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Biomedical subjects

J D George

Publications and source records attributed to J D George.

At least 37 records · Page 2Linked to original sources
PubMed1994

Assessment of the reproductive and developmental toxicity of pesticide/fertilizer mixtures based on confirmed pesticide contamination in California and Iowa groundwater.

Pesticides and fertilizers, as used in modern agriculture, contribute to the overall low-level contamination of groundwater sources. In order to determine the potential of pesticide and fertilizer mixtures to produce reproductive or developmental toxicity at concentrations up to 100 x the median level found in groundwater, we prepared and studied two mixtures of pesticides and a fertilizer (ammonium nitrate). One mixture containing aldicarb, atrazine, dibromochloropropane, 1,2-dichloropropane, ethylene dibromide, and simazine plus ammonium nitrate was considered to be a representative of groundwater contamination in California (CAL). The other, containing alachlor, atrazine, cyanazine, metolachlor, metribuzin, and ammonium nitrate, simulated groundwater contamination in Iowa (IOWA). Each mixture was administered in the drinking water of either Swiss CD-1 mice during a Reproductive Assessment by Continuous Breeding study or pregnant Sprague-Dawley rats (gd 6-20) at three dose levels (1x, 10x, and 100x) where 1x was the median concentration of each pesticide component as determined in the groundwater surveys in California or Iowa. Unlike conventional toxicology studies, the purpose of this study was to evaluate the health effects of realistic human concentrations. Thus, the testing concentrations are probably well below the maximally tolerated dose. Propylene glycol was used as the solubilizer for the pesticides in drinking water formulations in both studies. In the reproductive study, neither mixture caused any clinical signs of toxicity, changes in food or water consumption, or body weight in either F0 or F1 mice at doses up to 100x the median groundwater concentrations. There were no treatment-related effects on fertility or any measures of reproductive performance of either the F0 or the F1 generation mice exposed to either CAL or IOWA at up to 100x. Similarly, measures of spermatogenesis, epididymal sperm concentration, percentage motile sperm, percentage abnormal sperm, and testicular and epididymal histology were normal. In the developmental study, CAL- or IOWA-exposed females did not exhibit any significant treatment-related clinical signs of toxicity. No adverse effects of CAL or IOWA were observed for measures of embryo/fetal toxicity, including resorptions per litter, live litter size, or fetal body weight. CAL or IOWA did not cause an increased incidence of fetal malformations or variations. In summary, administration of these pesticide/fertilizer mixtures at levels up to 100-fold greater than the median concentrations in groundwater supplies in California or Iowa did not cause any detectable reproductive (mice), general, or developmental toxicity (rats).

Animals↗
PubMed1993

Developmental toxicity evaluation of diethyl and dimethyl phthalate in rats.

Diethyl phthalate (DEP) and dimethyl phthalate (DMP), phthalic acid ester (PAE) plasticizers, were evaluated for developmental toxicity because of reports in the literature that some PAE were embryotoxic and teratogenic. A previous study (Singh et al., '72) suggested that an increased incidence of skeletal defects in rats might result from gestational exposure to DEP (0.6-1.9 g/kg) or DMP (0.4-1.3 g/kg), ip, on gestational days (gd) 5, 10, and 15. In the current study DEP (0, 0.25, 2.5, and 5%) or DMP (0, 0.25, 1, and 5%) in feed (approximately 0.2-4.0 g/kg/day) were supplied to timed-mated rats from gd 6 to 15. Treatment with 5% DMP resulted in increased relative maternal liver weight. Also, animals exhibited reduced body weight gain during treatment (5% DEP or DMP) and during gestation (5% DEP). Weight gain corrected for gravid uterine weight was also reduced in animals fed 5% DEP. However, high-dose treatment with either DEP or DMP resulted in changes in food and water consumption paralleling the body weight reductions, suggesting that apparent toxic effects on maternal body weight may reflect PAE/feed unpalatability. Treatment with 2.5% DEP resulted in only transient changes in body weight during early treatment. The only maternal effects at 0.25 or 1% DMP were minor changes in food and/or water consumption, and there were no effects at 0.25% DEP. Thus, the NOAELs for maternal toxicity were 1% DMP and 0.25% DEP. In contrast to the observed maternal toxicity, there was no effect of DEP or DMP treatment on any parameter of embryo/fetal development, except an increased incidence of supernumerary ribs (a variation) in the 5% DEP group. These results do not support the conclusion of other investigators that DEP and DMP are potent developmental toxicants. Rather, they suggest that the short-chain PAE are less developmentally toxic than PAE with more complex substitution groups, e.g., di(2-ethylhexyl) phthalate, mono(2-ethylhexyl) phthalate, and butyl benzyl phthalate.

Abnormalities, Drug-Induced↗
PubMed1993

The effects of feed restriction on reproductive function in Swiss CD-1 mice.

Many test compounds used in toxicity studies produce a "systemic" toxicity manifested as reduced body weight gain. While it is known that reduced weight gain during juvenile growth reduces or delays reproductive competence, the effects of adult-onset feed restriction (FR) and inhibited weight gain on the reproductive system of mice are poorly known. To gain some information on the effects of graded body weight reduction, or reduced body weight gain, on commonly used reproductive endpoints, the studies reported below were conducted at two laboratories, using adult mice that were maintained at 90, 80, and 70% of concurrent control body weight (CBW) for up to 21 weeks. Estrous cyclicity and fertility in the females were significantly affected. While male fertility was variably affected, there was a significant decrease in the number of epididymal sperm and in the number of testicular spermatids in the 70% CBW groups. Testis weight was conserved in both studies; relative testis weight increased in all FR groups. These data can improve the interpretation of future studies by helping to separate chemically induced changes from those produced by reduced body weight gain.

Animals↗
PubMed1993

VO2max estimation from a submaximal 1-mile track jog for fit college-age individuals.

The primary purpose of this study was to develop a submaximal field test for the estimation of maximal oxygen uptake (VO2max) using a 1-mile track jog. A second purpose was to determine the accuracy of the 1.5-mile run in estimating VO2max for both male and female subjects. VO2max was measured in 149 relatively fit college students (males = 88, females = 61) 18-29 yr using a treadmill protocol (mean +/- SD; VO2max = 47.7 +/- 6.3 ml.kg-1 x min-1). Multiple regression analysis (N = 54) to estimate VO2max from the submaximal, steady-state 1-mile track jog yielded the following validation (V) model (r(adi) = 0.87, SEE = 3.0 ml.kg-1 x min-1): VO2max = 100.5 + 8.344* GENDER (0 = female; 1 = male) - 0.1636* BODY MASS (kg) - 1.438* JOG TIME (min.mile-1) - 0.1928* HEART RATE (bpm). To help ensure that a submaximal level of exertion was realized for the 1-mile track jog, elapsed jog time was restricted to > or = 8.0 min for males and > or = 9.0 min for females and exercise HR to < or = 180 bpm. Cross-validation (CV) of the 1-mile track jog comparing observed and estimated VO2max (N = 52) resulted in radj = 0.84, SEE = 3.1 ml.kg-1 x min-1. Multiple regression analysis (N = 50) to estimate VO2max from the 1.5-mile run (V:N = 49, radj = 0.90, SEE = 2.8 ml.kg-1 x min-1; CV: N = 47, radj = 0.82, SEE = 3.9 ml.kg-1 x min-1), used elapsed run time, body mass, and gender as independent variables.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1993

Development of a submaximal treadmill jogging test for fit college-aged individuals.

The purpose of this study was to develop a single-stage submaximal treadmill jogging test for the estimation of maximal oxygen uptake (VO2max). VO2max was measured in 129 relatively fit individuals (males = 84, females = 45), 18-29 yr, using a maximal treadmill protocol (mean +/- SD; VO2max = 48.3 +/- 6.2 ml.kg-1 x min-1, range = 35.6 to 62.3 ml.kg-1 x min-1). The treadmill test required subjects to sustain a comfortable, submaximal jogging pace (4.3-7.5 mph; level grade) until a steady-state heart rate was achieved (approximately 3 min). To help ensure that a submaximal level of exertion was realized for the treadmill jogging test, treadmill speed and exercise HR criteria were established that restricted treadmill speed to < or = 7.5 mph for males and < or = 6.5 mph for females and steady-state exercise HR < or = 180 bpm. Multiple regression analysis (N = 66) to estimate VO2max from the treadmill jogging test yielded the following validation (V) model (r(adj) = 0.84, SEE = 3.2 ml.kg-1 x min-1): VO2max = 54.07 + 7.062 * GENDER (0 = female; 1 = male) - 0.1938 * WEIGHT (kg) + 4.47* SPEED (miles.h-1) - 0.1453 * HEART RATE (bpm). Cross-validation (CV) of the treadmill jogging test comparing observed and estimated VO2max (N = 63) resulted in r(adj) = 0.88, SEE = 3.1 ml.kg-1 x min-1. The results indicate that this submaximal single-stage treadmill jogging test based on multiple linear regression provides a valid and convenient method for estimating VO2max.

Adolescent↗
PubMed1992

The developmental toxicity of ethylene glycol diethyl ether in mice and rabbits.

Timed-pregnant CD-1 outbred Albino Swiss mice and New Zealand White rabbits were dosed by gavage with ethylene glycol diethyl ether (EGdiEE) in distilled water during major organogenesis. Mice were dosed on Gestational Days (gd) 6 through 15 (0, 50, 150, 500, or 1000 mg/kg/day) and rabbits on gd 6 through 19 (0, 25, 50, or 100 mg/kg/day). Maternal clinical status was monitored daily during treatment. At termination (gd 17, mice; gd 30, rabbits), confirmed-pregnant females (22-24 per group, mice; 26-32 per group, rabbits) were evaluated for clinical status and gestational outcome; each live fetus was examined for external, visceral, and skeletal malformations. In mice, no maternal mortality was observed, but maternal body weight gain during gestation and treatment, and at termination was reduced at 1000 mg/kg/day. The reduction of maternal body weight gain during gestation was secondary to embryo/fetal toxicity, i.e., reduced gravid uterine weight as a consequence of decreased litter size and fetal weight. The no-observed adverse effect level (NOAEL) for developmental toxicity was 50 mg/kg/day. At greater than or equal to 150 mg/kg/day the number of litters of mice with malformed fetuses was increased. At greater than or equal to 500 mg/kg/day fetal body weight was reduced, and malformation incidence was significantly increased. Exencephaly and fused ribs were observed most often. In rabbits, maternal body weight was unaffected by treatment even though 6% maternal mortality was observed at 100 mg/kg/day. The developmental NOAEL was 25 mg/kg/day. Malformations were increased at greater than or equal to 50 mg/kg/day; short tail, small spleen, fused sternebrae, and fused rib cartilage were observed most often. In summary, oral administration of EGdiEE to mice and rabbits during organogenesis produced profound adverse developmental effects even in the absence of significant maternal toxicity. Developmental effects in rabbits were more varied.

Abnormalities, Drug-Induced↗
PubMed1992

Reproductive toxicity of triethylene glycol and its diacetate and dimethyl ether derivatives in a continuous breeding protocol in Swiss CD-1 mice.

Triethylene glycol and two of its derivatives were evaluated for reproductive toxicity in a continuous breeding protocol with Swiss CD-1 mice. Triethylene glycol (TEG: 0, 0.3, 1.5, and 3%), triethylene glycol diacetate (TGD: 0, 0.75, 1.5, and 3%), and triethylene glycol dimethyl ether (TGDME: 0, 0.25, 0.5, and 1%) were administered in drinking water to breeding pairs (20 pairs per treatment group, 40 control pairs) during a 98-day cohabitation period. Reproductive function was assessed by the number of litters per pair, live pups per litter, proportion of pups born alive, and pup weight. There were no apparent effects on reproductive function in the animals receiving TEG or TGD at doses up to 3% in the drinking water (representing 6.78 or 5.45 g/kg, respectively). However, some developmental toxicity was demonstrated for both TEG and TGD. Continuous exposure of dams to 1.5 or 3% TEG significantly reduced live pup weight at birth compared to control and 0.3% TEG, while exposure to 3% TGD during lactation significantly (but reversibly) reduced pup body weights on Postnatal Days 14 and 21. In contrast, TGDME was toxic to the reproductive system as evidenced by decreases at the highest dose (1% TGDME; 1.47 g/kg) in the proportion of pairs that produced at least one litter, live pups per litter, and proportion of pups born alive, with dose-related trends seen in the latter two parameters. A crossover mating trial showed that TGDME was more toxic to the female than the male reproductive system. These data indicate that TGDME (1.47 g/kg) is a reproductive toxicant in Swiss mice while reproductive toxicity was not demonstrated in mice receiving TEG or TGD (at doses up to 6.78 or 5.45 g/kg, respectively).

Animals↗
PubMed1992

The developmental toxicity of diethylene and triethylene glycol dimethyl ethers in rabbits.

Diethylene glycol dimethyl ether (diEGdiME) and triethylene glycol dimethyl ether (triEGdiME), widely used organic solvents, are structurally related to several compounds that produce reproductive and developmental toxicity, including teratogenicity in laboratory animals. In the present studies, diEGdiME (0, 25, 50, 100, or 175 mg/kg/day) or triEGdiME (0, 75, 125, 175, or 250 mg/kg/day) were administered by gavage in distilled water to timed-pregnant New Zealand white rabbits (15-25 dams/group) during major organogenesis [Gestational Days (gd) 6-19]. Treated females were euthanized on gd 30, uterine contents were examined, and live fetuses were examined for morphological alterations. In the diEGdiMe study, evidence of maternal toxicity, per se, was observed only at 175 mg/kg/day with 15% mortality among treated females compared to 4% among controls. No significant maternal toxicity was observed in the 25 mg/kg/day group, and only minimal maternal toxicity (decreased maternal weight gain during treatment) was observed at 50 and 100 mg/kg/day compared to the vehicle control group. The no-observed-adverse-effect level for developmental toxicity in rabbits for diEGdiME was 50 mg/kg/day. The incidences of prenatal mortality and malformed live fetuses were significantly above controls at 100 and 175 mg/kg/day. Malformations observed most frequently included fusion of ribs to each other and hydronephrosis; clubbing of the limbs without underlying bone deformities, a variation, was also observed. In the triEGdiME study, clinical signs of toxicity were minimal and there was no increased maternal mortality. Maternal body weight and gravid uterine weight were significantly reduced at 250 mg/kg/day, whereas maternal weight gain during treatment was significantly depressed at doses of 175 mg/kg/day and above.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Codeine: developmental toxicity in hamsters and mice.

Timed-pregnant LVG Syrian hamsters and Swiss CD-1 mice were dosed orally twice daily (b.i.d.) with codeine in water on Gestational Days (gd) 5-13 (0, 10, 50, or 150 mg/kg, b.i.d.--hamsters) or 6-15 (0, 37.5, 75, 150, or 300 mg/kg, b.i.d.--mice). Dams were necropsied on gd 14 (hamsters) or 17 (mice), and fetuses were weighed, sexed, and examined for external, visceral, and skeletal malformations. No maternal deaths were observed in hamsters, while 19% of the pregnant mice in the high-dose group died. Maternal weight gain (gestational and treatment periods) and gravid uterine weights were significantly depressed in hamsters (150 mg/kg, b.i.d.) and in mice (300 mg/kg, b.i.d.). However, the corrected weight gain for both species, although decreased, was not significantly different from that of the controls. In both species, maternal liver weights (relative) were significantly increased in the high-dose groups. There were increases in the percentage resorptions per pregnant dam and in the proportion of litters with 100% resorptions in the high-dose groups of both species. Considering only live litters, the number of live fetuses per litter and the sex ratio were unaffected in both species. Mean fetal body weights were also significantly decreased in the 50 and 150 mg/kg, b.i.d. (hamsters), and the 150 and 300 mg/kg, b.i.d. (mice), groups. The no-observed-adverse-effect levels (NOAELs) for developmental toxicity were 10 (hamsters) and 75 (mice) mg/kg, b.i.d., whereas the NOAELs for maternal toxicity were 50 (hamsters) and 150 (mice) mg/kg, b.i.d. The predominant structural malformation in hamsters was meningoencephalocele (high-dose group only), affecting 3% of fetuses and 19% of litters (neither statistically significant). Codeine did not induce any increase in structural malformations in mice. Thus, codeine produced developmental toxicity (as indicated by decreased fetal body weight) at doses below those producing maternal toxicity in both hamsters and mice. In the hamster, the more sensitive species to codeine developmental toxicity, effects were observed at a total daily dose of 100 mg/kg, which is only 11 times the maximum human therapeutic oral dose.

Abnormalities, Drug-Induced↗
PubMed1991

Reproductive toxicity of boric acid in Swiss (CD-1) mice: assessment using the continuous breeding protocol.

The potential reproductive toxicity of boric acid (BORA) in CD-1 mice (Swiss) was evaluated using the Reproductive Assessment by Continuous Breeding (RACB) Protocol. BORA was administered in the feed for 27 weeks to male and female Swiss (CD-1) mice at concentrations of 0, 1000, 4500, or 9000 ppm. Estimated doses, based on feed consumption and body weight, averaged 152, 636, and 1262 mg/kg body wt during Week 1 for males for 1000, 4500, and 9000 ppm, respectively. During 14 weeks of cohabitation, fertility of F0 mice was partially reduced at 4500 ppm and totally eliminated at 9000 ppm. No litters, dead or alive, were produced by 9000 ppm cohabited pairs. Among the litters born at 4500 ppm, live litter size and body weight were significantly reduced. A crossover mating trial of control and 4500 ppm groups confirmed the male as the affected sex, with fertility rates and the mating index significantly lower in the 4500 male x 0 ppm female group. At necropsy, after 27 weeks of BORA exposure, dose-related changes were present in F0 males for reduced body and reproductive organ weights, increased incidence of abnormal sperm, decreased sperm concentration and motility, and seminiferous tubule degeneration. In the 4500 ppm females, dietary BORA for 27 weeks caused significantly decreased weights of kidney/adrenals and livers; kidney/adrenal weight was also reduced in 4500 ppm males. The last litters of the control and 1000 ppm females, born in the 14-week breeding phase, were reared to 74 days of age and then mated in nonsibling pairs within treatment groups. These F1 mice had normal fertility, but the adjusted mean body weight of F2 pups was decreased. These data establish the reproductive toxicity of BORA in CD-1 mice and demonstrate that the male is the most sensitive sex.

Animals↗
PubMed1990

Reproductive effects of diethylene glycol and diethylene glycol monoethyl ether in Swiss CD-1 mice assessed by a continuous breeding protocol.

Diethylene glycol (DEG) and diethylene glycol monoethyl ether (DEGEE) were evaluated for reproductive toxicity in CD-1 mice using a continuous breeding protocol. Compounds were administered in the drinking water at 0, 0.35, 1.75, and 3.5% w/v (DEG) or 0, 0.25 1.25, and 2.5% w/v (DEGEE). Exposure of the breeding pairs to 3.5% DEG for 14 weeks produced statistically significant decreases in the number of litters per pair, live pups per litter, proportion of pups born alive, and live pup weight. There was also a significant increase in the cumulative days to litter and a significant decrease in the number of pairs producing the third, fourth, and fifth litters for the 3.5% DEG-exposed mice. A crossover mating trial of the F0 mice to determine the affected sex was inconclusive, but suggested that offspring development was compromised in females exposed to 3.5% DEG. Slight maternal (F0) toxicity was noted for the 3.5 DEG group (7% decrease in body weight). The F1 generation, at 3.5% DEG, had decreased body weights at birth and exhibited poor postnatal survival. At the intermediate dose of DEG, body weights of both sexes were depressed at weaning, at onset of mating, and at necropsy. However, no adverse effects on reproduction were observed. DEGEE had no effect on reproduction in the F0 or F1 generation mice despite a 34% decrease in cauda epididymal sperm motility in the F1 males at 2.5% DEGEE. Other signs of toxicity observed in these F1 mice included increased relative liver weights. These data indicate that DEG is a reproductive toxicant in Swiss mice affecting fertility and reproductive performance, albeit at high doses (equivalent to 6.1 g/kg/day). However, its monoethyl derivative, DEGEE, is without adverse effects on fertility and reproductive performance.

Animals↗
PubMed1990

The developmental toxicity of orally administered theophylline in rats and mice.

Theophylline (THEO), a widely prescribed anti-asthmatic, was evaluated for developmental toxicity. It was administered continuously on Gestational Days 6 through 15 to pregnant Sprague-Dawley (CD) rats in the feed (0, 0.15, 0.30, or 0.40%) and to pregnant Swiss (CD-1) mice in the drinking water (0, 0.075, 0.15, or 0.20%). Estimated intake of THEO for rats was 0, 124, 218, or 259 mg/kg/day, while for mice it was 0, 282, 372, or 396 mg/kg/day. In rats, maternal weight gain parameters (weight gain during gestation and treatment, as well as corrected weight gain) decreased at 0.40%. While food consumption was lower only in the 0.40% treatment group, water consumption was higher in all treated groups. There was a dose-related decreasing trend in gravid uterine weight. The number of live fetuses per litter decreased at 0.40% and the average male and female fetal weight per litter decreased at 0.30 and 0.40%. There was no increase in malformations. In mice, maternal corrected body weight and weight gain during gestation decreased at 0.15 and 0.20%, and weight gain during treatment and gravid uterine weight decreased at 0.20%. Water consumption was reduced by as much as 30-45% of controls at 0.15 and 0.20%, respectively, while food consumption did not change with THEO treatment. There was an increase in percentage resorptions per litter and a decrease in the average male and female fetal weight per litter at 0.15 and 0.20%. An increasing trend was noted for percentage malformed fetuses per litter, and percentage litters with externally malformed fetuses were slightly increased in the mid- and high-dose groups. However, these increases were not statistically significant. In summary, there were developmental effects seen in rats at a dose (0.30%) that did not produce overt maternal toxicity, but the adverse developmental effects in mice were observed at doses that caused reduced maternal water consumption and body weight gain. It is possible that water deprivation contributed to the effects seen in mice after THEO treatment. For maternal toxicity, no observable adverse effect levels (NOAELs) were 218 mg/kg for rats and 282 mg/kg for mice. NOAELs for developmental toxicity were 124 mg/kg for rats and 282 mg/kg for mice. These NOAELs are approximately 10- to 30-fold greater than doses required to maintain humans on serum THEO concentrations that are clinically useful.

Abnormalities, Drug-Induced↗
PubMed1989

Developmental toxicity of 1,1,1-trichloroethane in CD rats.

1,1,1-Trichloroethane (TCEN), a major industrial and household solvent, was evaluated for pre- and postnatal developmental effects in Sprague-Dawley rats. This study was designed to assess the repeatability of a report (S.C. Dapson, D.E. Hutcheon, and D. Lehr, Teratology 29, 25A, 1984) that indicated that 10 ppm TCEN in drinking water caused cardiac malformations in developing rats. In the present study, TCEN (97% pure) was administered in the drinking water at target concentrations of 3, 10, and 30 ppm, using 0.05% Tween 80 as an emulsifying agent. Two control groups, one receiving deionized/filtered water and the other receiving a vehicle control solution containing 0.05% Tween 80 and 0.9 ppm 1,4-dioxane, a stabilizing agent found in the bulk chemical, were also included. Male and female breeders (more than 30 per group) were exposed to the control solutions or test compound for 14 consecutive days prior to cohabitation and for up to 13 days during the cohabitation phase. Sperm-positive females (24-29 per group) continued to be exposed to these formulations during pregnancy and lactation to Postnatal Day (PND) 21. Parental animals exhibited a slight aversion to the 30-ppm drinking water during the premating exposure. No significant effect on reproductive competence of the parental animals or postnatal growth and development of the offspring to PND 21 was noted. A slight increase in mortality from implantation to PND 1, possibly due to high mortality in one litter, was observed in the 30-ppm dose group. There was no indication of an increase in the incidence of cardiac or other malformations in PND 21 pups. In summary, TCEN administered at 3, 10, and 30 ppm in the drinking water had no significant effect on the morphological development of CD rats.

Animals↗
PubMed1988

Reproductive toxicity of tricresyl phosphate in a continuous breeding protocol in Swiss (CD-1) mice.

The effects of a mixture of tricresyl phosphate isomers on reproductive performance in Swiss (CD-1) mice were evaluated using a continuous breeding protocol. Tricresyl phosphate (TCP) was mixed into the feed at 0, 0.05, 0.1, and 0.2% by weight. Although the fertility index was not changed in the animals consuming the high-concentration feed, the number of litters per pair decreased in a dose-related fashion, and the proportion of pups born alive, and their weight, was significantly decreased in the high-dose group. A crossover mating trial found impaired fertility in both males and females exposed to 0.2% TCP, with a greater effect in females. Histopathology of the F0 pairs revealed dose-related seminiferous tubule atrophy, and decreased testis and epididymal weights in the high-dose males, while the female reproductive tract showed no histopathologic changes. There were dose-related changes in the adrenals of both sexes, and body weight was depressed in both sexes at the highest concentration. The last litter born in the 98-day breeding phase was reared to age 74 days and then mated within the control and two of the treatment groups (0.0, 0.05, and 0.1% TCP; there were too few offspring in the 0.2% group). There was a decrease in the fertility index in the 0.1% TCP group, and a decreased proportion of liveborn and number of liveborn pups per litter. In the F1 males at necropsy, sperm concentration and morphology were normal at termination, although motility was decreased in both the 0.05% and the 0.1% groups compared to controls. These data show that TCP impaired fertility in both sexes of mice in the F0 generation and affected sperm motility at even the lowest dose in F1 males.

Adrenal Glands↗
PubMed1987

The developmental toxicity of diethylene glycol dimethyl ether in mice.

Diethylene glycol dimethyl ether (diEGdiME) is structurally related to several compounds which produce reproductive and developmental toxicity, including teratogenicity in laboratory animals. In the present study, diEGdiME (0, 62.5, 125, 250, or 500 mg/kg/day) was administered by gavage in distilled water to timed-pregnant CD-1 mice during major organogenesis [gestational days (gd) 6-15]. Clinical status of treated females was monitored daily during treatment and on gd 17. At sacrifice (gd 17), pregnancy was confirmed by uterine examination for 20-24 dams per group; each live fetus was examined for external, visceral, and skeletal malformations. No maternal deaths, morbidity, or treatment-related clinical signs were observed. Reduced maternal weight gain during treatment at greater than or equal to 250 mg/kg/day was primarily attributed to compromised pregnancy status resulting in reduced gravid uterine weight. Maternal weight gain during gestation corrected for gravid uterine weight, and relative liver weight (% body weight) were not affected. Average fetal body weight/litter was significantly reduced at greater than or equal to 125 mg/kg/day. The percentage of postimplantation loss/litter (5, 8, 7, 12, and 50% for control through high dose) and the percentage of malformed live fetuses/litter (0.4, 0, 2, 24, and 96%) were significantly increased at greater than or equal to 250 mg/kg/day. Developmental defects involved primarily the neural tube, limbs and digits, craniofacial structures, abdominal wall, cardiovascular system, urogenital organs, and both the axial and appendicular skeleton. In summary, oral administration of diEGdiME during major organogenesis did not produce any distinctive signs of maternal toxicity, but did produce selective and profound adverse effects upon fetal growth, viability, and morphological development at greater than or equal to 125 mg/kg/day.

Abnormalities, Drug-Induced↗
PubMed1987

The developmental toxicity of bisphenol A in rats and mice.

Bisphenol A (BPA) was evaluated for developmental toxicity in CD rats (0, 160, 320, or 640 mg/kg/day) and CD-1 mice (0, 500, 750, 1000, or 1250 mg/kg/day) dosed daily by gastric intubation on Gestational Days 6 through 15. Timed-pregnant dams were sacrificed 1 day prior to parturition, the uterine contents were examined, and all fetuses were examined for external, visceral, and skeletal malformations. In rats, maternal weight gain during gestation, weight gain corrected for gravid uterine weight, and weight gain during treatment were significantly reduced at all BPA doses. Gravid uterine weight and average fetal body weight per litter were not affected by BPA. No increase in percentage resorptions per litter or percentage fetuses malformed per litter was detected. In mice, maternal mortality occurred at all BPA doses, reaching 18% at the high dose, which also produced a significant decrease in maternal body weight gain during gestation and treatment. Weight gain corrected for gravid uterine weight was not affected by BPA. Reductions in gravid uterine weight and average fetal body weight were observed with the 1250 mg/kg dose of BPA. Relative maternal liver weight was increased at all doses of BPA. There was a significant increase in the percentage of resorptions per litter with 1250 mg BPA/kg/day. Malformation incidence was not altered by BPA. Thus, BPA treatment at maternally toxic dose levels during organogenesis produced fetal toxicity in mice but not in rats and did not alter fetal morphologic development in either species.

Animals↗