Biomedical subjects

R J Kavlock

Publications and source records attributed to R J Kavlock.

130 records · Page 8Linked to original sources

PubMedDate not supplied

Recent advances in mathematical modeling of developmental abnormalities using mechanistic information.

During the last several years, significant changes in the risk assessment process for developmental toxicity of environmental contaminants have begun to emerge. The first of these changes is the development and beginning use of statistically based dose-response models [the benchmark dose (BMD) approach] that better utilize data derived from existing testing approaches. Accompanying this change is the greater emphasis placed on understanding and using mechanistic information to yield more accurate, reliable, and less uncertain risk assessments. The next stage in the evolution of risk assessment will be the use of biologically based dose-response (BBDR) models that begin to build into the statistically based models factors related to the underlying kinetic, biochemical, and/or physiologic processes perturbed by a toxicant. Such models are now emerging from several research laboratories. The introduction of quantitative models and the incorporation of biologic information into them has pointed to the need for even more sophisticated modifications for which we offer the term embryologically based dose-response (EBDR) models. Because these models would be based upon the understanding of normal morphogenesis, they represent a quantum leap in our thinking, but their complexity presents daunting challenges both to the developmental biologist and the developmental toxicologist. Implementation of these models will require extensive communication between developmental toxicologists, molecular embryologists, and biomathematicians. The remarkable progress in the understanding of mammalian embryonic development at the molecular level that has occurred over the last decade combined with advances in computing power and computational models should eventually enable these as yet hypothetical models to be brought into use.

Abnormalities, Drug-Induced↗

PubMedDate not supplied

An in vivo teratology screen utilizing pregnant mice.

Twenty-eight compounds of known teratogenic potential were assayed by an in vivo screening procedure. Postnatal growth and viability of prenatally exposed offspring was used as a measure of developmental toxicity. Gravid CD-1 mice were administered maximum tolerated doses of the compounds for up to 5 consecutive days during the period of major organogenesis. The dams were allowed to give birth, and litter size and weight on postpartum d 1 and 3 were recorded and compared with concurrent controls. All 15 compounds that were teratogenic by standard teratology test criteria exhibited some form of developmental toxicity. Four chemicals known to produce only fetal toxicity (reduced weight or supernumerary ribs) were tested and the screen successfully identified those that reduced weight. Finally, of the 9 compounds that show no effect in standard tests, 6 were also negative in the screen and 3 demonstrated either reduced viability or weight.

Abnormalities, Drug-Induced↗

PubMedDate not supplied

Postnatal evaluation of morphological and functional effects of prenatal exposure to nitrofen in the Long-Evans rat.

The herbicide Nitrofen was administered to Long-Evans rats on d 11 of gestation (75 mg/kg, po) in an effort to further evaluate its reported ability to induce hydronephrosis and to affect Harderian-gland development. This regimen did not affect the litter size at birth or postnatal growth and viability. Eye opening, recorded on postnatal d 16 (PD 16), figure-eight maze activity (PD 24), and vaginal opening (PD 31) were unaffected by treatment. Lung weights were lower on PD 7 and 35 but not at PD 210. Harderian-gland weights were lower at PD 35 and 210, and 12% of the Nitrofen-treated offspring had missing glands, versus 0% of controls. Hydronephrosis was detected in 23% of the necropsied offspring and was represented in every treated litter. Only one control pup (1.5%) was hydronephrotic at necropsy. Treated pups, regardless of the presence or absence of hydronephrosis, had a diminished ability to concentrate urine in fluid deprivation tests applied on PD 3 and 6. By PD 50, however, treated offspring were not deficient in a similar test unless hydronephrosis was present. Microscopic examination on PD 7 of morphologically normal kidneys showed no treatment-related delay in nephrogenesis. Serum chemistry values evaluated at PD 210 showed no overall treatment effect, but animals with hydronephrosis had elevated phosphorus, urea nitrogen, creatinine, and potassium levels. This study has demonstrated that a single prenatal exposure to Nitrofen alters Harderian-gland development, lung growth, and renal development and function. Hydropenia tests applied to neonates detected renal dysfunction and were predictive of hydronephrosis, while a similar test in young adults did not detect dysfunction in morphologically normal animals. The neonatal hydropenia test appears to be an extremely useful tool in evaluating perinatally induced renal dysfunction.

Animals↗

PubMedDate not supplied

Perinatal toxicity of endrin in rodents. I. Fetotoxic effects of prenatal exposure in hamsters.

The potential of the insecticide endrin to induce fetal toxicity was determined in hamsters exposed to the compound on either day 8 or days 5--14 of gestation. Endrin was administered by oral gavage as a solution in corn oil. Doses used included 0.5--10.0 mg/kg on day 8 and 0.75 to 3.5 mg/kg/day on days 5--14. Exposure to a single dose of endrin resulted in significant incidences of fused ribs and meningoencephaloceles at levels of 5 mg/kg or greater. No significant effects were noted in either maternal mortality and weight gain or in fetal mortality or weight gain. The administration of multiple doses of endrin resulted in few fetal defects, although a significant dose-related increase in fetal mortality and decrease in fetal weight was seen. Significant maternal lethality and weight reductions were noted at doses of 1.5 mg/kg/day or greater. At sacrifice, maternal liver and fetal tissues were collected and subsequently analyzed for endrin and a major metabolite, 12-ketoendrin. Endrin was found to cross the placenta and 20 ppb were found in fetuses from litters exposed to 2.5 mg/kg/day. Maternal livers from this dose group contained an average of 2500 pbb of endrin.

Abnormalities, Drug-Induced↗