Biomedical subjects

R J Kavlock

Publications and source records attributed to R J Kavlock.

At least 73 records · Page 4Linked to original sources

PubMed1990

Dose-dependent effect of prenatal dexamethasone treatment on beta-adrenergic receptor coupling to ornithine decarboxylase and cyclic AMP.

Glucocorticoids regulate the coupling of beta-adrenergic receptors to cell function. In the current study, the potential role of these agents in the development of adrenergic responses was evaluated in the offspring of pregnant rats given 0.8 mg/kg of dexamethasone on gestational days 17, 18 and 19. We examined the postnatal development of beta-receptors coupling to ornithine decarboxylase in heart and kidney throughout neonatal life into young adulthood; this enzyme is involved in transduction of neural signals controlling cellular replication and differentiation. Dexamethasone exposure perturbed the basal pattern of cardiac ornithine decarboxylase activity and attenuated the response of the enzyme in both heart and kidney to acute challenge with the beta-agonist, isoproterenol. Subsensitivity persisted into the postweaning period. This dosage regimen of dexamethasone also suppressed renal cyclic AMP responses to isoproterenol, but exposure to a lower dose (0.2 mg/kg) enhanced the response. Thus, although low doses of glucocorticoids foster development of the coupling of beta-receptors to cellular transduction mechanisms, higher doses such as those used to stimulate lung function may lastingly obtund adrenergic sensitivity.

Aging↗

PubMed1990

Regulation of postnatal beta-adrenergic receptor/adenylate cyclase development by prenatal agonist stimulation and steroids: alterations in rat kidney and lung after exposure to terbutaline or dexamethasone.

Glucorticoids and adrenergic stimulation are both thought to control the development of beta-adrenergic receptors/responses. In the current study, rats were exposed to dexamethasone or terbutaline during late gestation and the development of beta-receptor binding capabilities and adenylate cyclase activity evaluated in membrane preparations from kidney and lung. Prenatal dexamethasone exposure produced postnatal adrenergic hyperreactivity of kidney adenylate cyclase; the effect resulted from increases in the enzyme itself, as both basal adenylate cyclase and forskolin-stimulation of the enzyme were also increased by dexamethasone. Similarly, prenatal terbutaline exposure evoked increases in basal, isoproterenol-stimulated and forskolin-stimulated adenylate cyclase in the kidney. In the lung, dexamethasone produced an initial postnatal deficit in basal adenylate cyclase and deficient responsiveness to isoproterenol, but the deficit resolved shortly after birth. Terbutaline selectively promoted the ability of isoproterenol to stimulate lung adenylate cyclase in the first few days after birth, without alterations in basal adenylate cyclase; this was followed by a period of prolonged subsensitivity of both basal and isoproterenol-stimulated activity. Although dexamethasone and terbutaline also caused significant changes in development of beta-receptor binding capabilities, in neither tissue could these effects account for the direction or magnitude of the changes in adenylate cyclase reactivity. Thus, glucocorticoids and beta-agonists can participate in the programming of development of postsynaptic reactivity by exerting actions upon post-receptor coupling mechanisms.

Adenylyl Cyclases↗

PubMed1989

An overview of maternal toxicity and prenatal development: considerations for developmental toxicity hazard assessments.

The objective of testing xenobiotics for potential developmental toxicity is to extrapolate laboratory animal information to the human species, thereby deriving biologically rational regulatory policies. One of the problems that significantly contributes to the difficulty of this task is the possibility that general effects on the maternal organism could affect the developing conceptus. Published data have indicated that factors intrinsic to the maternal organism affect developmental outcome. This overview examines factors which may bear directly or indirectly upon developmental outcome, with emphasis on those of greatest relevance to the hazard assessment process. Standard teratology testing protocols often call for dose levels that induce overt maternal toxicity, and the developmental effects of this toxicity (both alone, and with concurrent embryo/fetal insult) continue to present regulators with considerable interpretive difficulties. In response to these problems there have been both research and literature review efforts dealing with the relationship of maternal and developmental toxicity. Relevant studies are reviewed here, and suggestions for avenues of future research are offered including the identification of any syndromes of developmental effects occurring at maternally toxic levels irrespective of the causative agent, and experimental approaches for the characterization of maternal toxicity.

Animals↗

PubMed1989

Prenatal alpha-difluoromethylornithine treatment: effects on postnatal renal growth and function in the rat.

DFMO (alpha-difluoromethylornithine) is a specific irreversible inhibitor of ornithine decarboxylase (ODC), a key enzyme in the biosynthesis of polyamines, which in turn control macromolecule synthesis during cell proliferation. The current study was designed to investigate the effects of inhibition of ODC during discrete prenatal periods on renal growth and function. We administered 5 doses of 500 mg/kg DFMO or saline s.c. to timed pregnant Sprague-Dawley rats at 12 hr intervals beginning on gestation days (GD) 11, 14, or 17. Half the dams were killed on GD 20 for fetal morphological analyses and half were allowed to go to term. Renal function was assessed on postnatal days (PD) 3, 6, 10, and 14 by tests of basal renal clearance and urinary concentrating ability, and on PD 42-44 we measured serum chemistries. All three gestational treatment regimens resulted in postnatal deficits in general growth. Only in the GD 11-13 treatment group was there evidence of embryotoxicity and neonatal renal pathophysiology. Fetal weights and urogenital morphology were altered following GD 14-16 treatment and there were persistent deficits of renal growth. GD 17-19 treatment was associated only with transient postnatal deficits of renal growth. Thus, inhibition of ODC during critical prenatal periods induced distinct developmental effects. However, there were no associations between impaired renal growth and function. These data indicate that general tissue growth is not always a predictor of physiological development and support the necessity of multifaceted approaches to the understanding of adverse developmental effects.

Analysis of Variance↗

PubMed1989

Neonatal sympathectomy compromises development of responses of ornithine decarboxylase to hormonal stimulation in peripheral tissues.

The onset of sympathetic innervation has been shown to play a role in the development of postsynaptic reactivity to stimulation. In the current study, we examined whether this relationship extends to responses evoked by hormonal stimuli. Rats denervated at birth by 6-hydroxydopamine treatment showed an impaired ability of vasopressin or angiotensin to stimulate cardiac ornithine decarboxylase activity. In the kidney, responsiveness was affected only for vasopressin and in the lung denervation had only transient effects on the hormonal responses. These results confirm that sympathetic input is required for proper development of some, but not all hormonal responses; the tissue specificity suggests a role of neural factors selective for cardiac development.

Angiotensin II↗

PubMed1988

Teratogenic effects of nitrofen on cellular and functional maturation of the rat lung.

The herbicide nitrofen was administered to pregnant Sprague-Dawley and Fischer-344 rats on Days 10-13 of gestation (po, 20 or 40 mg/kg daily) and the effects of maturation of the perinatal lung were evaluated. Nitrofen interfered with the ontogenetic acquisition of lung cells as DNA, RNA, and protein content were subnormal. The hypoplastic lungs in the newborns were associated with structural deficits, resulting in a profound reduction of surface area available for gas exchange and depressed lung compliance. Other factors which influence pulmonary function and systemic delivery of oxygen were also considered. Adrenal catecholamines, which play an important role in surfactant production and fluid resorption in the lung during the transition to air-breathing, were markedly reduced. In addition, red blood cell concentration was significantly diminished. Taken together, these results suggest that the neonatal mortality observed in the nitrofen-treated rats is likely associated with respiratory distress caused by a number of cellular and functional aberrations. These include (a) hypoplasia and structural defects in the lung leading to deficient pulmonary function, (b) deficits in adrenal catecholamines potentially impeding the transition of the lung to air-breathing, and (c) impaired systemic delivery of oxygen due to reduced hemoglobin concentration.

Adrenal Medulla↗

PubMed1988

The significance of the dilated renal pelvis in the nitrofen-exposed rat fetus: effects on morphology and function.

Previously (R. J. Kavlock, B. F. Rehnberg, and E. H. Rogers, 1987, Teratology 36, 51-58) we reported that gestational exposure of rats to adriamycin induced alterations in development of the fetal renal papilla that persisted postnatally. The morphological effect was associated with functional deficits in neonatal animals as seen by their performance during a test of renal concentrating ability in the second postnatal week. In the present study, we utilized an experimental approach similar to that in the adriamycin study to evaluate the fate of the dilated renal pelvis that is induced in fetal rats following prenatal exposure to nitrofen. Groups of Long-Evans rats were exposed to 0, 6.25, 12.5, or 25 mg/kg of nitrofen on gestation Days 7-16. Renal morphology of the offspring were determined on gestation Day 21 and postnatal Week 5. The postnatal cohort was tested in the second postnatal week for their ability to excrete an osmotically concentrated urine. As was the case with adriamycin, the renal concentrating ability in the neonate was reduced and poor performance in the function test was associated with permanence of the morphological effect. By utilizing a standardized semiquantitative procedure to describe the status of the kidneys and ureters during development in combination with physiological assessment of organ performance, we were able to assess the morphological and functional development of the kidney. In the absence of other anomalies we suggest that offspring be monitored during postnatal development when alterations of the fetal renal papilla are observed in standard teratology bioassays in order to determine whether the effect is transient or permanent.

Animals↗

PubMed1988

Relationship of periventricular overgrowth to hydrocephalus in brains of fetal rats exposed to benomyl.

Benomyl, a benzimidazole fungicide, was administered by gavage to pregnant Sprague-Dawley rats in a daily dose of 62.5 mg/kg of maternal body weight beginning at gestational day (GD) 7. Fetuses examined histologically at GD16 or GD20 revealed a high incidence of craniocerebral anomalies--82.6% of those examined at GD16 and 100% of those examined at GD20. Hydrocephalus occurred in 65.2% of fetuses examined at GD16 and in 58.8% at GD20 but was more severe in the GD20 fetuses. A second common anomaly, termed periventricular "overgrowth" (PVO), consisted of subependymal cell masses that in some fetuses obliterated normal subcortical structures. PVO occurred in 34.8% of fetuses examined at GD16 and 76.5% at GD20. The size of the subependymal masses and the regions involved were considerably greater in the GD20 than the GD16 fetuses. Less common anomalies in the GD20 fetuses were periventricular necrosis (41.2%), a single fetus with exencephaly and another with porencephaly. In the majority of malformed fetuses, the severity of hydrocephalus did not parallel the severity of PVO around the lateral and third ventricles. PVO involved tissues surrounding the cerebral aqueduct in 17.4% of GD16 fetuses and 38.2% of GD20 fetuses. This "overgrowth" distorted the cerebral aqueduct in a large number of fetuses with ventriculomegaly, and at GD20 moderate and severe ventriculomegaly was in every instance associated with a narrow or completely occluded cerebral aqueduct. These relationships suggest that PVO in the midbrain may play a role in the production of aqueductal stenosis and hydrocephalus in this experimental model.

Abnormalities, Drug-Induced↗

PubMed1988

The mouse teratogen dinocap has lower A/D ratios and is not teratogenic in the rat and hamster.

The fungicide dinocap is currently used in the control of powdery mildew. We have reported that dinocap is teratogenic in the CD-1 mouse, causing cleft palate, otolith defects, and fetal weight deficits well below maternotoxic dose levels. In this study the maternal and fetal toxicity of dinocap was determined in the Sprague-Dawley rat and Syrian golden hamster, and adult-to-developmental (A/D) toxicity ratios were calculated and compared with the previously established A/D ratio of dinocap in the mouse. Dinocap in corn oil was administered by gavage to pregnant rats on gestation days 7-20 (0, 100, 150, 200 mg/kg/day) and to hamsters on gestation days 7-14 (0, 12.5, 25, 50, 75, 100, 200 mg/kg/day). Dams were killed on day 21 (rat) or day 15 (hamster), and litters were removed, counted, and weighed; half of each litter was necropsied for soft tissue defects, and the remaining half was processed for skeletal examination. In the rat, maternal extrauterine weight gain was significantly affected at 150 and 200 mg/kg/day, relative liver weight was elevated at 100 mg/kg/day and above, and fetal weight was lower at 150 and 200 mg/kg/day. In the hamster, maternal extrauterine weight was lower at 12.5 mg/kg/day and above; fetal weight was reduced, and the incidence of dilated renal pelvis was higher, at 25 mg/kg/day and above. Thus the A/D ratios for dinocap in the rat and hamster are similar, approximately 1.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1988

Pharmacologic probing of amphotericin B-induced renal dysfunction in the neonatal rat.

Acetazolamide, furosemide, chlorothiazide, and amiloride are pharmacologic agents that act primarily in the proximal tubule, loop of Henle, early distal tubule and late distal tubule and collecting duct, respectively. In order to investigate the renal pathophysiology induced by amphotericin B, these diuretic agents were used as probes of discrete segments of the nephron in the neonatal rat. Six-day-old rats were treated with amphotericin B (20 mg/kg, sc) or the vehicle. Twenty-four hours later, when evidence of amphotericin B-induced renal pathophysiology is detectable, the responses to the diuretic agents were assessed in a 2-hr clearance test, during which creatinine clearance (CCr) and the fractional excretion (FE) of water and various components of the filtrate were determined. Amphotericin B induced alterations in basal function including azotemia, hypostenuria, increases FE water and electrolytes, and a decreased FE urea (although CCr was normal). The diuretic responses to furosemide, chlorothiazide, and amiloride were not altered, indicating that the functional viability of the respective tubular segments was not affected by amphotericin B treatment. Although the maximal response to acetazolamide also remained unchanged in amphotericin B-treated pups, there was an attenuation in the half-maximal response, reflecting an apparent shift in the sensitivity to acetazolamide. All of the diuretic agents elicited an increase in urea excretion in amphotericin B-treated pups such that FE urea approached control values. Additionally, the magnitude of this increase was proportional to the magnitude of the increase in water excretion induced by each diuretic agent. These results indicate a disruption of urea recycling in the nephron and support the hypothesis that amphotericin B acts to increase the permeability of the distal tubule to urea. Thus, results from this study demonstrate the usefulness of pharmacologic agents as functional probes in the characterization of specific components of renal pathophysiology.

Amphotericin B↗

PubMed1988

Prenatal dinocap exposure alters swimming behavior in mice due to complete otolith agenesis in the inner ear.

Exposure to the fungicide dinocap during gestation produces behavioral abnormalities in the house mouse that are not apparent at birth but become obvious at weaning. Pregnant mice (CD-1) were exposed on Days 7 to 16 of gestation to dinocap at 0, 6, 12, or 25 mg/kg/day and the postnatal behavioral development of the offspring was assessed. Torticollis (head-tilting) appears in the treated offspring at 3 weeks of age (4.4% at 12 and 25.3% at 25 mg/kg/day) and, during a test of swimming ability, many of the mice (6.8% at 12 and 47.2% at 25 mg/kg/day) sink below the surface or are unstable and swim on their side in the water. These behavioral abnormalities are the result of agenesis of the otoliths in the inner ears. These were the only developmental defects noted in the 12 mg/kg/day dosage group. In this group 4.4% of the mice displayed torticollis, 9.2% did not swim normally, 19% were missing one or more whole otoliths (7.7% were missing all four otoliths), and partial agenesis of the crystalline material was seen in an additional 11.6% of the mice. The frequency of behavioral and inner ear defects increased in the higher dosage group, but the order of sensitivity of the effects did not change.

Animals↗

PubMed1988

Functional teratogens of the rat kidney. I. Colchicine, dinoseb, and methyl salicylate.

Substances known or suspected to cause subtle or transient anatomical alterations in renal development were administered prenatally or neonatally to rats in order to determine whether they are capable of altering renal functional development. Colchicine alters mitotic activity and cytoskeletal structure and is teratogenic in many species. Since the kidney of the newborn rat undergoes extensive cellular proliferation and nephron differentiation, it is possible that neonatal administration of colchicine may affect nephron development. Dinoseb and methyl salicylate have previously been reported to produce a high incidence of dilated renal pelvis in the term rat fetus. Colchicine was injected sc, at 75 micrograms/kg, to Postnatal Day (PD) 1 Sprague-Dawley rats. Dinoseb was administered ip to pregnant Sprague-Dawley rats on Gestation Days 10-12 at doses of 8 or 10.5 mg/kg/day, and methyl salicylate was administered ip at doses of 200, 250, or 300 mg/kg/day on Gestation Days 11-12. Renal function was examined in pups from immediately after birth through weaning. Maximal urine concentrating ability was measured after DDAVP (desmopressin acetate, a vasopressin analog) injection in suckling rats, and after 24 hr of water deprivation in weanlings. Proximal tubule transport was measured in renal cortical slices. Basal urinary parameters, including urine flow, osmolality, pH, and chloride content, were measured. Colchicine treatment had no effect on body weight or kidney weight. There was a significant decrease in maximal urine osmolality in PD 30 rats measured after 24 hr of water deprivation. The urine concentrating deficit detected in functionally mature PD 30 rats suggests that colchicine treatment during renal histogenesis causes a latent deficit in medullary function in the absence of any gross morphological effects. The 10.5 mg/kg/day dose of dinoseb caused a weight reduction in neonates which persisted after weaning. Urine volume after DDAVP challenge was increased over controls in both dose groups on PD 6, but maximal urine concentration was unaffected. On PD 14, maximal urine concentration after DDAVP injection was decreased in the 10.5 mg/kg/day group. By PD 30, urine concentrating ability was comparable to controls. Renal cortical slices from the 10.5 mg/kg/day dose group had an enhanced ability to accumulate organic anions on PD 3 and 31, but opposite effects were observed in the low-dose group. No other renal functional parameters were altered. Urine osmolality after DDAVP challenge was decreased over controls in the 250 mg/kg/day methyl salicylate group on PD 6, and urine volume was increased in this group after DDAVP injection on PD 14.(ABSTRACT TRUNCATED AT 400 WORDS)

2,4-Dinitrophenol↗

PubMed1988

Functional teratogens of the rat kidney. II. Nitrofen and ethylenethiourea.

Nitrofen and ethylenethiourea (ETU), agents known to prenatally induce hydronephrosis in rats, were assessed for their effects on postnatal renal functional maturation. Both were given by gavage to pregnant Sprague-Dawley rats on Gestation Day 11. Nitrofen was given at concentrations of 50 or 100 mg/kg, and ETU at 20, 40, or 60 mg/kg. Renal function was examined in the offspring from birth until after weaning, the period of renal functional maturation in the rat. Maximal urine concentrating ability was measured after DDAVP (desmopressin acetate, a vasopressin analog) challenge or water deprivation. Proximal tubule transport was measured in renal cortical slices. Various urinary parameters were measured. Both prenatal nitrofen and ETU exposure caused a large number of neonatal deaths at the high dose, and hydronephrosis was observed. The severity of the lesion increased with age. Hydronephrotic animals were deficient in urine concentrating ability, which became more pronounced after weaning. A few other urinary parameters were altered, but cortical function appeared to be unaffected. Rats prenatally exposed to nitrofen, but with apparently normal kidneys, were significantly compromised in their ability to produce a concentrated urine in response to DDAVP challenge, on Postnatal Days (PDs) 6 and 14. By PD 30, they were not different from controls in urine concentrating response. Rats prenatally exposed to the higher doses of ETU, but with grossly normal kidneys, had significantly decreased plasma clearances of certain electrolytes early in life, but by PD 27, they were not different from controls. Proximal tubule transport of PAH was increased on PD 7 in ETU-exposed pups, but this effect did not persist.

Animals↗

PubMed1988

In vitro culture of postimplantation hamster embryos.

In vitro culture of intact rat and mouse embryos has been described extensively, but information on the culture of other species is sparse. The present study examined some culture requirements of early somite stage hamster embryos and assessed the embryotoxic effects of sodium salicylate (SS), a direct acting chemical and cyclophosphamide (CP), a proteratogen, on these embryos. Hamster embryos explanted on gestation days (GD) 8 and 9 were cultured in Waymouth's embryo-hepatocyte co-cultivation medium (WEHC), 70% McCoy's 5A medium-30% male rat serum (MMRS) or 100% male rat serum (MRS) for 24 hours under various oxygen concentrations. Embryos cultured GD 8 to 9 in the various media grew and differentiated much as they did in vivo, while embryos cultured GD 9 to 10 grew best in MMRS as compared to embryos at the same stage in vivo. Embryos exposed to SS in MMRS at concentrations of 250, 300, or 400 micrograms/ml showed dose related embryotoxicity which included CNS defects, absence of hind limb bud formation, and lack of axial rotation. Hamster embryos co-cultivated with pregnant hamster hepatocytes and treated with 2.5, 6.25 and 12.5 micrograms/ml of CP, showed dose-dependent toxicity when compared to co-cultivated controls. Hamster embryos develop extensively in culture over a 24 hour period. This system may therefore provide a valuable tool for evaluating the species differences of a variety of potential teratogens and embryotoxins and allow the comparison of these embryotoxic effects between rat, mouse and hamster during similar stages of organogenesis.

Abnormalities, Drug-Induced↗

PubMed1988

Role of sympathetic neurons in biochemical and functional development of the kidney: neonatal sympathectomy with 6-hydroxydopamine.

Renal sympathetic function develops over the first 3 weeks of postnatal life in the rat. In the current study, the effects of neonatal sympathectomy with 6-hydroxydopamine were examined on renal biochemical and functional development. The completeness and persistence of sympathetic nerve loss were confirmed by direct measurement of norepinephrine levels and turnover. Evidence was obtained for adverse effects on cellular maturation, as shown by perturbations in the ornithine decarboxylase/polyamine system, which is controlled partially by beta adrenergic input and which regulates macromolecule synthesis in developing cells. A later phase of 6-hydroxydopamine-induced alterations in renal development was seen during the period in which synaptogenesis is prominent and sympathetic tone is high (end of the 2nd postnatal week to end of the 3rd week): the denervated kidneys displayed supersensitivity of beta adrenergically mediated cyclic AMP responses without changes in receptor binding. The alterations in biochemical indices of cellular maturation were accompanied by abnormalities of renal function. 6-Hydroxydopamine caused an increase in the fractional excretion of sodium and deficits in physiological responsiveness of the kidney to a vasopressin analog. Later on, alterations in glomerular filtration rate and basal urinary osmolality also were prominent. These results indicate that neonatal sympathectomy has an adverse effect on the biochemical and functional development of the kidney.

Animals↗

PubMed1988

Trophic control of lung development by sympathetic neurons: effects of neonatal sympathectomy with 6-hydroxydopamine.

The onset of peripheral sympathetic neuronal function is thought to provide trophic regulatory signals for development of adrenergic target tissues. In the current study, we examined the effects on lung development of neonatal sympathectomy with 6-hydroxydopamine. The completeness of the lesion and effectiveness in reducing sympathetic input to the tissue were confirmed by direct measurement of norepinephrine levels and turnover. Despite the denervation, no evidence of beta-receptor up-regulation was found; in fact, receptor binding sites tended to be reduced throughout development. The cyclic AMP response to isoproterenol challenge was initially suppressed in the lesioned animals, but became supersensitive even in the face of reduced receptor binding capabilities. Evidence was also obtained for ontogenetic abnormalities in the ornithine decarboxylase/polyamine system, which is partially controlled by beta-adrenergic input and which regulates macromolecule synthesis in replicating and differentiating cells. Eventually, the alterations were reflected in aberrant developmental patterns of DNA, RNA and protein in the lung. These results indicate that sympathetic neurons influence the biochemical development of the lung and may serve to program permanently the relationships among receptor sites, receptor coupling to cellular function, and control of cell maturation.

Animals↗

PubMed1987

Further evaluation of an in vivo teratology screen.

The in vivo teratology screening procedure described previously [Chernoff N, Kavlock RJ: J Toxical Environ Health 10:541-550, 1982] was further evaluated using a total of 46 chemicals in 50 different treatment regimens. Pregnant CD-1 mice were generally treated by oral gavage on days 8-12 of gestation at a dose level predicted from a preliminary range finding study to induce a slight degree of maternal toxicity. The effects on early postnatal growth and viability were compared to results generated from standard mouse teratology bioassays as reported in the literature (there were nine regimens for which no valid comparisons could be made). The procedure correctly categorized 25 of the 30 treatment regimens which were considered developmentally toxic in the mouse, as well as nine of 11 which were considered to be nondevelopmentally toxic in the mouse. Thus, based upon the criteria used in the present study, the assay correctly classified 83% of the chemicals tested as to their effect in a standard mouse bioassay. The five nonconcurring negative findings were likely due to a combination of pharmacokinetic differences between the studies, as well as to the cessation of dosing on day 12, while critical events of organogenesis are still occurring. The assay achieves the requirements for a teratology screening system, but improved predictability would result from the addition of a lower dose level and extension of the dosing period to include later stages of organogenesis.

Animals↗

PubMed1987

Workshop on the Chernoff/Kavlock preliminary developmental toxicity test.

The Chernoff/Kavlock assay, proposed as a preliminary screen for teratogenic potential, was the subject of a 2-day workshop sponsored by the National Institute for Occupational Safety and Health. Data from three large testing programs were presented, representing tests of 165 chemicals, of which 33 were tested at least twice. Applications of the test in industrial laboratories and product development, hazard identification, and risk assessment were discussed. Workshop participants recognized the assay as one of several valid ways to preliminarily evaluate chemicals with unknown developmental toxicity. Other preliminary tests were also discussed in terms of their relationship to this test, which was seen as having the advantage of providing information on neonatal viability. Other techniques, particularly an abbreviated conventional teratology study, were also recognized as appropriate screens. The preferred test in a particular laboratory will be dependent upon the particular skills and objectives of that laboratory. Standardized protocols were suggested, but flexibility in experimental design was considered necessary, and many variations on the basic test could be appropriate. This preliminary test has been used most often as a single-dose test in mice, but might provide more generally useful data if conducted in rats using two dose levels. Workshop participants viewed the test as highly reliable in correctly identifying developmentally toxic chemicals and suggested that a negative finding in a properly conducted Chernoff/Kavlock test could be a sufficient basis for regulatory agencies to determine that conventional teratology tests in the same species are not warranted.

Animals↗