SOURCES

A mean concentration of 15 μg of lead per gram of bone ash in contemporary Americans is 1000 times greater than the natural level of lead (Pb) in the bones of prehistoric North American Indians.¹ Lead concentrations in grasses have increased tenfold and there is a 100-fold increase in carnivores living in remote terrestrial ecosystems of the northern hemisphere. Clearly, anthropogenic redistribution of lead for some 6000 years has resulted in some level of lead contamination in the remotest regions of the world.

The potential for chronic, low-level multimedia lead exposure is arguably a concern for all animals. These sources of lead constitute a background level of exposure that results inevitably in some accumulation. The role of this existing body burden of lead in chronic and acute intoxications of companion animals is uncertain. Knowledge of the existence of background lead serves primarily as a threshold guide in the diagnosis of acute lead intoxication.

The most common source of lead involved in clinical intoxication of small animals is lead-based paint chips or dust.² Because lead-based paint was banned for use in residential dwellings in 1977 and largely restricted from home use in the early 1960s, only houses built before this time are likely to be contaminated with lead-based paint. House paints, which once contained up to 50% lead by weight, are now considered lead-free only when they contain less than 0.06% lead. In 1991, the Centers for Disease Control estimated that 74% of privately owned housing in the United States built before 1980 still contained hazardous quantities of lead paint.³ Other potential sources of lead include solder, lead weights, combustion residue from burned buildings, lead shot and bullets, stained-glass framing, toys-jewelry-trinkets, and older board-game tokens. Because of their fastidious eating habits, cats are less likely than dogs to ingest foreign objects. As sources of lead, solder and dust are inadvertently ingested during grooming by dogs and cats that inhabit contaminated areas where lead-laden particles settle on the floor.

Concern about retained lead projectiles is dictated by the anatomic location of the shot or bullet. Systemic availability of lead increases significantly when absorption occurs from synovial cavities or in acidic environments.⁴

TOXIC DOSE

The most toxic lead compounds include lead carbonate, lead acetate, and some lead oxides. Lead sulfide is relatively insoluble in the gastrointestinal tract and hence is poorly absorbed and of low toxicity. Lead from lead acetate was lethal to less than 50% of dogs dosed at 300 mg/kg compared with lead from lead sulfate given at 2000 mg/kg.⁵

Although lead is a cumulative toxicant, the contribution of stored lead (background body burden) to clinical intoxication remains primarily a subject of conjecture.

Specific data on lead toxicity in cats are meager. Dose-related signs, including behavioral changes, projectile vomiting, seizures, nervousness, and fear of people were induced in cats given lead at greater than 1000 ppm in the diet.⁶ The estimated dosage in this experiment was 3 mg of lead/kg body weight. Packed cell volume and reticulocyte counts in these lead-poisoned cats were shown to be normal.

TOXICOKINETICS

The kinetic behavior of lead is complex, but must be understood in order to be able to understand the syndrome of lead intoxication and the clinical response to chelation.⁷ The divalent forms of calcium and lead are both absorbed in the upper small intestine by energy-dependent and energy-independent mechanisms. Active transport mechanisms for calcium in the gastrointestinal tract parallel increased calcium requirements for bone growth and maturation of other tissue. Calcium-binding proteins involved in these mechanisms have a similar if not greater affinity for lead.⁸ This absorption mechanism is consistent with the greater absorption fraction of lead seen in immature animals. Enteric absorption of lead is influenced by physiological factors (e.g., age, diet, pregnancy, and disease) and by chemical and physical variables, such as the form of lead, particle size, and matrix association.⁹ Solubilization of lead in the proximal gastrointestinal tract is required for transport across the duodenal mucosa, the primary site of lead absorption. Whereas mature animals absorb an estimated 5% to 10% of solubilized lead, rapidly growing immature animals, which have an increased demand for calcium, may absorb 30% to 40% of solubilized lead. Although the amounts vary, about 10% to 20% of absorbed lead is retained, meaning that 80% to 90% is excreted. Taken together, the 10% to 20% enteric absorption rate and the 10% to 20% retention of absorbed lead suggest that only 1% to 4% of the amount of lead ingested is actually retained in the individual.

Blood is the central compartment and is the conduit for distribution of absorbed lead to all other compartments. In juvenile pigs, and by extrapolation to companion animals, blood lead levels reach a peak 1 to 2 hours after an oral dose in fasted animals and return to some equilibrium concentration, depending on the existing lead burden in soft and hard tissues.¹⁰ The ratio of serum lead to whole blood lead is 0.8% to 2.5% in humans.¹¹ This is consistent with the distribution of lead within the vascular compartment of animals, in which about 98% to 99% of blood lead is adsorbed to red blood cells. The author has documented similar partitioning of lead in pig blood in controlled studies.¹² The plasma lead concentration rises progressively with increases in whole blood lead. This rapidly exchangeable pool of lead is in dynamic equilibrium with intestinal fluid and the extravascular space to allow direct contact with tissue cells. Uptake of lead by peripheral compartments (e.g., liver, kidney, brain, and bone) depends on the rapid exchange fraction of lead and vascular flow and on tissue-specific binding factors.

Absorbed lead enters the bloodstream, where most of it binds to erythrocytes and is transported to soft tissues, where its half-life is relatively short compared to bone. An estimated 20% to 30% of absorbed lead is excreted in the urine, and a very small percentage undergoes biliary excretion in the dog. Concurrently, lead enters the bone reservoir, where the capacity for storage is comparatively large. Lead is incorporated into the bone mineral matrix in place of calcium during continuous dietary exposure and is also redistributed from soft tissue and blood. Bone lead accounts for about 93% to 95% of the total body burden of lead in mature animals and for about 70% to 75% in immature animals. The residence time of lead in blood and soft tissues is about 4 to 6 weeks, whereas the residence time in bone is on the order of decades. There is a steady accumulation of lead in bone during a lifetime of exposure. Thus the bone reservoir of lead represents the cumulative exposure, whereas the concentration in body fluids and soft tissue, which equilibrate relatively rapidly, reflect current and recent exposure. There is little correlation between lead concentrations in bone and blood.

MECHANISM OF TOXICITY

Lead is toxic to a multitude of organ systems, tissues, cell types, and enzymes. Lead forms complexes with various nucleophilic functional groups (e.g., COOH, NH₂, and SH) and attains maximum stability with sulfhydryl groups. Lead, in fact, inhibits a variety of enzymes by binding to exposed sulfhydryl groups. Any structural protein, transport system, receptor, or enzyme is potentially susceptible to the toxic action of lead, depending on its extracellular and/or intracellular availability.⁵

Chronic exposure to lead results in inhibition of heme synthesis and a delay in erythrocyte maturation. Another factor contributing to the anemia that develops is increased erythrocyte fragility leading to a shortened life span. The anemia of chronic lead poisoning is mild to moderate and usually normocytic and slightly hypochromic.¹³ The basophilic stippling of red blood cells rarely seen in canine lead poisoning cases is presumably accumulated ribosomal RNA aggregates that have not been degraded to their nucleotides and subsequently dephosphorylated by pyrimidine-5′-nucleotidase (P5NT). Lead inhibits the activity of P5NT in humans and cattle¹⁴ and presumably in other species as well.

The molecular basis for the neurotoxic effects of lead results from its interference with some aspect of endogenous divalent cations, especially intracellular calcium function.¹⁵ Acute exposure to lead causes a sudden increase in cytoplasmic calcium levels. Acute calcium-mediated cell death and a chronic impairment in neuronal differentiation and synaptogenesis have also been demonstrated.¹⁶ Several lines of research suggest that lead can act as a calcium-mimetic agent on specific intracellular functions, such as the activation of protein kinase C and calmodulin.¹⁷ The consequences of this disturbance in intracellular calcium-mediated regulatory function are not fully understood, but include impairment of smooth muscle contractility, blood pressure regulation, and platelet aggregation.

Lead also inhibits energy metabolism in brain capillaries of calves and directly affects neuronal tissue.¹⁸ Accumulation of lead in the microvasculature of the brain leads to endothelial cell alterations expressed as abnormal ultrastructural morphology and minimal edema, and minor swelling of perivascular astrocytic processes.¹⁹ These effects result in neurotoxicity and lead-induced encephalopathy. Lead reduces local cerebral blood flow in the hypothalamus and cerebral cortex of rabbits given lead from lead acetate at a dose of 20 to 40 mg/kg of body weight for 10 days.

Animal studies examining the time course of renal alterations following doses of lead acetate show intranuclear inclusion bodies and swelling of proximal tubular cells initially. Continuous lead administration induces tubular dilatation, atrophy of the tubular lining cells, and interstitial fibrosis. Glomerular sclerosis and interstitial scarring are seen only after months of lead exposure.

The gastrointestinal tract of lead-poisoned human subjects is affected in three ways: colic, dysfunctional disorders, and gastroduodenal lesions. Lead colic is a consequence of a spasmodic contraction of the smooth muscles of the intestinal wall. Colic is usually preceded and accompanied by constipation and is associated with vomiting, hypertension, and oliguria.²⁰ Radiography shows evidence of spasms of the esophagus and cardia, inflammation of the esophagus, inflammation of the gastric folds, and further symptoms of gastritis. Occupationally exposed workers with lead poisoning were found to have a high percentage of gastric and duodenal ulcers.