Toxic Effects on the Structure of DNA - Term Paper Example

INTRODUCTION LEAD Physical and chemical properties Lead (Pb), a metal with an atomic weight 207.2 and atomic number 82, is soft bluish-gray acid-soluble element, exhibiting a bright luster when freshly cut, but tarnishes in moist air to form a dull gray coating. The metal element belongs to Group 14 (IV A) of the periodic table and has a density of 11.3437 g cm-3 at 20º C. It is highly ductile and very malleable, resistant to corrosion and has a low melting point (327.35 º C). It is also a poor conductor of electricity (ATSDR., 2008) Naturally, Pb is a mixture of four isotopes: 208 Pb (51-53 %), 206 Pb (23.5-27%), 207 Pb (20.5-23%) and 204 Pb (1.35-1.5 %).These isotopes are the stable decay product of three naturally radioactive elements : 206 Pb from Uranium, 207 Pb from actinium and 208Pb from thorium(Agency for Toxic Substances and Disease Registry (ATSDR), 2005) . Lead rarely exists as a metal, but rather, in combination with two or more elements to form Pd compounds. The element has three oxidation states (0 or the metal state, +2 and +4), the most common oxidative state being +2. Lead generally exhibits has amphoteric properties; +2 (basic) and +4 (acidic) (APHA, 1999). Sources and uses of Pb Lead is an element that naturally occurs in the earth’s crust. Ore deposits of Pb include galena (PBS), anglesite (PbSO4) and cerussite (PbCO3). Anthropogenic sources of Pb in the environment , include : homes (household dust, peeling of lead-based paints, toys, furniture, table ware etc.), contaminated food (food grown in Pb-contaminated soil or sprayed with Pb insecticides), soils and dust (flaking or weathering paint, improper renovation and disposal of building materials, roadside - contamination from leaded gasoline, settled dust from industrial sources), water (leaded pipes or connectors and lead- lined tanks), and air (industrial emissions from smelters, incinerators, manufacturing operations, recycling efforts, and leaded gasoline) (Davies, 1995). Historically, Pb was widely used in plumbing, as anti-knock agent in petrol, and as an addictive in paints. However, these uses have recently reduced due to environmental concerns about cumulative lead poisoning. Presently, Pb is used in storage batteries , paints, pigments and colored inks as shielding from radiation, e.g., in x-ray rooms and nuclear reactors. Lead is also used as cable covering, as ammunition, as electrodes, in solder and roofing material.(Martiez , Nagae , Zaia , & Zaia 2004). Environmental fate and importance of Pb The fate and behavior of Pb in the environment is quite complex because of the many compounds of Pb and that can be found and the natural variability of natural systems. In the atmosphere, Pb is in the form of particles and is removed by rain of gravitational settling. In water, solubility of Pb is a function of pH, hardness, salinity and organic matter content of the receiving water. Lead is highly soluble in soft, acidic water (Gidlow, 2004). Soil and sediment is a sink for Pb. Because Pb strongly adsorbs to soil, it is mostly retained in the upper layers and does not leach appreciably into the subsoil and groundwater. There is no known physiologic role of Pb in biological systems. Plants and animals may bioconcentrate Pb, but it is not biomagnified in the aquatic or terrestrial food chain. Older organisms tend to contain higher body burdens of Pb. In aquatic ecosystems, concentrations of Pb are usually highest in benthic organisms and algae, and lowest in the upper trophic level predators (such as carnivorous fish).(Mager, 2011). TOXICITY AND EFFECTS Toxicity is the relative ability of a substance to cause harm to biological tissue. The dose (quantity of substance to which a test organism is exposed), determines if the effect of any substance are toxic, non-toxic, or beneficial (Gidlow, 2004). Toxicity results can be classified as acute or chronic. Acute toxicity involves adverse effects in organisms following single exposure to a substance. On the other hand, chronic toxicity occurs when a substance causes adverse effects over an extended period of time, sometimes lasting for the entire life of the exposed organism, due to continuous or repeated exposure (ATSDR., 2008; Parrish, 1995). A particular toxicity test exhibits dose-response relationship, when there is a consistent mathematical relationship between the proportion of individuals responding and a given dose, for a given exposure period. Often, the dose is described as lethal dose (LD), if the response is mortality, or effective dose (ED), when the response is some other observable effect (ATSDR., 2008). Lead toxicity is one of the most significant preventable causes of neurologic morbidity from an environmental toxin (Hardman, 2006; Plant, Baldock, & Smith, 1996). In humans, exposure to Pb results in pervasive, yet often subtle effects, with consequences ranging from cognitive impairment in children to peripheral neuropathy in adults (Murata, Iwata, Dakeishi, & Karita, 2009). Acute toxicity effects of Pb are not common in humans. Children are particularly susceptible because of high gastrointestinal uptake and the permeable blood-brain barrier (Davies, 1995). A battery of living organisms from various levels of the food chain, including bacteria, invertebrates and fish, have been used in bioassays to evaluate toxicity of environmental media. The test species selected must be a good model of humans; the response produced should not be subjective, and it can be consistently determined within a relatively short time period(APHA, 1999). The median lethal effective concentration (EC50 / LC50) is the concentration of a substance in an environmental medium that is expected to produce a certain effect or response, in 50 % of test organisms in a given population, under a defined set of conditions. In the specific case of LC50, the effect is the death of 50 % target organisms. Therefore, EC stands for ‘effective concentration’ and LC for ‘lethal concentration’ (ATSDR., 2008; McNaught & Wilkinson 1997). An example of sample data for an acute toxicity experiment of Pb on a freshwater fish species, common carp (Ciprinus carpio) by Hedeyati et al., (2013), is displayed in Table 1. Table 1: Fish mortality data for Ciprinus carpio over a period of 96 hours Time Fish Mortality in different concentrations of Pb Control 0 mg L-1 3 mg L-1 15 mg L-1 60 mg L-1 120 mg L-1 24 h 0 0 0 0 3 48 h 0 0 0 1 10 72 h 0 0 0 6 19 96 h 0 0 0 13 21 (n=21, LC50 = 58.0 mg L-1) The Finney’s method of probit analysis can be used to derive the LC50 for the sample data (Table 1), by fitting a regression equation arithmetically and interpolation. The logs of test chemicals are plotted on the x-axis and probit values of percentage mortality on y–axis (Hedayati, Jahanbakhshi, Shaluei, & Kolbadinezhad, 2013). Acute toxicity (Fish) In acute fish toxicity tests, at least five concentrations of the test substance and a control (water only), are used. The test organisms are exposed to the test chemical added to water in fibre glass tanks, in with two or more replicates. During the assay, no food is added to the tank and media is not renewed. Mortalities are measured at 0, 24, 48, 72 and 96 hours. As a rule of thumb, a toxicity test is valid if the mortality in the control is zero or less than 10% of the population (Hedayati, et al., 2013). The Common Carp (Ciprinus carpio), a fresh water fish species, is one of the most studied fish species, due to its high sensitivity to toxicants. In this report, it has been selected as the model species for acute toxicity testing. Sample data of 96 hour –LC50 values of Ciprinus carpio exposed to Pb are given as follows: 77.33 mg L-1 (Abedi, Khalesi, Eskandari, & Rahmani, 2012) , 0.44 mg L-1 and , 0.80 mg L-1 (Alam & Maughan, 1995 ) , 58.0 mg L-1 (Hedayati, et al., 2013) and 2.624 mg L-1 mg L-1. The differences in LC50 are due to variability in concentrations of Pb (Nekoubin, Gharedaashi, Hosseinzadeh, & Imanpour, 2012). Results of Chronic test EC50 Chronic tests are long term tests (lasting several weeks or years), relative to an organism’s lifespan and they use sub-lethal endpoints. In these tests, organisms are often exposed to low concentrations of test substances, repeatedly or continuously. The responses resulting from chronic exposure develop slowly. While the acute test uses LC50 as the endpoint, chronic tests use the No observable effect concentration (NOEC) and Lowest observed effect Level (LOEC)(Antilla, Keikkila, & Pukkala, 1995). There are several studies that have assessed the effects of prolonged exposure to Pb in freshwater fish. A wide range of effects are reported as having been induced by continuous exposure to Pb concentrations, over a long period of time. Chronic toxicity is manifested in form of neurological, hematological dysfunctions. Some of the effects include: pituitary function, gonadosomatic index, oocyte growth, anaemia, neurological disorders and scoliosis, among others (Mager, 2011). Few studies exist, that have examined the physiological and biochemical effects of prolonged exposure of freshwater invertebrates. However, there are plenty of reports on invertebrates’ mortality, due to Pb exposure. It is also documented in literature that toxicity arising from chronic toxicity from chronic Pb exposure is not likely to occur in rotifers and midge larvae(MacDonald & Ingersoll, 2002). Lead poisoning in human beings is a common cause of neurologic morbidity globally. Children are the most vulnerable to Pb exposure. Most pediatric cases result from exposure to Pb, although ingestion of foreign bodies is another common cause. They present symptoms such as irritability, inactivity, gastrointestinal discomfort, lethargy, and seizures(Murata, et al., 2009). The symptoms of Pb intoxication normally vary depending on route of entry and period of exposure and age of the patient (ATSDR., 2008) . Chronic effects of Pb exposure in humans include, but not limited to: anaemia, neurologic disorders (such as fatigue, sleep disturbance, headache, irritability, slurred speech, convulsions, muscle weakness, ataxia, tremor and paralysis), and, reproductive dysfunctions (Murata, et al., 2009) . From literature, it is evident that chronic effects of Pb are consistent between fish and mammals, involving primarily neurological and haematological dysfunctions. Sub-lethal effects of Pb generate higher order effects such as reduced swimming performance, with important ecological ramifications. Impaired swimming ability could be a consequence of Pb induced (anaemia) , (Hedayati, et al., 2013). Bio concentration factors (BCF) Bioconcentration is the accumulation of a chemical in the tissues of an organism, as a result of direct exposure to the surrounding medium such as water. It does not include food web transfer (MacDonald & Ingersoll, 2002). On the other hand, bioaccumulation involves the mechanism by which chemicals are taken up by an organism, either directly from exposure to a contaminated medium or by the consumption of food containing the chemical (U.S. Environmental Protection Agency, 2010). The Bioconcentration factor (BCF) and bioaccumulation factor (BCF) are used as criteria for identifying and classifying chemical substances that are hazardous to the environment. This criterion is applied to all environmental contaminants, including metals. Uptake and accumulation of Pb by aquatic organisms from water and sediment are influenced by various environmental factors including temperature, salinity, and pH, humic as well as alginic acid. In most cases, it is not clear whether Pb is absorbed onto the organism or actually ingested / inhaled. Consumers can take up Pb from the environment up to high concentrations ,without causing bioaccumulation (McGeer et al., 2003). Aquatic organisms have served a role in regulatory decisions concerning most potent environmental hazards. The uptake of substances from water via respiratory surface and / or skin by these organisms (both primary producers and consumers in aquatic ecosystems is a factor of their bioavailability(Hardman, 2006). Uptake of Pb by fish reaches equilibrium few weeks after they are exposed. Lead is mostly accumulated in the gill, liver, kidney and bone. Eggs of fish show increasing levels of PB with increased exposure concentration(MacDonald & Ingersoll, 2002). Carcinogenicity Lead is an established animal carcinogen. There is evidence from recent epidemiological and experimental studies that inorganic Pb compounds are associated with increased tumorigenesis. On the basis of “sufficient” animal data and “inadequate” human data, Pb and its compounds are currently considered as a possible human carcinogen (Group 2 B) by the International Agency for Cancer Research (IACR). According to the IACR, organic Pb compounds are not classifiable as to their carcinogenicity to humans (Group 3), meaning, that there is inadequate evidence for their carcinogenicity to humans (Silbergeld, Waalkes, & Rice, 2000). Several epidemiological studies on lead workers have found inconclusive evidence on the linkage between Pb exposure and the incidence of cancer. Most studies did not take into consideration, the confounding factors such as smoking and exposure to potential carcinogens(Antilla, et al., 1995). For example, a study in Sweden suggested a slight excess of lung cancer in certain Pb workers in a foundry(Lundstrom, Nordberg, & Englyst, 1997). To date, it has not been determined whether this effects or responses were due to the confounding effect of arsenic, which is a potential inducer of lung cancer. There is insufficient data for suggesting that Pb compounds are carcinogenic in humans (Gidlow, 2004). In animals, the risks of Pb causing cancer can be induced at doses that are not associated with organ toxicity and in mice that do not produce α-2 urinary globulin in the kidney. Plausible mechanisms of Pb carcinogenicity include direct DNA damage, clastogenicity, or the inhibition of DNA synthesis or repair. Also, Pb can generate reactive oxygen species ,ultimately resulting in oxidative damage to DNA(Silbergeld, et al., 2000). Teratogen The term teratogen is used to define agents or conditions, including viruses, drugs, chemical stressors and malnutrition, which have the ability to impair prenatal development and cause birth defects or even death. Teratogen bring about congenital malformations, most of which demonstrate multifactorial inheritance , with a threshold and are derived from a combination of environmental as well as genetic factors (Lundstrom, et al., 1997). Being a toxic metal, Pb can act as a teratogen by preventing implantation of the embryo, delaying its growth during the late r stages of pregnancy and sometimes cause malformations, particularly under conditions of calcium deficiency(ATSDR., 2008). Usually, the types and severity of birth defect/abnormality due to exposure to a potent teratogenic agent is a factor of genetic susceptibilities carried by the mother and foetus. For example, when the maternal metabolism of a drug is variable, it will determine the type of metabolites of the foetus will be exposed to. Also, the fetal genetic susceptibility will determine the effect on the final outcome. Lead is a reproductive toxin to both men and women. Generally, Pb exposure that can affect reproduction and health is work related / occupational. It is evident from study reports that uteri exposure to low levels of Pb causes infant and child neurodevelopment. For example, significantly lower scores on the Bayer Development Index (BMDI) were found in children with pre-natal Pb exposure. Other effects included lower scores on verbal IQ components, impaired hearing and motor development, increased learning disabilities and attention deficit disorders(Antilla, et al., 1995). Mutagenicity Agents or substances which cause alteration in genetic makeup or mutation are collectively termed as mutagens. Under experimental conditions, mutagens have carcinogenic properties and they also lead to birth defects (teratogens). Mutagenic substances induce DNA damage that kills cells or produces abnormal but stable changes in the DNA sequence which passes on to daughter cells. Such-like actions in turn will lead to birth defects by injuring developing organs. Lead is a clastogenic agent which is capable of causing chromosomal aberrations, micronuclei and sister chromatid exchanges in peripheral blood cells form Pb works(ATSDR., 2008). Scientific studies of the relationship between the genotoxic potential of Pb has received much attention in recent years, though most of the results obtained were inconclusive. Although studies conducted in bacteria gave negative results for potential for induction of mutation following exposure to Pb, an assay detecting the induction of λ prophage in Escherichia coli gave positive results(Davies, 1995). A similar study using mammalian cells determined induction of mutation in the hprt locus in Chinese Hamster V79 cells by Pb compounds. However ,the results from these studies, which involved induction of chromosomal aberrations ,both in vivo and in vitro showed ambiguous results ; the genotoxic response appears to be influence by synergistic effects. For example, it is reported that calcium-deficient animals that were exposed to Pb showed more severe chromosomal aberrations than those that were non-deficient. These, coupled with other factors, accounted for the high variability in results(Davies, 1995). Fish species have been widely used to study chromosomal aberrations .Lead compounds (oxidation state +2) showed significant increase in DNA damage by inducing single strand breaks. This is due to inactivation of DNA repair mechanisms. REFERENCES Abedi, Z., Khalesi, M., Eskandari, S. K., & Rahmani, H. (2012). Comparison of Lethal Concentrations (LC50-96h) of CdCl2,CrCl3 and Pb(NO3)2 in common carp (Cyprinus carpio) and Sutchi catfish (Pangasius hypophthalmus). Iranian Journal of Toxicology, 6(18). Agency for Toxic Substances and Disease Registry (ATSDR). (2005). Toxicological profile for lead. Atlanta: US Department of Health and Human Services, Public Health Service. Alam, M. K., & Maughan, O. E. (1995 ). Acute toxicity of heavy metals to common carp (Cyprinus carpio) Journal of Environmental Science and Health . Part A: Environmental Science and Engineering and Toxicology 30( 8). Antilla, A., Keikkila, P., & Pukkala, E. (1995). Excess lung cancer among workers exposed to lead. Scand J Work Environ Health, 21, 460-469. APHA. (1999). Standard Methods for the Examination of Water and Wastewater. American Water Works Association, Water Environment Federation. ATSDR. (2008). Draft Toxicological Profile for Lead. Atlanta, Georgia: US Department of Health and Human Services. Davies, B. E. (1995). Lead and other heavy metals in urban areas and consequences for the health of their inhabitants. . In S. K. Majumdar, E. W. Miller & F. J. Brenner (Eds.), Environmental Contaminants, Ecosystems and Human Health (pp. 287-307): The Pennsylvania Academy of Science, Easton PA, USA. Gidlow, D. A. (2004). Indepth Review: Lead toxicity. Occupational Medicine, 54, 76-81. Hardman, R. (2006). A toxicologic review of quantum dots: toxicity depends on physicochemical and environmental factors. Environmental Health Perspectives 114(2), 165-172. Hedayati, A., Jahanbakhshi, A., Shaluei, F., & Kolbadinezhad, S. M. (2013). Acute Toxicity Test of Mercuric Chloride (Hgcl2), Lead Chloride (Pbcl2) and Zinc Sulphate (Znso4) in Common Carp (Cyprinus carpio). . J Clinic Toxicol 3:156. . Lundstrom, N.-G., Nordberg, G., & Englyst, V. (1997). Cumulative lead exposure in relation to mortality and lung cancer morbidity in a cohort of primary smelter workers. Scand J Work Environ Health, 23, 24-30. MacDonald, D. D., & Ingersoll, C. G. (2002). A guidance manual to support the assessment of contaminated sediments in freshwater ecosystems--Volume I, An ecosystem-based framework for assessing and managing contaminated sediments: U.S. Environmental Protection Agency EPA-905-B02-001-A (pp. 149). Mager, E. M. (2011). Homeostasis and toxicology of non-essential metals. Fish Physiology (Vol. 31, pp. 185-236). Martiez , C. B. R., Nagae , M. Y., Zaia , C. T. B. V., & Zaia , D. A. M. (2004). Acute Morphological and Physiological Effects of Lead in the Neotropical Fish , Prochilodus lineatus. Braz. J. Biol. , 64(4), 797-807. McGeer, J. C., Brix, K. V., Skeaff, J. M., DeForest, D. K., Brigham, S. I., Adams, W. J., & Green, A. (2003). Inverse relationship between bioconcentration factor and exposure concentration for metals: Implications for hazard assessment of metals in the aquatic environment. Environmental Toxicology and Chemistry, 22(5), 1017-1037. doi: 10.1002/etc.5620220509 McNaught , A. D., & Wilkinson , A. (1997). IUPAC Compendium of Chemical Terminology. (2 ed.). Oxford, UK: Blackwell Scientific Publications Murata, K., Iwata, T., Dakeishi, M., & Karita, K. (2009). Lead toxicity: does the critical level of lead resulting in adverse effects differ between adults and children? J Occup Health., 51(1), 1-12. Nekoubin, H., Gharedaashi, E., Hosseinzadeh, M., & Imanpour, M. R. (2012). Determination of LC50 of Lead Nitrate and Copper Sulphate in Common Carp ( Ciprinus carpio). American-Eurasian Journal of Toxicological Sciences 4(2), 60-63. Parrish, P. R. (1995). Acute toxicity tests. In G. M. Rand (Ed.), Fundamentals of Aquatic Toxicology: Effects,Environmental Fate, and Risk Assessment. 2 ed (pp. 947±973). Washington DC: Taylor & Francis. Plant, J. A., Baldock, J. W., & Smith, B. (1996). The role of geochemistry in environmental and epidemiological studies in developing countries: a review. . In J. D. Appleton, R. Fuge & G. J. H. McCall (Eds.), Environmental Geochemistry and Health (pp. 7-22): Geological Society Special Publication No 113. Silbergeld, E. K., Waalkes, M., & Rice, J. M. (2000). Lead as a carcinogen: Experimental evidence and mechanisms of action. American Journal of Industrial Medicine, 38(3), 316-323. doi: 10.1002/1097-0274(200009)38:33.0.co;2-p U.S. Environmental Protection Agency. (2010). Solid waste and emergency response glossary-Bioaccumulation: . Retrieved June 29, 2010 Read More