P.J. Gehring

The effect of maternally inhaled trichloroethylene, perchloroethylene, methyl chloroform, and methylene chloride on embryonal and fetal development in mice and rats☆

Abstract These studies evaluated the effects of trichloroethylene, perchloroethylene (tetrachloroethylene), methyl chloroform (1,1,1-trichloroethane) and methylene chloride (dichloromethane) on mouse and rat embryonal and fetal development at a concentration two times the maximum allowable excursion limit for human industrial exposure as defined by ACGIH, 1973 (300, 300, 875, 1250 ppm, respectively). Groups of pregnant Sprague-Dawley rats and Swiss Webster mice were exposed to each solvent 7 hr daily on days 6–15 of gestation. None of these solvents caused significant maternal, embryonal or fetal toxicity and none was teratogenic in either species of animal at the concentrations studied. Elevated carboxyhemoglobin content was observed in mice and rats exposed to methylene chloride.

1,4-Dioxane. I. Results of a 2-year ingestion study in rats

Abstract Four groups of rats, 60/sex/level, were maintained on drinking water containing 0, 1.0, 0.1, or 0.01% 1,4-dioxane for up to 716 days. Male and female rats receiving 1% dioxane (equivalent to approximately 1015 and 1599 mg/kg/day, respectively) showed decreases in body weight gains, survival rates, and water consumption. Hepatocellular and renal tubular degenerative changes, accompanied by regenerative activity, were similar to those reported in previous studies following exposure to toxic levels of dioxane. Hepatocellular and nasal carcinomas, occurring at this dose level, were considered related to the lifetime exposure to these massive toxic dosages of dioxane. Male and female rats receiving 0.1% dioxane (equivalent to approximately 94 and 148 mg/kg/day, respectively) in the drinking water had variable degrees of renal and hepatic degenerative changes, but there was no indication of treatment-related tumor occurrence. Male and female rats receiving 0.01% dioxane in the drinking water (equivalent to approximately 9.6 and 19.0 mg/kg/day, respectively) showed no evidence of tumor formation or other toxic effects considered to be related to treatment. These data indicate a dose response for the toxicity of dioxane.

Embryo- and fetotoxicity of inhaled chloroform in rats

Abstract This study evaluated the effects of inhalation of subanesthetic concentrations of chloroform on rat embryonal and fetal development. Pregnant Sprague-Dawley rats were exposed to 30, 100 or 300 ppm chloroform for 7hr/day on days 6 through 15 of gestation. Exposure to chloroform caused an apparent decrease in the conception rate and a high incidence of fetal resorption (300 ppm), retarded fetal development (30, 100, 300 ppm), decreased fetal body measurements (30, 300 ppm) and a low incidence of acaudate fetuses with imperforate anus (100 ppm). Chloroform was not highly teratogenic but was highly embryotoxic. The results of this study disclosed no relationship between maternal toxicity and embryo or fetotoxicity as the result of exposure to chloroform by inhalation.

Studies of the acute and long-term oral toxicity of chlorpyrifos (O,O-diethyl-O-(3,5,6-trichloro-2-pyridyl) phosphorothioate)

The acute and long-term toxicity of orally administered chlorpyrifos (O,O-diethyl-O-(3,5,6-trichloro-2-pyridyl) phosphorothioate), a broad-spectrum insecticide, has been determined. No sex or strain differences in acute oral toxicity were detected using two strains of rat, and LD50 values determined in several tests ranged from 118 to 245 mg/kg. LD50 values (in mg/kg) for other species were approximately 2000 for rabbits, 504 for guinea-pigs and 32 for leghorn chicks. Rats and dogs were maintained on diets providing doses of 0·0, 0·01, 0·03, 0·1, 1·0 or 3·0 mg chlorpyrifos/kg/day. In dogs, ChE activity in plasma was depressed by the 3·0, 1·0 and 0·1 mg/kg/day doses, and receiving 3·0 or 1·0 mg/kg/day. ChE activity of the brain of rats was depressed by a dose of 3·0 mg/kg/day. In dogs, ChE activity in plasma was depressed by the 3·0, 1·0 and 0·1 mg/kg/day doses, and that in red cells by the 3·0 and 1·0 mg/kg/day doses. Brain ChE was slightly depressed in dogs receiving the highest dose. In the long-term study, no clinical evidence of induction of cholinergic activity was observed in either species at any time. Depression of ChE activity was readily reversible when the control diets were substituted for diets containing chlorpyrifos. No significant effects related to treatment were observed in rats or dogs receiving any dose of chlorpyrifos, using the following criteria:mortality, body weights, food intake, haematological studies, urine analyses, clinical chemistry studies, organ weights and organ to body weight ratios, tumour incidence and gross and histopathological examination of tissues. It was concluded that 0·1 and 0·03 mg chlorpyrifos/kg/day fed in the diet for 2 yr produced no significant toxicological effect in rats and dogs, respectively. Even in animals receiving 3·0 mg/kg/day, no effects were observed other than a reversible depression of cholinesterase activity.

Embryo- and fetotoxicity of inhaled carbon tetrachloride, 1,1-dichloroethane and methyl ethyl ketone in rats

Abstract These studies evaluated the effects of subanesthetic concentrations of carbon tetrachloride, 1,1-dichloroethane and methyl ethyl ketone on rat embryonal and fetal development. Groups of pregnant Sprague-Dawley rats were exposed to each solvent 7 hr/day on days 6 through 15 of gestation. All 3 solvents caused some degree of retarded fetal development, such as delayed ossification of sternebrae. In addition to this degree of embryotoxicity, exposure to methyl ethyl ketone, but not to carbon tetrachloride or 1,1-dichloroethane, also caused a low incidence of acaudia, imperforate anus and brachygnathia. These studies do not reveal a correlation between the toxicity incurred by the mother exposed to these solvents and that incurred by the embryos or fetuses.

The effect of purified and commercial grade pentachlorophenol on rat embryonal and fetal development

Abstract This study evaluated the effects of purified and commercial grade pentachlorophenol on rat embryonal and fetal development. Dose levels up to and including a maximum tolerated dose were administered po to pregnant Sprague-Dawley rats on days 6 through 15, 8 through 11 and 12 through 15 of gestation. Following the administration of pentachlorophenol, signs of embryotoxicity and fetotoxicity, such as resorptions, subcutaneous edema, dilated ureters and anomalies of the skull, ribs, vertebrae and sternebrae, were observed at an incidence which increased with increasing the dose. Purified pentachlorophenol, with its low nonphenolic content, was slightly more toxic than the commercial grade of pentachlorophenol containing a much higher level of nonphenolics. The developing rat embryo is most susceptible to the toxic effects of a given dose of pentachlorophenol during the period of early organogenesis. The no-effect dose level was 5 mg of the commercial grade of pentachlorophenol/kg/day.

Teratogenicity of acrylonitrile given to rats by gavage or by inhalation

Abstract The teratogenic potential of ingested or inhaled acrylonitrile (AN), a monomer used in the production of various plastics and fibres, was evaluated in Sprague-Dawley rats. Pregnant rats were given 0, 10, 25 or 65 mg AN/kg/day by gavage from day 6 to 15 of gestation. Additional rats were exposed for 6 hr/day to 0, 40 or 80 ppm AN by inhalation from day 6 to 15 of gestation. Oral administration of 65 mg AN/kg/day, a maternally toxic level, resulted in significant embryotoxicity, including an increased incidence of foetal malformations (short tail, short trunk, missing vertebrae and right-sided aortic arch). Findings suggestive of a teratogenic effect were noted at 25 mg AN/kg/day by gavage and at 80 ppm AN by inhalation. No evidence of embryotoxicity or teratogenicity was discerned in rats given 10 mg AN/kg/day orally or in those inhaling 40 ppm AN.

The fate of 2,4,5-trichlorophenoxyacetic acid (2,4,5-T) following oral administration to man

Abstract Five human male volunteers ingested a single dose of 5 mg/kg without incurring detectable clinical effects. Concentrations of 2,4,5-T in plasma and its excretion were measured at intervals after ingestion. The clearances of 2,4,5-T from the plasma as well as its excretion from the body occurred via apparent first-order rate processes with half-lives of 23.10 and 23.06 hr, respectively. Essentially all of the 2,4,5-T was absorbed into the body and excreted unchanged in the urine. In the body, 65% of the 2,4,5-T resided in the plasma where 98.7% was bound reversibly to protein. The volume of distribution was 0.079 liters/kg. Utilizing the kinetic constants from the single dose experiment, the expected concentrations of 2,4,5-T in the plasma of individuals receiving repeated daily doses of 2,4,5-T were calculated. From these calculations, it was determined that the plasma concentrations would essentially reach a plateau after 3 days. If the daily dose ingested in mg/kg is A 0 , the concentration in the plasma after attaining plateau would range from 12.7 A 0 to 22.5 A 0 μg/ml. This range would converge to approximately 17 A 0 μg/ml as the daily dose A 0 is distributed throughout the day.

In vitro analysis of transport of 2,4,5-trichlorophenoxyacetic acid by rat and dog kidney

Renal transport of 2,4,5-trichlorophenoxyacetic acid (2,4,5-T) was studied quantitatively in vitro using renal cortical slices from dogs and rats, in an attempt to explain species differences in the biological half-life of the compound. Addition of 2,4,5-T to slices of rat renal cortex competitively inhibited active transport of p-aminohippuric acid without altering transport of the organic cation, N-methylnicotinamide. Renal cortical slices from rats and dogs actively accumulated 2,4,5-T. Accumulation was oxygen dependent and saturable, and was reduced in the presence of other anions (p-aminohippurate and probenecid). A reduction in the potassium concentration of the medium reduced accumulation of 2,4,5-T by rat tissue but not by dog tissue. Acetate in the medium increased accumulation of the herbicide in dog but not in rat tissue. Finally, the ability of renal tissue from newborn rats to accumulate 2,4,5-T was significantly less than that of adult tissue. It is concluded that the primary route of renal elimination of 2,4,5-T is active secretion of the compound. The greater ability of adult rat tissue to transport PAH explains the shorter biological half-life of 2,4,5-T in this species.

The effect of 2,4-dichlorophenoxyacetic acid (2,4-D) and esters of 2,4-D on rat embryonal, foetal and neonatal growth and development.

Abstract This study evaluated the effects of 2.4-D, of the propylene glycol butyl ether ester of 2.4-D (PGBE) and of the isooctyl ester of 2.4-D (IO) on foetal development and neonatal growth and survival. Dose levels of 2.4-D up to a maximum tolerated dose of 87·.5 mg/kg4day or molar equivalents of PGBE or IO were administered to pregnant Sprague-Dawley rats on days 6–15 of gestation. Foetuses were delivered by Caesarean section on day 20 of gestation and were examined grossly, measured and weighed. Following routine preparations, the soft tissues and skeletons were examined. Signs of embryotoxicity and foetotoxicity, such as decreased foetal body weight, subcutaneous oedema, delayed ossification of bone, lumbar ribs and wavy ribs were observed at high dose levels; considered overall, the responses were dose-related. Teratogenic effects, however, were not seen at any dose level. 2.4-D did not affect fertility, gestation, viability or lactation. PGBE and IO had no effect on fertility and gestation indices, but the highest dose levels decreased viability and lactation indices. Neonatal growth and development were not altered by treatment during pregnancy.