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Environmental Health Perspectives Vol. 44, pp. 1-8, 1982

The and Visual : , Physiology and Toxicology by Connie S. McCaa*

The are at risk to environmental by direct exposure to airborne pollutants, to splash injury from chemicals and to exposure via the to numerous drugs and bloodborne toxins. In addition, drugs or toxins can destroy vision by damaging the visual nervous system. This review describes the anatomy and physiology of the eye and visual nervous system and includes a discussion of some of the more common toxins affecting vision in man.

the Eyeball to the eye. The posterior portion of the is the Anatomy of , a tissue composed almost entirely of vessels. A second portion of the uvea, the ciliary The eye consists of a -lined fibrovascular body, lies just anterior to the choroid and posterior sphere which contains the aqueous humor, the to the corneoscleral margin and provides nutrients and the as illustrated in Figure 1. by forming intraocular fluid, the aqueous humor. In The is the essential component of the eye addition, the contains muscles which and serves the primary purpose of photoreception. provide a supporting and focusing mechanism for All other structures of the eye are subsidiary and the lens. The most anterior portion of the uveal act to focus on the retina, to regulate the tract, the , is deflected into the interior of the amount of entering the eye or to provide eye. The iris acts as a diaphragm with a central nutrition, protection or motion. The retina may be rounded opening, the , which dilates to allow considered as an outlying island of the central more light to the retina in dim and con- nervous system, to which it is connected by a tract stricts in bright lighting. The iris also has some of fibers, the . degree of nutritive function, since it acts to help As in the case of the and the , regulate the fluid flow in the eye. the retina is within two coats of tissue which The lens, the focusing mechanism of the eye, is contribute protection and nourishment. On the located immediately behind the iris and is sup- outside of the sphere, corresponding to the dura ported from the ciliary body by a suspensory mater, a layer composed of dense fibrous tissue ligament, the zonule. The space between the iris serves as a protective envelope, the fibrous tunic. and the lens is called the posterior chamber. The The posterior part of the fibrous tunic, the , is anterior chamber consists of the space between the white and opaque. Although it retains its protective iris and the . Behind the lens is the vitreous, function, the anterior portion, the cornea, is clear a gel-like, transparent body which occupies the and transparent. space between the lens and the retina. Immediately internal to the sclera, and between it and the retina, lies the uvea, a vascular tunic analogous to the pia-arachnoid of the central ner- The Cornea vous system. Primarily, the uvea provides nutrients The cornea, the window of the eye, is unique because of its transparency. Corneal transparency *Division of , University of Mississippi School is dependent on a special arrangement of cells and of , Jackson, Mississippi 39216. collagenous fibrils in an acid mucopolysaccharide April 1982 1 Internal Structures of the Eye .f. *sq!

FIGURE 1. The internal structure of the eye. environment, to an absence of blood vessels, and to proper optical qualities ofthe cornea and its deficiency deturgescence (the state of relative dehydration of may result in corneal damage. corneal tissue). Any toxin interfering with any one Corneal . The of these factors may result in corneal opacification. consists of five or six layers of cells which rest on a . It is replaced by growth from its basal cells with perhaps greater rapidity than Structure of the Cornea any other stratified epithelium (1). As illustrated in Figure 2, the cornea is composed Bowman's Membrane. Bowman's membrane offive distinct layers: (1) epithelium, (2) Bowman's is not a true basement membrane but is a clear membrane, (3) stroma, (4) Descemet's membrane acellular layer which is a modified portion of the and (5) . In addition, a tear film always superficial stroma. It is a homogenous layer with- covers the cornea of a healthy eye. out cells and has no capacity to regenerate if in- The Tear Film. The tear film is made up of jured. three layers. The portion immediately next to the Corneal Stroma. The stroma makes up ap- epithelium is rich in glycoprotein produced by the proximately 90% of the thickness of the cornea. It goblet cells ofthe conjunctival epithelium; a middle, consists of alternating lamellae of collagenous tis- watery layer is secreted by the lacrimal glands; an sue parallel to the surface of the cornea. The cor- outside oily layer is produced by the meibomian neal cells, or keratocytes, are relatively few and lie glands and the glands of Moll and Zeis of the lid. within the lamellae (1). The tear film is essential for the maintenance of the Descemet's Membrane. Descemet's membrane 2 Environmental Health Perspectives FIGURE 2. Structure of the anterior compartment of the eye. is a strong, homogeneous true basement membrane. stances, and the stroma will allow the passage of It is produced by the endothelial cells and can be water-soluble substances. All drugs that readily regenerated if injured. Descemet's membrane is enter the eye after topical application have the elastic and is more resistant than the remainder of ability to exist in equilibrium in solution as ionized the cornea to trauma and disease. and nonionized forms. In the nonionized form they . The corneal endothe- traverse the endothelium and epithelium and in the lium consists of a single layer of flattened cuboidal ionized form penetrate the stroma (2). cells. The endothelium does not regenerate and is essential for maintaining dehydration of corneal tissue. Therefore, chemical or physical damage to the endothelium of the cornea is far more serious Toxic Agents Affecting the Cornea than epithelial damage. Destruction of the endo- thelial cells may cause marked swelling of the Caustic Agents. Accidental splashing of sub- cornea and result in loss of its transparency. stances into the eyes is the most common cause of toxic eye . Alkalies and acids may result in rapid, deep, penetrating damage to cornea and deeper eye structures. The injuries produced by Permeability of the Cornea alkalies and acids are principally a result of extreme change of the pH within the tissue, an almost to Drugs or Toxins immediate action which can be treated only by The penetration of drugs through the cornea is rapid emergency action. There may be rapid disso- by differential solubility. The epithelium and endo- lution of epithelium and clouding of corneal stroma thelium will allow the passage of fat-soluble sub- from alkalies or coagulation of epithelium by acids, April 1982 3 but many changes appear later, including edema, layer of pigmented epithelial cells. The sensory further opacification, vascularization and degenera- retina is attached only at two regions; the anterior tion of the cornea. Alkali injury notoriously results extremity is firmly bound to the epithe- in late changes with extreme corneal injury and lium at its dentate termination, the . opacification. Posteriorly, the optic nerve fixes the retina to the Organic Solvents. Organic solvents, especially wall of the . This potential space between the those which are good fat solvents, may cause loss of sensory retina and the retinal pigment epithelium some or all of the corneal epithelium. Yet, even if may fill with fluid and result in . all the epithelium is lost from the cornea as a result The fluid usually comes from the vitreous and enters of organic solvents, it generally regenerates in a the subretinal space through a tear or hole in the few days without residual permanent damage (3). retina (rhegmatogenous or tear-induced retinal Gases, Vapors and Dusts. A great many gases, detachment). Less commonly, fluid may leak from vapors and dusts induce stinging sensations in the blood vessels and cause an exudative retinal detach- eyes and stimulate tearing. Some of these may ment. cause permanent corneal damage. For example, The retina is 0.1 mm thick at the ora serrata and scarring and distortion of the cornea have disabled 0.23 mm thick at the posterior pole. It is thinnest at workmen many years after chronic industrial ex- the , the center of the macula. The posure to the dusts or vapors resulting from the fovea may suffer irreparable damage in a brief manufacture of hydroquinone, a chemical used in period of separation from its only blood supply, the photographic film development (3). underlying choriocapillaris, during retinal detach- Deposits in the Cornea. Some drugs such as ment. chloroquine, hydroxychloroquine and chlorproma- zine produce deposits in the corneal epithelium. These deposits generally appear as fine granules Composition of the Sensory Retina scattered throughout the epithelium. Usually the The sensory retina is composed of highly - deposits do not interfere with vision but may defract ized tissue consisting of nine histologic layers rest- light and produce an appearance of halos around ing on pigment epithelium. From the outside of the light. These deposits are generally reversible when eye the layers are in the following order: (1) the the drugs are discontinued. ; (2) the external limiting membrane; (3) the ; (4) the ; (5) the ; (6) the The Sciera ; (7) the layer; The sclera is hydrated and has large collagen (8) the nerve fiber layer; (9) the internal limiting fibrils arranged haphazardly; therefore, it is opaque membrane. and white rather than clear. The sclera has three layers: the episclera, the outer layer; the sclera; and the melanocytic layer, the inner lamina fusca. Retinal Pigment Epithelium The episclera, a highly vascular , The pigment epithelium consists of a single layer attaches Tenon's capsule to the sclera. The sclera of cells which is firmly attached to the basal lamina proper is relatively avascular and contains consid- of the choroid and loosely attached to the rods and erable elastic tissue. The sclera is approximately 1 cones. Microvilli form the apical parts of the cells mm thick posteriorly and gradually thins to about and project among the rods and cones. The pigment 0.3 mm just posterior to the insertions of the recti granules consist of melanoprotein and lipofuscin. muscles. Therefore, these sites posterior to the The functions of the pigment epithelium are not insertion of the muscles are the areas of the eye completely understood. It produces pigment which which are most liable to rupture with trauma to the acts to absorb light. Also, it has phagocytic func- globe. tions and provides mechanical support to the pro- cesses of the photoreceptors. The Retina The sensory retina covers the inner portion of the Photoreceptor Cells of the Retina posterior two-thirds of the wall of the globe. It is a The rods and cones, the light receptive elements thin structure which in the living state is transpar- of the retina, transform physical energy into nerve ent and of a purplish-red due to the visual impulses. Transformation of light energy depends purple of the rods. The retina is a multilayered on alteration of visual contained in the sheet of neural tissue closely applied to a single rods or cones. 4 Environmental Health Perspectives , a derivative of , is the icity is . There is a 75% incidence of visual pigment of the rods. Rhodopsin is composed retinopathy at a daily dosage level of 1200-2100 of retinal (vitamin A aldehyde) bound to a large mg/day (11). A pigmentary mottling of the macula , . The retinal is the same in both rods and posterior pole can be observed associated with and cones but the protein moiety differs. Light decreased and pericentral and central isomerizes the retinal from the 1 1-cis to an all-trans scotomata (12). Improvement in visual acuity is shape, releasing the retinal from the opsin. The common after the drug is stopped. chemical sequence following the isomerization of Quinine. Quinine may cause ocular damage when retinal produces a transient excitation of the recep- taken in large doses. It affects the ganglion cells tor which is propagated along its . The bipolar and nerve fibers resulting in degeneration. cell transmits this information to the inner plexi- form layer where it is modified through connections between amacrine, bipolar, and ganglion cells. The Aqueous Humor ganglion cells pass this analyzed information to the Aqueous humor, contained in the anterior com- brain (4). partment of the eye, is produced by the ciliary body and drained through outflow channels into the extraocular venous system. The aqueous circula- Toxins Affecting the Retina tion is a vital element in the maintenance of normal Chloroquine. A definite association of retinop- (IOP) and in the supply of athy with chloroquine was made in 1959 (5), and nutrients to avascular transparent ocular media, subsequently more than 200 cases have been report- the lens and the cornea. Circulatory disturbance of ed. There is a definite relationship with retinopathy the aqueous humor leads to abnormal elevation of and daily and total doses. Most cases of chloroquine the IOP, a condition known as , which can retinopathy occur at a dosage level of 500 mg per ultimately lead to blindness. day or more. A total dosage of 100 g can be retinopathic. The risk, however, significantly in- creases as the total dose becomes greater than 300 Aqueous Humor Formation g (6). Formation of aqueous humor is dependent upon Disturbance of the macula is almost always pres- the interaction of complex mechanisms within the ent in chloroquine retinopathy. Initially it may pres- ciliary body, such as blood flow, transcapillary ent as edema followed by development of pigmen- exchange and transport processes in the ciliary tary changes. The latter may vary from an extremely epithelium. Maintenance of the IOP is controlled by subtle abnormality to one having a "bull's eye" a delicate equilibration of aqueous humor formation appearance to complete loss of macular pigment. and outflow; aqueous formation and ocular blood Chloroquine-induced retinal damage occurs pri- flow are in turn influenced by the IOP (13). marily at the level of the pigment epithelium and rods and cones. There is loss of the rods and cones Formation of Aqueous by the Ciliary with migration ofpigment from the adjacent epithe- lium into the inner retinal layer. Electron micro- Epithelium scopic examination has shown additional abnormali- The ciliary epithelium is composed of two layers, ties of the ganglion cells consisting of membranous the outer pigmented and the inner nonpigmented cytoplasmic bodies and clusters ofcurvilinear tubules epithelium. ATPase is responsible for trans- (7). port to the posterior chamber and for aqueous The visual prognosis is guarded when a retinopa- formation. It is found predominantly in the non- thy secondary to chloroquine develops. In a significant pigmented epithelium (14). number of cases there is a progressive loss of visual Chemical analysis of the aqueous humor indicates acuity which can continue for several years follow- that this fluid is not a simple dialysate or ultrafiltrate ing the discontinuation of chloroquine (8). Hydroxy- of the blood plasma (15). Continuous aqueous pro- chloroquine causes a retinopathy similar to that of duction by the requires an active chloroquine (9). testing with a red test mechanism demanding metabolic energy. Aqueous object has been recommended as the most reliable humor formation is thereby thought to be due to a indicator ofimpending retinal to chloroquine secretory mechanism in the ciliary epithelium together in man (10). with ultrafiltration from the in the ciliary Thioridazine. Thioridazine is one of the most processes. The secretory mechanism involves active commonly used phenothiazines in the treatment of transport of electrolytes, coupled fluid transport, serious psychiatric illness. Its principal ocular tox- and carbonic anhydrase action. April 1982 5 Aqueous Humor Circulation and shape with greater refractive power. This process is known as . With age, the lens Drainage becomes harder and the ability to accommodate for The anterior ocular compartment containing aque- near objects is decreased. ous humor consists of two chambers of unequal volume, the anterior and posterior chambers (Fig. 2). Communication between the anterior and poste- Composition of the Lens rior chambers occurs through the pupil. The aque- The lens consists of about 65% water and about ous humor is secreted by the ciliary processes into 35% protein (the highest protein content of any the posterior chamber from which it flows into the tissue of the body). is more concentrated anterior chamber. It is drained from the anterior in the lens than in most body tissues and ascorbic chamber into the extraocular venous systems through acid and are both present in the lens. It porous tissue in the iridocorneal angle and Schlemm's contains no nerve fibers or blood vessels; therefore, canal (in man and ) or venous plexus (in its nutrition is derived from the surrounding fluids. lower ). This drainage system is called the Mechanical injury to the lens or damage from altered conventional drainage route. In man and primates, nutrient concentration in the aqueous may result in some aqueous leaves the eye by bulk flow via the formation. ciliary body, suprachoroid, and sclera to the episcleral space; this route is called the uveoscleral drainage route or unconventional route. Cataract A cataract is a lens opacity. Senile cataract is the most common type and is usually bilateral. Trau- Effect of on matic cataract, , and Intraocular Pressure secondary to mellitus, galactosemia, other Topical application of corticosteroids to normal systemic diseases, and toxins are less common. human eyes occasionally results in IOP elevation Cataract Formation. Cataractous ex- accompanied by an increase in the outflow resis- hibit protein alteration, lens edema, vacuole forma- tance (16). After discontinuation of steroids, the tion, necrosis, and disruption of the lens fibers. IOP usually returns to normal levels but may remain Cataract formation is characterized by a reduction irreversibly elevated. The hypertensive IOP response in oxygen uptake and an initial increase in water to steroids appears to be genetically determined content followed by dehydration. Sodium and cal- cium content is increased while potassium, ascorbic (17). acid, protein, and glutathione content is decreased. Sugar Cataracts. Examples of sugar type - aracts are those produced by galactose, xylose and The Lens . Galactose and xylose administered in large The lens is a biconvex, transparent, and avascular amounts to and blood glucose in excess, as structure. It is suspended behind the iris by the in severe diabetes with persistent severe hypergly- , a suspensory ligament, which con- cemia, can produce cataract. nects it with the ciliary body. The lens capsule is a Sugars in high concentration in the aqueous humor semipermeable membrane which will admit water readily enter the lens and are converted to sugar and electrolytes. A subcapsular epithelium is pres- alcohols by (galactose to dulcitol ent anteriorly. Subepithelial lamellar fibers are con- or galactitol, glucose to sorbitol, and xylose to tinuously produced throughout life. The nucleus xylitol). The sugar alcohols accumulate in the lens and cortex of the lens are made up of long concen- and have an osmotic effect causing water to enter tric lamellae each of which contains a flattened the lens and causing lens cells and fibers to swell nucleus in the peripheral portion of the lens near and become disrupted. These changes lead to for- the equator. mation of cataract (18). Cataracts. Posterior subcap- sular cataracts have been produced by a variety of Function of the Lens glucocorticoids used medically for long periods either The lens acts to focus light rays upon the retina. systemically or applied to the surface of the eye. To focus light from a near object, the The toxicologic mechanism of cataract induction by contracts, pulling the choroid forward and releasing the corticosteroids has not been defined. the tension on the zonules. The elastic lens capsule Toxic Cataracts. Many cases of toxic cataract then molds the pliable lens into a more spherical appeared in the 1930s as a result of ingestion of 6 Environmental Health Perspectives dinitrophenol, a drug taken to suppress appetite. peduncle to end in the lateral geniculate body with Triparanol (MER/29) was also found to cause cata- a smaller portion carrying pupillary impulses con- ract. Echothiophate iodide, a strong miotic used in tinuing to the and superior colliculi. the treatment of glaucoma, has also been reported to cause cataract. The Lateral Geniculate Nucleus The Vitreous The visual fibers in the lateral geniculate body. The cell bodies of this structure give rise to The vitreous is a clear, avascular, gel-like body final of the which comprises two-thirds ofthe volume and weight the geniculocalcarine tract, the of the eye. It fills the space bounded by the lens, visual pathway. retina, and . Its gelatinous form and con- sistency is due to a loose syncytium of long-chain The collagen molecules capable of binding large quanti- ties of water. The vitreous is about 99% water; The geniculocalcarine tract passes through the collagen and make up the remaining posterior of the internal capsule and then fans 1%. into the optic radiation which traverses parts of the temporal and parietal lobes en route to the occipital The Visual Pathway cortex. The visual pathway from the retina may be divided The into six levels: (1) the optic nerve, (2) the optic , (3) the , (4) the lateral genicu- Optic radiation fibers representing superior reti- late nucleus, (5) the optic radiation and (6) the nal quadrants terminate on the superior of the visual cortex. calcarine fissure, and those representing inferior retinal quadrants end in the inferior lip. The macula is represented in a large region posteriorly, and Anatomy of the Optic Nerve retinal areas close to the macula are represented The optic nerve consists of about 1 million more anteriorly. arising from the ganglion cells of the retina. The nerve fiber layer of the retina is comprised of these Toxins Affecting the Visual Nervous axons and they converge to form the optic nerve. The orbital portion of the nerve travels within the System muscle cone to enter the bony optic foramen to gain Methanol. Methyl alcohol (wood alcohol) has access to the cranial cavity. The optic nerve is made long been used as an intoxicating drink either acci- up of visual fibers (80%) and afferent pupillary dentally or as an adulterant of ethyl alcohol. Its fibers (20%). metabolic product, formaldehyde, can cause marked destruction of the ganglion cells of the retina as well as degeneration of nerve fibers in the optic nerve The resulting in permanent blindness. After a 10 mm intracranial course, the optic Nutritional (Tobacco-Alcohol Am- from each eye join to form the optic chiasm. blyopia). Nutritional amblyopia is the preferred At the optic chiasm the nasal fibers, constituting term for the entity sometimes referred to as about three-fourths of all the fibers, cross over to tobacco-alcohol amblyopia. Persons with poor dietary run in the optic tract of the opposite side. habits, particularly if the diet is deficient in thia- mine, may develop centrocecal that are usually of constant . Bilateral loss of central The Optic Tract vision is present in over 50% of patients, reducing In the optic tract, crossed nasal fibers and un- visual acuity below 20/200. Reduction in alcohol and crossed temporal fibers from the chiasm are rear- tobacco usage plus adequate diet and thiamine is ranged to correspond with their position in the usually effective in curing the disease. lateral geniculate body. All of the fibers receiving Drugs or Toxins Causing . Papil- impulses from the right visual field are projected to ledema as a toxic manifestation of drugs or chemi- the left cerebral hemisphere; those from the left cals can occur as an accompaniment of field to the right cerebral hemisphere. Each optic or as a manifestation of elevation of intracranial tract sweeps around the hypothalamus and cerebral pressure. The substances that have most clearly April 1982 7 produced papilledema by causing increase in intra- 8. Krill, A., Potts, A., and Johanson, C. Chloroquine retinopa- cranial pressure are the corticosteroids, ethylene thy, investigation of discrepancy between dark and electroretinographic findings in advanced stages. Am. glycol, nalidixic acid, tetracycline and vitamin A. J. Ophthal. 71: 530-543 (1971). Drugs or Toxins Causing Optic Neuritis. The 9. Crews, S. Chloroquine retinopathy with recovery in early diagnosis of optic neuritis has usually been made on stages. Lancet 7337: 436-438 (1964). the basis of clinical observations of reduction of 10. Percival, S., and Behrman, J. Ophthalmological safety of vision associated with central scotomas combined chloroquine. Brit. J. Ophthal. 53: 101-109 (1969). 11. Hagopian, V., Stratton, D., and Busiek, R. Five cases of with ophthalmoscopically visible changes in the optic pigmentary retinopathy associated with thioridazine admin- nerve , particularly hyperemia with variable istration. Am. J. Psychiat., 123: 97-100 (1966). degrees of edema. Some of these agents are etham- 12. Bernstein, H. N. Ocular side-effects of drugs. In: Drugs and butol, lead, chloramphenicol, isoniazid and digitalis. Ocular Tissues. S. Dikstein, Ed., S. Karger, Basel, 1977. 13. Mishima, S., Masuda, K., and Tamura, T. Drugs influencing aqueous humor formation and drainage. In: Drugs and REFERENCES Ocular Tissues. S. Dikstein, Ed., S. Karger, Basel, 1977. 14. Cole, D. F. Localization of ouabain-sensitive adenosine 1. Warwick, R. Eugene Wolfe's Anatomy of the Eye and triphosphatase in ciliary epithelium. Exptl. Eye Res. 3: . W. B. Saunders Co., Philadelphia and Toronto, 1976. 72-75 (1964). 2. Havener, W. H. Ocular Pharmacology. C. V. Mosby Co., St. 15. Kinsey. V. E. The chemical composition and the osmotic Louis, 1978. pressure of the aqueous humor and plasma of the . J. 3. Grant, W. M. Toxicology of the Eye. Charles C Thomas, Gen. Physiol. 34: 389-401 (1951). Springfield, Ill., 1974. 16. Armaly, M. Effect of corticosteroids on intraocular pressure 4. Moses, R. A. Adler's Physiology of the Eye. C. V. Mosby and fluid dynamics, I and II. Arch. Ophthal. 70: 482-491 Co., St. Louis, 1975. (1963). 5. Hobbs, H., and Calnan, C. The ocular complications of 17. Becker, B., and Hahn, K. Topical corticosteroids and chloroquine therapy. Lancet 1: 1207-1209 (1958). heredity in primary open-angle glaucoma. Am. J. Ophthal. 6. Nylander, U. Ocular damage in chloroquine therapy. Acta 57: 543-551 (1964). Ophthal. 44: 335-348 (1966). 18. Chylack, L. T., and Kinoshita, J. H. Biochemical evaluation 7. Ramsey, M., and Fine, B. Chloroquine toxicity in the human of a cataract induced in high glucose medium. Invest. eye. Am. J. Ophthal. 72: 229-235 (1972). Ophthal. 8: 401-412 (1969).

8 Environmental Health Perspectives