This review focusses on the mechanisms of testicular toxicity, and the underlying requirement for a detailed understanding of the characteristics of the testis. Factors such as active mitosis, the presence of a blood-testis barrier, the spermatogenic cycle, and hormonal control, complicate the situation with regard to toxicity. However, the general mechanisms of testicular toxicity types can be classified as follows: 1) Direct-action against spermatogenic epithelia; 2) Hormonal indirect effects on spermatogenesis; 3) Direct or indirect mechanisms affecting sperms; 4) Circulatory disturbances affecting the testis; 5) Other miscellaneous actions. In the histological evaluation of testicular toxicity, histological patterns of toxic lesions induced by different model chemicals, categorized on the basis of their mechanisms of action, are very helpful. For typical examples are cyclophosphamide, nitrobenzene, ethane-1, 2-dimethanesulfonate, and cadmium chloride. Studies with these compounds have strongly suggested that early changes, rather than those occurring at late stages, are of particular assistance for understanding their mechanisms of action.

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Possible promoting effects of phenylbutazone on carcinogenesis in various organs, including the hematopoietic system and liver, were reinvestigated in inbred female Donryu rats, using wide organ spectrum 2-stage carcinogenesis models. Phenylbutazone was given as a dietary supplement (0.25%) for 24 weeks subsequent to initiation with N-methyl-N-nitrosourea or N-ethyl -N-nitrosourea. No enhancement by phenylbutazone of nitrosourea-induced leukemogenesis was apparent, although a promoting effect was demonstrated, not only for renal and thyroid carcinogenesis as found earlier, but also for hepatocarcinogenesis. On the contrary, an inhibitory effect was shown for intestinal carcinogenesis.

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The carcinogenic effects of 1, 2-dimethylhydrazine (DMH) were investigated in virgin female Japanese house musk shrews, Suncus murinus (family: Soracidae, order: Insectivora). From 6 weeks of age, 15 shrews were given 14 doses of DMH (40mg per kg, s.c.), administered weekly (group 1) and another 15 animals were given 28 doses of DMH (20mg per kg, s.c.), also administered weekly (group 2); 5 untreated shrews served as controls. A high incidence of musk gland tumors, and some other tumors (carcinomas of the small intestine, pulmonary adenoma, liver adenoma, and leukemia) were induced in DMH-treated shrews, whereas no such tumors were seen in untreated shrews up to 60 weeks of age. Musk gland tumors developed in 82% (9/11) of animals in group I and in 92% (12/13) of animals in group 2 at 36 to 60 weeks of age. DMH, a colonotrophic carcinogen in rodents, did not evoke colon cancers in shrews.

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Effects of reproductive status on the health of aged and young multiparous female rats were pathologically, hematologically, and blood biochemically investigated. Aged females were repeatedly mated and sacrificed at 2 years of age. Young females which were pregnant from one to three times were sacrificed at weaning, and compared with nulliparous ones of the same age. Tissue calcification in the renal and cardiovascular systems was characteristically observed in the aged multiparous females, but not in the young ones. Although serum calcium level of the aged multiparous females did not change, that of the young ones revealed a consistent decrease. There were no differences of incidences in age-related changes including neoplastic and non-neoplastic changes between the multiparous and the nulliparous aged females. We concluded that multiparity induced the tissue calcification of the renal and cardiovascular systems in aged females. In addition, our result suggested that multiparity had no effect on the occurrence of age-related changes.

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Analysis of cell proliferation in spontaneous proliferative lesions in the adrenal medulla of Fischer 344 rats used in 2-year carcinogenicity studies was performed by determination of labeling indices for proliferating cell nuclear antigen (PCNA), mitotic indices, and numbers of silver-stained nucleolar organizer regions (AgNORs). The lesions were morphologically classified into hyperplasia, welldifferentiated medullary tumor (WMT), atypical medullary tumor showing cellular pleomorphism and atypia (AMT), and malignant medullary tumor with invasion or metastasis (MMT) categories. The mean values for PCNA labeling index in hyperplasia, WMT, AMT, and MMT were 2.9, 4.4, 9.9, and 43.6, respectively, in all cases significantly increased as compared with those in the normal medulla (labeling index: 0.3). The mean mitotic indices were also significantly increased in MMT. The mean numbers of AgNORs per nucleus in the cells of normal medulla, hyperplasia, WMT, AMT, and MMT were 1.72, 2.07, 2.12, 2.33, and 3.39, respectively. All proliferative lesions again demonstrated significant increase as compared to normal medulla. The results thus revealed cell proliferative activities of spontaneous proliferative lesions of the rat adrenal medulla to exhibit a stepwise increase from normal medullary cells through WMT to MMT. Furthermore, the proliferative potential of AMT was higher than that of WMT, but very much lower than that of MMT with both approaches to assessment.

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Focal chorioretinal atrophy observed in untreated Sprague-Dawley rats was clinically and histopathologically described. On ophthalmoscopical examination, the lesion consisted of discrete, hyperreflective, frequently rectangular foci with sharp margins. Petechial hemorrhages preceded to the development of these foci. No particular predilection sites were evident in the fundus. Histopathological characteristics on the perfusion-fixed eyes included: 1) the affected region was focal and well demarcated, 2) the retina in the lesion was devoid of the external layers, 3) in contrast, the internal retinal layers were unaffected, 4) abrupt disappearance of the underlying retinal pigment epithelium and choroid capillaries coincides with the retinal change, and 4) very little inflammatory cell response. These findings suggest that the primary defect may be either in the retinal pigment epithelium or choroid capillaries with subsequent retinal atrophy.

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To establish an experimental model of central hearing loss in the central auditory system, the auditory function (auditory brainstem response, ABR) and the histopathology of the inferior colliculus (IC) in rats in thiophene poisoning were studied. Undergoing abnormal ABR patterns at the acute stage, the lesions in the IC developed neuronal necrosis with karyolysis, pyknosis, and postsynaptic terminals, axonal swelling, and swollen astrocytic processes. Later, these abnormal features disappeared except for axonal swelling and slight gliosis. The degenerated neurons were localized characteristically in the rostral dorsomedial and medial side of caudal ventrolateral portions of the IC central nuclei, corresponding tonotopically to the high-frequency band. A morphometric study showed that mediumsized neurons were mainly involved. It is suggested that the thiophene poisoned rat could become a useful model of hearing loss in the central auditory system (IC), especially that involving the highfrequency band.

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Many of the patients with Minamata disease, caused by methylmercury have developed hypertension. In experimental methylmercury poisoning, the level of mercury and the mortality are higher in spontaneously hypertensive rats (SHR) than in Wistar-Kyoto rats (WKY). Thiophene induces cerebellar degeneration, which is also found in rats with methylmercury poisoning and hepatic necrosis. To clarify the pathophysiology of the thiophene-induced lesions female SHR and WKY aged 150 days were studied and a comparison was made between the two strains. Up to an age of 150 days, the body weight of SHR was less than that of WKY, but food consumption by SHR was higher than that of WKY. SHR were more susceptible to thiophene poisoning than WKY in terms of symptoms, changes in auditory brainstem response (ABR), and histopathological findings. Administration of pentobarbital was more effective in producing hepatic lesions in SHR than in WKY. Ultrastructurally, nuclear chromatin segregation and irregular distribution of rough endoplasmic reticulum (rER) were prominent in the hepatic cells of non-treated SHR. An osmiophilic homogeneous substance appeared to play an important role in the formation of cerebellar lesions in both SHR and WKY. The hepatic injury and disturbance of cerebellar blood vessels seem to cause the cerebellar lesions. It is suggested that a reduced ability for drug metabolism in SHR, which might be inherited or acquired, is one of the causes of the higher susceptibility of this strain to thiphene poisoning, compared with WKY.

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Thimerosal (ethylmercuric thiosalicylic acid, sodium salt) in an organic mercury compound which has been used as a preservative in some vaccines and human immunoglobulin products for intramuscular use.
This study was designed to examine the safety of thimerosal for mice. Thimerosal solutions of 0.2 ml at 0.01% (the concentration used in vaccines) or at 0.1% were injected twice a week into the intraperitoneal (IP) cavity or subcutaneous (SC) tissue of BALB/c mice. Clinical signs and symptoms such as crossing hind legs were observed in animals injected more than 17 times with the 0.1% thimerosal solution (total thimerosal dose; 70μg Hg/g body weight) into the IP cavity. But the IP administrations of 0.01% thimerosal did not effect the animals even after 35 injections, nor the SC administrations at any dose. At autopsy, nervous system, kidney, liver, heart, lung, spleen, intestine, and skin were examined under light-microscopy with hematoxylin and eosin stain and mercury-histochemistry by photoemulsion method. Peritonitis was observed in all animals that received IP injections with 0.1% thimerosal. Mercury granules were present in the kidney and spleen of the animals receiving IP injections of 7μg Hg/g body weight. Histochemically, mildly positive reaction to mercury was detected in the brain and the liver in the same group of mice. No peritonitis was found in this group of mice. The positive results observed in this series of experiments were obtained only with multiple injections of the high dose thimerosal solution. No toxic effects were found with the 0.01% dosis, which is the same concentration used in commercial vaccines. Thimerosal administered in mice was biotransformed into inorganic mercury, and it was readily degradated into inorganic mercury by four well-known reactive oxygen-producing systems, and the amounts of inorganic mercury produced from thimerosal were the same as those from ethyl mercury and were higher than those from methyl mercury.

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The contribution of extramedullary erythropoiesis in the spleen during recovery from anemia was examined in rats. Six- and 18-week-old female Wistar rats were subjected to a total splenectomy or sham-splenectomy, and anemia was induced by bleeding the next day. Removing approximately 20% of the total volume of blood in the body resulted in a 9-26% reduction in erythrocyte count, hematocrit, and hemoglobin 3 days after bleeding, but the values returned to normal within 8 days of bleeding in young rats and within 14 days of bleeding in adult rats. Histology, image analysis, and differential cell counts revealed a marked increase in erythropoiesis in the spleen and femoral bone marrow in shamsplenectomy rats after bleeding; however, there were no statistical differences in hematology or bone marrow histology between the splenectomy and sham-splenectomy groups. These results indicate that the contribution of splenic erythropoiesis to the recovery from anemia was negligible in both young and adult rats.

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Spontaneous true hermaphroditism in a rat is reported. This animal was a unilateral hermaphrodite composed of a testis on the left and an ovotestis on the right, although the external genitalia was masculine. In the present case, there were epididymides and vasa deferentia on both sides, an oviduct and a uterine horn on the right side, and seminal vesicles dorsal to the uterus, but prostate glands and the external orifice of vagina were absent. The ovotestis, unlike the other cases of hermaphroditic rats, was composed of a predominant ovarian tissue and a small area of testicular tissue.
The present animal died by a single administration, i.e. the first administration in a repeated dose oral toxicity study, of a test compound having sex difference in the lethal toxicity. The dose given to the animal is expected to cause lethal effects in females but not in males, and the sex difference is presumed to depend on the different activity of S-oxidation by cytochrome P-450, the drug-metabolizing exzyme of the liver. These matters suggest that this animal had been enzymatically female.

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The eye and cochlea are difficult tissues to be processed for histology sections without artifacts. Selection of embedding material is of primary importance to minimize common artifact such as retinal detachment which occurs frequently in the eye embedded in paraffin. The cochlea is frequently processed using celloidin as an embedding material. The celloidin section is, however, generally thick and requires a long time to polymerize. Glycol methacrylate (GMA) is a water soluble resin and has recently been widely used as an embedding material for various tissues. In the present study, a qualitative comparison was made on histology sections when the eye of rat and the cochlea of guinea pig are embedded in paraffin and GMA. The eye and cochlea were immediately fixed in combined fixative of formaldehyde and glutaraldehyde solution. The cochlea was then decalcified in EDTA solution. The tissues were dehydrated in a graded alcohol, and embedded either in paraffin or in GMA resin which was polymerized for 4 hours at room temperature. The sections were cut at 3 and 5 microns for the eye and cochlea, respectively, and stained with hematoxylin and eosin. In place of paraffin, use of glycol methacrylate resulted in superior histology sections.

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