Cheng-Chun Lee

Carcinogenicity of vinyl chloride and vinylidene chloride

Exposure of mice to 50, 250, or 1000 ppmm of vinyl chloride (VC) in the air for 6 h/d, 5 d/wk, caused a high incidence of bronchioloalveolar adenoma, mammary gland tumors, and hemangiosarcoma. Mammary gland tumors occurred in the females and included ductular adenocarcinoma and squamous and anaplastic cell carcinomas with metastasis to the lung. Hemangiosarcoma occurred in the liver and, to a lesser extent, in various other organs. The incidence and severity of these tumors increased with the concentration of VC and the length of exposure. Malignant lymphoma involving various organs was observed in several mice. Rats were more resistant to the carcinogenic effects of VC. Exposure of rats to 250 or 1000 ppm of VC caused hemangiosarcoma in the liver. Many rats with hepatic hemangiosarcoma also developed hemangiosarcoma in the lung. Extrahepatic hemangiosarcoma also occasionally occurred in other organs. Exposure to 55 ppm of vinylidene chloride (VDC) caused hepatic hemangiosarcoma and probably bronchioloalveolar adenoma in mice. Hemangiosarcoma also occurred in the mesenteric lymph node or subcutaneous tissue in two rats exposed to 55 ppm of VDC.

Follow‐up study on the carcinogenicity of vinyl chloride and vinylidene chloride in rats and mice: Tumor incidence and mortality subsequent to exposure

Carcinogenic and other toxic effects in rats and mice were examined during a 12-mo period following exposure to vinyl chloride (VC) or vinylidene chloride (VDC). Exposure of male and female mice to 50, 250, or 1000 ppm VC for 6 h/d, 5 d/wk, for 1, 3, or 6 mo resulted in increased numbers of deaths and increased moribundity at all dose levels during the exposure and postexposure periods, as compared with air-exposed controls. Similar observations were made with rats after 1, 3, 6, or 10 mo exposure to VC. Cumulative tumor incidence at various organ sites also increased in both species during the postexposure period in proportion to dose or duration of exposure at higher dose levels. However, except for mammary gland tumors in female mice, no significant increase in cumulative tumor incidence occurred in either species at 50 ppm VC or 55 ppm VDC, regardless of duration of exposure. These results suggest that exposure to vinyl halides at dose levels lower than those that elicit a significant increase in cancer incidence during the lifetime of the animal may, nonetheless, increase the risk of early death or moribundity from toxic pre- or subcarcinogenic effects. At dose levels higher than those consistent with the physiological defense or repair capabilities of the cell, ultimate tumor incidence becomes proportionate to length of exposure and may reflect the number of carcinogenic events elicited during the exposure period.

A dominant lethal study in male rats after repeated exposures to vinyl chloride or vinylidene chloride

Male CD rats were exposed 6 hr/day for 5 days/wk to 0, 50, 250, or 1,000 ppm of vinyl chloride or 55 ppm of vinylidene chloride. Starting on week 11 of exposure, these males were mated with untreated females. There was no evidence of either preimplantation loss or postimplanation loss in pregnant females that resulted from these matings. Consequently, it was concluded that these exposures did not produce germinal mutation, as manifested by a dominant lethal effect, in male rats.

Trinitroglycerol metabolism: denitration and glucuronide formation in the rat.

Abstract Approximately 80–90% of an oral dose of [1,3- 14 C]trinitroglycerol ([1,3- 14 C]TNG) was absorbed through the gastrointestinal tract of the rat at 24 hr. Most of the absorbed radioactivity was excreted in the expired air and in the urine, averaging 25.5 and 39.8% of the administered dose, respectively. A significant amount of radioactivity was recovered in the liver at 4 hr and remained unchanged at 24 hr. Only small amounts of radioactivity were found in the other tissues. In the urine, free dinitroglycerols (DNG) and mononitroglycerols (MNG) represented 1.1 and 10.6% of the administered dose, respectively. Only a negligible amount of free TNG was detected. Conjugation played a major role in the metabolism of TNG. DNG-glucuronides and MNG-glucuronides represented 13.5 and 1.5% of the administered dose, respectively. A conjugate of TNG was not detected. In addition, glycerol and two unidentified polar metabolites averaged 6.9, 4.9, and 1.3% of the administered dose, respectively.

Oral toxicity of ferric dimethyl‐dithiocarbamate (ferbam) and tetramethylthiuram disulfide (thiram) in rodents

Single oral doses of ferbam, thiram, zineb, or maneb produced central nervous system stimulation followed by depression and alopecia. Ferbam and thiram were more toxic on the basis of weight than zineb; maneb was relatively nontoxic. There was no species difference in acute toxicity between rats and mice. In 13- and 80-wk feeding studies, the toxic effects of ferbam and thiram in rats were similar; however, thiram was more toxic on the basis of weight than ferbam. During the 80-wk feeding study, weight gain was reduced in ferbam-treated rats starting at daily doses of 8 mg/kg in males and 37 mg/kg in females and in thiram-treated rats staring at daily doses of 5 mg/kg in males and 26 mg/kg in females. Food consumption was reduced in proportion to the reduced weight gain. Death occurred in males fed 109 or 331 mg/kg.d ferbam and in males fed 58 or 132 mg/kg.d thiram. Female rats fed 96 mg/kg.d ferbam or 67 mg/kg.d thiram developed alopecia and ataxia, which led to paralysis of the hind limbs. Male rats fed ferbam or thiram had a more severe incidence of squamous metaplasia in the thyroid and fatty infiltration in the pancreas than control males. Ferbam or thiram reduced the incidence of spontaneous nephritis in both males and females. The male rats that were fed 109 or 331 mg/kg.d ferbam and died betweeen 1 and 5 wk had golden pigment in the reticuloendothelial cells of the spleen and in the enlarged mesenteric lymph nodes, associated with hemosiderosis. Moderate tubular degeneration of the testes with atypical spermatids in the epididymis occured in some rats fed 132 mg/kg.d thiram for 13 wk but not in rats fed up to 52 mg/kg.d for 80 wk. Periodic hematologic examination and terminal clinical blood tests did not reveal any severe changes. Ferbam and thiram did not alter the occurrence or latent period of the spontaneous tumors seen in control rats.

Developmental toxicity of ferric dimethyldithiocarbamate and bis(dimethylthiocarbamoyl) disulfide in rats and mice

Abstract Ferric dimethyldithiocarbamate (ferbam) and bis(dimethylthiocarbamoyl) disulfide (thiram) are agriculturally important fungicides. The effect of these compounds on development was studied during gametogenesis in rats, organogenesis in rats and mice, and the peri- and postnatal period in rats. Ferbam administered in the diet to rats prior to mating did not affect reproduction in either males after at least 13 weeks of daily doses as high as 109 mg/kg or females after at least 14 days of daily doses as high as 51 mg/kg. Thiram, given during similar periods, produced infertility in male rats at doses of 132 mg/kg and delayed the female estrous cycle at doses of 96 mg/kg. Ferbam administered to rats during organogenesis by gavage at doses of 114 mg/kg reduced the maternal weight gain, litter size, and fetal body weight. Mice survived ferbam treatment during gestation at doses of 228 mg/kg without adverse effects on these parameters. Thiram treatment during organogenesis reduced maternal weight gain and fetal body weight in rats given 40 mg/kg or more. Litter size was decreased in rats given thiram at doses of 136 mg/kg or more. Some mice died at thiram doses of 300 mg/kg; however, development was not affected in the survivors. These fungicides were judged to have little teratogenic activity. The administration of ferbam at 0.15% and thiram at 0.10% of the diet during the peri- and postnatal period reduced the growth and survival of pups. These effects were reversed by cross-fostering. Since ferbam and thiram interfered with reproduction only at doses that produced toxicity in the adult, these compounds were judged to have little primary effect on reproduction.

Developmental toxicity of Guthion in rats and mice

The purpose of this study was to assess the effects of Guthion, a pesticide with anticholinesterase activity, on development in rats and mice. A preliminary toxicity study with Guthion indicated that a 35-day LD50 dose for virgin rats and a 10-day LD50 dose for virgin mice was between 4 and 8 mg/kg/day for both species. On the basis of these data, doses of 0, 1.25, 2.5, and 5.0 mg/kg/day were selected for the developmental study, which consisted of two phases. During the first phase, pregnant rats and mice were treated for 10 days starting on gestational day 6. The high dose affected maternal welfare only in rats. Guthion did not significantly increase in a dose-related manner any of the specific anomalies observed in either rats or mice. During the second phase, pregnant rats were treated from gestational day 6 to postpartum day 21. Dams in the high dose group were more sensitive to Guthion later in gestation with the result that deaths and signs of anticholinesterase toxicity increased during this time. Guthion also adversely affected maternal welfare in this group. As a result of Guthion toxicity, only one litter survived until weaning. The inability to dissociate toxicity in adult and developing animals suggests that Guthion has little primary effect on the development of rats or mice.

Cytotoxicity studies on dithiocarbamate fungicides.

The cytotoxicity of selected metal-containing dithiocarbamate fungicides was determined using Chinese hamster ovary cells (CHO-K1) in culture. Bis(dimethylthiocarbamoyl)disulfide (thiram) and ferric dimethyldithiocarbamate (ferbam) were more toxic, having LC50 values of 5 × 10−7 and 7 × 10−7 m, respectively, whereas manganese ethylene bisdithiocarbamate (maneb) and zinc ethylene bisdithiocarbamate (zineb) were less toxic, having LC50 values of 3 × 10−6 and 6 × 10−6 m, respectively. Analysis of the data using “target theory” showed that ferbam, thiram, maneb, and zineb have a common hit number. These studies suggest that these fungicides have a common mechanism of toxicity.

Toxicity of vinylidene chloride in mice and rats and its alteration by various treatments

The toxicity of vinylidene chloride (VDC) was studied in mice and rats exposed to various concentrations of the vapors for 23 hr/day. In addition, the ability of various compounds to alter parameters of toxicity was evaluated. Mice were more sensitive than rats to the lethal, hepatotoxic, and renal toxic effects of VDC. Disulfiram protected mice from these toxic effects of inhaled VDC and reduced the levels of covalently bound radioactivity in the liver and kidney after the ip administration of [14C] VDC. Diethyldithiocarbamate and thiram also protected mice from the acute lethal effects of VDC.

Comparative pharmacologic responses to antihistamines in newborn and young rats

Summary The acute subcutaneous and oral toxicities of two commonly used antihistaminic drugs, chlorpheniramine and diphenhydramine, were determined in newborn and young rats. The resistance of rats to both drugs increased with increasing age. The greatest change in resistance appeared between the ages of 16 and 25 days. There was no apparent difference in the activity of the enzymes concerned with the metabolism of both drugs in the livers of 15- and 40-day-old rats. The development of greater resistance to both drugs with increasing age can be explained, insofar as the subcutaneous route is concerned, by a decrease in the amount of absorption.