Review:
- Purpose of Monitoring
- Basic biology of cholinesterase and cholinesterase inhibiting pesticides, basic enzymology
- History and physical exam of the handler
- Appropriate testing methods and interpretation of monitoring results
- Responses to cholinesterase depression
- How to investigate for false positives
- Setting up a cholinesterase monitoring in the clinic/medical system
- Quality assurance evaluation
-
Identifies hazardous conditions/practices
- Increases worker/employer hazard awareness
- Assists in medical return to work
- Avoids problems from chronic exposure
- Influences economic decisions:
-
Increases costs of production
- May influence choice of pesticide
-
Present from paramecia to sapiens
- Very Fast enzyme (perfect kinetics)
- Ubiquitous in the human body
- Critical for many nervous system
functions
-
An enzyme with a sulfhydral active site
- Produced in tissues and blood
- Hydrolyses acetylcholine
- Present in the autonomic, central and peripheral nervous systems
Excellent web page on the enzyme
http://www.weizmann.ac.il/sb/faculty_pages/Sussman/projects/che.html
-
Thought to mediates a nucleophilic attack on
carbonyl carbon acylating it and liberating
choline and vinegar. Old model explains much
but is not accurate.
-
Different enzymes with some
behaviors in common
- Plasma Cholinesterase
- Butyrylcholinesterase,
pseudocholinesterase, PChE, or just
cholinesterase and ChE
- RBC Cholinesterase
- True cholinesterase, acetylcholinesterase, or AChE
- Floats freely in plasma
- Made by liver Rapid recovery from depression
- Rapid replacement by new synthesis
- Liver disease may affect levels
- Sensitive to most ChE inhibitor pesticide exposures
- Bound to red blood cells
- Made at the same time as the Rbc's
- Recovery from depression 0.8%/day
- Slower to depress, slower to recover
- Low RBC count may cause lower levels Identical to neuronal ChE
-
Autonomic Nervous System
- Parasympathetic
- Presynaptic Sympathetic
- PNS
- CNS
Found at the synapse It turns off the chemical messenger When inhibited the messenger builds Overstimulation results
- A buffer for poisons
- Potatoes
- The Calabar Bean
- Green Mamba Snake
-
Alzheimers Treatment with ChE inhibitors
- Tacrine, Donepezil, Metrifonate, Galantamine
- Metrifonate is converted to DDVP
- Myasthenia Gravis
- Edrophonium,
- Pyridostigmine bromide
- Glaucoma
- Prophylaxis for Nerve Gas Attacks
- Organophosphates
- Inhibit irreversibly
- "aging of complex"
- ChE must be replaced by the body
- Carbamates
- Inhibit temporarily
- No "aging"
- Reversal is rapid and level related
- ChE reactivates and is ready to go
Organophosphate |
Oral mg/kg |
Dermal |
Phorate |
2 |
6 |
Azinphos-Methyl |
13 |
220 |
Methamidaphos (rat) |
32 |
94 |
Oxydemeton (rat) |
75 |
250 |
Diazinon (rat) |
108 |
900 |
Phosalone (rat) |
130 |
1500 |
Chlorpyrifos (rat) |
155 |
202 |
Malathion (rat) |
1375 |
4444 |
Pesticide |
Oral mg/kg |
Dermal mg/kg |
Aldicarb |
0.5 |
3 |
Carbaryl |
5 -13 |
>1000 |
Propoxur! |
100 |
1000 -2400 |
Oxamyl |
5.4 |
3000 |
Carbofuran |
5-13 |
>1000 |
Methomyl |
17-24 |
>5000 |
Mild cases: tiredness, weakness, dizziness, nausea and blurred vision
Moderate cases: headache, sweating, tearing, drooling, vomiting, tunnel vision, and twitching
Severe cases: abdominal cramps, urinating, diarrhea, muscular tremors, staggering gait, pinpoint pupils, hypotension (abnormally low blood pressure), slow heartbeat, breathing difficulty, and possibly death
Extoxnet
http://ace.ace.orst.edu/info/extoxnet/
-
ChE reflects the toxicant on its target
- Integrates exposure over time
- The test is widely available
- A blood sample all that is needed
- BUT!
-
Baseline is needed
- Good lab methods needed
- Interpretation and timing important
- Sample handling important
Class I and II Carbamates & Organophosphates
DANGER or WARNING
LD 50 of < 50 mg oral or 100 dermal
LD 50 of >50 <500 oral or <1000 dermal
Threshold: 50 hrs in 30 days
Normal Range of cholinesterase activity Normal Range of cholinesterase activity
-
Relatively Stable in the Population
Presence of ChE inhibitor based symptoms
- Experience with pesticides
- Attitude toward inhibitors
- Medications
- Previous medical history
- Probable contraindications
- Treatment with ChE inhibitor
- myasthenia gravis
- Alzheimers
- glaucoma
- Other possible problems
- Anemia
- degenerative diseases of the central nervous system
- chronic colitis
- psychosis
-
Obtain before exposure
- 30 days since last handling
- Maintain records for future comparison
- If its abnormally low
- Recheck, average or discard
- More tests are better than less
- What does regression to the mean mean?
- How Often to Test?
- Retest with the same laboratory, same methods
- Retesting every 30 days
- When to do follow-up?
- Rules state within 3 days of reaching
threshold
- Why are you testing?
- To prevent future exposure
- To evaluate work exposure
- Decrease frequency with experience
Large difference between upper and lower range of normal
20% depression- Significant
30% AChE- Removal*
50% AChE- Poisoning
40% PChE- Removal*
60% PChE- Poisoning
*California, WHO and ACGIH recommendations on removal thresholds
-
Act promptly
- Evaluate for false positives
- Assure removal if meets
threshold
- Be sure the workplace is
evaluated
- Communicate with worker
and with employer
Plasma Cholinesterase
- Drugs: therapeutic and recreational
- BCPs, metaclopramide, cocaine?
- Liver Disease-alcoholism Congenital Deficiency (3%)
- Pregnancy
- Nephrotic syndrome
- Carbon disulfide, organic mercury
RBC Cholinesterase
- Drugs and Reticulocytosis
-
Hard to find, Hard to know
- Lack of depression when depression
is truly present
- Laboratory phenomena
- Low baseline
- Sample confusion
-
What else can they do?
- Thinning? Probably not in sprayed
orchards*
- Know the operation
- General work
*Engel and Keifer 1998, Keifer, Miller, Fenske 1995 Schnieder et al 1991)
Return to regular duty
- When both PChE and AChE get to 80%
File a Claim?
-
Records and Response
- Dry run your response
- Dry run you communication options
- Check out removal options
- Test the quality of your ChE
laboratory
- Blinded split samples to laboratory
- How far off should they be?
- If they approach thresholds, you're in
trouble
-
Know the rules of Monitoring (WA state)
- Obligations regarding confidentiality
- Know something of the pesticide practices
- Which pesticides, application frequency, PPE
- Know your population
- Language, culture, beliefs
- Know how to respond to a depression
- Check PPE & pesticides, removal options
- Know the non-pesticide related causes of
depression
- Assure quality performance and worker
protection
- False positives
- False negatives
- Laboratory accuracy
- Response to depressions
- Advise employer
- Counsel worker
-
Congenital cholinesterase
deficiency
- 3% of Anglos, 1% of Blacks
carry the gene
- May influence susceptibility
to ChE inhibitors
- Will have low baseline
values for PChE
- Will have normal RBC ChE
values
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