Inorganic Lead

The Peripheral Neuropathy Solution

Peripheral Neuropathy Solution By Dr. Randall Labrum

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Pathogenesis and Pathophysiology. In the human body, inorganic lead is not metabolized but is absorbed, distributed, and excreted unchanged. The rate of absorption is influenced by nutritional status and age. The amount of lead absorbed increases significantly with iron or calcium deficiency and under fasting conditions. Once absorbed, lead travels bound by erythrocytes. It is then distributed primarily into blood, soft tissues (kidney, bone marrow, liver, and brain), and mineralized tissues (bones and teeth). In adults, approximately 95 percent of the total body burden of lead is contained in bones and teeth. In conditions of physiological stress, such as pregnancy, lactation, menopause, or chronic disease, lead can be mobilized from the bones, thus increasing the level of lead in the blood. The turnover rate of lead in cortical and trabecular bone is slow; although quantitative estimates of its half-life vary, there is a consensus that it is on the order of years or even decades.^ Measures of the bone content of lead thus reflect the integrated or chronic lifetime lead exposure. [6] Unbound lead is excreted by the kidneys or through the biliary system into the gastrointestinal tract. In single exposed studies in adults, lead has a half-life of approximately 25 days in blood, about 40 days in soft tissue, and more than 25 years in bone. Therefore, while a person's blood level may begin to return to normal after a single exposure, the total body burden of lead may still be elevated. For lead poisoning to occur, significant acute exposures are not necessary. Since the body accumulates lead over time and releases it slowly, even small amounts can cause lead poisoning.

The nervous system is the most sensitive target of lead poisoning. Lead encephalopathy has been associated with softening and flattening of convolutions in the brain. At times punctate hemorrhages, dilation of the vessels, and dilation of the ventricular system, are seen, especially in the frontal portions of the brain. Histologically, extensive involvement of the ganglion cells is seen. The developing brain appears to be especially sensitive to levels of lead that were once thought to cause no harmful effects.

Epidemiology and Risk Factors. Lead poisoning has a very long clinical history. M Although lead as an etiological factor was identified as early as 200 bc, it remains a common entity even today. More than 1 million workers in over 100 different occupations have been exposed to lead

TABLE 39-1 -- OCCUPAT

ONS AND JOB-RELATED SOURCES OF CHEMICA

L EXPOSURE

Aluminum

Arsenic

Lead

Manganese

Mercury

Thallium

Acetone

Benzene

Carbon Tetrachloride

Ethylene Glycol

Formaldehyde

Gasoline

Isopropyl Alcohol

MBK

Airplane hangars

X

X

X

Aircraft manufacture and maintenance

X

Alcohol distillation

(brewing)

X

X

X

Antifreeze

X

Artificial flowers

X

X

X

Artificial leathers

X

X

X

Artificial pearls

X

X

Automobile painting

X

Automobile manufacture and repair

X

X

Bookbinding

X

X

Brass and bronze

X

X

X

X

Brickmaking

X

X

Cement-plastic mixing

X

X

X

Can sealing

X

Cosmetics

X

X

X

Deodorants

X

Degreasing and scouring

X

X

X

Dentistry

X

X

Dry cleaning

X

X

Disinfectants

X

X

X

Dyes

X

X

X

X

X

X

X

Enamels

X

X

X

Etching

X

X

X

X

Explosives

X

X

X

X

X

X

Feathers

X

X

Fertilizers

X

X

X

Fire extinguishers

X

Furniture polish

X

X

Fuel (airplane, auto)

X

X

Gardening

X

x

Glass

X

X

Glue

X

X

Insecticides

X

X

X

Insulators

X

X

X

Lacquer

X

X

X

X

X

X

Leather-tannery goods

X

X

X

X

X

Linoleum

X

X

X

X

X

Millenery (hats)

X

X

X

Mining

X

Metal cleaners, polishers

X

X

Paints

X

X

X

X

X

X

X

X

Paper workers

X

X

X

Perfumes

X

X

X

Pharmaceuticals

X

X

X

X

X

X

X

Painting and lithography

X

X

X

X

X

Plastics

X

X

X

X

Plumbing

X

Pottery/ceramics

X

X

X

Rayon

X

X

x

Refineries (petroleum)

X

X

X

Rubber

X

X

X

X

X

Shoe manufacture and repair

X

X

X

X

Soaps, detergents

X

X

X

X

X

Storage batteries

X

X

X

Taxidermy

X

X

X

Tobacco

X

X

Vegetable oil extraction

Waterproofing

X

X

x

Wax

X

X

Welding

X

X

X

X

TABLE 39-2 --

SYMPTOMS ASSOCIATED WITH HEAVY METAL EX

POSURE

Metal

Proposed Toxic Mechanism

Tissue

Assessed and Toxic Levels*

Associated Symptoms

Clinical Findings

Specific Treatments

Pathology

ALUMINUM

Decrease in glucose utilization; reduction of acetylcholine

Blood 6 pg/Lt

Urine (24 hr) 20 pg/L (NC)

Respiratory dysfunction

Cognitive decline; halting speech; ataxia

Deferoxamine (DFO)

ARSENIC

Prevents thiamine

Blood,

GI distress; respiratory

Headache; nervousness;

Chelation; gastric lavage

Cerebral congestion;

transformation into

unreliable

distress; cardiac distress;

vertigo; paralysis,

with electrolyte

white matter

acetylcholine; affects

elevated temperature;

seizures; myelopathy;

replacement; morphine for

hemorrhagic lesions;

Acute

pathways involved in

Urine (24 hr) 50

Mees lines

hyperreflexia; neuropathy

abdominal pain; IV fluids

demyelinization of

oxidative metabolism

pg/g creatine (B, D, NC)

for dehydration

peripheral nerves; reduction in number of axons

Chronic

Prevents thiamine

Blood,

Abdominal pain;

Headaches; fatigue;

Cerebral congestion;

transformation into

unreliable

dermatitis; increased risk

restlessness; vertigo;

white matter

acetylcholine; effects

of cancer

cognitive decline; visual

hemorrhagic lesions;

pathways involved in

Urine (24 hr) 50

changes or optic

demyelinization of

oxidative metabolism

pg/g creatine (B,

neuropathy; seizures;

peripheral nerves;

D, NC)

painful sensorimotor

reduction in number of

peripheral neuropathy

axons

LEAD

Changes in

Blood 10 pg/dl

Respiratory distress

Lethargy; cognitive

Removal from exposure;

Unclear

Acute

neurotransmitters;

(B, CW)

decline; gait disorder;

chelation with IV calcium

inhibits NMDA receptor

ataxia; seizures

disodium-EDTA, succimer

Children

complex

(DMSA), or oral penicillamine

Adults

Changes in

Blood 30 pg/dl

GI distress; miscarriages;

Fatigue; delinum;

Removal from exposure;

Unclear

neurotransmitters;

joint pain

seizures

chelation with IV calcium

inhibits NMDA receptor complex

Urine (24 hr) 150 pg/g creatine (B,

disodium-EDTA, succimer (DMSA), or oral

penicillamine

CW);

Zinc

protoporphyrin

in blood: 250

pg/dl

erythrocytes or

100 pg/dl blood

Chronic

Changes in

Blood 10 pg/dl

Changes in auditory

Learning disorders

Removal from exposure;

Unclear

neurotransmitters;

(B, CW)

threshold; behavioral

chelation

inhibits NMDA receptor

problems; cognitive

Children

complex

decline; learning disabilities; attention disorder

Adults

Changes in

Blood 30 pg/dl

Miscarriage/stillbirth;

Scotopic visual effects;

Removal from exposure;

Punctate hemorrhages

neurotransmitters;

arthralgia; anemia;

depression; irritability;

chelation

dilation of vessels and

inhibits NMDA receptor

Urine (24 hr) 150 pg/g creatine (B, CW);

hypertension; gout; renal

sleep disturbance;

ventricles, involvement

complex

effects; decreased sperm

decline in libido;

of ganglion cells;

count

decreased cognition

histologic changes in

(learning and memory);

hippocampus

fasciculations;

Zine

parathesias; sensorimotor

protoporphyrin

polyneuropathy; changes

in blood

in auditory threshold

250 pg/dl

erythrocytes or

100 pg/dl blood

MANGANESE

Promotes formation of

24 hour urine 3

Anorexia; manganese

Headaches; apathy;

Removal from exposure;

Histological changes

cytotoxic free radicals;

pg/L (NC)

pneumonia

fatigue; depression;

for chronic movement

of ganglion cells;

oxidative stress;

hyperexcitability;

disorders; levodopa;

damage to substantia

mitochondrial toxin

Blood

dysarthria; psychotic; behavior; termor; gait disorders; micrographia;

5-hydroxytryptophan

nigra and globus pallidus; nerve cell changes in basal

2 pg/dl (NC)

parkinsonism

nuclei, frontal and

parietal cortex, cerebellum, hypothalamus

MERCURY

Inorganic

Acute Chronic

Organic

THALLIUM

Alters cell membranes; causes combination of: metabolic disurbance, disturbance of Ca+ homeostasis, oxidative injury; aberrant protein phophorylation

Alters cell membranes causes combination of: metabolic disturbance, disturbance of Ca+ homeostasis, oxidative injury; aberrant protein phosphorylation

Alters cell membranes; causes combination of metabolic disturbance, disturbance of Ca+ homeostatis, oxidative injury, aberrant protein phosphorylation

Affects Na+ /K+ ATPase, porphyrin metabolism and SH groups

Blood 15 jg/L

Blood 15 pg/L

Urine 35 jg/g creatine (B, NC)

Blood 15 jg/L

Urine (24 hr) unreliable

jg/g creatine(NC)

Broncial irritation; chills; gingivitis; GI distress; bloody diarrhea; brownish mouth lesions; metallic breath; respiratory distress; renal failure

Salivary gland swelling; excessive salivation; gingivitis; renal dysfunction

Primarily affects the nervous system

GI distress; alopecia

Weakness; irritability; delirium; psychosis

Shyness; fatigue; weakness; personality changes; hyperirritability; insomnia; depression; cognitive decline; visual disturbances; intentional tremor; parkinonism; seizures; painful parasthesias; peripheral neuropathy (sensorimotor axonopathy)

Cognitive decline; neurasthenia; parasthesias; ataxia; restricted visual fields; cortical blindness; peripheral polyneuropathy; intention tremor, motor neuron disease (ALS-like)

Irritability; fatigue; depression; confusion; movement disorder; optic abnormalities; sensory neuropathy; ascending weakness (Guillain Barre, poliolike)

Removal from exposure

Removal from exposure; chelation

Chelation with D-penicillamine, BAL, or DMSA; selenium; vitamin E

BAL; Prusian blue (potassium fermihexacycinoferrate); combined hemoperfusion and hemodialysis

Lesions in cerebral gray matter, cerebellum, brain stem nuclei

Neuronal loss and gliosis of the calcarine cortex; atrophy of cerebellum, especially inferior vermis

Damages primary visual cortex, cerebellar cortex, pre and postcentral gyri, transverse gyrus, and putamen

Ganglion cell changes in cortex; demyelinization; axonal degeneration; segmental myelin degeneration in peripheral nerves

* Biological exposure indices (BEIs). American Conference of Governmental Industrial Hygienists (ACGIH) values from ACGIH: Threshold Limit Values and Biological Exposure Indices for 1994-1995. Cincinnati, ACGIH, 1994.

Serum.

Whole blood.

NC, Level correlates poorly clinical symptoms; D, diet significantly influences the measurement; B, present in significant amounts in individuals not occupationally exposed; CW, correlates well with clinical symptoms. GI distress: nausea, vomiting, stomach cramps; BAL, British antilewisite; DMSA, dimercaptosuccinic acid.

(see Table.39-1). In lead-related industries, workers not only inhale lead dust and lead oxide fumes but may eat, drink, and smoke in or near contaminated areas, increasing the probability of lead ingestion. If the worker does not properly "clean up" before leaving work, he can bring lead dust home on his skin, shoes, and clothing, thus exposing family members. Sources of lead exposure for nonoccupational populations include air, food, water, certain consumer products, surface dust, and oils. Automobile emissions had been an important source of lead exposure, especially for urban residents. However, the de-leading of gasoline has significantly altered environmental levels of lead. Periodic assessment of national blood lead levels support this inference. From 1976 to 1978, median blood levels for adults in the United States were approximately 13 |jg/dl[8] ; in 1991 lead levels were estimated at 6 pg/ dl (Environmental Protection Agency, National Advisory Council for Environmental Policy and Technology [NACEPT] committee, 1993). The current major sources of lead in the environment appear to be lead paint in homes built prior to 1950 and lead used in plumbing (which was not restricted until 1986).

Children are especially vulnerable to the effects of lead, especially before the age of 5. Elevated lead levels in children are due to pica (compulsive eating of nonfood items) or to the mouthing of items contaminated with lead from paint dust. In addition, children absorb and retain more lead in proportion to their weight than adults. Young children also have a greater prevalence of iron deficiency, a condition that can increase gastrointestinal absorption of lead. Lead absorption from the gastrointestinal tract appears to differ with age. For example, in adults, approximately 10 percent of ingested lead is absorbed. However, in children, it is estimated that 40 to 50 percent of ingested lead is absorbed. Fetuses are at risk, since lead readily crosses the placenta. Exposure in utero can cause adverse neurological effects in the developing child.

Clinical Features and Associated Findings. Acute signs of lead toxicity in children include listlessness, drowsiness with clumsiness, and possibly ataxia. With very high levels of lead, convulsions, coma, and respiratory arrest may occur. Therefore, a diagnosis of lead toxicity in a child should be considered when a child presents with a change in mental status, gait disorder, or a history of seizures. Chronic low-level lead exposure in children may result in behavioral disturbances, learning disabilities, attention deficit hyperactivity disorder (ADHD), or cognitive decline.

Currently, acute lead encephalopathy due to industrial lead exposure is rare. Symptoms generally include delirium, combative irrational behavior, and seizures. Early signs of lead exposure include sleep disturbances, decreased libido, increased distractibility, increased irritability, and mental status changes marked by psychomotor slowing and memory dysfunction.

Both sensory and motor peripheral nerve involvement is seen in adults with chronic lead intoxication. Sensory complaints include paresthesias and spontaneous pain. Motor signs include local weakness, atrophy, and fasciculations. In severe cases of lead toxicity, wrist drop and foot drop have been well documented. Extensive bilateral neuropathy involving the hands, fingers, deltoids, biceps, and triceps may also occur. In individuals with predominantly motor findings, nerve conduction velocity may not be altered even after significant occupational exposure. However, in other cases mild slowing in nerve conduction velocity has been reported even in asymptomatic lead workers.

Anemia may be seen in patients with chronically elevated lead levels. Long-term lead exposure may have a direct effect on kidney function and may be associated with hypertension and gout. Increased frequencies of miscarriage and stillborn births have been documented in women working in the lead trades. Low prenatal lead exposure may produce low birth weight and premature birth. Lead affects the male reproductive system by reducing sperm counts and sperm motility.

In one series of studies an association was found between the body burden of lead, corresponding to blood lead levels of 25 to 55 jg/dl, and a drop in mean verbal IQ score of 4.5 points in exposed children. [9] , U In another study of total body burden, primary school children with high lead levels in teeth but no known history of lead poisoning had larger deficits in psychometric intelligence scores, speech and language processing, attention, and classroom performance than children with lower levels of lead. In a 1990 follow-up report of children who 11 years previously had been found to have elevated lead levels in their teeth, a sevenfold increase was noted in the odds of failure to graduate from high school, lower class standing, greater absenteeism, reading disabilities, and deficits in vocabulary, fine motor skills, reaction time, and eye-hand coordination.

Differential Diagnosis and Evaluation. The laboratory pattern typical of patients with lead intoxication includes elevations in whole blood lead levels, free erythrocyte protoporphyrins (FEP), and urinary coproporphyrins. The blood lead level reflects more recent exposure to lead, while the free erythrocyte protoporphyrin level tends to reflect more chronic levels of exposure. Blood lead levels greater than 10 |jg/dl in children and 30 |jg/dl in adults are considered elevated. FEP levels begin to rise in adults once blood lead levels reach 30 to 40 jg/dl. The threshold blood zinc protoporphyrin level is 100 jg/dl. At present, the gold standard for measuring the body burden of lead is diagnostic chelation. Urinary lead excretion is measured after infusion of 1 g calcium ethylenediaminetetra-acetic acid (EDTA). Urinary excretion of more than 600 g of lead over a period of 72 hours is considered elevated. A new noninvasive method of measuring the body burden of lead in bone is x-ray fluorescence (XRF). y XRF promises in the future to become the noninvasive gold standard for estimating the total body burden of lead. Except for patients with acute high exposure, an EEG is not generally useful. In addition, neither CT nor MRI reveal any abnormalities. The neuropsychological evaluation may prove useful in assessing specific cognitive deficits in individuals exposed to lead. In some studies, workers with lead blood levels of below 30 jg/dl have demonstrated decreased muscle strain and affective complaints as well as decrements in visuomotor integration and psychomotor speed, short-term visual and verbal memory, attention or concentration, and problem-solving skills. y y y Nevertheless, it should be noted that a recent comprehensive review of the published literature on the neurobehavioral performance of individuals exposed to inorganic lead failed to find enough

evidence to draw definitive conclusions on the negative influence of lead on human performance on neurobehavioral tests. y

Management. In both children and adults with substantial lead levels, immediate removal from the sources of exposure to lead and administration of chelating agents presently comprise the treatment of choice. Specific chelating agents for lead include intravenous calcium disodium-EDTA and a new oral agent called succimer (dimercaptosuccinic acid, DMSA). Chelation with oral penicillamine may be used (up to 2 g/day). Multiple chelation cycles may be necessary, and at least 24 hours of rest between cycles is suggested. Adequate hydration should be maintained because chelating agents have been associated with renal toxicity and may dramatically increase circulating levels of lead owing to their ability to unbind lead from the bones. DMSA is a relatively new oral chelating agent that is reported to be safer than EDTA and penicillamine. Common side effects are renal sequelae and hypertension. The latest guidelines for treating children suggest starting chelation therapy for children with blood lead levels above 45 jg/dl. While chelation therapy may reduce symptoms of acute lead poisoning, amelioration of the neurological and renal sequelae of both acute and chronic lead intoxication is less likely. Prevention of lead toxicity in children includes removal of young children from contaminated environments, such as houses with peeling paints. Individuals who work in occupations where they might be exposed to lead should use mandatory personal protective equipment. Routine monitoring for lead levels is also advised.

Prognosis and Future Perspectives. As the work of Needleman and colleagues suggests,y complete recovery of higher cognitive functions may not occur in children with early childhood exposure to lead. Likewise, it is unclear how much central nervous system function is recovered in adults, since research in this area is limited.

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