摘要:

AbstractThe development and validation of short‐term tests that assess developmental toxicity have received increased attention due to the large number of agents that need to be tested and the desirability to reduce the overall use of animals in research and safety evaluation. The Short‐Term In Vivo Reproductive Toxicity Test was developed to help meet this need and to provide a method for prioritizing agents for further testing. This report provides a brief overview of the risk assessment process and a focus on the aspects of test validation that should be considered when evaluating short‐term tests. It is intended to give the reader an appreciation for many of the considerations that must go into developing and validating a short‐term test, and to indicate areas within the risk assessment process where inclusion of such a test may be appr

ISSN:0270-3211    

DOI:10.1002/tcm.1770070103

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1987

数据来源: WILEY

摘要:

AbstractThe 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 organoge

ISSN:0270-3211    

DOI:10.1002/tcm.1770070104

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1987

数据来源: WILEY

摘要:

AbstractFifty‐five chemicals, including known teratogens, known embryotoxins, equivocal teratogens, nonembryotoxins, and nonteratogens, as well as compounds of unknown teratogenic or embryotoxic potential, were evaluated in the Chernoff/Kavlock developmental toxicity screen. All chemicals were administered by gavage to pregnant ICR/SIM mice on gestation days 8 through 12. The mice were allowed to deliver, and several neonatal growth and viability parameters were measured in the offspring. Comparative statistical analysis of these parameters between treated animals and concurrent (vehicle‐treated) controls provided a data base to evaluate the validity of the developmental toxicity screen as an assay to detect teratogens and embryotoxins. Of the 26 compounds reported in the literature to be teratogenic or embryotoxic in mice following oral administration, 24 were positive in the developmental toxicity screen. Of the compounds previously tested in conventional assays and found to be devoid of teratogenic or embryotoxic activity in mice, 93% were negative in the developmental toxicity screen. The importance of experimental design, dose selection, and neonatal growth and viability measurements as they relate to interpretation and evaluation of the results of the developmental toxicity assay are discus

ISSN:0270-3211    

DOI:10.1002/tcm.1770070105

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1987

数据来源: WILEY

摘要:

AbstractThe number of chemicals in commerce which have not been evaluated for potential developmental toxicity is large. Because of the time and expense required by conventional developmental toxicity tests, an abbreviated assay is needed that will preliminarily evaluate otherwise untested chemicals to help prioritize them for conventional testing. A proposed short‐term in vivo assay has been used in a series of studies in which a total of 60 chemicals were tested. Some were independently tested two or four times each. In this preliminaly test, pregnant mice were dosed during mid‐pregnancy and were then allowed to deliver litters. Litter size, birth weight, and neonatal growth and survival to postnatal day 3 were recorded as indices of potential developmental toxicity. Results in this assay and conventional mouse teratology tests were generally concordant. Conventional data were available for 14 chemicals (ten teratogens, one fetotoxin, three nonteratogens), of which 11 (nine teratogens, one fetotoxin, one nonteratogen) produced evidence of developmental toxicity. This included conventional data for three chemicals (ethylene glycol, diethylene glycol dimethyl ether, and triethylene glycol dimethyl ether) that were untested before the present study. As high priority candidates for conventional testing on the basis of results here, all were subsequently studied in a standard teratology assay and were confirmed to be teratogenic in mice. Additionally, one of them (ethylene glycol) plus a fourth high priority candidate for conventional study (diethylene glycol monomethyl ether) were subsequently tested in rats and were found to be teratogenic in that spec

ISSN:0270-3211    

DOI:10.1002/tcm.1770070106

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1987

数据来源: WILEY

摘要:

AbstractThe statistical analyses of the data related to the teratogenic testing of 60 compounds utilizing the Chernoff/Kavlock test are the basis of this paper. The hypotheses chosen to be tested and the statistical tests utilized to test those hypotheses are discussed. The topics explored are the use of comparisonwise error rate versus experimentwise error rate, the use of nonparametric tests versus more “conventional” parametric tests and the use of “historical data” in assessing and interpreting group dif

ISSN:0270-3211    

DOI:10.1002/tcm.1770070107

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1987

数据来源: WILEY

摘要:

AbstractThis study was designed to compare an abbreviated evaluation of uterine contents at term (teratology probe) with a modified Chernoff‐Kavlock assay (postnatal study), [Chernoff N, Kavlock RJ: J Toxicol Environ Health 10:541–550, 1982]. Mice were intubated during gestation and were evaluated for signs of toxicity. In the teratology probe, uterine contents were examined at term. In the postnatal study, offspring were examined and weighed through day 22 postpartum.Ethylene glycol monoethyl ether (EGEE) produced embryo lethality and malformations, and decreased fetal weight at a dose level which was not maternally toxic in the teratology probe. In the postnatal study, EGEE decreased litter size and neonatal body weight; while litter size continued to decrease beyond the neonatal period, body weights of surviving pups were not significantly different from control. Pups exposed prenatally to EGEE developed kinked tail which was not apparent in fetuses or neonates.Maternally toxic dose levels of ethylene glycol monobutyl ether and ethanol were associated with increased embryo lethality in teratology probe studies. In postnatal studies, there were no significant effects on pup growth or survival at maternally toxic dose levels.Preliminary conclusions regarding maternal and developmental toxicity were comparable based on the teratology probe or postnatal study. Both assays measure litter size and offspring weight, but the teratology probe measures resorption incidence which may be a more sensitive index of prenatal death than number of live born. Neither fetal weight nor neonatal weight reliably predict permanent alteration of growth. A postnatal study permits detection of internal malformations or functional defects which reduce postnatal survival and gross abnormalities which appear postnata

ISSN:0270-3211    

DOI:10.1002/tcm.1770070108

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1987

数据来源: WILEY

摘要:

AbstractThe Chernoff‐Kavlock assay was initially designed to identify developmental toxins within a relatively short time frame, using a mammalian system. Although it has been used for initial prioritization of multiple agents studied concurrently or for dosage‐range evaluations, it has not gained wide usage in a commercial setting. As proposed, use of the Chernoff‐Kavlock assay in an industrial setting is relatively inefficient, in terms of animal usage and data produced, when compared with available alternative study designs. Only a single dosage level was studied, and the data obtained from the assay do not provide sufficient information to meet the minimum requirements of safety evaluations submitted for regulatory review. For these reasons, other methods of prioritization are generally used. Alternate methods used for initial screening and prioritization at our laboratory are: (1) the hydra developmental toxicity assay; and (2) a dosage‐range study in rats. When the results of several pilot and definitive developmental toxicity assays performed in rats were compared, it appeared that the described pilot study served the dual functions of predicting and prioritizing the developmental hazard of the test agent and providing a dosage‐range study that identified the appropriate dosages to be tested in the definit

ISSN:0270-3211    

DOI:10.1002/tcm.1770070109

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1987

数据来源: WILEY

摘要:

AbstractAs the rat is the preferred species for teratogenicity studies in our laboratories, the Chernoff‐Kavlock assay was modified and validated for use in this species. The Alpk:AP (Wistar‐derived) strain, which is also used routinely for toxicology studies, was used, under standard SPF conditions. Twenty‐six chemicals have been assayed to demonstrate the utility of the system as a predictor of rat teratogens and to develop a set of rules for interpretation of the results. Routes of chemical administration were largely gavage, with some dermal, subcutaneous, inhalation, and intraperitoneal applications. The use of the assay in five modes to assist the toxicological evaluation or understanding of chemicals is displayed. These modes are (1) as a pre‐screen, (2) to compare analogues/homologues, (3) to provide a rapid hazard estimate, (4) to generate a dose‐response, and (5) to test a h

ISSN:0270-3211    

DOI:10.1002/tcm.1770070110

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1987

数据来源: WILEY

摘要:

AbstractRecommendations are made for a standard protocol for the Chernoff/Kavlock preliminary developmental toxicity test, and a weighted scoring system is proposed to provide a numerical prioritization. Protocol recommendations include use of pregnant animals for dose‐finding studies and, in the testing phase, treatment on gestation days 6–15 at an overtly maternally toxic dose. This treatment period corresponds to the usual timing of a teratology test and provides an improved data base in the event a conventional test is deemed appropriate. Five indices of potential developmental toxicity are: the proportion of pregnant survivors at term that produces a viable litter (at least one liveborn pup), average litter size and pup weight at birth, and average neonatal survival and body weight gain to 3 days of age. Neither systematic examinations of pups (living or dead) for malformations nor counts of dead pups are considered productive. In the proposed method for point scores, each of the five indices is assigned a point value that varies according to broad classes of maternal toxicity. The maximum total point value is 22. When there is no statistically significant difference between treated and control groups, the assigned value is subtracted from 22. If there is a statistically significant treatment effect, or if statistics cannot be applied, then no points are subtracted. The points remaining after all five indices are considered constitute the priority score, which may range from 0 (low) to 22 (high priori

ISSN:0270-3211    

DOI:10.1002/tcm.1770070111

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1987

数据来源: WILEY

摘要:

AbstractThe underlying principle of the Chernoff/Kavlock assay—namely that prenatal toxicity can be detected by means of simple postnatal endpoints—is strongly supported by experience gained in performing reproductive and developmental toxicity studies to international requirements.Compared with the supposedly more sophisticated procedures of regulatory tests, the simpler endpoints of the assay offer greater speed, economy, consistency and reliability. At the most, there is only a marginal loss of sensitivity in respect of detecting the lowest dosage at which effects may occur.The assay is best used as a concept rather than as a protocol with, “tailored” variations providing effective means of priority selection from a series of chemicals, especially analogue series. The underlying principle is applicable at levels through and beyond formal regulatory

ISSN:0270-3211    

DOI:10.1002/tcm.1770070112

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1987

数据来源: WILEY