Endocrine-metabolic assessment checklist for cancer patients treated with immunotherapy: A proposal by the Italian Association of Medical Oncology (AIOM), Italian Association of Medical Diabetologists (AMD), Italian Society of Diabetology (SID), Italian Society of Endocrinology (SIE) and Italian Society of Pharmacology (SIF) multidisciplinary group.

Immunotherapy with immune checkpoint inhibitors (ICI) is increasingly employed in oncology. National and international endocrine and oncologic scientific societies have provided guidelines for the management of endocrine immune-related adverse events. However, guidelines recommendations differ according to the specific filed, particularly pertaining to recommendations for the timing of endocrine testing. In this position paper, a panel of experts of the Italian Association of Medical Oncology (AIOM), Italian Association of Medical Diabetologists (AMD), Italian Society of Diabetology (SID), Italian Society of Endocrinology (SIE), and Italian Society of Pharmacology (SIF) offers a critical multidisciplinary consensus for a clear, simple, useful, and easily applicable endocrine-metabolic assessment checklist for cancer patients on immunotherapy.

Monitoring of Metabolic, Cardiac, and Endocrine Indicators in Youth Treated With Antipsychotics as Reported by Health Care Professionals.

BACKGROUND: It is unclear how youth treated with antipsychotics are monitored. The purpose of this study was to assess monitoring of metabolic, cardiac, and endocrine indicators in youth (<18 years old) treated with antipsychotics as reported by health care professionals in the Netherlands. METHODS: A questionnaire was designed to collect information from health care professionals regarding the monitoring of youth treated with antipsychotics. Data were collected at a national conference. FINDINGS AND RESULTS: Fifty-nine health care professionals completed the questionnaire, of which 53 (89.8%) were child and adolescent psychiatrists (approximately 20% of all child and adolescent psychiatrists in the Netherlands). More than 80% of respondents reported monitoring physical indicators-weight, height, body mass index, heart rate, and blood pressure-and over 50% reported monitoring laboratory indicators-lipid profile, blood glucose, and prolactin level. Most of the respondents reported monitoring physical indicators more than twice per year and laboratory indicators once per year. Almost all respondents (56/59, 94.9%) reported monitoring according to a clinical guideline or protocol. Only 1 respondent reported monitoring the indicators completely according to the clinical guideline. Respondents mentioned that facilitating factors for monitoring, such as access to electrocardiogram facilities, were insufficiently available. CONCLUSIONS: Although all health care professionals reported monitoring metabolic, cardiac, and endocrine indicators in youth treated with antipsychotics, great variability exists in reported monitoring practices. Factors contributing to this variability must be assessed to optimize the benefit-risk ratio for the individual patient.

The environmental injustice of beauty: framing chemical exposures from beauty products as a health disparities concern.

The obstetrics-gynecology community has issued a call to action to prevent toxic environmental chemical exposures and their threats to healthy human reproduction. Recent committee opinions recognize that vulnerable and underserved women may be impacted disproportionately by environmental chemical exposures and recommend that reproductive health professionals champion policies that secure environmental justice. Beauty product use is an understudied source of environmental chemical exposures. Beauty products can include reproductive and developmental toxicants such as phthalates and heavy metals; however, disclosure requirements are limited and inconsistent. Compared with white women, women of color have higher levels of beauty product-related environmental chemicals in their bodies, independent of socioeconomic status. Even small exposures to toxic chemicals during critical periods of development (such as pregnancy) can trigger adverse health consequences (such as impacts on fertility and pregnancy, neurodevelopment, and cancer). In this commentary, we seek to highlight the connections between environmental justice and beauty product-related chemical exposures. We describe racial/ethnic differences in beauty product use (such as skin lighteners, hair straighteners, and feminine hygiene products) and the potential chemical exposures and health risks that are associated with these products. We also discuss how targeted advertising can take advantage of mainstream beauty norms to influence the use of these products. Reproductive health professionals can use this information to advance environmental justice by being prepared to counsel patients who have questions about toxic environmental exposures from beauty care products and other sources. Researchers and healthcare providers can also promote health-protective policies such as improved ingredient testing and disclosure for the beauty product industry. Future clinical and public health research should consider beauty product use as a factor that may shape health inequities in women's reproductive health across the life course.

Neurobehavioral deficits, diseases, and associated costs of exposure to endocrine-disrupting chemicals in the European Union.

CONTEXT: Epidemiological studies and animal models demonstrate that endocrine-disrupting chemicals (EDCs) contribute to cognitive deficits and neurodevelopmental disabilities. OBJECTIVE: The objective was to estimate neurodevelopmental disability and associated costs that can be reasonably attributed to EDC exposure in the European Union. DESIGN: An expert panel applied a weight-of-evidence characterization adapted from the Intergovernmental Panel on Climate Change. Exposure-response relationships and reference levels were evaluated for relevant EDCs, and biomarker data were organized from peer-reviewed studies to represent European exposure and approximate burden of disease. Cost estimation as of 2010 utilized lifetime economic productivity estimates, lifetime cost estimates for autism spectrum disorder, and annual costs for attention-deficit hyperactivity disorder. Setting, Patients and Participants, and Intervention: Cost estimation was carried out from a societal perspective, ie, including direct costs (eg, treatment costs) and indirect costs such as productivity loss. RESULTS: The panel identified a 70-100% probability that polybrominated diphenyl ether and organophosphate exposures contribute to IQ loss in the European population. Polybrominated diphenyl ether exposures were associated with 873,000 (sensitivity analysis, 148,000 to 2.02 million) lost IQ points and 3290 (sensitivity analysis, 3290 to 8080) cases of intellectual disability, at costs of €9.59 billion (sensitivity analysis, €1.58 billion to €22.4 billion). Organophosphate exposures were associated with 13.0 million (sensitivity analysis, 4.24 million to 17.1 million) lost IQ points and 59 300 (sensitivity analysis, 16,500 to 84,400) cases of intellectual disability, at costs of €146 billion (sensitivity analysis, €46.8 billion to €194 billion). Autism spectrum disorder causation by multiple EDCs was assigned a 20-39% probability, with 316 (sensitivity analysis, 126-631) attributable cases at a cost of €199 million (sensitivity analysis, €79.7 million to €399 million). Attention-deficit hyperactivity disorder causation by multiple EDCs was assigned a 20-69% probability, with 19 300 to 31 200 attributable cases at a cost of €1.21 billion to €2.86 billion. CONCLUSIONS: EDC exposures in Europe contribute substantially to neurobehavioral deficits and disease, with a high probability of >€150 billion costs/year. These results emphasize the advantages of controlling EDC exposure.

Effective risk communication practice.

Major public controversies over the management of health and environmental risks have been ongoing since the 1970s, starting with chemicals (pesticides and dioxins) and running through risks associated with many other industrial technologies. We can find in those controversies many common features, which cut across differences in both the technologies themselves and the types of risks they engender. This understanding also enables us to propose strategies to organizations to help them better respond to the public's needs (and the public interest) when concerns over risks arise. Effective risk communication practices are among the most important responsibilities for industry and governments in this regard. Since its origins in the late 1980s, risk communication practice has achieved a better understanding both of its goals and of how to achieve them. We are now in a position to specify with some precision what the fundamental requirements of good risk communication are, and they fall into three basic areas: (1) undertaking "science translation," (2) addressing uncertainties, and (3) dealing with the science/policy interface. Within these three areas there are a set of ten specific tasks, representing what may be called the minimum essential content requirements for every effective risk communication effort.

Assessment of DE-71, a commercial polybrominated diphenyl ether (PBDE) mixture, in the EDSP male and female pubertal protocols.

DE-71, a commercial mixture, was used to test the sensitivity of the female and male pubertal protocol to detect thyroid active chemicals. These protocols are being evaluated for the U.S. EPA's Endocrine Disruptor Screening Program as part of a Tier I Screening Battery. To examine the ability of these protocols to screen for chemicals that induce the clearance of thyroid hormone, we examined male and female Wistar rats following DE-71 exposure. Rats were gavaged daily with 0, 3, 30, or 60 mg/kg DE in corn oil from postnatal day (PND) 23-53 in the male or PND 22-41 in the female. The temporal effects of DE-71 on liver enzymes and thyroid hormones were measured in another group of males and females following only 5 days of dosing (PND 21 to 26 in females and PND 23 to 28 in males). Serum T4 was significantly decreased at 30 and 60 mg/kg following the 5-day exposures and in the 21-day exposed females. Doses of 3, 30, and 60 mg/kg decreased T4 in 31-day exposed males. Serum T3 was decreased and TSH elevated by 30 and 60 mg/kg in the 31-day exposed males only. Decreased colloid area and increased follicular cell heights (indicative of the hypothyroid state) were observed in thyroids of the 60 mg/kg groups of 20- and 31-day exposed female and males. Increased liver-to-body weight ratios coincided with a significant induction of uridinediphosphate-glucuronosyltransferase (UDGPT; two to four-fold), and ethoxy- and pentoxy-resorufin-O-deethylase (EROD and PROD) at the two highest doses in all exposures. Of the androgen dependent tissues in the 31-day exposed males, seminal vesicle (SV) and ventral prostate (VP) weights were reduced at 60 mg/kg, while testes and epididymal weights were not affected. Preputial separation (PPS) was also significantly delayed by doses of 30 and 60 mg/kg. In the female, the 60 mg/kg dose also caused a significant delay in the age of vaginal opening. Based upon the thyroid hormone response data, this study provides evidence that the 31-day alternative Tier 1 male protocol is a more sensitive test protocol than the 5-day or female pubertal protocol for thyrotoxic agents that act via up-regulation of hepatic metabolism. This apparent greater sensitivity may be due a greater body burden attained following the longer dosing regimen as compared with that of the female protocol, or to gender specific differences in thyroid hormone metabolism. Also, the delay in PPS and reduction in SV and VP weights may indicate a modification or inhibition of endogenous androgenic stimulation directly by DE-71 or a secondary effect that occurs in response to a DE-induced change in thyroid hormones.

Hazard identification and risk assessment of endocrine disrupting chemicals with regard to developmental effects.

Endocrine Disrupting Chemicals (EDC) may affect mammalian development either indirectly (by affecting implantation, placenta, lactation, etc.) or directly, altering the maturation of target tissues. Studies on reproductive and developmental effects are likely to provide the critical information for risk assessment of most EDC, when proper endpoints are investigated. Toxicity testing guidelines, and especially the two-generation test, are currently being updated with regard to risk assessment of EDC. Particular emphasis is put on selection and validation of the parameters most sensitive to given chemicals and/or mechanisms of action; therefore, a screening battery it is important to address further testing. Under this respect the future use of gene arrays might be a most promising development, when more data will be available. Further points to be considered in a biologically-based assessment of developmental risks include: the identification of critical effects also through the evaluation of dose-response curves; the assessment of the actual exposure and different susceptibility of target tissues; the identification of possible factors of susceptibility and gene-environment interactions; the elaboration of models to estimate the possible additional risk deriving from combined exposures to EDC having similar mechanisms and/or targets.

Assessment of endocrine disruptors: approaches, issues, and uncertainties.

This paper focuses on the quantitative risk assessment of environmental endocrine-disrupting chemicals (EDCs) to human health. An EDC can be defined as an exogenous agent that interferes with the normal endocrine signaling and communication mechanisms. The normal feedback control system of natural hormones is responsible for regulatory mechanisms that maintain homeostasis. Hormones deliver their message to target cells by interacting with receptors, initiating signal transduction, gene transcription, and mRNA translation, and ultimately leading to cellular response. Because effects of EDCs include diverse disease endpoints such as cancer, reproductive toxicity, developmental toxicity, immune system effects, acute toxicity, and neurotoxicity, risk assessment of EDCs is necessarily endpoint-specific. From the quantitative viewpoint, it is best to model the normal endocrinology and then extend the model to include impacts attributable to a particular exogenous agent. A practical approach to such a complex process is to break the spectrum of biochemical and biological events into modular components: e.g., pharmacokinetics, biochemical/molecular (including cellular signaling), and cellular response/dynamics. A flexible mathematical procedure that is capable of modeling each of these components is suggested. However, a real biologically based model is not yet feasible because of a lack of necessary biological information. A challenge to risk assessors is how to develop a hybrid risk assessment approach that can use the limited biological information available for a specific agent and avoid relying on a default approach that incorporates no biological information. The USEPA's default approach is to derive benchmark dose (BMD) or benchmark concentration (BMC) on the basis of a predetermined empirical dose-response model. BMD (or BMC) is the highest dose (or concentration and duration) of exposure that is considered unlikely to cause adverse effects in a human population, including sensitive subgroups. Data from two studies are used to stimulate discussion of issues and the needs for new quantitative approaches and data for assessing endocrine disruptors. Statistical concepts about threshold effect and the U-shaped dose-response relationship are also discussed. This report is a condensed version of the one to be published in the monograph of the NATO Advanced Research Workshop, Endocrine Disrupters and Carcinogenesis Risk Assessment" held May 8-12, 2001, in Bialystok, Poland.

Specific issues in health risk assessment of endocrine disrupting chemicals and international activities.

Specific issues in health risk assessment of EDCs and correlated international activities thereof are discussed. Risk characterization is a synthesis of all information including hazard assessment, dose-response relationship, and exposure information to identify clearly the strengths and weaknesses of the database, the criteria applied to evaluation and validation of all aspects of methodology, and the conclusions reached from the review of scientific information. In the case of EDCs, new models need to be developed taking into account possible new kinds of information, e.g., effects of EDCs on gene activation in response to hormonal challenge or effects on receptor expression. Such models should also account for homeostatic adaptive responses and consider the possibility of having windows of exposure for given effects. Work to compile and harmonize the definitions and terms appropriate to endocrine disruption will be conducted within the joint IPCS/OECD project on harmonization of risk/hazard assessment terminology reviews. The ICPS is the process of preparing a "State of the Science" report, and is implementing a global inventory of ongoing research on ECDs.

Problems in testing and risk assessment of endocrine disrupting chemicals with regard to developmental toxicology.

Endocrine disrupting chemicals (EDCs) may affect mammalian development either indirectly (by impairing implantation, placental development, lactation, etc.) or directly, altering the maturation of target tissues. Current regulatory tests for reproductive/developmental toxicity should be carefully evaluated with regard to risk assessment of EDCs, considering hazard identification (are relevant endpoints being assessed?) and dose-response assessment (are sensitive NOEL/dose-response curves being provided?). Many in vitro and in vivo assays for sex steroid disruption are available; provided that the metabolic capacities of the assays are defined, they could be integrated in a sensitive battery for early detection of steroid-disrupting potentials. The screening battery should address further regulatory in vivo tests (e.g. what specific parameters have to be investigated). As regards dose-response, qualitative differences may be observed between lower and higher exposures, showing primary hormone-related effects and frank embryotoxicity, respectively. Other problems concern (a) the identification of critical developmental windows, according to hormone concentrations and/or receptor levels in the developing target tissues; (b) the potential for interactions between chemicals with common mechanism/target (e.g. xenoestrogens); (c) most important, besides sex steroids more attention should be given to other mechanisms of endocrine disruption, e.g., thyroid effects, which can be highly relevant to prenatal and postnatal development.

Assessment in rats of the gonadotoxic and hepatorenal toxic potential of dibromochloropropane (DBCP) in drinking water.

This investigation was undertaken to assess the potential of ingested 1,2-dibromo-3-chloropropane (DBCP) to cause testicular and hepatorenal injury, in light of the paucity of data applicable to risk assessment of DBCP in drinking water. Adult male Sprague-Dawley rats were supplied ad libitum with water containing 0, 5, 50, 100, and 200 ppm DBCP for 64 days. A dose-related decrease in water consumption occurred during the study. The 200-ppm animals drank less than half as much water as controls, consumed less food, and subsequently exhibited significantly lower body weight gain. DBCP ingestion thus was not directly proportional to the level of chemical in the water, although daily and cumulative intake of DCP were concentration dependent. Average daily intake of DBCP for the 64-day exposure period was as follows: 5 ppm = 0.4 mg/kg/day; 50 ppm = 3.3 mg/kg/day; 100 ppm = 5.4 mg/kg/day; 200 ppm = 9.7 mg/kg/day. Blood samples were taken after 2, 4, and 6 weeks of exposure and at the terminal sacrifice and assayed for serum glutamic-oxaloacetic transaminase, glutamic-pyruvic transaminase, sorbitol dehydrogenase, and ornithine-carbamyl transferase activities and BUN levels. No evidence of liver damage at any exposure level was indicated by either the clinical chemistry indices or histopathology. Histologic examination revealed an apparent increase in the number of nuclei per renal proximal tubule cross-section in the 200-ppm group, possibly indicative of an increased turnover of proximal tubular cells. A slight, but statistically significant, decrease in absolute testicular weight was manifest in the 200-ppm animals, although the decrease was not significant when testicular weight was calculated as g/100 g body wt. Epididymal sperm counts and serum luteinizing hormone, follicle stimulating hormone, and intratesticular testosterone levels were not altered by any dose of DBCP. A qualitative histopathological examination of the testicular seminiferous epithelium failed to reveal any abnormalities in the spermatogenic process.

[Adjuvant chemotherapy of cancer: immediate costs and long-term risks]. / Chimiothérapie adjuvante des cancers: coûts immédiats et risques à long terme.

Medical, psychologic, socio-professional and economic side effects of adjuvant chemotherapy are frequent. Some of these are not easily recognized with accuracy. They influence directly the life of treated patients and perhaps later their medical future. They involve the quality of life for cancer patients, after initial curative treatments. Indications for adjuvant chemotherapy cannot be extended without comparative evaluation of their advantages and disadvantages. It is necessary to select patients with the highest probability of improvement in the duration and the quality of life and to give them so active but the least toxic treatments possible.