D. C. Villeneuve

Metabolism of a polychlorinated biphenyl (Aroclor® 1254) mixture in the rat

SummaryMale rats were orally dosed with Aroclor 1254 and residues were found in all tissues analyzed, with the greatest concentration in the fat. The GLC-EC pattern of the residues was different from the standard mixture administered, indicating that all components were not metabolized at the same rate. Higher residues were found in the carbon tetrachloride-treated rats. Aroclor 1254 residues in the brain, spleen, blood, testes, heart, kidney and fat were reduced by 90, 84, 80, 79, 78, 76, 64 and 33% respectively in 20 days. Aroclor 1254 significantly increased the size of the liver and also the percent lipid in the liver. Aroclor 1254 was found to potentiate the toxicity of carbon tetrachloride in the rat.

Uranyl Nitrate: 91-Day Exposure and Recovery Studies in the Male New Zealand White Rabbit

This study was undertaken to examine the reversibility of renal injury in the male New Zealand White rabbit subsequent to a 91-day exposure to uranyl nitrate (UN) in drinking water, followed by various recovery periods. Specific pathogen-free (SPF) animals were exposed for 91 days to UN in their drinking water (24 or 600 mg UN/L). Control groups were given municipal tap water (< 0.001 mg U/L). Regular clinical observations were recorded, and urine was collected periodically. Recovery periods between the last UN exposure and termination were 0, 8, 14, 45, or 91 days. Following the study, all animals were anesthetized and terminated by exsanguination, and multiple hematological and biochemical parameters were determined. Necropsies were conducted, and histopathological examination was performed. Exposure-related histopathological changes were observed only at much higher doses than in our previous male rabbit study where non-SPF-free animals had been used. Minor increases in kidney to body weight ratios were observed in the high-dose groups following exposure and early recovery. Renal tubular injury with degenerative nuclear changes, cytoplasmic vacuolation, and tubular dilation was seen in the high-dose group, without consistent resolution even after 91 days recovery. Animals ingested approximately 33% more uranium per day in this study than did males in a comparable dose group in the previous study, yet their kidney tissue uranium residues were 30% lower. These results suggest that SPF rabbits are less sensitive to uranyl injury than the non-SPF animals. The lowest-observed-adverse-effect level is estimated to lie at or below 24 mg UN/L.

Toxicity of 2,2′,4,4′,5,5′-Hexachlorobiphenyl in Rats: Effects Following 90-Day Oral Exposure

The subchronic toxicity of 2,2′,4,4′,5,5′‐hexachlorobiphenyl (PCB 153) was investigated in rats after 13 weeks of dietary exposure. Groups of 10 male and 10 female rats were administered PCB 153 in their diet at levels of 0.05, 0.50, 5.0 or 50 ppm for 13 weeks. The control groups received the diet containing 4% corn oil. Growth rate and dietary consumption were not affected by treatment. Clinical signs of toxicity were not observed. Enlarged, fatty liver was observed in treated animals at necropsy, but most were confined to the two highest dose groups. Increased hepatic microsomal ethoxyresorufin‐O‐deethylase, aminopyrine‐N‐demethylase and aniline hydroxylase activities occurred in high‐dose groups of both sexes, with increased ethoxyresorufin‐O‐deethylase activity being observed starting at 0.05 ppm in females and at 0.5 ppm in males. Treatment‐related reduction in hepatic and pulmonary vitamin A was seen in the highest dose group of both sexes. Changes in brain biogenic amines and intermediate products were observed mainly in females; these included decreased dopamine and 5‐hydroxytryptamine concentrations in the frontal cortex region, and dihydroxyphenylacetic acid in the caudate nucleus region at 5.0 and 50 ppm. Female rats appeared to be more sensitive to the neurotoxic effects of PCB 153 than males. Dose‐dependent histological changes were observed in the thyroid and liver of rats of both sexes and significant changes occurred at 5.0 and 50 ppm. Based on these data, the no‐observable‐adverse‐effect level (NOAEL) of PCB 153 was judged to be 0.5 ppm in the diet or 34 μg kg−1 body wt. day−1.

Toxicological response of rats fed lake Ontario or Pacific Coho salmon for 28 days

Abstract The present study was undertaken to determine if the feeding of Lake Ontario salmon containing a mixture of chemical contaminants, could produce a toxicological response in rats. Male and female rats were fed freeze‐dried Lake Ontario or Pacific Coho salmon for 28 days at levels of 1.45%, 2.90% and 5.80% of their normal diet. Body weight changes, organ weights, food intake, routine hematology, biochemical parameters, residue levels and gross and microscopic pathological changes were determined. Body weight gain was decreased in all groups of male rats fed Lake Ontario or Pacific salmon but this was attributed to the unpalatibility of the diet since the food intake in these groups was decreased during the first week of the study. No effects were observed on body weight gain or food intake in female rats. Hematological parameters including hemoglobin, hematocrit, white blood count and red blood count were not affected by treatment. Serum potassium levels were significantly decreased in all three gr...

A teratological assessment of four trihalomethanes in the rat

Four trihalomethanes were administered by gavage to Sprague-Dawley rats from day 6 to day 15 of gestation. Chloroform (Ch) was administered at levels of 100, 200 and 400 mg/kg and bromoform (Br), bromodichloromethane (BDCM) and chlorodibromomethane (CDBM) were administered at levels of 50, 100 or 200 mg/kg/day. A separate control was used for each compound. Maternal weight gain was depressed in all groups receiving Ch and at the highest dose levels of BDCM and CDBM. Ch administration caused decreased maternal hemoglobin and hematocrit values at all dose levels and also produced increased serum inorganic phosphorus and cholesterol at the highest dose. Liver enlargement was observed at all dose levels of Ch but in no other treatment groups. Evidence of a fetotoxic response was observed with Ch, CDBM and Br but not BDCM. No dose-related histopathological changes were observed in either mothers or fetuses as a result of treatment. None of the chemicals tested produced any teratogenic effects.

Hexachlorobenzene toxicity in the monkey primordial germ cell without induced porphyria

Hexachlorobenzene is a persistent chlorinated organic chemical that has been detected in many tissues from a variety of species including human ovary and human ovarian follicular fluid. When administered in high dosage to nonhuman primates, hexachlorobenzene causes destruction of ovarian primordial germ cells in association with systemic toxicity. The purpose of these experiments was to assess relative ovarian germ cell sensitivity at much lower dosages of hexachlorobenzene that do not produce systemic effects and additionally to evaluate oocyte function by means of the response to superovulation, fertilization, and embryo cleavage during a cycle of in vitro fertilization in the cynomolgus monkey. Hexachlorobenzene in dosages of 0.1, 1.0, and 10.0 mg/kg/day was administered orally by gelatin capsule for 90 days. There was a dose-dependent accumulation of HCB in serum and other tissues without any change in the serum estradiol response to human menopausal gonadotropin, oocyte recovery, oocyte maturation, oocyte fertilization in vitro, and early embryo cleavage rate. There was a dose-related toxic effect observed in primordial germ cells at the lowest dose despite no evidence of systemic or hepatic effects. As there were no changes in the urinary porphyrin excretion, the mechanism of hexachlorobenzene ovotoxicity may be distinct from hexachlorobenzene-induced cytochrome P-450-dependent inhibition of uroporphobilinogen decarboxylase in the liver, although such intraovarian metabolism cannot be excluded.

Subchronic Oral Toxicity of Triethyl Lead in the Male Weanling Rat. Clinical, Biochemical, Hematological, and Histopathological Effects

This study was designed to ascertain the effects of low level exposure of triethyl lead (3EL) to the male weanling rat. Groups of 20 animals were administered by gavage 3EL at 0.05, 0.10, 0.20, 0.50, and 1.00 mg/kg body wt for 91 days, 5 days/week. Lead acetate (PbHOAC) at 200 mg/kg body wt/day was given as a positive control. Weight gain was reduced in those animals receiving 1.0 3EL. Spleen and kidney weights were elevated in the PbHOAC group. Residues of 3EL and its metabolites diethyl lead (2EL) and lead (Pb) accumulated in a dose-dependent manner in blood, liver, kidney, and brain; 3EL accumulated preferentially in the liver while inorganic lead accumulated in the kidney. Dose-dependent changes occurred in serum calcium which was decreased and in phosphorus which was elevated for all dose groups. Serum cholesterol was elevated in the three highest 3EL groups as was alkaline phosphatase. LDH was lowered in the PbHOAC-treated group but microsomal aniline hydroxylase was elevated. Hematological changes consisted of elevated platelet counts in the 1.0 3EL group and decreased mean corpuscular hemoglobin content and mean corpuscular volume in the PbHOAC-treated group. Treatment related histopathological changes were seen in thyroid, liver, kidney, and bone marrow. Based on these data a no observed adverse effect level for 3EL was set at 0.10 mg/kg/body wt.

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.

Toxicological response and its reversibility in rats fed Lake Ontario or Pacific coho salmon for 13 weeks

Lake Ontario coho salmon were known to contain a mixture of chemical contaminants. A previous study demonstrated that rats fed the Lake Ontario fish-supplemented diet for 28 days exhibited mild biochemical and histological changes. The purpose of the present study was to determine the effects due to a longer term of exposure and the reversibility of these effects. Growth rate and food consumption were not affected by feeding the animals with Lake Ontario or Pacific fish-supplemented diets for 13 weeks. No deaths were observed. Decreased spleen weights were observed in groups of males fed 1.45%, 5.8% Lake Ontario and 2.9% Pacific diet. After a 13 week recovery the spleen weights returned to normal. Decreased serum potassium was observed in male rats fed 2.9% Lake Ontario diet, and all levels of Pacific diet for 13 weeks, and was not evident following maintenance on normal diet. Serum glucose was not affected by the 13-week period of treatment, however; a reduction in this parameter occurred in male rats fed the two highest doses of Lake Ontario diet and all doses of Pacific diet following the 13-week recovery period. Minor hematological changes occurred only in the male rats fed either Lake Ontario or Pacific diet following a 13 week recovery period and included reduced marrow myeloid cells and myeloid/erythroid ratio. Hepatic microsomal ethoxyresorufin deethylase activity was significantly increased in rats ingesting Lake Ontario diet. Mild histological changes occurred in the liver and thyroid of the treated males, and in the liver and kidney of the treated females. These changes were attributed to the chemical residues and/or the fish diet. Data presented here indicated that the Lake Ontario fish-supplemented diet can cause mild biochemical, hematological and histological changes but most of these were reversible when exposure was terminated.

Comparative toxicity of 1,2,3,4-, 1,2,4,5-, and 1,2,3,5-tetrachlorobenzene in the rat: results of acute and subacute studies

Groups of 10 male and 10 female rats were dosed orally with 1,2,3,4-, 1,2,4,5-, or 1,2,3,5-tetrachlorobenzene (TCB) at levels that ranged from 200 to 4000 mg/kg, and were observed clinically for 14 d. LD50 values for 1,2,3,4-, 1,2,4,5-, and 1,2,3,5-TCB were found to be 1470, 3105, and 2297 mg/kg, respectively, in male rats. In females, the LD50 values were found to be 1167 and 1727 mg/kg for 1,2,3,4- and 1,2,3,5-TCB, respectively. Clinical signs of toxicity included depression, flaccid muscle tone, prostration, piloerection, loose stool, hypothermia, dacryorrhea, coma, and death. In a subacute study, groups of 10 males and 10 females were fed diets containing 0, 0.5, 5.0, 50, or 500 ppm 1,2,3,4-, 1,2,4,5-, or 1,2,3,5-TCB for 28 d. No deaths or clinical signs of toxicity were observed, and neither growth rate nor food consumption was affected. At 500 ppm, 1,2,4,5- but not 1,2,3,4- or 1,2,3,5-TCB caused a significant increase in the liver weight and serum cholesterol of male and female rats. Hepatic microsomal aniline hydroxylase and ethoxyresorufin deethylase were induced by 500 ppm 1,2,4,5-TCB. Hepatic microsomal aminopyrine demethylase activity was increased by the administration of this compound at 50 ppm and higher in males and at 500 ppm in the females. Rats fed 1,2,3,4- and 1,2,3,5-TCB at 500 ppm also showed a significant increase in aminopyrine demethylase activity. Moderate to severe histological changes were found in the liver, thyroid, kidney, and lungs of rats fed 500 ppm 1,2,4,5-TCB. Histological changes in the tissues produced by the administration of the 1,2,3,4- and 1,2,3,5-isomer were mild even at the highest dose levels. Tissue residue data showed that 1,2,4,5-TCB accumulated at much higher levels than the other two isomers. The results suggest that the position of chlorine substitution can affect the tissue accumulation and toxicity of chlorinated benzenes in rats.