Saku disease is referred to as Optico-autonomic-peripheral neuropathy and as a visual disease syndrome related to
use of agricultural Organophosphorus (OP) pesticides.
Japanese studies from 1965 involved Ethylthiometon,
Fenthion, Fenitrothion, Malathion, Parathions, Dipterex, Vamidothrin and Diazinon.
Symptoms were dose dependant and range from lenticular changes to serious histopathalogical changes in tissues
of e.g. ciliary body and retina. Little study has been done other than in Japan (and perhaps some in Italy) and
results are inconclusive, but the association with OPs is probable and studies conclusively reveal the effects of
OPs on the visual system e.g -
Myopia -short sightedness
Narrowing of the Visual Fields
Astigmatism - due to refractive errors from distorted cornea
Reduced vision
Histipathological Evidence of degeneration - of extra occular muscle, Ciliary Muscle, Retina and other
tissues.
Certain Visual parameters e.g. Pupillary responses and electroretinographs (ERG)
All show effects from OPs at levels BELOW those that inhibit the blood cholinesterases and therefore
such effects would go unrecognized with current test procedures.
* * * * * * * * * * *
The incidence of Saku disease is only in the agricultural areas of Japan and increased from 1965.
Usual problems were linked to increased use of OPs with symptoms similar to those found in cholinesterase
inhibition by OP medicines used in Ophthalmology.
Reduction in Erythrocyte anticholinesterase (AChe) responded to treatment with OP antidote 2PAM.
The use of Malathion and Ethyl and Methyl Parathions and subsequently Fenthion, Dipterox,Fenitrothion and
Diazinon corresponded with increased Myopia in the population. The usual problems were linked to helicopter
applications of Malathion, Vamidothrin and 2 carbamates Hopcide and BPMC (Hopcin) but mainly involved
OPs. Parathion was also used on the ground. Saku children showed signs of reduced visual acuity with high
vertical astigmatism, refractive abnormalities, narrowing of visual field, abnormal eye movements, abnormal
pupillory response, optic nerve abnormality - including optic neuritis, pallor of the optic disc, and or optic
atrophy. Some had lowered serum cholinesterase and one or more non-visual system problems such as sensorial
neuropathy, dysmetria, abnormal electroencephalogram (EEG) and OPs in the blood plus mild clinical
complications of central, peripheral and automotive nervous systems. (Typical nicotonic & muscarinic reactions
of intoxification were not observed) Pseudo-cholinesterase (pseudo-CHe) levels recovered within days of
spraying. Plasma pseudo-CHe reduced by 22% of normal and erythrocyte ACHe by 24% - both significant.
Cholinesterase in lateral rectus muscles was totally inhibited indicating that they may be more affected
by OPs. Plasma pseudo-CHe reduction was linked to the narrowing of the visual fields. Patients displayed
Retinochoroidal atrophy and abnormal retinal pigment. The highest OP levels in the blood was linked to the
worst problems.
Vision usually improved some months after therapy as cholinesterase activity normalized but refractive changes
were not improved with treatment.
Strong myopic astigmatism was common but occular symptoms were not necessarily neurological.
In all cases the Optic nerve was swollen.
Chronic intoxication produced a fading optic nerve and finally atrophy. Strong OPs such as Parathion produced
external congestion of the optic nerve. A considerable amount of time is required for improvement of optic
nerve symptoms. Retinal disease halts with 2PAM and Atropine treatment.
The disease progresses with worsening optic disc, retina, retinal vasculature and ERG response. Macular
changes in workers exposed to Fenthion for 8.6 years include; Perifoveal areas of hypopigmentation of 1/8 to
1/3 of disc diameter, irregular background pigmentation and dull foveal reflex, reduced visual acuity, abnormal
colour vision and constriction of visual fields.
Corneal opacity and lenticular change was found with direct contact of eye and the OP pesticide.
Workers exposed to Fenitrothion and Dichlorovos (DDVP) also suffered with:- Forgetfulness, heavy head
feeling, headache, pressure feeling in chest, sweating in sleep, nausea, dry throat, twinkling in eyes, eye
trembling, easy tiring etc.
Hematology and urinalysis assays were normal. Opthalmological study showed nothing.
Animal studies reveal adverse effects on the visual system caused by OPs.
Dogs given 5mg+ / day Ethylthiometon all developed myopia in 1 year.
Electron Microscope examination showed abnormal mitochondria (swollen, huge and degenerated
huge).
Damage was not limited to cholinesterase inhibition. Extraocular muscle changes were
found in the nerves at Neuromuscular junctions and in muscle fibres as a state of neuromyopathy.
Retina degeneration was evident in the pigment epithelial cell layer near the papilla with myelin like structure in
the cells of the retina.
Some demyelinated nerves of extraocular muscles, small sparse functional folds in the motor end plate and optic
nerves decreased in number and there was increased septal tissue (Astrocytes and their processes), and
peripheral neuropathy in sciatic and sural nerves.
Miosis was found in rat studies as was general muscle tremor, exophthalmus and conjunctival discharge. Animals
dosed with Fenthion showed signs of toxicity; Exophthalmus, shivering, diarrhoea etc, and Fenthion has the
otential to cause retinal degeneration.
Myopia was induced in dogs by Fenitrothion and it persisted for a year after last exposure. It produced swollen
muscle fibres in the ciliary muscle and thickening of the lens.
The retinal physiology is sensitive to OPs at dosage levels far lower than detectable by cholinesterase assays.
Cholinesterases in the Occular Tissues.
Lateral rectus muscle has highest total cholinesterase of all extraoccular muscles. High levels are also found in
the Retina, Choroid and Ciliary body. Cholinesterase, Choline acetyltransferase and acetylcholine activity is
found in the corneal epithelium which contains the highest concentration of acetylcholine of any animal tissue.
Organophosphate cholinesterase inhibitors cross the anterior chamber and enter the lens and iris. The Retina is
an extracranial extrusion, part of the Central Nervous System, and contains 6 types of neuron:- Photoreceptor
Cells -rods and cones, Horizontal Cells, Interplexiform Cells, Bipolar Cells, Amacrine Cells and Ganglion Cells
(located in Retina but axons from them form the optic nerve)
All synapses between these cells are affected by chemical mediation and employ neuro-transmitter substances
including Gamma-Aminobutyric Acid (GABA), Glycine, Doxamine, Idolamine,and Acetycholine (the latter is
essential to the visual system) Cholinergic drugs affect the horizontal cells, ganglion cells etc.
This system is vulnerable to a host of visual anomalies as a consequence of cholinesterase
inhibition.
OCCULAR TESTING SHOULD BE A REGISTRATION REQUIREMENT FOR THIS CLASS OF CHEMICALS FOR THE
PURPOSE OF HAZARD CHARACTERIZATION AND RISK ASSESSMENT.
Sources: Eye Injury by Organic Phosphorus Insecticides, Japanese Journal of Ophthalmology, Vol.15 (1)
60-67,(1971) by Satoshi Ishikawa, and the Journal of Applied Toxicology, Vol.14 (2), 119-129 (1994).
Dated 16/9/2000
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