Windows of sensitivity to toxic chemicals in the development of the endocrine system: an analysis of ATSDR's toxicological profile database.

This review utilizes the robust database of literature contained in toxicological profiles developed by the Agency for Toxic Substances and Disease Registry. The aim was to use this database to identify developmental toxicity studies reporting alterations in hormone levels in the developing fetus and offspring and identify windows of sensitivity. We identified 74 oral exposure studies in rats that provided relevant information on 30 chemicals from 21 profiles. Most studies located provided information on thyroid hormones, with fewer studies on anterior pituitary, adrenal medulla, ovaries, and testes. No studies pertaining to hormones of the posterior pituitary, pancreas, or adrenal cortex were located. The results demonstrate that development of the endocrine system may be affected by exposure to environmental contaminants at many different points, including gestational and/or lactational exposure. Moreover, this review demonstrates the need for more developmental toxicity studies focused on the endocrine system and specifically alterations in hormone levels.

Per- and polyfluoroalkyl mixtures toxicity assessment "Proof-of-Concept" illustration for the hazard index approach.

The 2018 ATSDR mixture framework recommends three approaches including the hazard index (HI) for environmental mixture toxicity assessment. Per- and polyfluoroalkyls (PFAS) are found in our environment and general populations. Recent experimental mixture toxicity studies of perfluorooctane sulfonic acid (PFOS) and perfluorooctanoic acid (PFOA) and an assessment of 17 PFAS indicate the use of additivity for their joint toxicity assessment. The aim of this investigation was to detail the stepwise procedures and examine the extent and use of the HI approach for PFAS mixture assessment. Using estimated general public lifetime exposures (high, medium, and low), binary mixtures of PFOS and PFOA yielded, respectively, hazard indices (HIs) of 30.67, 8.33, and 3.63 for developmental toxicity; 10.67, 5.04, and 2.34 for immunological toxicity; 3.57, 1.68, and 0.78 for endocrine toxicity; 4.51, 1.73, and 0.79 for hepatic toxicity; and 15.08, 2.29, and 0.88 for reproductive toxicity. A heterogeneous mixture of PFOA, PFAS, dioxin (CDD), and polybrominated compounds (PBDE) for high exposure scenario yielded HIs of 30.99 for developmental, 10.77 for immunological, 3.64 for endocrine, 4.61 for hepatic, and 17.36 for reproductive effects. The HI values are used as a screening tool; the potential concern for exposures rises as HI values increase. For HI values >1, a follow-up including further analysis of specific exposures, use of internal dosimetry, and uncertainty factors is conducted before recommending appropriate actions. The HI approach appears suitable to address present-day PFAS public health concerns for initial assessment of multiple health effects, until further insights are gained into their mechanistic toxicology.The findings and conclusions in this article are those of the author(s) and do not necessarily represent the official position of the Centers for Disease Control and Prevention/the Agency for Toxic Substances and Disease Registry.

Blood cadmium and depressive symptoms in young adults (aged 20-39 years).

BACKGROUND: Genetic and environmental factors contribute to the risk of depression and several studies have noted an association between tobacco smoke and depression. Cadmium is a neurotoxicant and the main source of non-occupational exposure is tobacco smoke. METHOD: We conducted a cross-sectional analysis of data from 2892 young adult (aged 20-39 years) participants of the National Health and Nutrition Examination Survey (NHANES) 2007-2010. Multivariate logistic regressions, adjusted for age, sex, race/ethnicity, education, poverty income ratio (PIR), obesity, alcohol intake, blood lead (BPb) and smoking status, were used to analyze the association between blood cadmium (BCd) and depressive symptoms, as determined by the score on the nine-item Patient Health Questionnaire (PHQ-9). RESULTS: Individuals in the highest BCd quartile had higher odds of having depressive symptoms [odds ratio (OR) 2.79, 95% confidence interval (CI) 1.84-4.25] than those in the lowest BCd quartile. Smoking status, but not BPb, was statistically significantly associated with depressive symptoms. Stratification by smoking status found that BCd was significantly associated with depressive symptoms in both non-smokers (OR 2.91, 95% CI 1.12-7.58) and current smokers (OR 2.69, 95% CI 1.13-6.42). CONCLUSIONS: This is the first study to report an association between BCd levels and depressive symptoms using a nationally representative sample. The association of cadmium with depressive symptoms was independent of smoking status. If this association is further confirmed, the continued efforts at reducing cadmium exposures, mainly through tobacco smoking cessation programs, may decrease the incidence of depression.

Windows of Sensitivity to Toxic Chemicals in the Development of Cleft Palates.

Cleft lip and cleft palate are among the most common birth defects worldwide. There is a genetic component to the development of these malformations, as well as evidence that environmental exposures and prescription drug use may exacerbate or even produce these manifestations. Thus, it is important to understand the underlying mechanisms and when these exposures affect development of the growing fetus. The purpose of this investigation was to critically review the available literature related to orofacial cleft formation following chemical exposure and identify specific time frames for windows of sensitivity. Further, an aim was to evaluate the potential for predicting effects in humans based on animal studies. Evidence indicates that chemical causes of cleft palate development are due to dose and timing of exposure, susceptibility of the species (i.e., the genetic makeup), and mechanism of action. Several studies demonstrated that dose is a crucial factor; however, some investigators argued that even more important than dose was timing of exposure. Data show that the window of sensitivity to environmental teratogens in the development of cleft palates is quite narrow and follows closely the window of palatogenesis in the fetus of any given species.

Tracked ultrasound registration for intraoperative navigation during pediatric bone tumor resections with soft tissue components: a porcine cadaver study.

PURPOSE: Resection of pediatric osteosarcoma in the extremities with soft tissue involvement presents surgical challenges due to difficult visualization and palpation of the tumor. Therefore, an adequate image-guided surgery (IGS) system is required for more accurate tumor resection. The use of a 3D model in combination with intraoperative tracked ultrasound (iUS) may enhance surgical decision making. This study evaluates the clinical feasibility of iUS as a surgical tool using a porcine cadaver model. METHODS: First, a 3D model of the porcine lower limb was created based on preoperative scans. Second, the bone surface of the tibia was automatically detected with an iUS by a sweep on the skin. The bone surface of the preoperative 3D model was then matched with the bone surface detected by the iUS. Ten artificial targets were used to calculate the target registration error (TRE). Intraoperative performance of iUS IGS was evaluated by six pediatric surgeons and two pediatric oncologic orthopedists. Finally, user experience was assessed with a post-procedural questionnaire. RESULTS: Eight registration procedures were performed with a mean TRE of 6.78 ± 1.33 mm. The surgeons agreed about the willingness for clinical implementation in their current clinical practice. They mentioned the additional clinical value of iUS in combination with the 3D model for the localization of the soft tissue components of the tumor. The concept of the proposed IGS system is considered feasible by the clinical panel, but the large TRE and degree of automation need to be addressed in further work. CONCLUSION: The participating pediatric surgeons and orthopedists were convinced of the clinical value of the interaction between the iUS and the 3D model. Further research is required to improve the surgical accuracy and degree of automation of iUS-based registration systems for the surgical management of pediatric osteosarcoma.

Malignancies in families of women with medullary, tubular and invasive ductal breast cancer.

Breast cancer seems to represent a heterogeneous group of neoplasia originating from the parenchymal epithelium of the mammary gland. Family studies combined with genetic epidemiological analyses and histological evaluations were used to gain an insight into this nosological entity. Special emphasis was given to the type and frequency of neoplasia in close relatives. This study represents pedigrees of 36 histologically defined pure tubular and 22 pure medullary breast cancer patients as well as 171 with the invasive ductal form. The incidence of cancer in the first degree relatives of all three groups is compared to that of the local population. The first degree relatives did not have a higher risk (RR) for the neoplastic diseases. However, breast cancer occurs more frequently in the female relatives of all three groups. Other cancers have different relative risks.

Beta-endorphin and neurotensin in brainstem and cerebrospinal fluid in the sudden infant death syndrome.

Beta-endorphin (BE) and neurotensin (NT) are two neuropeptides which induce apneas. In infants who died of Sudden Infant Death Syndrome (SIDS) we measured, in brainstem and CSF, BE and NT by IRMA and RIA respectively. BE and NT levels are compared to same aged infant and adult controls. CSF BE level was significantly higher in SIDS than in the two control groups (86 +/- 14 vs 33 +/- 13 and 16 +/- 5 pmol/l). In 6 SIDS victims NT and BE were assayed in 5 brainstem sections, each of them divided in median, intermediate and lateral parts. We found high levels of BE in every fragment (3-11 pmol/mg protein) while NT elevated values were restricted to the mesencephalic regions (1.4-12 pmol/mg), the medial pons (6 pmol/mg) and the intermediate parts of the medulla (including the olive: 1.3-1.6 pmol/mg). These results support the hypothesis that NT and/or BE could induce or participate to the fetal issue of SIDS.

Smoking and hypertension: risk factors for carotid stenosis.

The prevalence of smoking, hypertension and diabetes mellitus was assessed in 221 patients suffering from internal carotid stenosis and compared with the prevalences in two sex- and age-matched control groups composed of subjects having normal Doppler findings and from non-neurological outpatients. Of the subjects with carotid stenosis 27.6% were hypertensive smokers in comparison with 9.5% and 17.2% in the two control groups. The difference of the stenosis cohort from the two control groups was significant (P less than 0.01 and P = 0.016 respectively). There was no statistically significant differences between the occurrence of diabetes and hypertension in non-smokers and patients who smoked. In 394 investigated patients suffering from carotid stenosis or occlusion an obstruction index, based on the Doppler shift frequency, was calculated. This index was lowest in the normotensive smokers [corrected]. It was only insignificantly higher in the hypertensive non-smokers but significantly so in the normotensive smokers. The index was highest in the hypertensive smokers [corrected]. It was concluded that cigarette smoking, especially if associated with hypertension, is a determinant risk factor for carotid stenosis and occlusion.

High intensity transcranial Doppler signals (hits) after prosthetic valve implantation.

High intensity transcranial Doppler signals (HITS), assumed to be caused by microemboli, have been reported to occur in many patients with mechanical heart valve prostheses. The aim of our study was to quantify these phenomena and to find possible differences. Furthermore, parameters which might influence the prevalence of HITS were investigated. Monitoring of both middle cerebral artery frequency shift spectra was carried out for 10 minutes in 100 patients having an aortic (n = 64) and (n = 5)/or (n = 31) mitral mechanical heart valve prosthesis. The spectra were off-line screened for HITS by ear. The findings were correlated with the degree of anticoagulation and with the time period since implantation. To examine if platelet aggregates would be the underlying cause, another HITS count was done for 10 minutes prior to and 40 minutes after i.v. injection of 250 mg aspirin (ASA) as well as after four days of 100 mg/day ASA orally in a group of seven patients. Prior to surgery, HITS were present in only one patient. Postoperatively, HITS were detected in 54 of 100 patients. There was no significant difference between left and right sides, no correlation with anticoagulation, and only a borderline correlation with the time interval since implantation. Sixty-six percent of the 50 patients monitored within the first three postoperative weeks had HITS as compared to only 42% in 50 subjects who were examined three months or later after surgery (p < 0.05). With regard to the number of HITS an inverse behaviour was observed.(ABSTRACT TRUNCATED AT 250 WORDS)

A simple "expert system" for morphometric evaluation of cells in pleural effusions.

Quantitation in diagnostic pathology serves to improve both diagnostic reliability and the prognosis of various malignant tumors. Unfortunately, flexible, user-friendly, reasonably priced and compatible morphometric systems are hardly available on the market. A modular Apple II PC-based system was therefore developed in-house. It records stereologic, planimetric and digital image analysis data and calculates secondary parameters. Detailed statistical analyses can be performed, after data transfer, on larger computers. A typical application of diagnostic morphometry is to determine whether, and with which probability a patient with an unclear histopathologic finding can be assigned to one or more groups of patients with known diseases and prognoses. To this end morphometric data of the patient under investigation are compared with other patient data stored in an expert system. This paper describes the concept of an expert system carried out on the Apple II PC system mentioned above and outlines the evaluation procedures. Invariant moments were used to describe nucleus textures. Results obtained from the cytological analysis of pleural effusions demonstrate that with this approach it is possible to differentiate between normal mesothelium, mesothelioma and metastases of adenocarcinomas.

Morphological, immunohistochemical, stereological and nuclear shape characteristics of proliferative Leydig cell alterations in rats.

Proliferative Leydig cell (LC) alterations (hyperplasia, adenoma) of laboratory rats often pose diagnostic problems because the progression from normal to hyperplasia to neoplasia is continuous. The LC compartments of 130 Wistar rats (kfm: WIST strain) of approximately 2 years of age were examined. Ten typical cases conventionally classified as being normal or as showing diffuse or focal hyperplasia or small or large adenomata were investigated in more detail. In large adenomata, areas with large and small LC nuclei were identified. Immunohistochemical characterization, EM examination, as well as stereologic and planimetric investigations were performed. Hyperplastic and neoplastic LC essentially retained their normal appearance and immunohistochemical characteristics, but were found to contain more lipid droplets, fibroblast-like cells and patches of collagen than normal LC at the EM level. LC proliferation was accompanied by significant LC hypertrophy. LC nuclei of hyperplastic LC compartments were slightly larger while those of LC adenoma were markedly larger than nuclei of normal LC. The values for circle-related and ellipticity factors indicated that the nuclei of normal and hyperplastic LC were more markedly oval than nuclei of neoplastic LC. Concavity factor and bending energy measurements revealed that the small and oval nuclei of normal and hyperplastic LC had significantly more and deeper indentations than the larger and somewhat rounder nuclei of neoplastic LC. It is concluded that LC proliferations conventionally diagnosed as hyperplasia or adenoma on the basis of their size were composed of cytologically different LC populations.

[Community prevention by the "Turning Aarau into a Healthy City Foundation". 10 years' activity 1977-1987. Retrospect and prospect]. / Gemeindenahe Prävention der Stiftung "Aarau eusi gsund Stadt". 10 Jahre Aktivitäten 1977-1987. Rückblick und Ausblick.

In 1987, the foundation "Aarau-healthy city" celebrated the 10th anniversary of its activities in community-oriented prevention (including the National Research Program No. 1 NRP 1). This article presents the prevention activities within the last four years, discusses the results of a random sample survey among the Aarau population and draws conclusions for the future.

Improvements in physical and mental domains of quality of life by anti-ischaemic drug and revascularisation treatment in elderly men and women with chronic angina.

BACKGROUND: The severity of angina is related to a reduction in global quality of life (QoL), which may be improved by anti-ischaemic treatment. It is not known, however, whether improvements relate only to physical or also to mental and social domains of QoL and whether women benefit in a similar way to men. OBJECTIVES: To relate improvements in angina severity through anti-ischaemic treatment to physical and mental domains of QoL in elderly men and women and to assess differences in this relation between the sexes. METHODS: Angina severity and full assessment of QoL by structured, self-administered and validated questionnaires were measured prospectively at baseline and after 6 months' optimal drug or revascularisation treatment in all 301 patients of the Trial of Invasive versus Medical therapy in Elderly (TIME) patients with chronic angina. RESULTS: At baseline, angina severity correlated significantly with physical domains of QoL (trend test at least p<0.02) and daily activities (p = 0.05). At similar angina levels, women had significantly lower QoL scores than men. With anti-ischaemic treatment, physical as well as mental and social QoL domains and daily activities improved, together with a relief in angina (trend tests at least p<0.02). This was true for women and men and was more pronounced after revascularisation than with medical treatment. CONCLUSIONS: These findings confirm the relation between angina severity and physical limitation. In addition, they show that anti-ischaemic treatment not only relieves angina and improves physical components of QoL but also improves mental and social domains. This is true for women as well as for men despite the lower overall scores for women.