Module 3: Toxicology - Section 11: Lead

TOX 11.4: Lecture: Lead (Occupational Aspects - Continued)

INORGANIC LEAD:

Toxicology:

Routes of entry:

1. Inhalation (typically dust or fume)
2. Ingestion (occupationally from smoking, eating while exposed, ?swallowing sputum)
3. (Skin - not normally.)

Compartments (complex "4 compartment model"):

1. Blood (half life 36 days)
2. Soft tissues (half life: > 40 days)
3. Trabecular (surface) bone: circulating (half life of the order of months)
4. Cortical (deep) bone: non-circulating (half life: 20 yrs plus)

Chemical actions :

1. Binds to ligands, (-OH, -SH, -NH₂)
2. Enzyme inhibition
3. Cell membrane site of action

Rate of exposure in relation to effects:

1. Acute: high dose over relatively short period
2. Delayed post-acute: High dose, e.g. in childhood, followed by adverse effects many years later
3. Chronic: steady dosage - typical occupational exposure

Clinical effects:

I. Classic syndrome of acute lead poisoning

• abdominal pain/colic
• constipation
• myalgias, arthralgias
• fatigue
• "lead line" on gums (historically associated with poor periodontal hygiene)
• anaemia
• wrist drop
• encephalopathy

This textbook syndrome is very uncommon today.

II. Organ system effects of chronic exposure (or delayed effects of acute exposure)

1. Haematologic

• Normocytic, normocytic anaemia
• Reticulocytosis
• Basophilic stippling of red blood cells (this textbook feature is not a common finding)

Mechanism:

1. Reduced red cell survival
2. Inhibition of red cell formation

Reversible? Yes.

2. Renal (including hypertension)

Acute: Fanconi like syndrome - mainly with acute exposures, e.g. in children.

Chronic:

• Chronic nephritis
• Hyperuricaemia / gout ("saturnine gout")
• Hypertension

Mechanisms:

1. Proximal tubular damage
2. Diffuse tubulo-interstitial lesion
3. ? Increased reabsorption of urate
4. ? Impaired renin-aldosterone function (hypertension)

Reversible? No/partly.

3. Neurologic

• Peripheral: motor neuropathy clinically
     (? "Amyotrophic lateral sclerosis" syndrome - not proven).
      Early or mild effect: abnormalities on nerve conduction studies
     Severe: wrist (or ankle) drop.
  
• Central:
     Subjective: irritability, fatigue, insomnia, headache
        Psychiatric disturbances have been described.
  
• Objective:
     Neuropsychological deficits
     Acute encephalopathy/seizures (rare in adults).

Mechanism: Axonal degeneration, demyelination, neurotransmitter disturbance.

Reversible: No/partly.

4. Reproductive:

• Impotence, decreased libido (part of CNS effect?)
• Infertility - women and men (altered sperm morphology)
• Foetotoxicity, adverse pregnancy outcomes
     - abortion, stillbirths
     - deficits in child (interference with growth and neuropsychological development)

Mechanisms:

1. Defective spermatogenesis
2. Central gonadotrophic defect
3. Teratogenic, pregnancy effects?

5. Other endocrine

1. Hypothyroidism
2. Impaired adrenocortical axis

Reversible: ?

6. Carcinogenic:

IARC 2B: possible human carcinogen

Biologic monitoring:

See Lead Regulations 2001 (Open up the book on Regulations, and then the book on Lead Regulations 2001

1. Blood lead (µg/dl or mmol/l) (Be aware of laboratory error or inter laboratory variation)

NB: distinction between blood lead in those newly exposed (measures recent exposure) vs those chronically exposed who have high bone stores (integrates recent and distant exposure).

2. Zinc protoporphyrin (ZPP) or free erythrocyte protoporphyrin (FEP)

• Haematofluorometer (fingerprick) - easier in workplace
• More integrated exposure over past few months than blood lead in recently exposed.
• May be elevated in iron deficiency (false positive)

Other:

3. Urinary lead -not useful for inorganic lead unless following chelation challenge to determine body load.

4. Urinary delta ALA (delta aminolaevulinic acid) - very sensitive, specific; not routine.

Biological effect monitoring and clinical investigation:

1. Blood pressure
2. Urinalysis (note: proteinuria may be absent in chronic renal effects)
3. Full blood count (anaemia not common at lower lead levels)
4. Renal function: - urea, creatinine (insensitive)
   • creatinine clearance - (ensure proper 24 hour urine collection)
   • concentrating ability following overnight fast
5. Nerve conduction studies (if symptomatic)
6. Neurobehavioural test battery for CNS effects
7. Semen analysis (after fertility history)
8. Endocrine workup (uncommon)

Dose-effect relationships:

• Complex relationship lead in air with blood lead.
• Acute vs chronic loading important because of bone stores.
• Thresholds of effect being lowered with improved information.

Treatment:

1. Removal from exposure (Lead Regulations):

• Blood Pb ³ 60 µg/dl
• or ZPP ³ 10 µg/g Hb
• or, if symptomatic, or other clinical indication.

2. Monitor

• Return when blood Pb < 50 µg/dl, or ZPP < 6 µg/g Hb

3. Chelation: clinical decision!

• Acute symptoms
• Blood lead > 120 µg/dl?
• Chronic deficits - no evidence from trials. Empirical.

Never:

• Prophylactic
• While still exposed

Chelating agents available in SA:

   1. Dimercaprol: IM x 5 days (painful)
   2. Pencillamine orally, 600-1100 mg/daily x 2 months

• Monitor: urine, FBC, allergic reaction

Chelating agents unavailable in SA:

   3. Calcium EDTA (Calcium Versenate)

• 5 days IV as inpatient; monitor output, renal function
• (Also used for diagnostic body burden challenge: - 1 g. IV or IM - measure urine lead)

   4. Dimercaptosuccinic acid (DMSA)

• Oral
• Less toxic

Reporting/recording:

Excess absorption: (Pb > 60 µg/dl, ZPP > 10 µg/g Hb)
   Should be recordable incident under OHSA Lead Regulations.
   Not compensatable under COIDA.

Occupational lead poisoning, i.e. clinical disease
    Compensatable disease under COIDA

Community lead poisoning:
   Notifiable disease under Health Act, 11177

ORGANIC LEAD:

Very different from inorganic lead

Tetraethyl lead is more toxic and less volatile than tetramethyl lead.

Exposure

1. Manufacture, transport (spills!), blending at refinery
2. Cleaning and maintenance of storage tanks:
   • highest risk
   • skin and respiratory route
   • difficult to predict

Toxicology:

1. Highly lipid soluble ® CNS
2. Liver metabolism to water soluble trialkyl lead

Clinical:

1. Nervous instability (insomnia,agitation)
2. Nausea, vomiting
3. Normal blood count
4. Severe: hyperactivity, delusions ® coma

Treatment:

Sedation, hydration.

Prevention:

1. Enclosure
2. Air supplied full body protection in tanks

Biological monitoring (See Lead Regulations, HT notes on lead regulations)

Urine lead: < 150 µg/l

Postgraduate Diploma in Occupational Health (DOH) - Modules 3: Occupational Medicine & Toxicology (Basic) by Profs Mohamed Jeebhay and Rodney Ehrlich, Health Sciences UCT is licensed under a Creative Commons Attribution-Noncommercial-Share Alike 2.5 South Africa License. Major contributors: Mohamed Jeebhay, Rodney Ehrlich, Jonny Myers, Leslie London, Sophie Kisting, Rajen Naidoo, Saloshni Naidoo. Source available from here. For any updates to the material, or more permissions beyond the scope of this license, please email healthoer@uct.ac.za or visit www.healthedu.uct.ac.za. Last updated Jan 2007.
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