 24].

Animal studies have shown that it can produce disorders in the metabolism of zinc, copper and calcium, being able to decrease their absorption and resulting in low dietary intake [5, 32, 33]. The hepatotoxicity and nephrotoxicity of Cd was also observed, after administration of certain doses of cadmium [5, 33]. At cellular level, changes in cell-cell adhesion, autophagic response, changes in cellular signaling pathways, cell death [5], mitochondrial swelling, decrease in antioxidant levels, increases in urinary proteins, more vacuoles and lysosomes in proximal tubule cells were observed [17].
