Metal Toxicity II Flashcards
Does metal in general metabolize?
No the have a long half life in the body.
What occurs when As is absorbed as soluble As salts?
80-90% Oral bioavailability.
As has good dermal what?
absorption
As inhalation is mainly in what?
As2O3, it is size dependent.
As distribution for skin is what?
predilection for skin, excreted in sweat (cancer).
As is found accumulated where for forensic uses?
concentrated in nails and hair.
Elimination of As in blood t1/2?
10-30hr
What is the main route of elimination for As?
urine (50-80% excreted in about 3 days)
Which As is recovered in urine?
High recovery as As (V) in urine.
DMA as a major form is what?
excreted in urine.
What does elemental Hg do to the renal system?
Kidney dysfunction
What are the symptoms for elemental Hg?
Asthenic vegetative syndrome: severe salvation, increased tremor, depression.
What does inorganic Hg salts do to renal?
predominant glomerular injury (model toxicant)
What is pink disease?
acrodynia
What is Acrodynia?
Erythema of extremities, chest, and face with photophobia.
What element causes pink disease?
Inorganic Hg salts.
What are the neurological implications of Organic Hg(MeHg)?
Visual disturbance, hearing loss, mental deterioration, muscle tremors, movement disorder (cerebral cortex), microcephaly.
6% of woman of childbearing age have what?
blood mercury levels in excess of the EPA reference dose.
uncharged Hg is what?
very lipophilic
inhaled mercury vapor produces what?
selective damage to brain function.
Mercury vapor readily crosses pulmonary membranes and enters what?
the bloodstream where is dissolves in plasma.
Once passing the blood-brain barrier what occurs to Hg0?
is oxidized to a highly reactive metabolite, Hg++ by catalase.
Demethylation increases what?
Mercury toxicity.
What occurs in demethylation of methymercury?
Lipid peroxidation and it binds to soft tissue ligands.
Cysteine complex of MeHg enters what?
brain using amino acid carrier.
The hemolytic cleavage of the carbon-Hg bond produces what?
methyl free radicals that initiate the lipid peroxidation.
MeHg-Cysteine complex mimics what?
Methionine
What does MeHg-Cysteine complex inhibits?
Protein synthesis in neuronal cells.
MeHg initiates what?
Free radical reactions
What does Fe-catalyzed what?
Free radical reactions.
Lipid peroxidation causes what?
membrane damage
What does DNA oxidation cause?
strand breaks, mutations.
What does protein oxidation cause?
loss of enzyme activity, transport system.
What does the Fenton reaction portray?
Fe-Catalyzed Free radical reactions.
Transcriptional alteration of DNA is an example of what?
Alteration of gene expression
Translational alteration at mRNA level is an example of what?
Alteration of gene expression.
Post-Translational alteration at proteins expression level is an example of what?
Alteration of gene expression.
What can take over Sp1 and will bind to DNA?
Lead
Lead may alter brain development through modulation of what?
The zinc finger protein SP1 It will take the place of zinc easily.
Sp1 is a component of what?
Transcriptional complex for gene regulation.
Target genes encode what?
MBP, PLP, and other proteins.
What is MBP?
Myelin basic protien
What is PLP?
proteolipid protein
What kind of cancer does Cr cause?
Respiratory cancer in chrome worker
What kind of cancer does Cd cause?
Cancer in lung, prostate, testes, and kidney.
What kind of cancer does Ni cause?
Lung and Nasal cancers via air.
What kind of cancer does As cause?
Lung cancers via air, Skin cancer via drinking water.
What kind of cancer does Si cause?
Lung cancer via air.
What is known as asbestos main reactant?
Si.
Who is sensitive to cadmium via inhalation?
Humans and rats
Who is NOT sensitive to cadmium via inhalation?
Mice and hamster
Who is sensitive to Arsenic via all routes?
Human
Who is not sensitive to arsenic via any route?
Rats and Mice
What is direct genotoxicity of metal induced carcinogenesis?
DNA damage, altered infidelity of DNA synthesis, altered gene expression due to DNA binding.
What is indirect genotoxicity of metal induced carcinogenesis?
Inhibition of DNA repair, generation of free radicals.
What are the interactions with regulatory proteins in the metal induced carcinogenesis?
Finger loop proteins.
What is the immunotoxicity of metal induced carcinogenesis?
Immunosuppression.
What type of damage to DNA does metal induced carcinogenesis cause?
Single strand damage, Double strand damage, DNA-DNA crosslink damage, DNA protein crosslink damage, and Free radical damage.
All metal carcinogens act by the same what?
Mechanism
What is the mechanism for all metal carcinogens.
The same mechanism
An individual metal has what?
The same mechanism in all target tissue.
An individual metal has exclusive what?
Genotoxic or non-genotoxic mechanisms.
Ionic form of the metal is what?
The carcinogenic species.
Slenium has what so special about it?
Anti- Carcinogenic property.
What metal is associated with Alzheimers etiology?
Lead exposure.
What metal is associated with Parkinson’s etiology?
Manganese exposure.
What are there neurodegenerative symptoms that lead cause?
Learning deficiency causes of Alzheimer disease presumed.
What are the the neurodegenerative symptons that manganese cause?
High concentration in striatum in Manganism patients and implication in mad cow.
What does Cu overload cause?
ATP7B genetic defect leading to Wilson’s Disease.
What causes Wilson’s disease?
an overload of copper due to the defective ATP7B gene.
What causes Menkes disease?
A copper deficiency due to the defective ATP7A gene.
What does a copper deficiency due to the defective ATP7A gene cause?
Menke’s disease.
Iron is found in the implication of what disease?
Parkinson’s
Mercury causes what type of neurodegenerative symptoms?
Developmental learning deficit.
Al will cause what type of neurodegenerative symptoms?
Dialysis encephalopathy, motor neuron degeneration.
What can be seen at high concentrations of Zn and Cu in the brain in imaging?
Most distinct distribution pattern in the hippocampus up to 15ug/g
Lead shows what type of distribution in brain imaging?
A more homogenous distribution throughout all regions and at a low concentration in ng/g range.
What is bone made up of?
5-10% of water, 50-70% apatite, 20-40%organics aka collagen, 10% non collagen proteins (osteocalcin and etc)
What has 80% of compact bone?
Cortical bone
What has 20% of spongy bone?
Trabecular bone
Explain bone remodeling?
Life time, cycles of resporption and accretion
What is the bone toxicity in Cd exposure?
Causes Itai-Itai disease
What is Itai-Itai disease?
Osteoporotic bone loss and increased fragility.
What is the bone toxicity in Pb exposure?
Lead line in long bones occurs. It inhibits osteoblasts and slows bone formation.
What is the bone toxicity in Al exposure?
Osteitis, osteodystrophy; altered bone metabolism.
Borne is a major storage site for which metals?
Ca, Mg, Zn, and Cu.
What is lead in bone linked to?
Children with Pb toxicity and Alzheimer’s risk.
Why do metals store in bones?
A defense mechanism for body protection.
Give an example of Bone as an internal source of exposure?
Slow release Pb form bone is a known source of chronic Pb exposure.
What are industrial sources of Al exposure?
Modern industrial uses of Al: occupation environmental exposure.
What are medical sources of Al exposure?
Dialysis dementia: renal failure.
What are prenatal sources of Al exposure?
Parental nutrition to preterm infants.
What bone diseases that Al cause?
Osteodystrophy, osteomalacia, and adynamic bone disease.
What causes hematopoietic toxicity?
Aluminum in the bone
What is the t1/2 of Al in bone?
7.2 years
Al is known to have a large volume of distribution (T/F)
True
34% of total body Al is where?
In bone.
Al inhibits what?
Bone remodeling
Al hinders both what?
Osteoblast and osteoclast activities.
Al disrupts what?
Parathyroid hormone levels
Al forms a physical barrier to for what reason?
to interfere bone calcification.
Infants having parenteral nutrition have significantly less what?
Less lumbar spine bone mineral contents and smaller bone area at age 13-15y/o
Subjects with neonatal Al exposure have what type of bone issues?
Significantly lower hip bone mass, independent of their bone or body size.
Parenteral nutrition in preterm infants can lead to what?
cognitive deficiency.
Al modifies the response of what?
Bone cells to external stimuli such as subsequent loading from physical activity or nutritional exposure.
Manifestation of Al neurotoxicity mechanism is what?
Al toxicity on hypothalamus affects the secretion of neuropeptides that controls bone remodeling.
t 1/2 of Mn in rat bone is what?
143 days
for the t 1/2 life of Mn in rat bones being 143 days, how does that translate to human bone half life?
8.6 years for Mn.
What is the MOST important thing you can do in treatment f metal poisoning and NEEDS to be done first!?
Remove the person from the environment in which metal exposure occurs.
What is the number 2 thing that needs to be done in order to treat metal poisoning?
Treat symptoms that may threat individual’s life.
What is the last thing done in metal poisoning treatment.
Treat with metal mobilizing drug: chelator or chelating agent to reduce body burden.
Chelate comes from what root?
Greek word chele meaning crab’s claw.
Chelating agents provide what?
An electron rich group to form covalent bonds with metals in a coordinate ring structure.
Chelates form stable complexes between what?
Chelator and metals.
What do the stable complexes that chelator and metal form do?
Prevent or reverse the binding of metals to cellular ligands.
The formed complexes are soluble in what?
Water soluble and more readily excreted from the body.
What is the chelating regimen?
four days and then pause for 3 days.
Why does the chelating regimen pause?
to give the body time to recooperate and release more metal from the bones.
Why is EDTA an issue with kids for administration?
It is IV injection and not oral dose.
What is provacative or challenge test for Pb burden?
EDTA
EDTA causes what type of toxicity?
Renal tox.
DMSA has what type of toxicity?
Low tox and doesn’t interfere with essential metals.
DMSA is administered how for lead eposure?
Orally and has no CNS redistribution.
D-PEN is commonly used for what?
Hg poisoning
What will facilitate Hg absorption?
D-PEN
DMSA is beneficial effects are similar to what for Hg?
those of DMPS
What may limit the intracellular distribution of DMSA in Hg exposure?
Two carboxyl groups
DMPS was created for what?
Increase urinary excretion of Hg.
DMPS administration and side effects for Hg exposure?
low side effects and available in IV and orally
For As what was the firs chelating agent to treat organic arsenical war gas?
British Antilewisite aka BAL
What is BAL primarily used for?
Severe As poisoning, deep intramuscular injection, and CNS redistribution.
DMPS for As increases what?
Urinary excretion of arsenic
DMPS formed water soluble complex that is what?
Less penetrable to CNS
DMPS clinically is what for As?
Improves significantly the symptoms.
DMSA for As has similar benefits to what?
the effects of DMPS
DMSA Chelates As where?
Extracellular As
What is Cd therapy?
No therapeutic agent.
Cd tightly binds to what?
Metallothionein.
What do chelators potentiate in Cd?
nephrotoxicity
What does EDTA reduce in Mn exposure?
Serum Mn concentration
What does EDTA increase in Mn exposure?
Urinary Mn elimination
What does EDTA improve in Mn exposure?
Symptoms improve and varies widely.
What does DMSA neglect in Mn exposure?
It has a negligible effect
What does DMSA possible unable to do in Mn exposure?
Unable to access intracellularly distributed Mn ions.
What does PAS do in Mn exposure?
Alleviate signs and symptoms
What is PAS?
An antibacterial drug for treatment for tuberculosis.
What is the chelator for Uranium?
No proven chelator available.
What is an effective treatment in Wilson’s diseases in regards to copper?
D-Penicillamine
What is a general chelator for copper?
DMPS and Mercaptodextran
What are chelation agents for Zinc?
N-Acetylcystein and Clinoquinol
Metals are known to participate in the what of human disease?
Etiology
What should therapeutic intervention consist of?
removal of patient from exposure, followed by symptomatic relief, then chelation Tx.
