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C A Kimmel

Publications and source records attributed to C A Kimmel.

At least 19 recordsLinked to original sources
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

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

Relationship between fetal weight and malformation in developmental toxicity studies.

Exposure to developmental toxicants may cause fetal malformations, increase prenatal death rates and reduce fetal weight at term. However, there has been little formal study of the relationship among these effects. Certainly, no statistical methods are currently available to jointly analyze these effects of exposure. As a preliminary step in developing such methods, simple exploratory analyses were conducted using a series of ten studies conducted for the National Toxicology Program. Because fetal weight and malformation status were both reported for all live fetuses, the data permitted an exploration of the correlation between these two outcomes. The data show a clear pattern wherein malformed fetuses tended to be lighter at term than nonmalformed fetuses. While these patterns cannot be used to draw inferences regarding the biological relationship between fetal weight and malformation, they do suggest the potential value in developing statistical models for the joint effect of exposure on fetal weight and malformations.

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↗
PubMed1990

Proceedings of the Workshop on the Acceptability and Interpretation of Dermal Developmental Toxicity Studies.

The workshop on The Acceptability and Interpretation of Dermal Developmental Toxicity Studies, held April 13-14, 1988, was organized by the U.S. EPA's Office of Research and Development and Office of Toxic Substances and was supported by the Agency's Risk Assessment Forum. The purpose of the workshop was to review the current state of knowledge on the use of the dermal route of exposure in developmental toxicity studies. In evaluating this area, three major issues were considered by the participants: (1) the evaluation of maternal toxicity in dermal developmental toxicity studies, (2) what types of pharmacokinetic data are necessary or desirable for the appropriate design and interpretation of these studies, and (3) what factors are important to consider in the design of dermal developmental toxicity studies. The participants concluded: (1) dermal developmental toxicity studies without any indication of maternal or developmental toxicity are inadequate for risk assessment unless accompanied by absorption data, (2) absorption data and limited pharmacokinetic data should be collected in every dermal developmental toxicity study, and (3) dermal developmental toxicity studies in which skin irritation is too marked should be considered inadequate for risk assessment. General recommendations made for all developmental toxicity studies regardless of the route of exposure were: signs of local irritation should be examined, and absorption/pharmacokinetic data should be developed. Areas in which additional research is needed to permit more complete assessment of dermal developmental toxicity studies were also identified.

Absorption↗
PubMed1990

Qualitative and quantitative comparability of human and animal developmental neurotoxicants: a workshop summary.

A Workshop on the Qualitative and Quantitative Comparability of Human and Animal Developmental Neurotoxicity was held in Williamsburg, Va. on April 11-13, 1989. Based upon data presented at the Workshop, the degree of qualitative and quantitative comparability between data obtained from humans and experimental animals is reviewed for several developmental neurotoxicants (lead, agents of abuse, alcohol, PCBs, phenytoin, methylmercury, and ionizing radiation). Qualitative comparability was considered for the following functional categories: motor development and function, cognitive function, sensory function, motivation/arousal behavior, and social behavior. Quantitative comparability was assessed by comparing administered dose as well as measures of internal dose (e.g., blood levels) for selected agents. Comparability of qualitative changes between humans and rodents was most apparent when comparisons were made on the basis of general categories of behavioral function. These data support the use of animal models in assessing risk for developmental neurotoxicants and provide guidance on the types of functional end points that can be incorporated into a developmental neurotoxicity testing battery. Evidence of quantitative comparability was most apparent when an internal measure of dose (e.g., blood level) was used.

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↗
PubMed1990

Quantitative approaches to human risk assessment for noncancer health effects.

The estimation of risk for health effects due to chemical exposure is important to the development of standards for regulating the manufacture, use and release of chemicals into the environment. The quantitative data used to develop risk estimates usually come from laboratory animal studies employing relatively high dose levels. Thus, both interpolation from high to low dose levels and extrapolation from laboratory animals to humans are required. The approach most widely used for noncancer end points is to determine the no-observed-adverse-effect level (NOAEL) for the critical effect and then apply uncertainty factors (UFs) to account for scientific uncertainties in the total data base, such as response variability within and between species, the lack of chronic exposure data, the lack of a NOAEL, etc. The resulting value is a reference dose (RfD), i.e., the dose at or below which there is unlikely to be any excess risk. One difficulty with the NOAEL/UF approach is that it does not provide a basis for estimating risk at doses above the RfD; thus, if the exposure assessment indicates that human exposure is above the RfD, there is no way to judge the risk of that exposure. Alternative quantitative approaches for risk estimation of noncancer end points have been proposed and include both statistical and biologically-based dose-response modeling. Research is currently underway to further develop and explore the application of such approaches.

Dose-Response Relationship, Drug↗
PubMed1989

Developmental exposure of mice to pulsed ultrasound.

Exposure of pregnant mice on gestation day (gd) 8 to 1 MHz continuous-wave ultrasound (0, 0.05, 0.50, or 1.00 W/cm2) was reported previously to result in a slight (nonsignificant) increase in malformations. The present study was conducted in a similar fashion using pulsed ultrasound but was designed to maximize the likelihood of finding effects of gd 8 ultrasound exposure on prenatal development. Pregnant ICR mice (approximately 60 animals/group) were exposed on gd 8 to pulsed ultrasound with a center frequency of 1 MHz at levels of 0 (sham control), 0.05, 0.50, or 1.00 W/cm2 (spatial average, temporal average intensities; ISATA) with a spatial peak, pulse average intensity (ISPPA) of 90 W/cm2 and pulse duration of 6.5 microseconds. Anesthetized animals were placed in a degassed water bath (30 degrees C) and exposed for two 10 min intervals during which the beam was centered 1 cm on either side of the abdominal midline. On gd 17, dams were killed; the uterus and its contents were weighed and examined; and live fetuses were weighed and examined for external, visceral, and skeletal malformations. Although one female in the 0.50 W/cm2 group and seven animals in the 1.00 W/cm2 group died following exposure, no other significant change from controls was seen in any maternal or fetal parameter evaluated. Thus the results of this study indicate that there was no detectable effect on prenatal development of mice following exposure to ultrasound on gd 8 (a time of maximal sensitivity), even at exposure intensities that were lethal to some maternal animals.

Analysis of Variance↗
PubMed1989

Overview of a workshop on quantitative models for developmental toxicity risk assessment.

A workshop was held to discuss potential advancements to improve the precision of risk estimates for developmental toxicity. This paper presents an overview of the discussions at the workshop, focusing on the risk assessment process and science policy considerations important in the use of quantitative models. Some of the pertinent biological considerations are reviewed, particularly those related to the repair capacity of the developing organism and how this affects the concept of a threshold for developmental toxicity effects, as well as the maternal and litter influences on developmental toxicity outcomes. Finally, the current status of use of quantitative approaches is described, possible short-term approaches are discussed, and future research needs in this area are outlined.

Abnormalities, Drug-Induced↗
PubMed1989

Characterization of a developmental toxicity dose-response model.

The Rai and Van Ryzin dose-response model proposed for teratology experiments has been characterized for its appropriateness and applicability in modeling the dichotomous response data from developmental toxicity studies. Modifications were made in the initial probability statements to reflect more accurately biological events underlying developmental toxicity. Data sets used for the evaluation were obtained from the National Toxicology Program and U.S. EPA laboratories. The studies included developmental evaluations of ethylene glycol, diethylhexyl phthalate, di- and triethylene glycol dimethyl ethers, and nitrofen in rats, mice, or rabbits. Graphic examination and statistical evaluation demonstrate that this model is sensitive to the data when compared to directly measured experimental outcomes. The model was used to interpolate to low-risk dose levels, and comparisons were made between the values obtained and the no-observed-adverse-effect levels (NOAELs) divided by an uncertainty factor. Our investigation suggests that the Rai and Van Ryzin model is sensitive to the developmental toxicity end points, prenatal deaths, and malformations, and appears to model closely their relationship to dose.

Abnormalities, Drug-Induced↗
PubMed1989

Prenatal reserpine exposure alters cardiovascular parameters in rat offspring.

Electrocardiograms (ECGs) and blood pressures (BPs) were recorded and evaluated in postnatal rats that had been exposed in utero to 0.375 or 0.75 mg reserpine/kg/day sc on Gestational Days (GD) 12-15. These doses caused reduced maternal weight gain during pregnancy and decreased pup body weight at birth, as well as reduced heart weight during the preweaning period. There were no changes in other maternal parameters or in litter size. During the postweaning period, pup body weight was reduced only at the highest dose at Postnatal Days (PND) 30 and 60. By PND 342, the weight reduction was no longer significant when compared to controls. Lead II ECGs were recorded in conscious animals on PND 30, 60, and 342; BPs were recorded in anesthetized animals on PND 346. Several ECG parameters were attenuated by prenatal reserpine exposure: R wave and S wave amplitudes and the QRS interval in males, and the PR interval in females. The BP recordings showed that low-dose males had significantly higher pulse pressures than did high-dose males, but neither group was significantly different from controls. Following an intraarterial norepinephrine challenge, resultant peak pulse pressure was greater in high-dose females than in controls. These results indicate that subtle, long-term, sex-specific alterations in cardiovascular parameters were produced by prenatal reserpine treatment at doses that altered body weight in young animals at PNDs 30 and 60, but this change was no longer apparent at PND 342.

Animals↗
PubMed1988

Developmental toxicity evaluation of Bendectin in CD rats.

Bendectin, composed of doxylamine succinate and pyridoxine HCl (1:1), is an antinauseant previously prescribed for nausea and vomiting during pregnancy. The present study examined the maternal and developmental effects of Bendectin (0, 200, 500, or 800 mg/kg/day, po) administered to timed-pregnant CD rats (36-41/group) during organogenesis (gestational days [gd] 6-15). At death (gd 20), all live fetuses were examined for external, visceral, and skeletal abnormalities. At 500 and 800 mg/kg/day, maternal toxicity included reduced food consumption during treatment and for the gestation period, increased water consumption in the posttreatment period, reduced weight gain during treatment, and sedation; water consumption was reduced during treatment and for the gestation period, and maternal mortality (17.1%) was observed only at the high dose. Developmental toxicity included reduced prenatal viability (800 mg/kg/day) and reduced fetal body weight/litter (500 and 800 mg/kg/day). In addition, reduced ossification of metacarpals (800 mg/kg/day), phalanges of the forelimbs (500 and 800 mg/kg/day), and of caudal vertebral centra (all doses) was observed. No increase in percent malformed live fetuses/litter was observed. The proportion of litters with one or more malformed fetuses was higher than vehicle controls only at 800 mg/kg/day, with short 13th rib (to which the test species is predisposed) as the predominant observation. By contrast, a positive control agent (nitrofen, 50 mg/kg/day, po, 14 dams) produced 85% malformed fetuses/litter with the predominant malformation being diaphragmatic hernia. In conclusion, the incidence of litters with one or more malformed fetuses was increased only at a dose of Bendectin which produced maternal mortality (17.1%) and other indices of maternal and developmental toxicity (see Discussion).

Abnormalities, Drug-Induced↗
PubMed1988

Developmental toxicity evaluation of dietary di(2-ethylhexyl)phthalate in Fischer 344 rats and CD-1 mice.

Di(2-ethylhexyl)phthalate (DEHP), a widely used plasticizing agent, was evaluated for developmental toxicity in timed-pregnant Fischer 344 rats (22-25 dams/dose) and CD-1 mice (24-30 dams/dose). DEHP was administered in the diet on gestational Days (gd) 0 through 20 at 0.0, 0.5, 1.0, 1.5, or 2.0% (rats) and on gd 0 through 17 at 0.00, 0.025, 0.05, 0.10, or 0.15% (mice). At termination (gd 20, rats; gd 17 mice), all fetuses were examined for external, visceral, and skeletal malformations and variations. In rats, maternal toxicity and reduced fetal body weight per litter were observed at 1.0, 1.5, and 2.0%. Increased resorptions and decreased number of live fetuses/litter were observed at 2.0%. Maternal food consumption was reduced and water consumption was increased in all DEHP groups. The number and percentage of fetuses malformed per litter were unaffected by treatment. In mice, maternal toxicity, increased resorptions and late fetal deaths, decreased number of live fetuses, and reduced fetal body weight per litter were observed at 0.10 and 0.15%. Maternal food and water consumption exhibited a dose-related upward trend with food consumption significantly increased at 0.15%. The number and percentage of fetuses malformed per litter (open eye, exophthalmia, exencephaly, short, constricted, or no tail, major vessel malformations, fused or branched ribs, and fused or misaligned thoracic vertebral centra) were elevated at 0.05, 0.10, and 0.15% DEHP. In conclusion, DEHP was not teratogenic at any dose tested in Fischer 344 rats when administered in the feed throughout gestation but did produce maternal and other embryofetal toxicity at 1.0, 1.5, and 2.0%. In contrast, DEHP administration throughout gestation in CD-1 mice resulted in an increased incidence of malformations at doses which produced maternal and other embryofetal toxicity (0.10 and 0.15%) and at a dose (0.05%) which did not produce significant maternal toxicity. No treatment-related embryofetal toxicity including teratogenicity was observed in mice at 0.025% or in rats at 0.5% DEHP.

Animals↗
PubMed1988

Issues in qualitative and quantitative risk analysis for developmental toxicology.

The qualitative and quantitative evaluation of risk in developmental toxicology has been discussed in several recent publications. A number of issues still are to be resolved in this area. The qualitative evaluation and interpretation of end points in developmental toxicology depends on an understanding of the biological events leading to the end points observed, the relationships among end points, and their relationship to dose and to maternal toxicity. The interpretation of these end points is also affected by the statistical power of the experiments used for detecting the various end points observed. The quantitative risk assessment attempts to estimate human risk for developmental toxicity as a function of dose. The current approach is to apply safety (uncertainty) factors to the no observed effect level (NOEL). An alternative presented and discussed here is to model the experimental data and apply a safety factor to an estimated risk level to achieve an "acceptable" level of risk. In cases where the dose-response curves upward, this approach provides a conservative estimate of risk. This procedure does not preclude the existence of a threshold dose. More research is needed to develop appropriate dose-response models that can provide better estimates for low-dose extrapolation of developmental effects.

Animals↗
PubMed1988

Current status of behavioral teratology: science and regulation.

The field of behavioral teratology has advanced rapidly in recent years since the advent of recommendations or requirements by several countries for behavioral teratology testing as part of safety evaluation procedures for pharmaceutical agents. A number of large-scale efforts in methods development have been undertaken and supported by U.S. regulatory agencies, and several recent documents have reviewed the state of the science and identified research needs in this area. Although U.S. regulatory agencies do not routinely require behavioral teratology testing, data on existing chemicals are reviewed and evaluated in the risk-assessment process. Currently, such data can be of value in at least three ways: (1) data from postnatal studies may be useful in elucidating the consequences of perinatal findings; (2) behavioral data may help to further define the lower end of the dose response curve; and (3) for chemicals where human exposure is likely, behavioral studies may help to focus on types of effects that may be important to monitor in the exposed human population.

Animals↗