INVESTIGATION INTO THE EFFECT OF THE TOXICANTS ARSENIC AND MANGANESE ON MALE REPRODUCTIVE SYSTEM OF WISTAR RAT.
INTRODUCTION AND LITERATURE REVIEW
In today’s industrialized world, exposure to pollutants in which heavy metals like arsenic, lead, manganese are an example is of high risk. These metals are present even in drinking water. Arsenic is mostly present in underground water. These metals are highly distributed in our environment and are thus consumed in quantities greater than what by the body requires (Ferrer, 2003).
Increased levels of arsenic in the environment, is an attribute to industrial product and waste, agricultural pesticides and herbicides. Although manganese is an essential element, toxicity can be gotten from drinking water, food, occupation and so on. Exposure to these heavy metals can cause poison and damage to models (the human body. Effects of arsenic have been reported in both human and experimental ATSDR a, 2012; Kannan et al., 2001). Mn exposure can also cause neurotoxicity (ATSDR b, 2007). Manganism, a consequence of exposure to high Mn levels, is a known neurological syndrome with many symptomatic analogies to Parkinson’s disease (Santamaria, 2008). Manganese and arsenic also target the same organ in the body, namely the brain (ATSDR, 2007a,b,c).
Given their co-existence in soil and atmosphere, exposure to toxicity does not occur in isolation (Kordaset al., 2010). Indeed, in the real world, exposures to complex mixtures are the rule, rather than exception (Scherer, 2005). Over the last several decades, the incidence of neurological diseases has increased (WHO, 2006).Mn poisoning results in an irreversible condition known as “manganism,’’ a neurodegenerative disorder that resembles Parkinson disease in both symptomatology and the underlying cellular mechanisms (Ellingsen et al., 2008; Martinez-Finley et al., 2012).
Neurological disorders induced by chronic metal exposure can be progressive and manifest clinically decades after the initial exposure (Gil and Pla, 2001). The onset of neurotoxic effects is largely subtle, insidiously manifested and unidentifiable as a clearly defined disease (Shy, 1993).
Exposure to arsenic- and lead-contaminated drinking water has been associated with an increased occurrence of congenital heart defects (CHDs). Groundwater is a vital hidden natural resource
(Tularam and Krishna 2009; Lashkaripour and Ghafoori 2011). Groundwater can be found in most environments and generally requires no prior treatment and can be found close to the points of demand often at low cost (MacDonald and Calow 2009). Arsenic poisoning or arsenicosis is a condition caused by the ingestion, absorption or inhalation of dangerous levels of arsenic, higher than the normal 10ppb which the body can tolerate.
The male reproductive system consists of two major parts: the testes, where sperm are produced, and the penis, according to Merck Manuals. The penis and urethra belong to both the urinary and reproductive systems in males. The testes are carried in an external pouch known as the scrotum, where they normally remain slightly cooler than body temperature to facilitate sperm production.Metals may cause a wide spectrum of reproductive and developmental adverse effects such as reduced fertility, abortions, retarded growth at the intrauterine cavity, skeletal deformities, malformations and retarded development especially of the nervous system.
Arsenic and manganese tend to decrease motility of sperm in the male reproductive system even though the sperm are active.
The important mechanisms of action of arsenic are placental transfer, oxidative stress, direct binding with thiol group etc.
The toxicity of arsenic in male and female reproductive organs is also explained. It also throws some light on the therapeutic strategies for metal toxicity.Manganese is a suspected reproductive toxicant and exposure to it has the potential to negatively affect the human reproductive system. The severity and nature of the adverse effect is variable and can be influenced by factors such as level of exposure and individual sensitivity to the chemical. Effects on the male reproductive system can include such things as altered sexual behavior, altered fertility and problems with sperm shape or count.
Manganese also have some positive effects on the reproductive system, they include It helps to produce sex hormones and sperm. Manganese acts as a catalyst for breaking down fatty acids and cholesterol. Manganese has a positive effect on the male reproductive system,It also enhances the brain's aptitude for receiving and sending messages,Sex hormones are produced in the pituitary gland, where a considerable amount of manganese exists. Because of this, manganese is believed to assist in sexual health.
Studies have been carried out on the individual effect of manganese and arsenic on the male reproductive system, this research however concentrates on both their individual effect and also their combined effect on the reproductive system. Earlier studies have shown that both accumulate in the brain and affect production of hormones.
Apart from affecting the reproductive system of man, arsenic and manganese cause other side effect including cancer. Arsenic and manganese have been shown to induce oxidative damage in the membrane leading to production of free radicals that may induce cancer and apoptosis. On the other hand some studies have suggested that arsenic can aid cancer treatment as it assists blood thinning.
These studies however have not been confirmed. The effects of arsenic and manganese can be assessed in male induced rats using assays like H202, Lipid Peroxidation, GSH, GST, SOD etc.
Pollution of the environment by these heavy metals is indeed a cause for alarm and have caused adverse effect to the human body as stated by WHO, unsuspected sources like underground water have shown lack of awareness by individuals.
1.2 LITERATURE REVIEW
Any foreign substance that enters the body is called xenobiotics. These substances can undergo any of the following pathways;
1. Excretion from the body unchanged
2. Undergo spontaneous reaction of its own
3. Undergo metabolism.
Most xenobiotics undergo the third pathway, however if the body is over exposed to a compound it will induce its own reaction and might likely undergo the above second pathway. Arsenic and managanese are foreign compounds which enter the body through various means.
Arsenic is a chemical element with symbol Asandatomic number 33. Arsenic occurs in many minerals, usually in conjunction with sulfur and metals, and also as a pure elemental crystal. Arsenic is a metalloid. It can exist in various allotropes, although only the gray form has important use in industry.A few species of bacteria are able to use arsenic compounds as respiratory metabolites. Trace quantities of arsenic are an essential dietary element in rats, hamsters, goats, chickens, and presumably many other species, including humans. However, arsenic poisoning occurs in multicellular life if quantities are larger than needed.
Arsenic contamination of groundwater is a problem that affects millions of people across the world (Mameli et al., 2001).
Arsenic and its compounds, especially the trioxide, are used in the production of pesticides, treated wood products, herbicides, and insecticides. However, these applications are declining. Arsenic can be found naturally on earth in small concentrations. It occurs in soil and minerals and it may enter air, water and land through wind-blown dust and water run-off (Martinez-Finley et al., 2012).
Despite its notoriety as a deadly poison, arsenic is an essential trace element for some animals, and maybe even for humans, although the necessary intake may be as low as 0.01 mg/day. Most arsenic is found in conjuction with sulfur in minerals such as arsenopyrite (AsFeS), realgar, orpiment and enargite. None is mined as such because it is produced as a by-product of refining the ores of other metals, such as copper and lead. A very high exposure to inorganic arsenic can cause infertility and miscarriages with women, and it can cause skin disturbances, declined resistance to infections, heart disruptions and brain damage with both men and women (Dhatrak and Nandi, 2009; Mejı´a et al., 1997).
Finally, inorganic arsenic can damage DNA. A lethal dose of arsenic oxide is generally regarded as 100mg. Organic arsenic can cause neither cancer, nor DNA damage. But exposure to high doses may cause certain effects to human health, such as nerve injury and stomachaches.
1.2.2 PHYSICAL AND CHEMICAL PROPERTIES OF ARSENIC.
Arsenic occurs in nature as a monoisotopic element, composed of one stable isotope, As. As of 2003, at least 33 radioisotopes have also been synthesized, ranging in atomic mass from 60 to 92. The most stable of these is 33As with a half-life of 80.30 days. All other isotopes have half- lives of under one day ( Gokcen, N. A,1989).
Fig 1.1: crystal structure of arsenic
When heated in air, arsenic oxidizes to arsenic trioxide; the fumes from this reaction have an odor resembling garlic. This odor can be detected on striking arsenide minerals such as arsenopyrite with a hammer. Arsenic (and some arsenic compounds) sublimes upon heating at atmospheric pressure, converting directly to a gaseous form without an intervening liquid state at 887 K (614 °C). The triple point is 3.63 MPa and 1,090 K (820 °C). Arsenic makes arsenic acid with concentrated nitric acid, arsenious acid with dilute nitric acid, and arsenic trioxide with concentrated sulfuric acid.Arsenic compounds are used in making special types of glass, as a wood preservative and, lately, in the semiconductor galliumarsenade, which has the ability to convert electric current to laser light. Arsine gas AsH3, has become an important dopant gas in the microchip industry, although it requires strict guidelines regarding its use because it is extremely toxic (Norman, Nicholas C 1998}. Arsenic compounds resemble in some respects those of phosphorus which occupies the same group (column) of the periodic table. Arsenic is less commonly observed in the pentavalent state, however. The most common oxidation states for arsenic are: −3 in the arsenides, such as alloy-like intermetallic compounds, +3 in the arsenites, and +5 in the arsenates and most organoarsenic compounds. Arsenic also bonds readily to itself as seen in the square As3−4 ions in the mineral skutterudite. In the +3 oxidation state, arsenic is typically pyramidal owing to the influence of the lone pair of electrons.
Arsenic forms colorless, odorless, crystalline oxidesAs2O3 ("white arsenic") and As2O5 which are hygroscopic and readily soluble in water to form acidic solutions. Arsenic(V) acid is a weak acid. Its salts are called arsenates which are the basis of arsenic contamination of groundwater, a problem that affects many people. Synthetic arsenates include Paris Green (copper(II) acetoarsenite), calcium arsenate, and lead hydrogen arsenate. These three have been used as agriculturalinsecticides and poisons ((Martinez-Finley et al., 2012),(Madelung, Otfried 2004).
All trihalides of arsenic(III) are well known except the astatide which is unknown. Arsenic pent fluoride (AsF5) is the only important pent halide, reflecting the lower stability of the 5+ oxidation state. A large variety of organoarsenic compounds are known. Several were developed as chemical warfare agents during World War I, including vesicants such as lewisite and vomiting agents such as adamsite. Cacodyl acid, which is of historic and practical interest, arises from the methylation of arsenic trioxide, a reaction that has no analogy in phosphorus chemistry (Chisholm, Hugh, et al., 1911)
Atomic number 33
Atomic mass 74.9216 g.mol -1
Electronegativity according to Pauling 2.0
Density 5.7 g.cm-3 at 14°C
Melting point 814 °C (36 atm)
Boiling point 615 °C (sublimation)
Vanderwaals radius 0.139 nm
Ionic radius 0.222 nm (-2) 0,047 nm (+5) 0,058 (+3)
Electronic shell [ Ar ] 3d10 4s2 4p3
Energy of first ionization 947 kJ.mol -1
Energy of second ionization 1798 kJ.mol -1
Energy of third ionization 2736 kJ.mol -1
Standard potential - 0.3 V (As3+/ As )
Manganese is a chemical element with symbol Mn and atomic number 25. It is not found as a free element in nature; it is often found in combination with iron, and in many minerals. Manganese is a metal with important industrial metal alloy uses, particularly in stainless steels.Proposed to be an element by Carl Wilhelm Scheele in 1774, manganese was discovered by Johan Gottlieb Gahn, a Swedish chemist, by heating the mineral pyrolusite (MnO2) in the presence of charcoal later that year. Today, most manganese is still obtained from pyrolusite, although it is usually burned in a furnace with powdered aluminum or is treated with sulfuric acid (H2SO4) to form manganese sulfate (MnSO4), which is then electrolyzed. Manganese phosphating is used as a treatment for rust and corrosion prevention on steel. Depending on their oxidation state, manganese ions have various colors and are used industrially as pigments. The permanganates of alkali and alkaline earth metals are powerful oxidizers. Manganese dioxide is used as the cathode (electron acceptor) material in zinc-carbon and alkaline batteries(Lide, David R. et al, 2004.)
In biology, manganese(II) ions function as cofactors for a large variety of enzymes with many functions Manganese enzymes are particularly essential in detoxification of superoxide free radicals in organisms that must deal with elemental oxygen. Manganese also functions in the oxygen-evolving complex of photosynthetic plants. The element is a required trace mineral for all known living organisms but is a neurotoxin. In larger amounts, and apparently with far greater effectiveness through inhalation, it can cause a poisoning syndrome in mammals, with neurological damage which is sometimes irreversible ((ATSDR b,et al 2007).
1.2.4 PHYSICAL AND CHEMICAL PROPERTIES OF MANGANESE
Manganese is a pinkinsh-gray, chemically active element. It is a hard metal and is very brittle. It is hard to melt, but easily oxidized. Manganese is reactive when pure, and as a powder it will burn in oxygen, it reacts with water (it rusts like iron) and dissolves in dilute acids. Manganese is one of the most abundant metals in soils, where it occurs as oxides and hydroxides, and it cycles through its various oxidation states. Manganese occurs principally as pyrolusite (MnO2), and to a lesser extent as rhodochrosite (MnCO3). More than 25 million tonnes are mined every year, representing 5 million tons of the metal, and reserves are estimated to exceed 3 billion tonnes of the metal. The main mining areas for manganese ores are South Africa, Russia, Ukraine, Georgia, Gabon and Australia. Manganese is an essential element for all species. Some organisms, such as diatoms, molluscs and sponges, accumulate manganese. Fish can have up to 5 ppm and mammals up to 3 ppm in their tissue, although normally they have around 1 ppm (Rancke-Madsen, E., 1975)
Manganese metal and its common ions are paramagnetic Manganese tarnishes slowly in air and "rusts" like iron, in water containing dissolved oxygen. Naturally occurring manganese is composed of one stable isotope, Mn. Eighteen radioisotopes have been characterized, with the most stable being Mn with a half-life of 3.7 million years, Mn with a half-life of 312.3 days, and Mn with a half-life of 5.591 days. All of the remaining radioactive isotopes have half-lives that are less than three hours and the majority of these have half-lives that are less than one minute. This element also has three metal states.The most stable oxidation state for manganese is +2, which has a pale pink color, and many manganese(II) compounds are known, such as manganese(II) sulfate (MnSO4) and manganese(II) chloride (MnCl2) (Corathers, Lisa A., 2009)
This oxidation state is also seen in the mineral rhodochrosite (manganese (II) carbonate). The +2 oxidation number of Mn results from removal of the two 4s electrons, leaving a "high spin" ion in which all five of the 3d orbitals contain a single electron. Absorption of visible light by this ion is accomplished only by a spin-forbidden transition in which one of the d electrons must pair with another, to give the atom a change in spin of two units. Manganate (VI) salts can also be produced by dissolving Mn compounds, such as manganese dioxide, in molten alkali while exposed to air. Solutions of potassium permanganate were among the first stains and fixatives to be used in the preparation of biological cells and tissues for electron microscopy (Corathers, L. A.; Machamer, J. F., 2006).
Atomic number 25
Atomic mass 54.9380 g.mol -1
Electronegativity according to Pauling 1.5
Density 7.43 g.cm-3 at 20°C
Melting point 1247 °C
Boiling point 2061 °C
Vanderwaals radius 0.126 nm
Ionic radius 0.08 nm (+2) ; 0.046 nm (+7)
Electronic shell [ Ar ] 3d5 4s2
Energy of first ionization 716 kJ.mol -1
Energy of second ionization 1489 kJ.mol -1
Standard potential - 1.05 V ( Mn2+/ Mn )
1.2.5 TOXICITY OF ARSENIC AND MANGANESE
Arsenic and many of its compounds are especially potent poisons. Arsenic toxicity inactivates up to 200 enzymes, most notably those involved in cellular energy pathways and DNA replication and repair, and is substituted for phosphate in high energy compounds such as ATP. Unbound arsenic also exerts its toxicity by generating reactive oxygen intermediates during their redox cycling and oxygen intermediates during their redox cycling and metabolic activation processes that cause lipid peroxidation and DNA damage. 29As III, especially, binds thiol or sulfhydryl groups in tissue proteins of the liver, lungs, kidney, spleen gastrointestinal mucosa, and keratin-rich tissues (skin, hair, and nails) (Vigo, J. B., and J. T. Ellzey, 2006)
Arsenic disrupts ATP production through several mechanisms. At the level of the citric acid cycle, arsenic inhibits pyruvate dehydrogenase and by competing with phosphate it uncouples oxidative phosphorylation, thus inhibiting energy-linked reduction of NAD+, mitochondrial respiration, and ATP synthesis. Hydrogen peroxide production is also increased, which might form reactive oxygen species and oxidative stress. These metabolic interferences lead to death from multi-system organ failure (see arsenic poisoning) probably from necrotic cell death, not apoptosis. A post mortem reveals brick red colored mucosa, due to severe hemorrhage. Although arsenic causes toxicity, it can also play a protective role. Studies have demonstrated that the oxidative stress generated by arsenic may disrupt the signal transduction pathways of the nuclear transcriptional factors. PPAR’s, AP-1, and NF-κB, as well as the pro-inflammatory cytokines IL-8 and TNF-α. The interference of oxidative stress with signal transduction pathways may affect physiological processes associated with cell growth, metabolic syndrome X, glucose homeostasis, lipid metabolism, obesity, insulin resistance, inflammation, and diabetes-2. Recent scientific evidence has elucidated the physiological roles of the PPAR’s in the ω- hydroxylation of fatty acids(Vahter M, Concha G July, 2001).
1.2.6 MECHANISM OF ACTION OF ARSENIC.
Arsenite inhibits not only the formation of acetyl-CoA but also the enzyme succinic dehydrogenase. Arsenate can replace phosphate in many reactions. It is able to form Glc-6-Arsenate in vitro; therefore it has been argued that hexokinase could be inhibited. (Eventually this may be a mechanism leading to muscle weakness in chronic arsenic poisoning.) In the glyceraldehyde-3-P-dehydrogenase reaction arsenate attacks the enzyme-bound thioester. The formed 1-arseno-3-phosphoglycerate is unstable and hydrolyzes spontaneously. Thus, ATP formation in Glycolysis is inhibited while bypassing the phosphoglycerate kinase reaction. (Moreover, the formation of 2,3-bisphosphoglycerate in erythrocytes might be affected, followed by a higher oxygen affinity of hemoglobin and subsequently enhanced cyanosis) As shown by Gresser (1981), submitochondrial particles synthesize Adenosine-5’-diphosphate-arsenate from ADP and arsenate in presence of succinate. Thus, by a variety of mechanisms arsenate leads to an impairment of cell respiration and subsequently diminished ATP formation. This is consistent with observed ATP depletion of exposed cells and histopathological findings of mitochondrial and cell swelling, glycogen depletion in liver cells and fatty change in liver, heart and kidney (Hughes MF July, 2002).
Experiments demonstrated enhanced arterial thrombosis in a rat animal model, elevations of serotonin levels, thromboxane and adhesion proteins in platelets, while human platelets showed similar responses. The effect on vascular endothelium may eventually be mediated by the arsenic-induced formation of nitric oxide. It was demonstrated that +3 As concentrations substantially lower than concentrations required for inhibition of the lysosomal protease cathepsin L in B cell line TA3 were sufficient to trigger apoptosis in the same B cell line,
while the latter could be a mechanism mediating immunosuppressive effects. Another aspect is the similarity of arsenic effects to the heat shock response. Short-term arsenic exposure has effects on signal transduction inducing heat shock proteins with masses of 27, 60,70,72,90,110 kDa as well as metallotionein, ubiquitin, mitogen-activated [MAP] kinases, extracellular regulated kinase [ERK], c-jun terminal kinases [JNK] and p38. Via JNK and p38 it activates c-fos, c-jun and egr-1 which are usually activated by growth factors and cytokines. The effects are largely dependent on the dosing regime and may be as well inversed (Gresser MJ June, 1981).
As shown by some experiments reviewed by Del Razo (2001), ROS induced by low levels of inorganic arsenic increase the transcription and the activity of the activator protein 1 (AP-1) and the nuclear factor-κB (NF-κB) (maybe enhanced by elevated MAPK levels), which results in c-fos/c-jun activation, over-secretion of pro-inflammatory and growth promoting cytokines stimulating cell proliferation. Germolec et al. (1996) found an increased cytokine expression and cell proliferation in skin biopsies from individuals chronically exposed to arsenic-contaminated drinking water.
Increased AP-1 and NF-κB obviously also result in an up-regulation of mdm2 protein, which decreases p53 protein levels.] Thus, taking into account p53’s function, a lack of it could cause a faster accumulation of mutations contributing to carcinogenesis. However, high levels of inorganic arsenic inhibit NF-κB activation and cell proliferation. An experiment of Hu et al. (2002) demonstrated increased binding activity of AP-1 and NF-κB after acute (24 h) exposure to +3 sodium arsenite, whereas long-term exposure (10–12 weeks) yielded the opposite result. The authors conclude that the former may be interpreted as a defense response while the latter could lead to carcinogenesis. As the contradicting findings and connected mechanistic hypotheses indicate, there is a difference in acute and chronic effects of arsenic on signal transduction which is not clearly understood yet (Hu Y, Su L, Snow ET September, 1998).
1.2.7 ABSORPTION AND METABOLISM OF ARSENIC
The major site of absorption is the small intestine by an electrogenic process involving a proton (H+) gradient. The optimal pH for arsenic absorption is 5.0,38 though in the milieu of the small bowel the pH is approximately 7.0 due to pancreatic bicarbonate secretion. The absorbed arsenic undergoes hepatic biomethylation to form monomethylarsonic acid and dimethylarsinic acid that form monomethylarsonic acid and dimethylarsinic acid that are less toxic but not completely innocuous. About 50% of the ingested dose may be eliminated in the urine in three to five days. Dimethylarsinic acid is the dominant urinary metabolite (60%–70%) compared with monomethylarsonic acid. A small amount of inorganic arsenic is also excreted small amount of inorganic arsenic is also excreted unchanged. After acute poisoning electrothermal atomic absorption spectrometry studies show that the highest concentration of arsenic is in the kidneys and liver (Vahter M, Concha G July 2001).
In chronic arsenic ingestion, arsenic accumulates in the liver, kidneys, heart, and lungs and smaller amounts in the muscles, nervous system, gastrointestinal tract, and spleen. Though most arsenic is cleared from these sites, residual amounts remain in the keratin-rich tissues, nails, hair, and skin. After about two weeks of ingestion, arsenic is deposited (Styblo M, Thomas DJ April, 2001).
1.2.8 TOXICITY OF MANGANESE
Manganism or manganese poisoning is a toxic condition resulting from chronic exposure to manganese. It was first identified in 1837 by James Couper.Chronic exposure to excessive manganese levels can lead to a variety of psychiatric and motor disturbances, termed manganism. Generally, exposure to ambient manganese air concentrations in excess of 5 micrograms Mn/m3 can lead to Mn-induced symptoms(Kulig et al., 1996).
In initial stages of manganism, neurological symptoms consist of reduced response speed, irritability, mood changes, and compulsive behaviors. Upon protracted exposure symptoms are more prominent and resemble those of idiopathicParkinson's disease, as which it is often misdiagnosed, although there are particular differences in both the symptoms (nature of tremors, for example), response to drugs such as levodopa, and affected portion of the basal ganglia. Symptoms are also similar to Lou Gehrig's disease and multiple sclerosis(Santamaria, 2008).
Excess manganese interferes with the absorption of dietary iron. Long-term exposure to excess levels may result in iron-deficiency anemia. Increased manganese intake impairs the activity of coppermetallo-enzymes. Manganese overload is generally due to industrial pollution. Workers in the manganese processing industry are most at risk. Well water rich in manganese can be the cause of excessive manganese intake and can increase bacterial growth in water. Manganese poisoning has been found among workers in the battery manufacturing industry (Stansbie, John Henry,2007).
Symptoms of toxicity mimic those of Parkinson's disease (tremors, stiff muscles) and excessive manganese intake can cause hypertension in patients older than 40. Significant rises in manganese concentrations have been found in patients with severe hepatitis and posthepaticcirrhosis, in dialysis patients and in patients suffering heart attacks.
Manganese influences the copper and ironmetabolism and estrogen therapy may raise serum manganese concentration, whereas glucosteroids alter the manganese distribution in the body. Calcium deficiency increases manganese absorption. Elevated calcium and/or phosphorus intake suppress the body's ability to absorb manganese, while an increase in Vitamin C improves cellular exchange. Manganese overload is generally due to industrial pollution. Workers in the manganese processing industry are most at risk. Drinking water should be analyzed when manganese toxicity is suspected. Long term parenteral nutrition has been associated with high blood concentrations of manganese in children who displayed symptoms of toxicity (Silva Avil et al,2013).
Dark hair dyes can contain manganese and thus falsely elevate hair levels. In the case of extremely high manganese levels obtained from scalp hair, pubic hair should be tested as a control.Manganism is a biphasic disorder. In its early stages, an intoxicated person may experience depression, mood swings, compulsive behaviors, and psychosis. Early neurological symptoms give way to late-stage manganism, which resembles Parkinson's disease. Symptoms include weakness, monotone and slowed speech, an expressionless face, tremor, forward-leaning gait, inability to walk backwards without falling, rigidity, and general problems with dexterity, gait and balance. Unlike Parkinson's disease, manganism is not associated with loss of smell and patients are typically unresponsive to treatment with L-DOPA. Symptoms of late-stage manganism become more severe over time even if the source of exposure is removed and brain manganese levels return to normal( Finley, John Weldon; Davis, Cindy D. ,1999).
1.3.0 EPIDERMOLOGY OF ARSENIC AND MANGANESE WORLDWIDE
Establishment of the maximum contaminant level that regulates the concentration of arsenic in public water supplies in the United States was a protracted process. The Public Health Service (PHS) set an interim standard of 50 ug/I in 1942 and stated that the goal should be 10 ug/L in 1962, but it was another forty years before the U.S. Environmental Protection Agency actually lowered the standard to 10 ug/1. Despite extensive epidemiological evidence of significant cancer risks accumulated over many years, the US flip-flopped on the drinking water standard before and after the transition from the Clinton to the Bush Administrations. One problem is that regulators, and many scientists, having learned the terms "confounding" and "exposure misclassification", appear to be more comfortable with the results of experimental animal studies than human epidemiological studies. In the case of arsenic, there are clear increased risks of human cancer once concentrations reach 200ug/L in drinking water, whereas there is little response in standard animal bioassays, even at concentrations of 50,000ug/L and above. Furthermore, at concentrations above 500ug/L, the human risks are extraordinarily high, with one in ten exposed persons dying from arsenic-caused cancers. Such contrasts in cancer risks between animals and humans are unprecedented. Furthermore, the lung may be the main site of long-term human health effects from ingestion of arsenic in water (which is hard to swallow), and epidemiological data suggest that the risk from arsenic inhalation may be equivalent to that from ingestion (also hard to swallow). There are important lessons to be learned from the history of arsenic drinking water regulations and a lot more yet to learn from epidemiological studies of the health effects of human exposure to arsenic.
The epididymis is a tube that connects a testicle to a vas deferens in the male reproductive system. It is present in all male reptiles, birds, and mammals. It is a single, narrow, tightly-coiled tube (in adult humans, six to seven meters in length connecting the efferent ducts from the rear of each testicle to its vas deferens.
Fig1.2: structure of epididymis
The epididymis can be divided into three main regions:
⦁ The head: The head of the epididymis receives ⦁ spermatozoa via the ⦁ efferent ducts of the ⦁ mediastinium of the ⦁ testis. It is characterized ⦁ histologically by a thin ⦁ myoepithelium. The concentration of the sperm here is dilute.
⦁ The body
⦁ The tail :This has a thicker myoepithelium than the head region, as it is involved in absorbing fluid to make the sperm more concentrated.
In reptiles, there is an additional canal between the testis and the head of the epididymis and which receives the various efferent ducts. This is, however, absent in all birds and mammals.