Toxicology of Metals and Metal Compounds

1. Toxicology of Metals and Metal Compounds

2. Toxic Effects of Metals on Humans • Metal compounds are probably among the oldest toxicants known to Mankind • classical authors have described the toxic effects of such compounds • About 80 of the 105 or so elements are regarded as metals, but less than 30 have been reported to produce toxicity in humans • Historically, metal toxicity concerned acute or overt effects • Today, with the improvement in occupational and environmental standards, the interest is more in chronic, long-term effects • e.g. effect of childhood lead exposure on intelligence

3. What are Metals? • A metal in contrast to most non-metals is defined by chemists as: • having a characteristic lustrous appearance • being a good conductor of electricity • considered to consist of positive ions surrounded by a cloud of mobile electrons • generally entering chemical reactions as positive ions (cations) • Elements intermediate in properties between metals and non-metals are often referred to as metalloids or semi-metals

4. Periodic Table - Metals, Semi-Metals, and Non-Metals

5. Particular problem with Metals? • Metal compounds are non-biodegradable • compare many organic pesticides - eventually broken down to less harmful compounds (ideally CO2 and water) • Detoxication of compounds of metals consists of sequestering or hiding them away • in the environment • removal of the pollutants and placing them in a non-available form or situation • in vivo • complexation with the biological sequestering agent, metallothionein (rich in cysteine SH groups which bind covalently to compounds of metals such as Cd, Zn and Cu) • deposition in an insoluble form in intracellular granules for long-term storage or excretion in faeces

6. Essential Elements

7. Essential and Non-Essential Elements - Relation between Performance and Concentration

8. Currently, greatest amount of concern with regard to human health, agriculture and ecotoxicology from: As ("metalloid" or "semi-metal"); Cd; Hg; Pb; Tl (thallium) and U US EPA list of priority pollutant metals includes the following further metals: Sb; Be; Cr; Cu; Ni; Se; Ag; Zn Agriculture adversely affected by deficiencies of "essential" trace elements ("micronutrients"), e.g. for crops - Zn; Cu; Mn for livestock - Zn; Cu; Mn; Co "Heavy Metals" or "Potentially Toxic Elements" (PTE) of Concern

9. Natural processes weathering of rocks leaching degassing (Hg, Rn) biological action Human activity burning of fossil fuels mining discharging industrial, agricultural and domestic waste smelting deliberate environmental application - pesticides, fertilisers sporting activities warfare and military training Dispersion of Metals - Natural Processes and Human Activities

10. Factors influencing Toxicity of Metals • Interactions with essential elements with similar characteristics • Chemical speciation • Ability to sequester metal in stable complexes • metallothionein complexing of Cd and Cu • formation of intracellular insoluble inclusion bodies • Lifestyle factors • Age and stage of development • Immune status of host

11. Factors influencing Toxicity of Metals - Interactions with essential elements with similar characteristics • Calcium and lead • inverse relation between dietary calcium and lead absorption and retention • lead immobilized in bone • lead interferes with calcium messenger (signalling) systems by binding to signal proteins in place of calcium • Iron and lead • inverse relation between dietary iron and lead absorption in experimental animals

12. Factors influencing Toxicity of Metals - Chemical Form or Speciation • Alkyl compounds pass lipophilic membrane barriers more readily • e.g. tetraethyl lead and methyl mercury, • Insoluble compounds may only be fractionally available following inhalation or ingestion • e.g. only about 0.01% of the insoluble 239PuO2 is absorbed following ingestion • The ionic species or oxidation state • e.g. Cr(III) as Cr3+ does not readily cross cell membranes, in contrast to Cr(VI), for example the chromate ion (CrO42-), which can use sulfate and possibly phosphate active transport systems to enter cell, where it is reduced to Cr(III)

13. The Global Cycle of Mercury

14. Toxicities of Different Mercury Species • Main forms: Hg0, Hg2+, and organic mercurials [e.g. dimethylmercury, (CH3)2Hg] • All potentially toxic but toxicities differ considerably • Inorganic mercurials - least toxic: • not readily absorbed from GI tract • can accumulate in kidney but normally excreted rapidly in urine • of these, mercury vapour most hazardous • able to diffuse through lungs to blood and brain to affect CNS • Major human health effects from dimethylmercury (produced by biotransformation): neurotoxic effects

15. Biotransformation of Mercury • Global cycle of mercury believed to involve almost exclusively inorganic forms • These do not normally accumulate in human food chains • Change in speciation from inorganic to methylated forms is first crucial step in bioaccumulation process e.g. Hg0 → Hg2+ → CH3Hg+ → (CH3)2Hg

16. Toxicity of Alkylmercurials • Properties • lipophilic • relatively stable - only slowly transformed into inorganic mercury • long retention times in tissues • markedly neurotoxic • Consequences • bioaccumulative • persistent • toxic

17. Formation of Dimethylmercury • Methylation is brought about by bacterial action mostly on sediments in fresh and ocean waters • Once released from bacteria, dimethylmercury enters the food chain by rapid diffusion and tight binding to proteins in aquatic biota • It attains its highest concentration in the tissues of predatory fish at the top of the aquatic food chain through biomagnification

18. Poisoning Disasters involving Mercury - Minamata Bay incident • In 1950s chemical factory was using (inefficiently) a mercuric salt as catalyst in an acetaldehyde plant • Relatively non-toxic inorganic mercury released in effluent into river running into Minamata Bay • The inorganic mercury was converted into dimethylmercury by bacteria in sediments in the bay • This accumulated in shellfish and fish • These were eaten by the local inhabitants: by 1975, 115 people had died; many were left paralysed for life or suffered permanent neurological damage

19. Uptake of Lead • Taken in by animals by inhalation or ingestion • only lipophilic tetraethyllead can be absorbed through intact skin (in IC engine tetraethyl lead combusted to particulate inorganic lead) • Inhaled lead • up to 50% of inhaled lead may be absorbed • Ingested lead • in adult humans, up to 10% of dietary lead absorbed • in infants and young children proportion can be 50% • diets deficient in various factors (e.g. Ca, phosphate, Se, Zn) may result in increased absorption

20. Metabolism of Lead • Lead compounds initially taken up in blood (90% in erythrocytes, bound to haemoglobin), and circulated throughout body and into soft tissue • Thereafter, slower redistribution to bone (t1/2 can be 20 years - compare about a month in soft tissue) • fraction of lead in bone ranges from about 70% of body lead in childhood to 95% with advancing years • mobilisation from maternal bone of particular concern during pregnancy and lactation, and in persons with osteoporosis

21. Effects on Humans • Enzyme inhibition • inhibits haemoglobin synthesis by inhibiting certain biosynthetic pathway enzymes, causing anaemia • Neurological effects • excess lead levels associated with adverse CNS effects, particularly in children (evidence of IQ deficits in lead-exposed children) • peripheral neuropathy in occupationally exposed persons • reduction in peripheral nerve conductivity • Other effects • kidney damage in occupationally exposed persons • associated with a lead-protein complex in inclusion bodies in renal tubular cells

22. Self Assessment Questions (1) • What proportion of the elements comprises metals? • What differentiates metals from non-metals? • What terms are used to describe elements intermediate in properties between metals and non-metals? • As metal compounds are non-biodegradable, how can they be made safe both in vivo and in the environment? • How, in principle, can essential and non-essential elements be distinguished? • What are “micronutrients”? • What natural processed can give rise to the dispersion of metals?

23. Self Assessment Questions (2) • Why, do you suggest, is there an inverse relationship between dietary calcium and lead absorption? • Why is Cr3+ considered less toxic (oral RfD 1.5 mg kg-1 bw day-1) than chromate ion (RfD 310-3 mg kg-1 bw day-1), although within the cell the active toxic form is Cr(III)? • What is meant by the “Global Cycle of Mercury”? • Why is mercury vapour particularly hazardous among the inorganic forms of that element? • In what form does mercury normally bioaccumulate in aquatic species, and why? • By what routes and in what forms can lead in the environment be taken up by humans? • What are the toxic effects of lead on humans?