B.A. Schwetz

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.

Teratogenicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin in CF-1 mice☆

Abstract The effect of TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin) on the developing embryo and fetus of CF-1 mice has been evaluated. Pregnant CF-1 mice were given TCDD by oral gavage on Days 6 through 15 of gestation at dosages of 0, 0.001, 0.01, 0.1, 1, and 3 μg/kg/day. Little or no maternal toxicity was observed at any dosage. Cleft palate and dilated renal pelvis were found at 3.0 μg/kg/day. Cleft palate was found at 1.0 μg/kg/day. No malformations were found at the intermediate dosages of 0.1 or 0.01 μg/kg/day. Teratogenic effects observed, i.e., cleft palate and dilated renal pelvis, were comparable to those seen in studies utilizing other strains of mice. The incidence of malformations was not statistically significant at the 0.1-μg/kg/day dosage and below. The experimental nonteratogenic dosage for TCDD in the developing embryo and fetus of CF-1 mice was estimated to be 0.1 μg/kg/day.

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.

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.

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.

Toxicity of inhaled chloroform in pregnant mice and their offspring

Abstract The effect of inhaled chloroform on embryonal and fetal development was evaluated in CF-1 mice. Bred mice were exposed to 0 or 100 ppm of chloroform for 7 hr/day from Days 1 through 7, 6 through 15, or 8 through 15 of gestation. Exposure to chloroform from Days 1 through 7 or 6 through 15 significantly impaired the ability of the female rats to maintain pregnancy but was not significantly teratogenic. In comparison, a significant increase in the incidence of cleft palate was observed among the offspring of mice inhaling chloroform from Days 8 through 15 of gestation, but no effect on the ability of the female rats to maintain pregnancy was discerned. Other signs of toxicity observed among the litters of mice exposed to chloroform included: decreased ossification of bones (all experimental groups), decreased incidence of resorptions (Days 1 through 7), and reduced fetal body measurements (Days 1 through 7 and 8 through 15).

The effects of maternally inhaled vinyl chloride on embryonal and fetal development in mice, rats, and rabbits.

Abstract These studies evaluated the effects of inhaled vinyl chloride on mouse, rat, and rabbit embryonal and fetal development. Groups of pregnant CF-1 mice, Sprague-Dawley rats and New Zealand white rabbits were exposed to 500 ppm of vinyl chloride 7 hr daily during the period of major organogenesis. Subsequently, other groups of mice were similarly exposed to 50 ppm of vinyl chloride and rats and rabbits were exposed to 2500 ppm of vinyl chloride. While maternal toxicity was observed, vinyl chloride alone did not cause significant embryonal or fetal toxicity and was not teratogenic in any of the species at the concentrations tested. Maternal toxicity was more prominent among mice than among rats and rabbits. Simultaneous exposure of some of the pregnant animals to vinyl chloride by inhalation plus 15% ethanol in the drinking water resulted in toxic effects greater than those associated with exposure to vinyl chloride alone in the three species. The maternal toxicity was enhanced to an extent greater than the embryotoxicity.

Cleft palates in CF-1 mice after deprivation of water during pregnancy.

Abstract Pregnant CF-1 mice were deprived of water for 48-hr intervals between Days 11 and 15 of gestation. Water deprivation on Days 12 and 13, or on Days 13 and 14 of gestation resulted in a high incidence of cleft palate in the offspring of CF-1 mice. Water deprivation caused a significant decrease in food consumption, which by itself was adequate to cause an increase in the incidence of cleft palate comparable to that observed in mice deprived of water. Therefore, the teratogenic effect resulting from deprivation of water is perhaps medicated through a decrease in the food consumption in CF-1 mice. These results also demonstrate the importance of being attentive to the housing conditions of mice as well as the importance of measuring food and water consumption of mice in teratological studies.

Results of a reproduction study in rats fed diets containing hexachlorobutadiene

Abstract Hexachlorobutadiene (HCBD) is a by-product of certain processes associated with the chlorination of hydrocarbons. Very small amounts of HCBD may also be produced in chlorine cells. This study evaluated the effects of HCBD on reproduction in rats. Groups of male and female adult rats were fed diets containing HCBD at dose levels of 0, 0.2, 2.0, or 20 mg/kg/day for 90 days prior to mating, 15 days during mating, and subsequently throughout gestation and lactation. Signs of toxicity among the adult rats were observed at the two higher dose levels and included decreased weight gain and food consumption as well as alterations in kidney structure. There was no effect on pregnancy or neonatal survival and development. The body weight of neonates at the time of weaning, 21 days of age, was slightly but significantly less than that of control litters. This effect was found only at the high dose level. No toxic effects were observed among the adults at a dose level of 0.2 mg/kg/day or among the neonates at dose levels of 0.2 or 2.0 mg/kg/day.