In 1965, a mysterious illness, diagnosed chronic organic mercury poisoning, began to affect the inhabitants, especially fishermen, farmers and their families, who lived in around the mouth area of river AGANO, situated in suburbs of Niigata city, Japan. They had taken ocasionally at table fishes and shelfishes, which were contaminated with mercury compounds, products of chemical manufacturing processes.
25 cases of them were investigated otologically and audiologically. And 14 cases were pointed out some audiological disturbances. The peculiar findings of them: 1) outwardly normal or very little hearingloss in pure tone audiometries at least in early stage, 2) pure tone thresholds appeared to be unsettled in a few cases, 3) speech articulation score were growing worse in spite of normal pure tone thresholds, 4) in middle stage, pure tone thresholds became to worse slowly at all frequencies or at high frequencies and speech intelligibility functions became systematically poorer, 5) recruitment (SISI and others) were negative in all cases except 4 cases of inner ear deafness, 6) Békésy audiometries (T. T. S) showed two types, unsettled wide amplitude and severe abnormal adaptation characterizing the type III pattern.
As above mentioned, hearing impairment of chronic organic mercury poisoning was revealed to be retrocochlear disturbance, especially cortical deafness.

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1) 6 cases of carbon monoxide poisoning revealed 2 cases of both central and peripheral deafness, a ease of central one, 2 cases of peripheral one and a case of only tinnitus.
2) All the 3 cases of acute hydrogen sulfide poisoning revealed central and peripheral deafness.
3) A case of acute methyl bromide poisoning revealed central deafness.
4) A case of chronic cadomium poisoning showed Carhart notch's audiogram.
5) A case of chronic thinner poisoning had normal audition.
6) A case of acute sulfurous acid gas revealed only head noises.
7) A case of acute inorganic mercury poisoning revealed only head noises.

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The ototoxic action of nitrogen mustard N oxide, gentamicin and ethacrynic acid on guinea pig and mice was studied. Shaker-l-mice and Hedlund white mink cochlea were also studied with the comparison of drug intoxicated cochlea.
NM was found to be more toxic than kanamycin, streptomycin and gentamicin with regard to their dosages. Toxic reactions were mainly observed in the cochlear sensory epithelia. Degeneration appeared first in the outer hair cells in the basal turn of the cochlea starting with the formation of whorls and proliferation of smooth endoplasmic reticula and ending with the complete degeneration of the sensory cells, but the stria vascularis showed little change. Even after the disappearance of the hair cells, some efferent nerve endings were still present in the organ of Corti.
Ototoxic reactions of gentamicin were first appeared in the mitochondria in the cochlear sensory epithelia, but the stria vascularis showed little change as was observed in NM intoxication. On the other hand, severe changes of the stria vascularis were found in case of ethacrynic acid administration.
Shaker 1 mice have a fairly normal stria vascularis with normal filling of scala media but show severe degeneration of organ of Corti. This cochlea shows pathological changes somewhat similar to those of ototoxic antibiotics intoxicated cochlea. On the other hand, Hedlund white mink showed the degeneration of the organ of Corti caused by severe degeneration of the stria vascularis and collapse of scala media.
We have demonstrated similar final cochlear degeneration following different pathological pathways in five species of animals.

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Nitrogen Mustard-N-Oxide was given to six guinea pigs intraperitoneally, and morphological changes of the outer hair cells in the cochlea were investigated with electron microscopy. The results obtained were as follows:
1. Swelling of the cytoplasma of the cuticle free area at the top of the cell was found in various degrees. In some of them, cuticular plate was covered and the auditory hairs were partially surrounded by the swelled cytoplasma.
2. Formation of double membranes was found. The double membranes were parallel to the cytoplasmic membrane, or whorl of the membranes was made in the cytoplasma.
3. A rod-shaped structure was presented in a large number of the cells.
4. No vacuolization was observed in any case.
5. With the increase of degeneration, the outer hair cell became atrophic, then it was destroyed and disappeared, while the supporting cells were remarkably swollen.

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The KM transfer into the inner ear fluid under injection of the vitamin B complex were studied. 56 adult guinea pigs were separated in two groups, one group were injected KM 200mg/kg intra musculary and another group were injected KM 200mg/kg intra musculary and VB complex (VB₁ 25mg, VB₆ 25mg and VB₁₂ 250mcg) 10mg/kg intra peritoneary. Each groups were devided in 4 subgroups and the drugs were injected 1, 2, 3, and 4 weeks. The animals were sacrificed after 24 hours of each last injection togather blood serum and the inner ear fluid. The KM concentration were measured by paper disc bioassy. Two animals of each subgroups were observed cochlear microphonics from the round window and observed histologically under light microscope. The result were as follows.:
The concentration of KM in the serum and the perilymph is almost equal between two groups such as KM injection group and KM+VB injection group.
KM were not detectable in the endolymph
Electrophysiological and histological study, the VB injected group are less affected than only KM injection group.
From these results the author concluded that the VB has prophylactic effect of ototoxity of KM but prophylactic mechanism is not influence the KM transfer into the inner ear fluid.

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Present study was done for the purpose of explaining the process of Kanamycin intoxication to cochlear hair cell.
Using isolated hair cell the affection of Kanamycin to the cell membrane was mainly investigated.
Changes of the cell membrane were found primarily in becoming wrinkled and the structure of the cell membrane became to obscure.
And then changes in the intracellular structures were resulted in.
It was suggested that the changes observed in the cell membrane would be due to the action of Kanamycin as a cation.

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Engström and Kohonen 1965, Kohonen 1965, Engström 1967 established the general tendency in the pattern of outer hair cell and inner hair cell loss, in the ototoxicosis due to antibiotics by the application of surface specimen technique of the spiral organ. The general tendency is considered as very important for understanding the fundamental pathologic change of the spiral organ due to various kind of antibiotics on the one hand and for the evaluation of ototoxicity due to newly developed antibiotics on the other hand.
The present authors intended to reevaluate the general tendency in the pattern of outer hair cell and inner hair cell loss of the spiral organ in the ototoxicosis due to antibiotics by the observation of the horizontally sectioned serial celloidin sections of the cochleas in 140 Hartley guinea pigs received various kinds of antibiotics. The antibiotics used in the present study were divided into 3 groups, that is, aminoglycoside antibiotics (Aminodeoxykanamycin, Aminosidine, Dihydrostreptomycin, Gentamicin, Lividomycin, Kanamycin A and Vistamicin), polypeptide antibiotics (Capreomycin, Enduracidin, Tuberactinomycin and Viomycin), and Rifampicin (Rifamycin). The results obtained were as follows:
1) In the present study, hair cell loss of the spiral organ occurred in 62% (87 guinea pigs).
2) Outer hair cell loss was found in 100% of the 87 guinea pigs and the pattern of the outer hair cell loss showed the general tendency similar to the tendency reported by Engström et al.; that is, loss of the outer hair cell almost always started at the basal end of the spiral organ and then spread upwards.
3) Inner hair cell loss occured in 22% (20 guinea pigs) and was always associated with the loss of the outer hair cell. The damage frequently occurred in the apical and 4th turns.
4) There was distinct difference in sensitivity to ototoxic antibiotics between the outer hair cell and the inner hair cell. The outer hair cells were more sensitive in the basal and 2nd turns, while the inner hair, cell was more sensitive in the apical and 4th turns.
5) There was some difference in the pattern of the hair cell loss between the animals received the aminoglycoside antibiotics and those treated with the polypeptide antibiotics. In the animals received the aminoglycoside antibiotics the loss of the outer hair cell alone occurred more frequently than in the animals received the polypeptide antibiotics. On the contrary, the inner hair cell loss was found more frequently in the animals treated with the polypeptide antibiotics.
6) Detection of the loss of the outer hair cell confined to the basal end of the spiral organ is very important in the evaluation of the ototoxicity of the newly developed antibiotics.

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