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26° C
21° C
LL
LD
DD
LL
LD
DD
6.05 ± 0.62
0.76
8.33 ± 1.7
0.56
0.32
0.66
5.33 ± 0.02
0.67
7.18 ± 0.42
0.49
0.26
0.58
4.64 ± 0.38
0.58
7.05 ± 0.23
0.47
0.34
0.54
7.97 ± 0.11
1.14
13.83 ± 2.24
0.99
0.83
1.07
6.90 ± 0.32
0.99
13.96 ± 0.96
1.00
1.01
1.00
7.30 ± 0.33
1.04
13.20 ± 0.89
0.94
0.84
0.99
19
39
36
8%
36
24
21
22%
peratures which approach the upper limits of their
physiological range, membrane addition may already be proceeding at a near-maximum rate which
cannot be further accelerated by light stimulation.
I thank Donna Medford and Mary E. Rayborn for
their assistance with the autoradiography and Laun
Pearson for typing the manuscript.
From the Cullen Eye Institute, Baylor College of
Medicine, Houston, Texas. This study was supported by
a grant from the Retina Research Foundation, Houston,
Texas, and by NIH grants EY 02362 and EY02363. Joe
G. Hollyfield is the recipient of Research Career Development Award EY00112. Submitted for publication
March 30, 1979. Reprint requests: Joe G. Hollyfield,
Cullen Eye Institute, Baylor College of Medicine, Houston, Texas 77030.
Key words: photoreceptors, membrane renewal
REFERENCES
1. Besharse JC, Hollyfield JG, and Rayborn ME: Photoreceptor outer segments: accelerated membrane renewal in rods after exposure to light. Science
196:536, 1977.
2. Besharse JC, Hollyfield JG, and Rayborn ME: Turnover of rod photoreceptor outer segments. II. Membrane addition and loss in relationship to light. J Cell
Biol 75:507, 1977.
3. Young RW: The renewal of photoreceptor outer segments. J Cell Biol 33:61, 1967.
4. Hollyfield JG, Besharse JC, and Rayborn ME: Turnover of rod photoreceptor outer segments. I. Membrane addition and loss in relationship to temperature. J Cell Biol 75:490, 1977.
5. Leuenberger PM and Hollyfield JG: GERL in photoreceptor inner segments. J Cell Biol 79:211a, 1978.
6. Besharse JC and Hollyfield JG: Turnover of mouse
photoreceptor outer segments in constant light and
darkness. INVEST OPHTHALMOL VISUAL SCI (in press).
Polychlorinated biphenyls poisoning in monkey eye. YOSHITAKA OHNISHI AND TOSHIHIKO
KOHNO.
Poisoning by polychlorinated biphenyl(s) (PCB) in humans leads to cutaneous and ocular findings. A white,
cheeselike secretion issuing from the orifice of the
Meibomian gland duct when the eyelid is squeezed is one
sign of this intoxication. In the rhesus monkey, abnormal
hyperkeratosis of the ductal epithelium was observed histopathologically.
Polychlorinated biphenyl(s) (PCB) have been
extensively utilized in industry as materials for
electric current transformers, condensers, carbonless copy papers, printing ink, and many other
uses.1 The extensive use of these compounds,
coupled with their stable structure, has resulted
in their gradual accumulation in nature. Environmental pollution by PCB poses a problem of
grave concern throughout the world.2' 3 In 1968 in
western Japan, an outbreak of PCB (commercial
brand: Kanechlor 400) poisoning occurred in those
who ingested contaminated rice oil. PCB had accidentally been mixed with the oil in the manufacturing process.4 Over 1600 cases of food poisoning
(referred to as "Yusho" disease) due to this compound were registered by 1978. Many still suffer
from the symptoms of this intoxication. The main
ocular manifestations are hypersecretion of Meibomian glands and abnormal pigmentation of the
conjunctiva.4 Despite the fact that almost all
Yusho patients exhibit ocular involvement,5' 6 few
investigations concerning the eye have been
reported.4' 7
Materials and methods. Twelve adult rhesus
monkeys, six male and six female, weighing 4.1 to
0146-0404/79/090981 +04$00.40/0 © 1979 Assoc. for Res. in Vis. and Ophthal., Inc.
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Reports
B
Fig, 1. Lower eyelids. A, Normal monkey eyelid. The Meibomian glands (G) and hair follicles
(H) are well developed. F, Follicle of cilium; S, skin; M, muscle; C, palpebral conjunctiva. B,
Eyelid of monkey fed 86.6 mg of PCB in 1 month. The Meibomian glands have atrophied. The
ducts of the glands (D) are filled with hyperkeratotic cell debris. Although the follicle of the
cilium appears intact, no hair follicle is seen. (x34.)
6.5 kg were used in these experiments. Eight
animals were each day fed a banana injected with
PCB (0.5 mg/kg body weight) dissolved in salad
oil. During the 1 to 5 months duration of the experiment the animals were given a dose of 79,2 to
253.6 mg of PCB. Two out of eight animals were
also fed a diet containing PCB with polychlorinated dibenzofuran (PCDF; 2.5 jug/kg body
weight) which had contaminated the rice oil ingested by Yusho patients. Four untreated animals
were used as controls.
Experimental animals were killed at 1, 2, 3, and
5 months, The eyelids and globes were excised
and dissected. One half of each specimen was fixed
in 10% neutral formalin for light microscopy, and
the other half in 4% glutaraldehyde followed by
1% osmium tetroxide for electron microscopy.
After dehydration the specimens were embedded
in paraffin or Epon 812, as the case might be, and
studied morphologically.
Results. One month after the first ingestion of
PCB, there was a 17.3% reduction in the body
weight in the experimental animals. There was
little spontaneous discharge from the eyes, but
when pressure was applied to the eyelids of experimental animals, white secretions extruded.
Within 3 months, three experimental animals had
hair loss from the head and upper extremities.
Swelling of the eyelid and acneform eruptions
were present but not conspicuous in these animals. Since histopathological changes of eyelids
were identical in PCB-fed animals and PCB +
PCDF-fed animals, the results will be described
together.
The Meibomian glands in the normal eyelid
consist of groups of acini, formed by numerous
secretory cells, and ducts passing through central
zone (Fig. 1, A). One month after the PCB intoxication, the glands in the experimental animals
were compressed by a keratin cyst and had atrophied (Fig. 1, B). Squamous metaplasia and
hyposecretion of the glands (Fig. 2) were also observed. Five months after the intoxication, no
acini remained. On the other hand, epithelial cells
of the ducts of Meibomian glands were hyperplastic. Although in normal ducts there were four to
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Volume 18
Number 9
Reports
Fig. 2. Secretory cell in the Meibomian gland of monkey fed 88.1 mg of PCB and 440.5 /xg of
PCDF in 1 month shows hypoftmction. Nu, Nucleus; SG, secretory granule, (x 10,700.)
Fig, 3. Epithelial cell in the duct of the Meibomian gland of monkey fed 88.1 mg of PCB and
440.5 jLtg of PCDF in 1 month. Many keratohyalin granules (K) are seen in the cytoplasm. Note
the abnormal keratinization. (X 19,800.)
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Reports
five layers of stratified squamous epithelial cells,
in the duct of an experimental animal seven to 10
cell layers were observed by 1 month of experimental treatment. In the basal layer of the epithelium, there were many mitotic cells, and in the
superficial layer irregular shaped keratohyaline
granules were evident in the cytoplasm (Fig. 3).
The lumen of the duct was enlarged and was filled
with keratinized cells. The orifice of the duct was
also enlarged. Because of the variety of the pigment granules in the conjunctiva of the control
monkeys, it was difficult to determine whether
abnormal pigmentation had been induced. The
retina and choroid of the experimental animals
were morphologically similar to those of the control animals.
Discussion. Since the outbreak of PCB poisoning in humans, numerous experiments in small
animals have been reported. However, none of
the small animals has had findings similar to those
observed in humans. In the monkey, Allen et al.7
have reported a decrease in body weight, hair loss,
swollen eyelids, purulent discharge from the eyes,
acne, and hyperplasia of the gastric mucosa. Our
study shows that the cause of the discharge from
the eyes of PCB-intoxicated monkey is not hypersecretion of the Meibomian glands but rather
hyperkeratinization of the epithelial cells of the
duct. This explains the "sticky" nature of the discharge of the Yusho patients prior to visual loss.
Ocular symptoms in Yusho patients appeared first;
2 or 3 months later, acneform eruptions and the
pigmentation of the skin became evident.4 Accordingly, the secretion of white, cheeselike material from the ducts of Meibomian glands when
the eyelid is squeezed byfingersis the first clinical
sign. A primary loss of Meibomian substance
might result in a secondary keratinization.
It is generally held that a cyst of the human
Meibomian gland follows obstruction of the duct
and that the cystic contents differ from the keratin
material filling an epidermal inclusion cyst.8' 9
Therefore the keratic cyst of this gland may be
considered one of the characteristic findings of
PCB-intoxicated mammals. On the basis of our
experiments, the photograph of the eyelid reported by McNulty and Griffin as "Possible polychlorinated biphenyl poisoning in rhesus monkey"
does indeed identify the cause as PCB.10
We are grateful to members of a Study Group of
Yusho.
From the Department of Ophthalmology, Faculty of
Medicine, Kyushu University, Fukuoka, Japan. This
work was supported by a Yusho grant from Ministry
984
of Health and Welfare in Japan. Submitted for publication March 23, 1979. Reprint requests: Yoshitaka Ohnishi, M.D., Department of Ophthalmology, Faculty of
Medicine, Kyushu University, Fukuoka, 812, Japan.
Key words: polychlorinated biphenyls, polychlorinated
dibenzofuran, Meibomian gland, hyperkeratosis, squamous metaplasia
REFERENCES
1. Masuda Y and Kagawa R: Polychlorinated biphenyls
in carbonless copying paper. Nature 237:41, 1972.
2. Risebrough RW, Rieche P, Peakall DB, Herman
SG, and Kirven MN: Polychlorinated biphenyls in
the global ecosystem. Nature 220:1098, 1968.
3. Jensen S, Johnels AG, Olsson M, and Otterlind G:
DDT and PCB in marine animals from Swedish water. Nature 224:247, 1969.
4. Higuchi K: PCB Poisoning and Pollution. New
York, 1976, Academic Press, Inc.
5. Ikui H, Sugi K, and Uga S: Ocular signs of chronic
chlorobiphenyls poisoning (Yusho). Fukuoka Acta
Medica 60:432, 1969.
6. Ohnishi Y, Ikui I, Kurimoto S, and Kawashima K:
Further ophthalmic studies on patients of chronic
chlorobiphenyls poisoning. Fukuoka Acta Medica
66:640, 1975.
7. Allen JR and Norback DH: Polychlorinated biphenyl- and triphenyl-induced gastric mucosal hyperplasia in primates. Science 179:498, 1973.
8. YanoffM and Fine BS: Ocular Pathology, a Text and
Atlas. New York, 1975, Harper & Row, Publishers,
p. 202.
9. Straatsma BR: Cystic degeneration of the Meibomian glands. Arch Ophthalmol 61:918, 1959.
10. McNulty WP and Griffin DA: Possible polychlorinated biphenyl poisoning in rhesus monkeys. J Med
Primatol 5:237, 1976.
Effect of iontophoretic and topical application of antiviral agents in treatment of experimental HSV-1 keratitis in rabbits.*
BYOUNG SE KWON, LOUIS P. GANGAROSA,
NO-HEE PARK, DAVID S. HULL, EDWARD
FINEBERG, CAROL WIGGINS, AND JAMES M.
HILL.
Cathodal (—) iontophoresis of 9-fl-D-arabinofuranosyladenine 5'-vionophosphate (vidarabine monophosphate;
Ara-AMP) was performed once daily for 3 days for the
treatment of experimental herpes simplex virus type 1
(HSV-1) keratitis in rabbit eyes, and the therapeutic
efficacy was compared with that of topical treatment of
Ara-AMP and idoxuridine (IDU) adtninistered five times
daily for 4 days. With the treatment initiated 24 hr after
viral inoculation, Ara-AMP cathodal iontophoresis resulted in significant suppression of epithelial and an-
0146-0404/79/090984 +05$00.50/0 © 1979 Assoc. for Res. in Vis. and Ophthal., Inc.
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