Algis P. Yagminas

Mixture effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin and polychlorinated biphenyl congeners in rats.

Concern of the toxic effects and bioaccumulation of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and polychlorinated biphenyls in the environment continues to be a focus of research in persistent organochlorine contaminants. Groups of five adult female S.D. rats were administered by gavage 0, 2.5, 25, 250 or 1000 ng TCDD/kg body weight/day or TCDD in combination with a mixture of PCB congeners (PCBs) at 2 or 20 microg/kg b.w./day for a period of 28 days. Growth suppression, increased absolute and relative liver weights, and decreased thymic weight were observed in either the 1000 ng TCDD group alone, or the groups receiving a mixture of 1000 ng TCDD + 2 microg PCBs. The TCDD induced increases in liver and thymic weights were not altered by co-administration with PCBs, however, growth suppression appeared to be more pronounced in the group receiving 1000 ng TCDD + 2 microg PCBs than with TCDD alone. Treatment with TCDD at 250 ng and 1000 ng/kg resulted in a significant increase in hepatic microsomal methoxy resorufin-O-demethylase and ethoxy resorufin-O-deethylase activities which were antagonized by co-administration with PCBs. Similarly, effects of 250 ng TCDD on serum cholesterol and liver UDP glucuronosyl transferase activity and ascorbic acid were significantly reduced by co-administration with 20 microg PCBs. Other biochemical effects elicited by treatment with 1000 ng TCDD, but not affected by co-administration with PCBs include the following: increased serum albumin, decreased liver vitamin A, and increased kidney vitamin A and liver microsomal glutathione-S-transferase activity. While decreased hemoglobin, platelet, packed cell volume and red cell indices were observed in TCDD treated rats, no interactive effects were seen. The above results indicate that the mixture effects of PCBs and TCDD may be additive or antagonistic depending on the dose level and endpoints measured. For the purpose of predicting mixture effects, knowledge of mechanisms of action and toxicokinetics is required.

An automated continuous-flow assay for serum sorbitol dehydrogenase activity and its use in experimental liver damage

Abstract An automated continuous-flow assay to monitor sorbitol dehydrogenase activity (EC 1.1.1.14) in serum has been developed. The amount of serum required is 240 μl and 50 samples can be analyzed per hour. The method features an automatic blank substraction and a linear range from 0 to 500 mU/ml. In order to validate the method, sera from control rats and rats preexposed to carbon tetrachloride were analyzed and compared to results obtained using a manual reaction-rate assay. The resulting correlation coefficient was 0.99.

Effects of tris(4-chlorophenyl)methanol on the rat following short-term oral exposure.

The systemic toxicity of tris(4-chlorophenyl)methanol (TCPM) was studied in male and female rats following 4 weeks dietary exposure dosed at 1, 10 and 100 ppm. An increased spleen to body weight ratio was observed in males at 10 and 100 ppm and in females at 100 ppm. An increased liver to body weight ratio was detected in both sexes at 100 ppm. Dose-related increases in hepatic Phase-I (AH, APDM, EROD and PROD) and Phase-II (UDPGT, GST) enzyme activities were observed generally at 10 and 100 ppm, with the elevation in PROD activity being the most marked. Increased urinary ascorbic acid was detected in both males and females after 1 week of treatment at 100 ppm and after 4 weeks of treatment at 10 and 100 ppm. At 10 and 100 ppm, elevated % lymphocytes were found in males, and higher white blood cell and lymphocyte counts were observed in females. In the liver, mild to moderate cytoplasmic changes consistent with proliferation of smooth endoplasmic reticulum were present in rats of both sexes at 10 and 100 ppm, and increased number of hepatocytes undergoing apoptosis were observed in male rats at 100 ppm. Mild splenic changes consisting of sinus hyperplasia in males and females at 100 ppm and mantle zone atrophy in males at 100 ppm were also observed. It was concluded that TCPM at a dietary concentration of 10 ppm (equivalent to 1.2 mg/kg/day) produced systemic changes in rats that included various hepatic effects, increased splenic weight, and modulations in white blood cells and lymphocyte counts.

Systemic toxicity of coal liquefaction products: Results of a 14-day dermal exposure

Increasing energy demands, coupled with rising prices and an unstable world oil market have stimulated international interest in developing alternative sources of fuel. Direct coal liquefaction processes (CLP) hold great potential for Canada because of its large coal reserves. The conversion of coal to liquefied fuels results in many fractions of differing hydrocarbon content and includes many toxic substances such as polynuclear aromatic hydrocarbons. Since the major route of occupational exposure would be via the dermal route and since studies of systemic toxicity following dermal exposure are lacking, preliminary studies were conducted on the toxicity of SRC-II process coal liquefaction products applied dermally to the rat. Samples of the light (L), intermediate (I), and heavy, (H) fractions produced during the SRC-II coal liquefaction process, were kindly provided by the Sandwell Beak Research Group (Mississauga, Ontario, Canada). Diesel Fuel (D) was purchased from an Esso Gasoline Station. Male and female Sprague-Dawley rats weighing 200 +/- 25 grams were used.

Systemic toxicity of a bitumen upgrading product in the rat following subchronic dermal exposure

The subchronic toxicity following dermal exposure to a synthetic fuel, heavy gas oil No. 2 fraction of bitumen upgrading product (B-HGO II) was studied in the rat. B-HGO II was applied on the dorsal skin of rats at doses of 8, 20, 50 and 125 mg/kg bw/day daily for 13 weeks. Control animals received normal saline and positive controls received a medium-boiling coal liquefaction product (CLP) at 125 mg/kg bw/day. Both male and female rats in the treatment groups had reduced body weight gain, and males in the highest dose group were terminated in the 5th week due to overt toxicity. Increased liver weight relative to body weight was observed in males and females starting at 8 mg/kg. Increased relative heart and spleen weights were observed in males and females starting at the two intermediate doses (20, 50 mg/kg). Increased relative kidney weight was detected in males at 50 mg/kg and females at 125 mg/kg. Increased serum cholesterol was observed in both sexes starting at 50 mg/kg while elevated serum glucose was present in females starting at 8 mg/kg. Significant changes in AH, APDM and EROD activities were observed in treated rats of both sexes. Reduced red blood cell counts were detected in males starting at 8 mg/kg and females at 20 mg/kg. Microscopic examination of blood smears, spleen and hemosiderin accumulation patterns, as well as analysis of FEP and serum TIBC levels indicated that the cause of anemia was primarily intravascular hemolysis and secondarily iron deficiency. Marked thymic atrophy and thyroid abnormalities were the most prominent histological changes followed by changes in bone marrow (myelofibrosis) and liver. Both B-HGO II and CLP (positive control) caused kidney changes characterized by cytoplasmic inclusions and lesions in the tubular cells, which were observed in 50 mg/kg males but not in the females. B-HGO II was considered to be toxic at a subchronic dermal exposure level as low as 8 mg/kg/day.

Toxicity studies on chlorinated guaiacols in the rat

TrichloroguaiacoJ (3CG) and tetrachloroguaiacol (4CG) are formed by the reaction of chlorination agents with phenolic lignins during the bleaching process in the manufacture of pulp and paper. These compounds have been identified in river water receiving pulp mill effluents and have been shown tobe toxic to fish (LEACH and THAKORE 1975). Since chloroguaiacols present in river water can occur in drinking water, it fs important to have information on the toxicity of these compounds. The present study was carried out as part of a general program to evaluate the toxicity of pulp rnill effluent (VILLENEUVE 1977) and was designed specifically to investigate the acute and subacute toxicities of 3CG and 4CG. MATERIALS AND METHODS Trichloroguaiacol was prepared in the following manner: Chiorine gas was bubbled into a stirred solution of guaiacol (12.4 g) in glacial acetic acid for a period of 50 rein while the reaction mixture was kept at 12~ by external cooling. The mixture was then poured onto crushed ice (500 g) and the solids that formed were filtered, washed and dried. One recrystallizatio n from hexane produced 3CG (22 g) as white needles, top 112-114 ~ lit. rnp. 107-108 ~ (HEILBRON 1965). Tetrachloroguaiacol was synthesized in quantitative yield by a similar method described for 3CG except that chlorine gas was bubbled into the reaction mixture for 2 h. Mp. 122-124 ~ lit. mp 119-120 ~ (HEILBRON 1965). NMR and GC-MS of the synthesized products were round tobe consistent with those of 3CG and 4CG. Purities were established to be greater than 99% by GC. Acute Toxicity Study. Maie 5prague-Dawley rats (Biobreeding Laboratories, Ottawa, Canada) weighing 250-300 g were intubated with single oral doses of 3CG and 4CG dissolved in corn oil (Mazola Corn oil, 0.~ rnL/100 g body weight). There were rive dose groups (888, 1333, 2000, 3000 and 4500 mg/kg body weight) each with ten animais. The animais were fed ad libitum with standard laboratory feed (Master Feed). LDsn values were calculated according to the method of LITCHFIELD and WILCOXON (1949) based on an observation period of 14 days.

Effects of food deprivation in rats previously exposed to mirex

Food deprivation has been shown to alter the toxicity and tissue distribution of organohalogens in animals previously exposed to these compounds (DAHLGREN et al., 1972; DALE et al., 1963; ECOBIOCHON and SASCHENBRECKER, 1969; VILLENEUVE, 1975; ZABIK and SCHEYNEL, 1973). Such effects are attributed to the mobilization of fat stores and subsequent release of the organohalogen. The present study was carried out as part of a general program designed to investigate the effects of food deprivation on the toxicity of pesticides. Mirex (perchlorocyclopentanodecane) was chosen for this study because of lipophilicity, low biodegradability and demonstrated presence in the environment. Mirex is currently under close scrutiny by regulatory and environmental agencies in Canada and the United States because of its appearance in Lake Ontario fish.

The subchronic toxicity of acridine in the rat

The subchronic toxicity of acridine was investigated in rats following dietary exposure at 0, 1, 10, 100 and 500 ppm for 13 weeks. The growth rate and food consumption were not affected by treatment and no clinical signs of toxicity were observed. There was a slight but significant decrease in spleen weight, both in absolute terms and as a percent of body weight, in the 500 ppm males and a slight increase in absolute thymus weight in the females of the same dose group. Both hepatic ethoxyresorufin O-deethylase (EROD) and pentoxyresorufin O-dealkylase (PROD) activities were slightly, but significantly, elevated in females in the 500 ppm dose group. No haematological or other biochemical changes were observed. Females also displayed dose-related increases in inorganic phosphate and uric acid levels. Treatment-related histopathological changes were seen in the thyroid, liver and kidney and included hepatic anisokaryosis and vesiculation of nuclei and glomerular adhesions, reticulin sclerosis and nuclear pyknosis in the kidney. Residue data showed a dose-dependent accumulation of acridine in liver, kidney and adipose with the highest concentration being found in the fat of the 500 ppm dose group. Based on these data, the no observable adverse effect level of acridine was judged to be 100 ppm or 12 mg/kg bw/day.

Effect of phenobarbital and polychlorinated biphenyls on the toxicity and disposition of 1,2,4,5‐tetrachlorobenzene in the rat

Control and phenobarbital (PB) or polychlorinated biphenyl (PCB) pretreated rats were given single oral doses of 14C-1,2,4,5-tetrachlorobenzene (TCB) at 30 or 300 mg/kg b.w. Urine and feces were collected daily for the determination of 14C-content. Five animals per group were killed 2 days after dosing and another five animals were killed 7 days later for the determination of hepatic microsomal enzyme activities, histological changes and 14C-content in the major organs and tissues. Pretreatment with PCB or PB did not alter the effects of TCB biochemically or histologically. Both PB and PCB increased the rate of TCB excretion and decreased the levels of radioactivity in most tissues examined at 7 days after dosing. It was concluded that, at the dose ranges studied, pretreatment with PB or PCB did not significantly alter the toxic effects produced by TCB.