Agency for Toxic Substances and Disease Registry
Case Studies in Environmental Medicine (CSEM) 

Cholinesterase Inhibitors
Including Insecticides and Chemical Warfare Nerve Agents
Part 4: The Cholinergic Toxidrome
Section 5: Signs and Symptoms by Route of Exposure and Chemical Structure of the Involved Cholinesterase Inhibitor (Optional Reading)

Learning Objectives (Optional Reading)

Upon completion of this portion of the case study, the learner should be able to describe how:

• Signs and symptoms of cholinesterase toxicity vary with the route of exposure.
• Cholinesterase toxicity relates to the chemical structure of the cholinesterase inhibitors.

Signs and Symptoms by Route of Exposure (Optional Reading)

Cholinesterase inhibitors may be rapidly absorbed via dermal, conjunctival, respiratory, and gastrointestinal routes. (Carlton, Simpson et al. 1998) Other factors being equal (e.g., chemical structure), signs and symptoms may vary by route of exposure (although any constellation of findings can occur with significant exposure by any route). (Sidell 1997; Carlton, Simpson et al. 1998; Leikin, Thomas et al. 2002; Erdman 2004)

Note: Very high doses of nerve agents can act within minutes, even with dermal exposures. (Sidell 1997)

Chemical Structure versus Toxicity (Optional Reading)

Among other factors, the toxicity of cholinesterase inhibitors varies with chemical structure.

For example: (Besser and Gutmann 1994)

• Organophosphorus compounds having a quaternary nitrogen (ammonium) attached to the phosphorus atom have the highest toxicity.
• Also very toxic are those containing an attached fluorine atom (This includes the chemical warfare nerve agents).
• Less toxic are those containing a cyanide or halogen other than fluorine.
• Less toxic still are those with attached alkyl, alkoxy, alkylthio, aryloxy, arylthio, heterocyclic analogs, or nonquaternary nitrogen. Most organophosphorus compounds belong to this category.

Vapor Exposure (Namba, Nolte et al. 1971; Tareg, B et al. 2001) (Conjunctival and Respiratory) (Optional Reading)

Note: Mild vapor exposure may produce eye and respiratory symptoms due to localized tissue contact even in the absence of other systemic findings.

Dermal Exposure (Sidell 1997; Tareg, B et al. 2001) (Optional Reading)

Notes:

With dermal exposure to nerve agents onset of clinical findings of the cholinergic toxidrome may be delayed up to 18 hours. (Sidell 1997) Thus, patients with suspected dermal exposure should be observed and monitored. No definite minimum, safe duration of observation has yet been established because of lack of clinical experience and clinical studies. (Leikin, Thomas et al. 2002)

Respiratory symptoms may be absent in mild to moderate exposures. (Leikin, Thomas et al. 2002)

A substantial proportion of those with isolated dermal exposure do not develop miosis (pupillary constriction). (Sidell 1997)

Oral Exposure (Optional Reading)

The frequency and sequence of clinical findings after ingesting cholinesterase inhibitors have received less attention in the literature. Generally, with this route, gastrointestinal signs and symptoms are the first to appear. (Carlton, Simpson et al. 1998; Tareg, B et al. 2001; Erdman 2004)

• Abdominal cramps.
• Anorexia.
• Diarrhea.
• Nausea.
• Vomiting.

Note: Cholinesterase inhibiting insecticides are often dissolved in hydrocarbons, and ingestion may be associated with pulmonary aspiration and chemical pneumonitis, as well as a solvent-like breath odor. (Durham and Hayes 1962; Clark 2002)

Reasons for Delayed Onset of Clinical Findings (Optional Reading)

Delayed onset may occur with:

• Dermal exposure.
• Cholinesterase inhibitors which can be stored in fat tissue and released over time (e.g., dichlofenthion). (Clark 2002)
• Cholinesterase inhibitors whose toxicity requires metabolic conversion (e.g., malathion).

Note: In some cases, deceptively mild initial symptoms may be followed by a rapid worsening up to 48 hours later. This may occur even while the patient is undergoing antidotal treatment. (Erdman 2004)

Key Points (Optional Reading)

• Cholinesterase inhibitors may be rapidly absorbed via dermal, conjunctival, respiratory, and gastrointestinal routes.