Toxic effects of inorganic salts Elaine Leslie eleslie email unc edu 962 0089 Room 2308 Kerr Hall Source Material not reading assignments Klassen CD Heavy metals and heavy metal antagonists In Hardman JG Limbird LL eds Goodman and Gilman s The Pharmacological Basis of Therapeutics 10th edition Chapter 67 McGraw Hill 2001 Bhattacharyya MH et al Biochemical Pathways in Cadmium Toxicity In Zalups RK and Koropatnick J eds Molecular Biology and Toxicology of Metals Chapter 2 Taylor and Francis 2000 Tchounwou et al 2003 Environmental Exposure to Mercury and Its Toxicopathologic Implications for Public Health Envirn Toxicol 18 149 175 Metals and other inorganics Why are they of such concern Widely distributed in the natural environment Non biodegradable Persistent in the environment Neither created nor destroyed by humans Concentrated due to industrial use Global dispersion due to human use Human Industry and Environmental Metals Lead in Greenland Ice Lead Content ng kg snow 250 200 150 100 50 0 1750 1800 1850 1900 Date of Samples Modified From Clarkson et al 1950 2000 What is a Metal Physical properties electrical conductivity thermal conductivity luster deformed without cleavage under stress Chemical properties tendency to donate electrons cationic formation of basic oxides Types of Metals Alkali metals Metalloids Alkaline earth metals Other metals Transition heavy metals Inner transition metals rare earths Metals as Toxic Agents The toxic metals often follow essential metal metabolic pathways atomic or molecular mimicry Metal compounds can also mimic organic compounds Metals often accumulate in biological systems Metals as elements are indestructible cannot be broken down into less toxic subunits Molecular Mimicry with Metals Uptake of Ionic Cadmium Cell Cellular Cadmium Uptake 12 10 8 Cd Cd 2 6 4 ATP Zn 2 2 0 Control NEM KCN Zinc SH SH Zn Highly Toxic Inorganics Several metals metalloids are considered to be high priority hazardous substances Metals considered highly toxic include arsenic beryllium cadmium chromium lead mercury and nickel Many are potent neurotoxins eg lead Out of 30 known human carcinogens 5 are metals Example Metals Metalloids Considered Human Carcinogens As Be Cr Ni Cd Carcinogenic Metals Metalloids Known human carcinogenic metals arsenic skin bladder lung liver beryllium lung cadmium lung possibly prostate chromium lung sino nasal cavity nickel lung sino nasal cavity Metals Metalloids as Toxic Agents Many metals are essential Essential metals have intentional accumulation transport and storage mechanisms to allow safe use Examples metallothionein for copper or zinc storage transferrin and ferritin for iron transport and storage Essential Metals Examples of essential metal nutrients Co Cr Cu Fe Zn Other possible essential metals As Ni Examples of metal functions that are essential to life regulation of gene expression DNA synthesis and repair enzyme activity and structure oxygen transport Life could not continue without metals Factors Influencing Metal Toxicity Standard factors exposure related dose route duration frequency subject related age sex species biotransformation agent related speciation form Essentiality essential metals have safe transport storage utilization systems Sensitive subpopulations Acquired tolerance Toxic Metal metal Exposure site Presystemic elimination Excretion Target distribution Detoxication Reabsorption Toxication Target Site Delivery Absorption Distribution away from target Ultimate Ultimate Toxicant toxicant Target Molecule Factors Influencing Metal Toxicity Sensitive Subpopulations and Environmental Exposure Sensitive subpopulations have been observed in several diseases induced by environmental metal exposure Examples Minimata disease in utero exposed populations most affected Itai Itai disease post menopausal multiparous women most affected Lead toxicity children much more vulnerable Factors Influencing Metal Toxicity Acquired Tolerance Examples enhanced sequestration activation of MT gene and cadmium sequestration reduced uptake or enhanced excretion arsenic nickel cadmium altered metabolism arsenic and upregulation of glutathione S transferase facilitates efflux General Mechanisms of Metal Toxicology Several general mechanisms of metal toxicity extensive overlap General mechanisms include osmotic cell death not trivial usually at a point of locally high metal concentrations inhalation of metal particles metal fragments or devices in chronic contact with tissues General Mechanisms of Metal Toxicology continued disruption of normal cellular metabolism leading to aberrant metabolism or altered homeostasis frequently occur through atomic or molecular mimicry examples disruption of essential metal metabolism depletion of cofactors e g S adenosyl methionine depletion of GSH could result in altered cellular redox status etc General Mechanisms of Metal Toxicology continued direct binding to cellular components direct binding leading to dysfunction enzyme inhibition DNA adduction etc direct binding through mimicry leading to aberrant function gene activation receptor activation etc direct binding through mimicry leading to displacement of essential metal adverse effect of released essential metal disrupted homeostasis General Mechanisms of Metal Toxicology continued indirect attack on cellular components generation of radicals that attack cellular components directly with redox active metals eg Ni Cr Cu etc indirectly with metals that displace redox active essential metals eg Fe Cu adverse effects of radical attack disruption of protein conformation leading to dysfunction diminished or enhanced oxidative DNA damage or base modification leading to aberrant gene expression or mutation lipid peroxidation and membrane disruption Inorganics of highest environmental concern cadmium mercury lead and arsenic Cadmium Relatively rare metal present in the earth s crust Occurs in only one valency state Cd2 Used as Protective coating on steel Colored pigments in paints and plastics bright yellow orange and red Rechargeable nickel cadmium batteries Biproduct of burning fossil fuels esp coal Exposure workplace food cigarette smoke 1 2 g cigarette plants accumulate Cd in leaves Cadmium accumulates in body over time increases with age 50 years of age kidney Cd concentrations Smoker 25 g g Non smoker 12 g g Targets Kidney more on mechanism Lung emphysema Bone exposure associated with risk of osteoporosis height loss bone fractures Cd interacts with