Organophosphorus and Carbamate Insecticides
Organophosphorus (OP) compounds and carbamates, also known as cholinesterase inhibitors, are widely used pesticides. These agents, which comprise thousands of structurally related substances, are responsible for a large number of suicidal or accidental poisonings, with the greatest mortality (an estimated 200,000 deaths per year) in rural areas of developing countries.
During the 1930s, German military scientists synthesized numerous OP compounds, including parathion and several highly potent chemical warfare agents (eg, GA [tabun], GB [sarin], and GD [soman]; see Warfare Agents–Chemical and Table II–57). Because these chemical weapons affect the autonomic nervous system, they are sometimes referred to as “nerve agents.” Terrorist attacks in Japan (1994 and 1995) affected thousands of urban civilians who were exposed to the OP compound sarin.
Carbamates, although less deadly than OP agents, are used frequently as pesticides, fungicides, herbicides, rodenticides, and medications (eg, pyridostigmine) to treat neurologic disorders such as myasthenia gravis.
Mechanism of toxicity
Organophosphorus compounds inhibit two enzymes: acetylcholinesterase (AChE), found in synaptic junctions and in red blood cells (RBCs), and butyrylcholinesterase, also known as pseudocholinesterase (PChE) or plasma cholinesterase, found in the blood. Each of these enzymes breaks down acetylcholine.
Blockade of AChE is the most clinically significant effect of OPs and carbamates because this leads to the accumulation of excessive amounts of acetylcholine at muscarinic receptors (found on various cholinergic secretory cells), at nicotinic receptors (located on skeletal neuromuscular junctions and autonomic ganglia), and in the CNS.
Permanent inhibition of AChE (“aging”) may occur when there is covalent binding by the OP to the enzyme. The rate of aging is highly variable, from several minutes to days, depending on the route of exposure as well as the specific OP. Dimethyl OP compounds (eg, dimethoate) generally age more quickly than diethyl agents (eg, chlorpyrifos), and lipophilic OP compounds can be released into the systemic circulation from fat stores for many days to weeks following exposure, prolonging both the duration of clinical toxicity and the aging window. Antidotal treatment with an oxime (see “Pralidoxime”) is considered beneficial only if administered before aging occurs.
Carbamates also inhibit the AChEs and lead to accumulation of acetylcholine, with similar acute clinical effects.
CNS effects from carbamates are often less pronounced because they have more difficulty crossing the blood-brain barrier.
Carbamates do not “age” the AChE enzyme, and toxicity is therefore usually more brief and self-limited than with the OP compounds.
Patients with myasthenia gravis and related neurologic disorders may be at increased risk for carbamate-induced cholinergic toxicity because they are frequently prescribed pyridostigmine or related “-stigmine” compounds.
Aldicarb is relatively more potent and is translocated systemically by certain plants (eg, melons) and concentrated in their fruit. An acute outbreak of poisoning occurred in California in 1985 after ingestion of watermelons that had been grown in a field previously sprayed with aldicarb. The use of an imported rodenticide (Tres Pasitos, “three little steps”) led to an epidemic of aldicarb poisoning in New York in 1994–1997.
Additionally, the effects of the hydrocarbon solvents in which these compounds are frequently formulated (eg, xylene, cyclohexanone, naphtha) must also be considered in evaluating the clinical toxicity from these compounds.
Pharmacokinetics. Signs and symptoms of acute OP poisoning may be immediate or delayed several hours, depending on the agent, route, co-ingested toxins, and degree of exposure. Most OPs and carbamates can be absorbed by any route: inhalation, ingestion, or absorption through the skin. Highly lipophilic organophosphates (disulfoton, fenthion, and others) are stored in fat tissue, with the potential to cause prolonged toxicity. The severity and tempo of intoxication are also affected by the rate of exposure (acute vs chronic), the ongoing metabolic degradation and elimination of the agent, and, for some OP compounds (eg, malathion, parathion), the rate of metabolism to their clinically active “oxone” derivatives.
Toxic dose. There is a wide spectrum of relative potency of the OP and carbamate compounds (Tables II–44, II–45, and II–46).
Table II-44 Organophosphorus and Carbamate Pesticides
Table II-44 Organophosphorus and Carbamate Pesticides
Agent
CAS Number
Chemical Structurea
WHO Classificationb
GHS Classificationc
Acephate
30560-19-1
OP (diM)
II
4
Alanycarb
83130-01-2
C
II
4
Aldicarb
116-06-3
C
I
1
Anilofos
64249-01-0
OP (diM)
II
4
Azamethiphos
35575-96-3
OP (diM)
II
4
Azinphos-methyl
86-50-0
OP (dM)
2
Azinphos-ethyl
2642-71-9
OP (diE)
Ib
2
Bendiocarb
22781-23-3
C
II
3
Benfuracarb
82560-54-1
C
II
3
Bensulide
741-58-2
OP
II
3
Butamifos
36335-67-8
OP
II
4
Butocarboxim
34681-10-2
C
Ib
3
Butoxycarboxim
34681-23-7
C
Ib
3
Cadusafos
95465-99-9
OP
Ib
2
Carbetamide
16118-49-3
C
U
5
Carbaryl
63-25-2
C
II
3
Carbofuran
1563-66-2
C
Ib
1
Carbosulfan
55285-14-8
C
II
3
Chlorethoxyfos
54593-83-8
OP (diE)
Ia
1
Chlorfenvinphos
470-90-6
OP (diE)
Ib
2
Chlormephos
24934-91-6
OP (diE)
Ia
2
Chlorpropham
101-21-3
C
U
5
Chlorpyrifos
2921-88-2
OP (diE)
II
3
Chlorpyrifos-methyl
5598-13-0
OP (diM)
III
5
Coumaphos
56-72-4
OP (diE)
Ib
2
Cyanophos
2636-26-2
OP (diM)
II
4
Demeton-S-methyl
919-86-8
OP (diM)
Ib
2
Diazinon
333-41-5
OP (diE)
II
4
Dichlorvos (DDVP)
62-73-7
OP (diM)
Ib
3
Dicrotophos
141-66-2
OP (diM)
Ib
2
Dimethoate
60-51-5
OP (dM)
II
3
Disulfoton
298-04-4
OP (diE)
Ia
1
Edifenphos
17109-49-8
OP
Ib
3
EPN
2104-64-5
OP
Ia
2
Ethiofencarb
29973-13-5
C
Ib
3
Ethion
563-12-2
OP (diE)
II
3
Ethoprophos
13194-48-4
OP
Ia
2
Famphur
52-85-7
OP (diM)
Ib
2
Fenamiphos
22224-92-6
OP
Ib
2
Fenitrothion
122-14-5
OP (diM)
II
4
Fenobucarb
3766-81-2
C
II
4
Fenoxycarb
79127-80-3
C
U
5
Fenthiocarb
62850-32-2
C
II
4
Fenthion
55-38-9
OP (diM)
II
3
Formetanate
22259-30-9
C
Ib
2
Fosamine
25954-13-6
OP
III
5
Furathiocarb
65907-30-4
C
Ib
2
Heptenophos
23560-59-0
OP (diM)
Ib
3
Isoprocarb
2631-40-5
C
II
4
Isoxathion
18854-04-8
OP (diE)
Ib
3
Malathion
121-75-5
OP (diM)
III
5
Mecarbam
2595-54-2
C
Ib
2
Methacrifos
62610-77-9
OP (diM)
II
4
Methamidophos
10265-92-6
OP (diM)
Ib
2
Methidathion
950-37-8
OP (diM)
Ib
2
Methiocarb
2032-65-7
C
Ib
2
Methomyl
16752-77-5
C
Ib
2
Metolcarb
1129-41-5
C
II
3
Mevinphos
26718-65-0
OP (diM)
Ia
1
Monocrotophos
6923-22-4
OP (diM)
Ib
2
MPMC (xylylcarb)
2425-10-7
C
II
4
Naled
300-76-5
OP (diM)
II
4
Omethoate
1113-02-6
OP (diM)
Ib
2
Oxamyl
23135-22-0
C
Ib
2
Oxydemeton-methyl
301-12-2
OP (diM)
Ib
3
Parathion
56-38-2
OP (diE)
Ia
1
Parathion-methyl
298-00-0
OP (diM)
Ia
1
Phenthoate
2597-03-7
OP (diM)
II
4
Phorate
298-02-2
OP (diE)
Ia
1
Phosalone
2310-17-0
OP (diE)
II
3
Phosmet
732-11-6
OP (diM)
II
3
Phosphamidon
13171-21-6
OP (diM)
Ia
2
Phoxim
14816-18-3
OP (diE)
II
4
Piperophos
24151-93-7
OP
II
4
Pirimicarb
23103-98-2
C
II
3
Primiphos-methyl
29232-93-7
OP
II
4
Profenofos
41198-08-7
OP
II
4
Propetamphos
31218-83-4
OP
Ib
3
Propoxur
114-26-1
C
II
3
Prothiofos
34643-46-4
OP
II
4
Pyraclofos
77458-01-6
OP
II
3
Pyrazophos
13457-18-6
OP (diE)
II
4
Pyridaphenthion
119-12-0
OP (diE)
II
4
Quinalphos
13593-03-8
OP (diE)
II
3
Sulfotep
3689-24-5
OP (diE)
Ia
1
Tebuprimifos
96182-53-5
OP (diE)
Ia
1
Temephos
3383-96-8
OP (diM)
III
5
Terbufos
13071-79-9
OP (diE)
Ia
1
Tetrachlorvinphos
22248-79-9
OP (diM)
III
5
Thiodicarb
59669-26-0
C
II
3
Thiofanox
39196-18-4
C
Ib
2
Thiometon
640-5-3
OP (diM)
Ib
3
Triazophos
24017-47-8
OP (diM)
Ib
3
Trichlorfon
52-68-6
OP (diM)
II
3
Vamidothion
2275-23-2
OP (diM)
Ib
3
XMC (cosban)
2655-14-3
C
II
4
Table II-45 Definition of World Health Organization Hazard Classification
Table II-45 Definition of World Health Organization Hazard Classification
LD50 for the Rat (mg/kg of body weight)
WHO Class
Oral
Dermal
Ia
Extremely hazardous
<5
<50
Ib
Highly hazardous
5–50
50–200
II
Moderately hazardous
50–2000
200–2000
III
Slightly hazardous
>2000
>2000
U
Unlikely to present acute hazard
≥5000
≥5000
Table II-46 Globally Harmonized System Classification
Table II-46 Globally Harmonized System Classification
Oral Classification Criteria
Dermal Classification Criteria
GHS Category
LD50 (mg/kg)a
Hazard Statement
LD50 (mg/kg)b
Hazard Statement
1
<5
Fatal if swallowed
<50
Fatal in contact with skin
2
5–50
Fatal if swallowed
50–200
Fatal in contact with skin
3
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