Update on heavy metals toxicity (Proceedings)

Lead (Pb)

Sources

Lead-based paints, lead-based gasoline, solder, combustion residues, caulking compounds, improperly glazed pottery, batteries, buck-shots, sewage sludge, some canned commercial dog foods, electronic wastes, etc.

Canned foods dogs and cats - 2.6 (1.0-5.6) and 3.0 (0.9-7.0) respectively

Hankin, L. et al., 1975

Toxicokinetics

Exposure – Primarily by ingestion

Rapid and variable absorbed – 2-10% (mature) 30-40% (young/immature) animals

Unabsorbed lead (immature); Widely distributed - bone and teeth; soft tissues, kidneys, brain (grey matter and various nuclei) and blood: T1/2 in bones (10-30 years); soft tissues (40 days); blood (28-36 days) soft tissues.

Tightly bound (95%) to red blood cells (RBC) – membrane and hemoglobin

Excretion–Urine (20-30% of absorbed Pb – Dogs), bile >> feces, sweat, sloughed skin cells and hair).

Affects many organ systems.

The gastrointestinal, nervous, and heme synthesis are the most commonly affected

Clinical signs – common to all species

Gastrointestinal – abdominal pain, constipation, vomiting, anorexia, hypertension, oligurea, and weight loss.

Encephalopathy – seizures, blindness, depression (days post exposure), anemia, protein-urea. Dog/cats – Vomiting anorexia, constipation, anemia, basophilic stippling, nucleated RBC in peripheral blood (reticulocytosis), increased zinc proto-porphyrin.

Pathophysiology

Complexes with SH and other functional groups of enzymes, structural proteins, transport systems, and receptors.

Binds to delta-aminolevulenic acid dehydratase >> depress activity; Inhibits essential enzymes (delta-aminolevulinic acid dehydratase, ferrochelatase and coproporphyrinogen oxidase) in heme synthesis (presence of substrates – urine, plasma and blood are supportive of diagnosis) >> anemia. Zinc replaces ferrous iron at its binding sites within the porphyrin ring thereby forming zinc protoporphyrin. (diagnostic test for lead exposure/intoxication. Increased RBC fragility, normo-cyclic/normo-chromic erythrocytes. Increased cytoplasmic calcium leading to cell death. Inhibits energy metabolism in the brain capillaries – microvascular, accumulation >> encephalopathy

Renal - Intranuclear bodies and swelling

Diagnosis

Increased blood lead levels > 0.35ppm with appropriate clinical signs.(do not used blood lead alone diagnostically).

Confirm – Whole blood lead level (kidney and liver lead – supportive)

     0.35ppm in addition to appropriate clinical signs – Diagnostic

     0.20ppm - Excessive exposure

     10ppm - liver and kidney (wet weight) Diagnostic

Elevated nucleated RBC in peripheral circulation

               15 nucleated /10,000 RBC suggestive

               40 nucleated/10,000 RBC – diagnostic

Urinalysis – increased heme synthesis intermediates (Pb is inhibitory to Enzymes: aminolevulinic acid dehydratase, ferrochelatase and coproporphyrinogen oxidase)

Radiographic lesions – increased growth plate opacity, soft tissue lead deposits

Treatment

Cathartics – move unabsorbed lead from GI tract

Surgical intervention

Chelation: Dimercaprol (BAL): 6mg/kg deep IM for 3-5 days (do not exceed five days – nephrotoxicity). Crosses blood brain barrier and will chelate brain lead.

Meso-2,3-dimercapto-succinic acid "succimer" Dogs – 10 mg/kg,3x daily for 10 days PO.

Calcium disodium EDTA – 27 mg/kg, 4 daily for 5 days – slow IV or SQ

Drawbacks – does not cross blood brain barrier, nephrotoxic, induces hypocalcemia

D-Penicillamine – 8 mg/kg 4x daily (toxic response – anorexia, listlessness, vomiting).

Evaluate response to treatment and retreat if necessary.

Supportive care

Differential diagnosis

Distemper, GI parasitism, foreign body, Acute pancreatitis, Encephalitis, Rabies, Strychnine or Organo-chlorine toxicity.

Iron (Fe)

A major essential mineral – central to hemoglobin, myoglobin, and Cytochrome P-450 metabolic enzyme system. Exposure by ingestion.

Sources

Iron salts

Multivitamin-minerals preparations

Toxicity

Ingestion of large doses of soluble, fine particulate iron salts >> overwhelm iron homeostasis >> high levels of free iron in circulation (overdose).

Factors affecting toxicity

Exposure route – parenteral >> ingestion; endogenous iron levels – most animal lack iron excretory mechanism and growth rate.

Toxicokinetics

Body burden regulates absorption.

Absorption >> carrier mediated and transferred to systemic circulation (intra-cellular (ferritin bound – iron binding protein). Loss – sloughing of normal GI mucosal cells (cell turnover). Systemic circulation (iron/transferrin). Saturation >> free iron and transferrin bound (circulation)

Constant elimination rate – excess stores bound to ferritin and/or hemosiderin (spleen and liver) mineralized iron deposit. Excretion – feces hair, sweat, urine (more relevant to toxicity)

Pathophysiology

No active elimination of iron

Ferrous iron (selective absorption) oxidizes to ferric iron bound to transferring

Excess – results in increased blood iron concentration >> anaphylactic shock and death

Excess damages gastric mucosa – diarrhea, electrolyte loss, shock, metabolic acidosis and death. Transferrin saturation >> increased hepatic iron >> mitochondrial damage >> liver necrosis. Increased serum iron >> free radical damage (membranes) >> increased permeability and hemorrhage >> vascular dilation, shock, acidosis and death

Clinical signs

Severe depression, shock, acidosis, per-acute anaphylactic-like reaction.

GI – vomiting, black colored feces, hypovolemic shock (death or coagulation defects), metabolic acidosis, hemolytic anemia, icteric, depression, hemoglobinemia, coma, and death

Diagnosis

History of exposure – excess iron and Clinical signs

Gastric ulceration and edema (oral exposure)

Hydro-pericardium/peritoneum

Total serum iron (increased 50%-100% of normal) – 100 - 300ug/dl, acidosis, increased hepatic enzyme activities and bilirubin.

Increased hemoglobinuria

Liver iron levels – difficult to evaluate. Normal (adult) liver iron < 400ppm; Puppies – as high as 900ppm

Abdominal radiographs

Treatment

GI – decontamination

Supportive care – shock, dehydration, cardiovascular.

Chelation therapy

Deferoxamine – 15mg/kg/hour (slow): Caution – cardiac arrhythmias, promote histamine release leading to hypotension. Normal serum iron reached in 2-3 days post treatment. Note initial reddish-brown discoloration of urine

Oral ascorbic acid

Differential diagnoses

Garbage intoxication, Gastric torsion intoxication – caustic/corrosive agent, Snake bite, Heat prostration, Bacterial/viral enteritis

Prognosis

Fair to good (note severity of clinical signs)

Arsenic (As)

Sources

Pesticides – Ant and termite baits, heartworm adulticides (iatrogenic), and the ash from burning copper-chromium arsenic treated wood.

Toxicokinetics

Gastrointestinal absorption

Rapid excretion – kidney, bile and intestine

Toxicity

Purity/solubility/particle size

Valance state (trivalent/pentavalent, organic/ Inorganic (trivalent 4-10x more toxic than pentavalent. arsenate 3-10x less toxic

Health state of exposed species (weak, dehydrated animal are more sensitive)

Exposed species: Cats > dogs; young > mature of the species

Lethal dose: 1-25 mg/kg except cats (<5 mg/kg) (in all animals).

Inorganic arsenic > Organic arsenic

Organic forms (Arsenic trioxide) > Organic forms (melarsomine, arsenilic acid)

Trivalent (Sodium arsenite ) > Pentavalent forms (Sodium arsenate); Soluble forms (Arsenic acid) > Insoluble form

Clinical signs

Inorganic/Trivalent

Acute - Vomiting, weakness, ataxia, bloody/watery diarrhea, weak rapid pulse, dehydration, hypothermia, and death. Subacute – GI signs persist (watery-bloody diarrhea) polyuria/oliguria/anuria, anorexia, weakness, proteinuria, azotemia, acidosis, increased PCV and BUN,

Pathophysiology

Binds to SH groups – Enzymes, cellular proteins, >> energy depletion thereby affecting cellular respiration. Affects tissue of high oxidative state – GI tract (intestines). Death from cardiovascular/GI/pathology with kidney ischemia >> fibrosis >> hyperkeratosis

Pentavalent – Phosphate substitute in oxidative phosphorylation >> uncoupling >> cellular deficit. No hyperthermia

Diagnosis

History of exposure, clinical signs; arsenic levels in urine; vomitus, feces, and GI contents; liver and kidney. Urine levels (< 1ppm background level) – helpful within the first 48 hours; blood levels are unreliable. Hair and skin levels - not helpful.

Differential Diagnosis

Enteritis, GI hemorrhage, pancreatitis, garbage toxicity, zinc phosphide toxicosis

Treatment

Gastrointestinal detoxification – emesis if caught early (within first hour)

Fluid therapy to prevent hypovolemic shock, blood transfusion, correct acid-base, electrolyte balance, cardiac arrhythmia

Chelation

BAL (chelating agent); effective before clinical signs are observed.

Supportive therapy

Correct for shock dehydration and acidosis and monitor blood pressure, hydration, acid-base status, and renal values.

Prognosis

Good with early treatment and mild clinical signs; poor with more severe clinical signs.

Zinc (Zn)

Essential mineral; component of numerous metallo-enzymes; essential for T helper cell functions – Immunity

Sources

Desitin (topical baby rash treatment) – contains 40% zinc oxide; Metallic hardware (concentrations vary); Pennies – contain 96% zinc since 1983, prior (before 1982) – 4% zinc.

Toxicity

Frequently reported in dogs, less so in cats. Primary route of exposure – ingestion

Toxicokinetics

Absorption (5%) – carrier mediated process. Initially bound to plasma albumin and beta-2 microglobulin. Deposited in liver, kidney, prostate, third eye-lid, intestinal tract and bile.

Mechanism

No well defined. High levels (dietary) interfere with copper storage, and may compete for calcium (intestinal absorption). High dietary copper can induce zinc deficiency.

Toxic effects

Direct irritation to GI mucosa – ulcers, hemolytic anemia – function and production of RBCs (inhibits glutathione reductase – essential for the mono-phosphate shunt reactions

Heinz body formation >> membrane damage

Clinical signs

GI – lethargy, anorexia, vomiting, diarrhea, generalized seizures, and depression

Cardiovascular – hemolytic anemia, hemoglobinuria, heinz body, murmurs, nucleated red blood calls, and icterus

Renal/urinary – azotemia, cast port color wine urine

Lameness, pale membranes, polyuria/polydipsia, exophthalmia, basophilic stippling (chronic manifestation), and seizures

Increased alkaline phosphatase and transaminases (liver), amylase and lipase, BUN and creatinine, and generalized hemolytic anemia

Diagnosis

Radiographic evaluation – GI (objects like pennies); Elevated blood/serum zinc levels – note possible contamination (use royal blue top trace element tubes)

Cats and dogs: Normal zinc levels 0.7-2.0 ug/dl but increases with stress

Urinary zinc – not reliable

Treatment s

Stabilize animal; Surgical – remove object; Chelation – Succimer, CaNa EDTA

Supportive therapy (control hemolytic crisis)