Ophthalmic toxicity exposure

Current guidelines for toxicity evaluation of ophthalmic formulations involve both single and multiple applications, dependent on the proposed clinical use [39]. The multiple applications may extend over a 9-month period and incorporate evaluations of ocular irritation and toxicity, systemic toxicity, and determinations of systemic exposure (toxicokinetics). In many cases the systemic exposure from an ocular route is less than by parenteral administration, information that will assist in determining whether additional studies may be needed to establish systemic safety of the ophthalmic preparation. U.S. and international guidance documents are available [71,72], and regulations and tests have been summarized for ophthalmic preparations [39,73,74],... 

In studies involving human exposure (Rengstorff and Mershon, 1969a, b), CS (0.1% or 0.25% in water 1.0% in triocyl phosphate) sprayed or administered as ophthalmic drops onto the eyes, caused apraxia of eyelid opening with blepharospasm upon eyelid closure for 10 to 135 s. It also caused a transient conjunctivitis but no comeal damage upon further inspection with a slit lamp. Rabbit eyes contaminated with CS as a solution (0.5-10% in polyethylene glycol), as a solid, or thermally dispersed as a smoke (15 min at 6,000 mg/m ) showed a greater toxicity with solution. CS in solution caused profuse lacrimation, conjunctivitis, iritis, chemosis, keratitis, and corneal vascularization at concentrations at or above 1%. 

The patient with toxic keratitis or medicamentosa generally reports recent exposure to the offending substance or the use of an ophthalmic preparation on a short- or long-term basis. In the case of mild toxic keratitis, the patient may have few or no symptoms. More involved cases may produce very definite symptoms of redness, irritation, burning, tearing, and ocular discomfort upon instillation. 

Ophthalmic effects due to direct ocular exposure to OPs include optic neuropathy, retinal degeneration, defective vertical smooth pursuit, myopia, and miosis. Respiratory effects, including muscarinic, nicotinic, and central effects, contribute to respiratory distress in acute and delayed OP toxicity, Muscarinic effects, such as bronchospasm and laiyngeal spasm, can lead to airway obstruction. Nicotinic effects can lead to weakness and paralysis of respiratory oropharyngeal tiiuscles. Central effects can lead to cessation of respiration. 

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