Reproductive toxicity and toxicokinetics of 2,3,7,8-tetrachlorodibenzo-p-dioxin

Possible effects on the next generation after long-term exposure (subcutaneous administration) of male rats to very high doses of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) were studied. Two dose regimes were applied: TCDD-25 (initial dose: 25 g/kg body wt; maintenance dose: 5 g/kg body wt, once weekly) and TCDD-75 (initial dose: 75 g/kg body wt; maintenance dose: 15 g/kg body wt). Male rats were treated for 10 weeks before mating and then throughout the entire 12 week mating period. They were mated to unexposed virgin females. One group of pregnant females was used for teratological evaluations, and another group was allowed to deliver. No significant differences were observed in the number of implantations or fetuses per litter, and resorption rate, and fetal weight between the controls and TCDD-treated groups. No gross-structural anomalies occurred in any of the fetuses sired by TCDD-treated males. In the TCDD-25 group an increased frequency of two types of variations was observed which also occur in controls: incompletely ossified fingers (TCDD-25=5.1%, controls=2.6%), and incompletely ossified ossa zygomatica (TCDD-25=1.8%, controls=0.5%). In the TCDD-25 group a slight but statistically significant increase was observed in the rate of stillbirths (TCDD-25=1.3%, controls=0.1%), apparently due to an unusually low frequency occurring in the controls (overall historical controls=0.6%). There was no difference in postnatal mortality (TCDD-25=1.3%, controls=1.3%). Taken together, despite the very high doses of TCDD used, the data do not provide evidence for biologically significant paternally-mediated developmental toxicity in the fetuses and newborn.     

Reproductive toxicity and toxicokinetics of 2,3,7,8-tetrachlorodibenzo-p-dioxin

The effects of a single dose of TCDD on the testis were studied in rats. The animals were treated (subcutaneously) once with TCDD doses of 0, 0.5, 1.0, 3.0, 5.0 g/kg body weight. Doses of 3.0 or 5.0 g TCDD/kg reduced the number of spermatids/testis significantly (60% of the controls). Electron microscopic inspection revealed that both doses led to a dissolution on the germinal epithelium. Altered germ cells at all developmental stages occurred in all testes evaluated. Doses of 0.5 or 1.0 g TCDD/kg did not induce any effects in the testis; therefore, under these experimental conditions of single exposure to rats the dose of 1.0 g TCDD/kg can be considered as NOAEL.     

The effect of social media on patient acceptance of temporary anchorage devices:: A cross-cultural study

ObjectivesTo investigate the relationship between the use of social networking sites (SNSs) on patient perceptions, acceptance, and expectations of treatment using temporary anchorage devices (TADs) and to compare differences between patients from the United Kingdom and Brazil.Materials and MethodsCross-sectional questionnaires were administered to 39 participants at orthodontic practices in the United Kingdom and Brazil about patients'' use of SNSs, exposure to TADs on SNSs, and thoughts on extractions, jaw surgery, or TADs as treatment options.ResultsUK patients prefer for clinicians to have SNS profiles (P = .022). Most UK and Brazilian patients want to see their clinician''s work online (76.7%) and use SNSs to get information about treatment options (76.6%). There was a statistically significant difference in Brazilian patients'' acceptance of TADs as a treatment option compared with UK patients, particularly if it meant avoiding extractions (P = .002), avoiding jaw surgery (P = .004), or reducing treatment time (P = .010). Knowledge of TADs was greater in Brazilian patients (P < .001).ConclusionsPatients use SNSs to obtain information about treatments and prefer clinicians to have social media accounts. Patients exposed to TADs on SNSs are more likely to accept them as an orthodontic treatment option. UK patients have less knowledge of TADs and are therefore less sure to consider TADs as an option. Brazilian patients are more confident in considering the use of TADs. Clinicians should consider increasing their social media presence to accommodate patients'' expectations and acceptance of TADs.     

Maternal protein-and-energy restriction reduces the developmental toxicity of cyclophosphamide and hydroxyurea in rats

In this study, we examined the relationship between maternal weight gain deficits induced by protein-and-energy restriction (PER) and pregnancy outcome. We also evaluated whether PER would potentiate the developmental toxicity of cyclophosphamide (CP) and hydroxyurea (HU). Two independent experiments--employing two different methods of inducing protein-and-energy malnourishment-were performed. In the first experiment, well-nourished (fed ad libitum, normal diet, 22% of protein, 11.9 kJ/g) and food restricted (fed approximately half of ad libitum food intake, i.e. 12 g/day) rats received CP (0, 5 and 7.5 mg/kg sc) on pregnancy day 11. In the second experiment, well-nourished (normal diet, 24% of protein, 12.4 kJ/g) and malnourished (protein-and-energy deficient diet, 8% of protein, 6.2 kJ/g) rats received HU (0, 300 and 500 mg/kg ip) on pregnancy day 11. PER alone caused pronounced reductions of pregnancy weight gain and low fetal body weight, but induce no embryolethality and, except for a few sternum anomalies, no malformation. PER attenuated embryolethal and teratogenic effects of CP. PER reduced teratogenicity but did not alter effects of HU on embryolethality and fetal body weight. Therefore severe maternal weight gain deficits are not necessarily associated to embryolethality and terata and PER attenuates the teratogenic effects of CP and HU.     

In utero exposure to low doses of bisphenol A lead to long-term deleterious effects in the vagina

The origins of the "endocrine disrupter hypothesis" may be traced to reports on adolescent daughters born to women who had taken the highly potent synthetic estrogen, diethylstilbestrol, while pregnant, and who developed a rare form of vaginal cancer and adenocarcinoma. Bisphenol A (BPA) is an estrogenic chemical that is highly employed in the manufacture of a wide range of consumer products. Some observational studies have suggested that the amounts of BPA to which we are exposed could alter the reproductive organs of developing rodents. We examined the influence of BPA at low doses to address the questions of (a) whether in utero exposure affects the vagina of the offspring and (b) which mechanisms cause the toxic effects. Gravid Sprague-Dawley dams were administered either 0.1 (low dose) or 50 mg/kg per day BPA, the no observed effect level, or 0.2 mg/kg per day 17 alpha-ethinyl estradiol by gavage. Striking morphological changes were observed in the vagina of postpubertal offspring leading us to examine vaginal estrogen receptor (ER) expression because BPA binds to the ER alpha, which is important for growth of the vaginal epithelium. We show that the full-length ER alpha is not expressed during estrus in the vagina of female offspring exposed to either dose of BPA when compared to the control group, whereas ER alpha expression does not differ from the control group during the diestrus stage. ER alpha downregulation seems to be responsible for the observed altered vaginal morphology.     

Intrauterine bisphenol A exposure leads to stimulatory effects on Sertoli cell number in rats

Using the optical disector for quantifying cell numbers, we investigated whether oral treatment of rats on days 6-21 of gestation with the weakly estrogenic bisphenol A (BPA, 0.1 or 50 mg/kg) or the highly estrogenic ethinyl estradiol (EE, 0.02 mg/kg) alters testicular histology, in those offspring 9-12 month of age. Since production of male germ cells depends on Sertoli cell number, possible changes in that parameter were investigated using unbiased stereology. Spermatogenesis was qualitatively normal in all groups. BPA increases Sertoli cell number per organ but not when expressed as per gram testis. EE did not affect cell number per organ but did affect numbers on a per gram testis basis due to a lowered testis weight. In contrast to the lowering of Sertoli cell numbers that might have been expected according to the estrogen hypothesis, intrauterine administration of these xenoestrogens in fact resulted in minor increases in Sertoli cell numbers and had no qualitative effect on spermatogenesis.     

Principles and problems in assessing prenatal toxicity

(1) The terminology to be used in reproductive (or in prenatal) toxicology has to be in accord with other fields and principles of toxicology; the reasons are briefly discussed. In addition it is essential to assess prenatal toxicity in comparison to adult (maternal) toxicity. (2) Since pharmacokinetics in laboratory animals (e. g. rodents) usually differ considerably from that in man, this fact has to be considered when planning and evaluating studies on prenatal toxicity. Up till now this aspect has seldom been taken into account. (3) A special problem in prenatal toxicity is the inter- and intralitter variability of the toxic manifestation (especially in polytocal animals). This problem has to be recognized by the investigators and means of dealing with it have to be developed. (4) Like all other toxic effects, embryo-/fetotoxic manifestations occur dose dependently. Little information is available in the literature on clean dose-response-curves for teratogenic effects. Some data from our laboratory are presented. (5) Risk assessment of teratogenic effects up till now represents a major problem. While qualitative risk assessment for man on the basis of animal data is possible, quantitative extrapolation from such data to the situation possibly existing in man is still difficult, because basic principles and strategies are largely lacking (e. g. may a “threshold” be assumed or not?). The results of some activities towards this goal are presented from our laboratory.     

Dose-response relationships of rat fetal skeleton variations: Relevance for risk assessment

In developmental toxicity studies, skeleton abnormalities found in fetuses at term are classified as variations or malformations. The relevance of skeleton variations for human risk assessment, however, is a controversial issue. This paper is a contribution to the discussion on the interpretation of fetal skeleton variations in the context of risk assessment. Dose-response relationships of skeleton variations and malformations induced by three antineoplastic drugs (FUDR: 5-fluoro-2′-deoxyuridine, HU: hydroxyurea and 6-MPr: 6-mercaptopurine-riboside) were evaluated. FUDR (0, 3, 14, 25, 35, 45, 55 and 65 mg/kg body wt sc) and HU (0, 250, 300, 350, 400, 450, 500 and 550 mg/kg body wt ip) were administered to rats on gestation day 11 (GD 11) while 6-MPr (0, 3, 7, 10 and 14 mg/kg body wt sc) was given on GD 11, or on GD 12. Caesarean sections were performed on GD 21 and all fetuses were cleared and stained with alizarin red S for skeleton examination. Drugs given on GD 11 increased the incidence of thoracic and lumbar vertebra (dumbbell-shaped and bipartite ossification center (o.c.) and sternum (misaligned sternebrae) variations in a dose-dependent manner. Occurrence of zygomatic bone fused with maxilla (a variation in our rats) was also increased by HU and 6-MPr (GD 11) but it was not altered by FUDR. Spontaneous occurrence of wavy ribs was reduced by all treatments. Malformations such as cleft palate, tympanic bone absent and tibia absent were also increased in a dose-dependent manner by the three compounds. No observed effect levels (NOEL) for variations, irrespective of the compound administered, were generally lower than NOELs for malformations. In the discussion, we supported the view that any dose-related increase in the incidence of variations should be taken into account for determination of NOELs in routine studies. Increased occurrences of skeleton variations in term fetuses are also to be considered in risk assessment, unless experimental evidence exists that a particular change has no detrimental effect on the animal survival or health after birth or that it does not occur in humans.     

Commentary on “Cancer Biology and Hormesis: Human Tumor Cell Lines Commonly Display Hormetic (Biphasic) Dose Responses” by Edward J. Calabrese

We evaluated epidemiologic evidence pertaining to the human carcinogenic potential of triazine herbicides in general and of atrazine, the most common triazine. Cancers for which data are available included non-Hodgkin's lymphoma, Hodgkin's disease, leukemia, multiple myeloma, soft tissue sarcoma, colon cancer, and ovarian cancer. The investigations had methodologic limitations, including lack of in-depth exposure measurements and small numbers of subjects with heavy exposure and/or with many years since starting exposure, possibly required for the induction of cancer. The relation between triazines and non-Hodgkin's lymphoma has been assessed in four independent population-based case-control studies, reporting odds ratios ranging from 1.2 to 2.5. However, chance and/or confounding by other agricultural exposures may have produced these weak statistical associations. Furthermore, a pooled analysis of three of the case-control studies and the combined analysis of two retrospective follow-up studies did not demonstrate the types of dose-response or induction time patterns that would be expected if triazines were causal factors. The epidemiologic data pertaining to Hodgkin's disease, leukemia, multiple myeloma, soft tissue sarcoma, colon cancer, and ovarian cancer were inadequate for determining whether associations with atrazine or triazines exist in humans. For each of these cancers, only one or two studies evaluating the relationship were available, and the results of the studies typically were imprecise.