Retrospective study of the relationship between agricultural use of 2,4,5-T and cleft palate occurrence in Arkansas.
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2,4,5-Trichlorophenoxyacetic Acid↗
Biomedical subjects
J F Holson
Publications and source records attributed to J F Holson.
Accuracy of birth certificate data for detecting facial cleft defects in Arkansas children.
A comparison of facial cleft defects reported on birth certificates during the period 1943 to 1974 that were reported on birth certificates was made with records maintained by the Arkansas Crippled Childrens Services (CCS). A total of 506 cases were reported of which 331 (65%) were recorded on the birth certificate. Moreover, the accuracy of the reporting was not good. Only 243 (48%) cleft malformations were correctly classified on the birth certificate. Birth certificate information is an inadequate measure of the true facial cleft occurrence in Arkansas. Caution must be exercised when this data source is used in epidemiological surveys because over one-third of such defects were not recorded. These findings serve to reemphasize the national need to improve the quality of such vital health statistics sources.
Arkansas↗
Comparative stability of physiological parameters during sustained anesthesia in rats.
Rats were anesthetized with pentobarbital, pentobarbital and atropine, inactin [5-ethyl-5-(1'-methyl-propyl)-2-thiobarbiturate], ether and inactin, or urethane. Cardiovascular and arterial acid-base parameters were monitored over a 3-hour period of anesthesia. Heart rate, arterial pressures, and pH progressively decreased with duration of pentobarbital anesthesia. Changes observed in rats anesthetized with the thiobarbiturate, inactin, were similar although generally less severe. Most subjects treated with the barbiturates were markedly hypercapnic. Urethane anesthesia was characterized by a higher and more stable heart rate and greater pulse pressure. Arterial carbon dioxide and bicarbonate levels in the urethane group were substantially lower at all sampling times than the values obtained in the barbiturate groups.
Acid-Base Equilibrium↗
Weight differences in rat embryos prior to sexual differentiation.
Sex of day-12 rat embryos was determined using Barr body counts made on spreads of amniotic membranes examined histologically. Embryonic weight, protein content and rate of thymidine incorporation were compared in male and female embryos. Male embryos were found to be heavier and accordingly to contain more protein on absolute but not on per unit weight basis. The rate of thymidine incorporation did not differ in the two sexes. Since gonadogenesis in day-12 rat embryos is rudimentary, with gonadal differentiation of sex not yet apparent, the increased weight suggests that sex-linked genes exist which influence body growth prior to gonadal endocrine activity.
Animals↗
Reduced interlitter variability in rats resulting from a restricted mating period, and reassessment of the ""litter effect''.
Rats were mated for two or 15 hours and variability of day-12-embryos in weight, protein content, and [3H]thymidine incorporation was compared in the long mating period (LMP) and short mating period (SMP) groups by a 2-level nested analysis of variance. Variability in day-20 fetal weight was similarly compared. In both groups day-12 embryonic weight was relatively more variable than day-20 fetal weight, and variability was less in SMP than LMP animals for each comparison made, although statistical significance was attained only for thymidine incorporation. ""Litter effects'' were noted but not of the magnitude reported by other investigators. It was concluded that inappropriate statistical methods have encouraged the belief that among-litter variability usually exceeds within-litter fetal weight variability. The teratological implications of reduced development variability and the ""litter effect'' are discussed.
Abnormalities, Drug-Induced↗
Teratological evaluation of FD&C red no.2-a collaborative government-industry study. I Introduction, experimental materials, and procedures.
Because of recent studies indicating possible embryolethality and teratogenicity of FD&C Red. No 2, and ad hoc committee was convened by the Food and Drug Administration to consider these questions. The committee suggested a collaborative study by three laboratories [Food and Drug Administration (FDA), Industrial Bio-Test Laboratories (IBT), and National Center for Toxicological Research (NCTR)] in which Red No. 2 was given at 200 mg/kg body weight, by gavage during days 0-19, 6-15, or 7-9 of gestation. FD*C Red No. 2 was also given at the same dose level via water bottle. Appropriate controls were utilized. FDA used Osborne-Mendel strain rats, IBT used Charles River strain also showed an increase in the same parameter for the same dose level and in addition showed a significant increase in the percentage of resorptions per litter. It was concluded that because of the inherent variation and the absence of an increase in abnormalities or other indications of embryotoxicity, there is reason to doubt that this effect is either biologically significant or reproducible.
Amaranth Dye↗
Teratological evaluation of FD&C Red No. 2-a collaborative government -industry study. IV. NCTR's study.
Because of recent studies indicating possible embryolethality and teratogenicity of FD&C Red No. 2, an ad hoc committee was convened by the Food and Drug Administration to consider these questions. The committee suggested a collaborative study by three laboratories [Food and Drug Administration (FDA),Industrial Bio- Test Laboratories (IBT), and National Center for Toxicological Research (NCTR)] in which Red No. 2 was given at 200 mg/kg body weight, by gavage during days 0-19, 6-15, or 7-9 of gestation. FD&C Red No. 2 was also given at the same dose level via water bottle. Appropriate controls were utilized. FDA used Osborne-Mendel strain rats, IBT used Charles River, and NCTR used both strains. No significant increases in skeletal or visceral abnormalities were seen. No significant increase in resorptions was seen in the Osborne-Mendel strain, but the Charles River strain at IBT showed a showed a significant increase in litters with two or more resorptions after dams had been given 200 mg/kg at 0-19 days of gestation. The NCTR study on the Charles River strain also showed an increase in the same parameter for the same dose level and in addition showed a significant increase in the percentage of resorptions per litter. It was concluded that because of the inherent variation and the absence of an increase in abnormalities or other indications of embryotoxicity, there is reason to doubt that this effect is either biologically significant or reproducible.
Abnormalities, Drug-Induced↗
Teratological evaluation of FD&C Red no. 2-a collaborative government -industry study. V. Combined findings and discussion.
Because of recent studies indicating possible embryolethality and teratogenicity of FD&C Red No. 2, anad hoc committee was convened by the Food and Drug Administration to consider these questions. The committee suggested a collaborative study by three laboratories [Food and Drug Administration (FDA), Industrail Bio- Test Laboratories (IBT), and National Center for Toxicological Research (NCTR)] in which Red No. 2 was given at 200 mg/kg body weight, by gavage during days 0-19, 6-15, or 7-9 of gestation. FD&C Red No. 2 was also given at the same dose level via water bottle. Appropriate controls were utilized. FDA used Osborne-Mendel strain rats, IBT used Charles River, and NCTR used both strains. No significant increases in skeletal or visceral abnormalities were seen. No significant increase in resorptions was seen in the Osborne-Mendel strain, but the Charles River strain at IBT showed a significant increase in litters with two or more resorptions after dams had been given 200 mg/kg at 0-19 days of gestation. The NCTR study on the Charles River strain also showed an increase in the same parameter for the same dose level and in addition showed a significant increase in the percentage of resorptions per litter. It was concluded that because of the inherent variation and the absence of an increase in abnormalities of other indications of embryotoxicity, there is reason to doubt that this effect is either biologically significant or reproducible.
Amaranth Dye↗
An assessment of the developmental toxicity of inorganic arsenic.
A critical analysis of the literature base regarding the reproductive and developmental toxicity of arsenic compounds, with emphasis on inorganic arsenicals, was conducted. The analysis was stimulated by the great number of papers that have purported to have shown an association between exposure of pregnant laboratory animals to arsenic compounds and the occurrence of offspring with cranial neural tube defects, particularly exencephaly. For the most part, the literature reports of arsenic developmental toxicity in experimental animals are inadequate for human risk assessment purposes. Despite the shortcomings of the experimental database, several conclusions are readily apparent when the animal studies are viewed collectively. First, cranial neural tube defects are induced in rodents only when arsenic exposure has occurred early in gestation (on Days 7 [hamster, mouse], 8 [mouse], or 9 [rat]). Second, arsenic exposures that cause cranial neural tube defects are single doses that are so high as to be lethal (or nearly so) to the pregnant animal. Third, the effective routes of exposure are by injection directly into the venous system or the peritoneal cavity; even massive oral exposures do not cause increases in the incidence of total gross malformations. Fourth, repetition of similar study designs employing exaggerated parenteral doses is the source of the large number of papers reporting neural tube defects associated with prenatal arsenic exposure. Fifth, in five repeated dose studies carried out following EPA Guidelines for assessing developmental toxicity, arsenic was not teratogenic in rats (AsIII, 101 micromol/kg/d, oral gavage; 101 micromol/m3, inhalation), mice (AsV, 338 micromol/kg/d, oral gavage; est. 402 micromol/kg/d, diet), or rabbits (AsV, 21 micromol/kg/d, oral gavage). Data regarding arsenic exposure and adverse outcomes of pregnancy in humans are limited to several ecologic epidemiology studies of drinking water, airborne dusts, and smelter environs. These studies failed to (1) obtain accurate measurements of maternal exposure during the critical period of organogenesis and (2) control for recognized confounders. The lone study that examined maternal arsenic exposure during pregnancy and the presence of neural tube defects in progeny failed to confirm a relationship between the two. It is concluded that under environmentally relevant exposure scenarios (e.g., 100 ppm in soil), inorganic arsenic is unlikely to pose a risk to pregnant women and their offspring.
Abnormalities, Drug-Induced↗
Developmental toxicity assessment of arsenic acid in mice and rabbits.
To evaluate potential effects of exposure to inorganic arsenic throughout major organogenesis, CD-1 mice and New Zealand White rabbits were gavaged with arsenic acid dosages of 0, 7.5, 24, or 48 mg/kg/d on gestation days (GD) 6 through 15 (mice) or 0, 0.19, 0.75, or 3.0 mg/kg/d on GD 6 through 18 (rabbits) and examined at sacrifice (GD 18, mice; GD 29, rabbits) for evidence of toxicity. Two high-dose mice died, and survivors at the high and intermediate doses had decreased weight gains. High-dose-group fetal weights were decreased; no significant decreases in fetal weight or increases in prenatal mortality were seen at other dosages. Similar incidences of malformations occurred in all groups of mice, including controls. At the high dose in rabbits, seven does died or became moribund, and prenatal mortality was increased; surviving does had signs of toxicity, including decreased body weight. Does given lower doses appeared unaffected. Fetal weights were unaffected by treatment, and there were no effects at other doses. These data revealed an absence of dose-related effects in both species at arsenic exposures that were not maternally toxic. In mice, 7.5 mg/kg/d was the maternal No-Observed-Adverse-Effect-Level (NOAEL); the developmental toxicity NOAEL, while less well defined, was judged to be 7.5 mg/kg/d. In rabbits, 0.75 mg/kg/d was the NOAEL for both maternal and developmental toxicity.
Animals↗
Interpreting the toxicologic significance of alterations in anogenital distance: potential for confounding effects of progeny body weights.
Anogenital distance (AGD) is an endpoint that was recently added to the U.S. EPA testing guidelines for reproductive toxicity studies. This endpoint is sensitive to hormonal effects of test chemicals. It is possible that apparent alterations in AGD might occur after treatment with agents that affect overall pup body size. In such cases, hormonal activity might be associated incorrectly with the test treatment. The analyses in this report evaluated statistical correlations between pup body weight and AGD in control litters. AGDs were measured on postnatal day 1 in 1501 pups derived from 113 untreated female Sprague-Dawley rats in two independent two-generation reproductive toxicity studies. Significant correlations were detected between AGD and body weight and between AGD and the cube root of body weight. In males, AGD increased 0.26 mm for each 1 g increase in body weight. In females, AGD increased 0.13 mm per 1 g increase in body weight. Although there were essentially no differences between the regression models developed to predict AGD in either males or females using body weight as a covariate and those based on the cube root of body weight, such similarities in predictivity might not occur in larger animals with broader weight ranges than those encountered in this analysis. Normalization of AGD by dividing by body weight significantly overcompensated for differences in body size. Normalizing with the cube root of body weight resulted in an AGD/cube root of body weight ratio that was constant across the range of body weights observed in this study. In conclusion, as a preferred method to account for body size effects on AGD, analysis of covariance is recommended. If a normalization is done directly, the ratio of AGD to the cube root of body weight is the more appropriate metric.
Animals↗
A communicating intestinal duplication in a Sprague-Dawley rat.
Duplications of the gastrointestinal tract are exceedingly rare in laboratory animals. We report a case of a communicating intestinal duplication in a 17-wk-old Sprague-Dawley (SD) rat. The duplication was present in the mesenteric border of the ileum, and both proximal and distal ends were communicated with the lumen of ileum. Histologically, the duplicated portion had a thick muscle wall and a mucosa similar to that of the small intestine. This is the first reported case of intestinal duplication in an SD rat.
Animals↗
Utility of pharmacokinetics in designing toxicological protocols and improving interspecies extrapolation.
Key terms such as pharmacokinetics, pharmacodynamics, time course-concentration, and dosimetry and how they apply to predictive toxicology are defined and differentiated. The importance of utilizing pharmacokinetic techniques in teratology and developmental toxicology are discussed from the viewpoints that (1) agent's access to target tissue is modulated by the placenta, (2) interspecies sensitivities differ, (3) dose-response curves are steep, and (4) dosimetry information improves the validity of regulatory standards. We review the teratology literature where attempts were made to correlate embryonal/fetal exposure to teratogenic endpoints. The strengths and weaknesses of these papers are discussed as well as our suggested changes in their protocols, which would have improved interspecies extrapolation.
Age Factors↗
Statistical analysis of teratologic data: problems and advancements.
A large scale replicated dose-response teratology study of 2,4,5-T was done in mice. Variability and variance of fecundity parameters and fetotoxicity endpoints are discussed. Another study on rats indicated less variation among teratologic endpoints than in mice. Calculations for the number of animals in strains of mice and rats needed to detect a 5 percent and 10 percent reduction in mean fetal weight or increase in resorptions are given. We concluded that at least 3 replicates with appropriate numbers of pregnant animals are needed to estimate variance for comparison among laboratories or among species. The utility of these calculations for standardizing teratologic studies is discussed.
2,4,5-Trichlorophenoxyacetic Acid↗