Charles H. Frith

Neurochemical and neurohistological alterations in the rat and monkey produced by orally administered methylenedioxymethamphetamine (MDMA)

MDMA is an amphetamine analog prescribed by some health professionals in the field of psychotherapy and used as a recreational drug by the general public. In recent reports, investigators have suggested that MDMA produces acute neurotoxicity when administered by subcutaneous injection. In order to determine if MDMA produces lasting neurochemical alterations after oral administration, groups of six rats (adult male Sprague-Dawley) were dosed by gavage with either 40 or 80 mg/kg of MDMA or saline vehicle once every 12 hr for 4 days. These rats were terminated 2 weeks after the first dose along with an additional group of rats (80 mg/kg) terminated 4 weeks after the first dose. Brain regions including the hippocampus (H), caudate nucleus (CN), hypothalamus (HY), frontal cortex (FC), and brain stem (BS) were analyzed by HPLC with electrochemical detection for concentrations of dopamine (DA), dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), serotonin (5-HT), 5-hydroxyindoleacetic acid (5-HIAA), and norepinephrine (NE). In the CN, 40 mg/kg MDMA produced no change in DA, DOPAC, or HVA, but a 50-60% decrease in 5-HT and 5-HIAA concentrations was observed at 2 weeks. Similar effects were observed at 80 mg/kg at both 2 weeks and 4 weeks. A temporary decrease was also seen in DA (21%) and in HVA (34%) 2 weeks but not 4 weeks after the 80 mg/kg dose regimen. In the H, MDMA (40 or 80 mg/kg) produced no change in NE, but a 50-60% decrease was seen in 5-HT and 5-HIAA concentrations at 2 weeks. Concentrations of 5-HT and 5-HIAA were significantly decreased in the HY and FC by all MDMA treatments, but DA and DOPAC concentrations were not altered as compared to vehicle controls. BS was least affected by treatment with no change in DA, DOPAC, or 5-HIAA concentrations and only a slight decrease in 5-HT (19-33%) concentrations at 2 weeks but not at 4 weeks. To determine the sensitivity of the nonhuman primate to MDMA, a total of nine rhesus monkeys were dosed with vehicle or 5 or 10 mg/kg MDMA (n = 3) by gastric intubation twice per day for 4 days. One month after MDMA dosing, a dose-related reduction from vehicle control values for 5-HT and 5-HIAA was observed. These results indicate that the monkey may be more sensitive than the rat to the persistent serotonergic neurotoxicity of MDMA.(ABSTRACT TRUNCATED AT 400 WORDS)

The Morphology, Immunohistochemistry, and Incidence of Hematopoietic Neoplasms in Mice and Rats:

Hematopoietic neoplasms in the rodent may be classified into lymphoid or nonlymphoid neoplasms. Lymphoid neoplasms include the following morphologic types: follicular center cell, lymphoblast (lymphocytic), immunoblast, plasma cell, and large granular lymphocyte (LGL). Nonlymphoid hematopoietic neoplasms include histiocytic sarcoma, granulocytic leukemia, erythroid leukemia, and mast cell tumors. Most types of hematopoietic neoplasms, exclusive of LGL lymphoma (leukemia), are more common in mice than in rats. Specific strains of mice have a hematopoietic tumor incidence of more than 50% in aged animals. Some strains of rats (i.e., Fischer-344) may have an incidence of over 50% of LGL lymphoma in aged animals. The tumor type and incidence are characteristic for each rat or mouse strain. Hematopoietic neoplasms have been better characterized immunomorphologically in mice than in rats. The specific cell type and tissue of origin for hematopoietic neoplasms may be important for safety evaluation of chemicals. Specific chemicals may induce specific types of these tumors, which may be the same or different from the spontaneous types. Lymphoid cell neoplasms should not be grouped with nonlymphoid neoplasms in determining the toxicity and carcinogenicity of test substances.

Spontaneous neoplasms in aged CD-1 mice.

Spontaneous neoplasms in untreated control CD-1 mice (725 males and 725 females) used in carcinogenicity studies were evaluated and tabulated. The most common neoplasms in male mice were alveolar-bronchiolar adenomas (19.3%) followed by hepatocellular adenomas (11.0%), lymphoreticular neoplasms (6.8%), hepatocellular carcinomas (5.7%), Harderian gland adenomas (2.9%), alveolar-bronchiolar carcinomas (2.5%), and testicular interstitial cell tumors (1.9%). In the females, the most frequently occurring neoplasms were lymphoreticular neoplasms (16.4%) followed by alveolar-bronchiolar adenomas (12.3%), uterine endometrial polyps (4.3%), uterine leiomyomas (3.5%), mammary adenocarcinomas (2.5%), hepatocellular adenomas (1.8%), hemangiomas (1.7%), Harderian adenomas (1.7%), alveolar-bronchiolar carcinomas (1.5%), and pituitary adenomas (1.1%). Tumors in other various organs were found at a low incidence.

Spontaneous neoplasms in B6C3F1 mice

Spontaneous neoplasms in untreated B6C3F1 mice (200 males and 200 females) used as controls in 4 carcinogenicity studies were evaluated and tabulated. The most common neoplasms in male mice were hepatocellular adenomas/carcinomas (24.5%) followed by alveolar-bronchiolar adenomas/carcinomas (10.0%), lymphoreticular neoplasms (7.0%) [malignant lymphomas mixed (4.5%), histiocytic sarcomas (3.5%)], harderian gland adenoma (6.5%), and hemangiomas/hemangiosarcomas (5.5%). In the females, the most frequently occurring neoplasms were lymphoreticular neoplasms (22.0%) [malignant lymphoma mixed (10.0%), malignant lymphoma lymphocytic (6.5%), histiocytic sarcomas (5.5%)] followed by pituitary adenomas (15.5%), alveolar-bronchial adenomas/carcinomas (11.5%), hepatocellular adenomas/carcinomas (7.0%), harderian gland adenomas, uterine stromal polyps (2.5%), and hemangiomas/hemangiosarcoma (2.0%). The incidence of tumors in various other organs was found to be low.

Immunohistochemistry and Morphology of Reactive Lesions in Lymph Nodes and Spleen from Rats and Mice

The use of immunohistochemistry with anatomical and systematized classifications of nonneoplastic lesions in hematopoietic pathology of lymph nodes and spleens from rats and mice is described. Polyclonal antisera and monoclonal antibodies to leukocyte and other antigens can be used with frozen or fixed tissue sections to identify changes in cell populations in these tissues in response to tissue injury and aging. A classification for reactive lesions of lymph nodes and spleen is proposed that can be utilized for computerized pathology and toxicology data systems. These classifications are based on a systematized anatomic distribution of the lesions with the aid of immunohistochemistry. The association of some lesions with early leukemia or lymphoma of rats and mice is also discussed.

Morphological observations on the epithelium of the developing urinary bladder of the mouse and rat.

Bladders from fetal and neonatal BALB/cStCrlfC3H/Nctr mice and Sprague-Dawley rats were studied to establish the sequence of events in their morphological development by using scanning electron, transmission electron and light microscopy. On fetal day 18 or 19 the epithelium from the mouse and the rat displayed 2 or 3 distinct cell layers. With transmission electron microscopy a star-like contraction of the cell surface of the mouse bladder occurred which was not seen in the developing rat bladder. In both the mouse and the rat, some of the superficial cells sloughed between fetal day 18 or 19 and the day of birth. On the day of birth, the epithelium was composed of only 2 layers. The nuclei of both the superficial and basal layers contained prominent euchromatin, and mitotic figures were often present in the basal layer. By the 5th postnatal day, some of the superficial cells contained autophagic vacuoles, and the epithelium was still 2 cell layers thick. One week after birth the epithelium consisted of 2 to 3 cell layers. Three weeks after birth the epithelium was 3 cell layers thick and appeared as the adult pattern with both transmission and scanning electron microscopy. The study demonstrated that the fetal and neonatal mouse and rat urinary bladders undergo a series of rapid developmental changes and suggest that the fetal and neonatal urinary bladder may be a target organ susceptible to toxic insult.

The influence of sex, dose, time, and cross on neoplasia in mice given benzidine dihydrochloride

Abstract Mice were provided ad libitum water containing 0, 30, 60, 120, 200, or 400 ppm benzidine dihydrochloride for 40, 60, or 80 weeks. Initially there were 864 mice of both sexes of two crosses, monohybrid cross and F-1 cross. The monohybrid cross was genetically heterogeneous and was produced from the genetically homogenous F-1 cross. Groups of mice from both crosses and both sexes were terminated at 40, 60, and 80 weeks for pathological evaluation. Statistical analyses of animal weights, water consumption, hepatic cellular alteractions, liver tumor incidence, liver tumor survival, and time-to-first appearance of a liver tumor were performed. Average animal weights decreased as the dose of benzidine increased. There was a corresponding decrease in water consumption with increased dose. Positive associations between incidences of basophilic and acidophilic hepatic foci of cellular alterations, hepatocellular adenomas, and hepatocellular carcinomas were noted in females but similar associations were not noted in males. ED50s calculated from liver tumor incidence for the three termination periods ranged from a low of 54 ppm (F-1 cross and monohybrid cross 80-week females) to a high of 2799 ppm (F-1 cross 40-week males). There were significant differences among the liver tumor survival distributions for all four cross-sex combinations, attributable in all four cases to significant dose-related trends. The estimated time-to-first appearance of a liver tumor was also dose related. The estimated mean time-to-liver tumor ranged from 9 months at 400 ppm to 18 months at 60 ppm in females and 15 months at 400 ppm to 23 months at 60 ppm in males. Five months was estimated for an animal to die of a tumor following the first appearance of the tumor for both sexes and both crosses, irrespective of dose. In all responses mentioned above there were minor differences observed between the two crosses but major differences in response were observed between the sexes for both crosses.

Morphologic Classification and Incidence of Hematopoietic Neoplasms in the Sprague-Dawley Rat

Hematopoietic and related neoplasms were morphologically studied in a total of 1,765 male and 1,765 female Sprague-Dawley rats from 6 chronic toxicity studies conducted at a large toxicology testing laboratory. The most common types of lymphoid neoplasms seen included the lymphoblastic lymphoma (0.65%) and the large granular lymphocyte lymphoma (LGL, Fischer or mononuclear cell leukemia) (0.60%). The most common type of nonlymphoid neoplasm with morphologic features similar to lymphoid tumors was histiocytic sarcoma (1.1%). A small number of cases of myelogenous leukemia were also seen. Additional work is needed in the classification of hematopoietic neoplasms in rats including refined immunomorphological studies.

Sequential morphogenesis of liver tumors in mice given benzidine dihydrochloride

Abstract Benzidine dihydrochloride induced hepatic foci of cellular alteration, hepatocellular adenomas and hepatocellular carcinomas in mice. All three lesions occurred more frequently in the female, and all three lesions sometimes occurred in the same liver. The data suggest that the foci of cellular alteration would be precursors for the hepatocellular adenomas which are in turn precursors for the hepatocellular carcinomas.

Histiocytic lymphoma in the mouse

Abstract This investigation studied the occurrence, distribution and morphology; and the transplantation, ultrastructural and in vitro characteristics of histiocytic lymphoma in the BALB/c and C57BL/6 strains of mice. The disease was more common in aged females of both strains. The liver was the major organ involved in the males and the liver and uterus were commonly involved in the females. Subcutaneous transplants readily metastasized to the lungs. Ultrastructurally the neoplastic cells resembled histiocytes and did not contain microfilaments or a basement membrane. The results suggest that this neoplasm is histiocytic in origin.