Page 473 - Veterinary Toxicology, Basic and Clinical Principles, 3rd Edition

440 SECTION | V Metals and Micronutrients

VetBooks.ir from the GI tract than do adults. Animals with a calcium Intracranial pressure rises as edema accumulates in the
brain because of the physical restraint of the skull. When
deficiency have increased absorption of lead. Pregnancy
the intracranial pressure approaches the systemic pressure,
or lactation as well as deficiencies of iron, zinc, or vita-
min D can also enhance lead absorption. Lead crosses the cerebral perfusion decreases, and brain ischemia occurs.
placental barrier, and the residue can be detected in sig- Many of the neurotoxic effects of lead appear related
nificant amounts in fetal blood and organs. Among the to the ability of lead to mimic, or in some cases, inhibit
fetal organs, the highest concentrations are found in the the action of calcium as a regulator of cell function
blood and liver (Kelman and Walter, 1980; O’Hara et al., (Bressler and Goldstein, 1991). At a neuronal level, expo-
1995; Flora and Agrawal, 2017). Lead also passes through sure to lead alters the release of neurotransmitters (dopa-
the milk. mine, acetylcholine and γ-aminobutyric acid) from nerve
Adult monogastric animals absorb approximately 10% endings. Spontaneous release is enhanced and evoked
of dietary lead, and adult ruminants absorb less than 3%. release is inhibited. The former may be due to activation
Young animals can absorb up to 90% of the ingested of protein kinases in the nerve endings and the latter to
lead. Following absorption, a large proportion of lead is blockade of voltage-dependent calcium channels. Lead
carried on erythrocyte membranes (60% 90%, species also inhibits N-methyl-D-aspartate receptors containing
dependent) with most of the remainder of lead bound to NR2A, NR2C and NR2D subunits, thereby causing
protein or sulfhydryl compounds, with only a very small decreased calcium influx and reduced brain derived neu-
proportion found free in the serum. Lead is widely distrib- rotrophic factor, leading to neuroinflammation and neuro-
uted in the body, including crossing the blood brain bar- nal injury and death.
rier (BBB) (Seimiya et al., 1991). In the soft tissues, lead Brain homeostatic mechanisms are disrupted by expo-
binds to various proteins as well as metallothionein but sure to higher levels of lead. The final pathway appears to
accumulates in the active bone matrix (about 90%) serv- be a breakdown in the BBB. Again, the ability of lead to
ing as a relatively inert reservoir of lead in the body. This mimic or mobilize calcium and activate protein kinases
reservoir can be mobilized by lactation, pregnancy, or the may alter the properties of endothelial cells, especially in
action of certain chelating agents. Otherwise, lead has a an immature brain, and disrupt the barrier. In addition to a
very slow turnover rate from the bone. Lead is normally direct toxic effect upon the endothelial cells, lead may alter
very slowly excreted via the bile with very little in the indirectly the microvasculature by damaging the astrocytes
urine. Chelation therapy greatly increases the urinary out- that provide signals for the maintenance of BBB integrity,
put of lead. and necrosis in neurons with shrunken cytoplasm, pyknotic
nuclei and increased perineuronal space.
Recent studies provide evidence of increased produc-
MECHANISM OF ACTION
tion of reactive oxygen species following lead exposure.
Lead interferes with several biochemical processes in the Lead induces oxidative damage in several tissues by
body by binding to sulfhydryl and other nucleophilic enhancing lipid peroxidation through Fenton reaction or by
functional groups causing inhibition of several enzymes direct participation in free radical-mediated reactions, such
and changes in calcium/vitamin D metabolism. Lead also as inhibition of δ-aminolevulinic acid dehydratase (ALAD)
contributes to oxidative stress within the body. Lead inhi- activity or accumulation of ALA, a metabolite that can
bits the body’s ability to make hemoglobin by interfering release Fe 21 from ferritin and induce oxidative damage.
with several enzymatic steps in the heme pathway.
Specifically, lead decreases heme biosynthesis by inhibit- TOXICITY
ing delta-aminolevulinic acid dehydratase and ferrochela-
tase activity. These changes contribute to the anemia that Mammals, birds and reptiles have all been found to
develops in chronic lead poisoning. An increased fragility develop lead poisoning. The toxic dose of lead has been
of red blood cells also contributes to the anemia. determined for several species but is difficult to apply to
From various experimental studies, biochemical and clinical cases where the exposure history is unclear
pathological evidence demonstrates that lead is a neuro- (Gwaltney-Brant, 2004). In general, young animals are
toxicant, as it significantly disrupts certain brain struc- more susceptible to lead toxicosis because they are more
tures and functions. High-dose exposure to lead (i.e., prone to lead pica and have a higher rate of absorption
blood levels in excess of 4 μM 5 0.83 ppm) disrupts the (about 90%) from the intestinal tract. Cattle have been
BBB. Molecules such as albumin that normally are most widely reported with lead toxicosis, probably
excluded will freely enter the brain of immature animals because of their propensity to ingest discarded lead acid
exposed to these concentrations of lead (Clasen et al., batteries and construction materials including paints.
1973; Goldstein et al., 1974; Bressler and Goldstein, Dogs are also commonly reported with lead toxicosis,
1991). Ions and water follow, and edema is produced. probably because of their chewing habits and ingestion of