فایل ورد کامل اثرات ترکیب در دوز های بسیار پایین با ترکیبی از آفت کش های ضد آندروژنی، آنتی اکسیدان ها، آلاینده های صنعتی و مواد شیمایی مورد استفاده در محصولات مراقبت شاخصی

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تعداد صفحات این فایل: ۲۶ صفحه

ما نشان دادیم که  اثرات ضد اندروژنی ترکیب  انتاگونیست های AR از طیف وسیعی از منابع و مسیر های انتقال و ورود در این  مطالعه در غلظت های  بسیار پایین افزایشی هستند. از ان جا که انتخاب ترکیب ما بر اساس قرار گیری یا ابتلا  تقریبی و یا واقعی انسان ها در اروپا و یا امریکا  در برابر این  انتاگونیست ها بود،حداقل یکی از  اجزای ترکیب احتمالا به طور همزمان در افراد دیده می شود. این که ایا  اثرات ترکیبی در معرض قرار گیری در انتاگونیست های AR ممکن است در دوره ی جنینی ایجاد شود و یا نه و توجیهاتی را برای روند افزایشی کریپتوکریدیس و هیپوس پادیاس در اختیار بگذارد،بایستی تحت تاثیر یک سری انتاگونیست های AR موجود در  بافت و قابلیت ان ها می باشد. با این حال مطالعه ی ما نشان داد که اغلب سطوح پایین اندازه گیری  شده برای تک تک انتاگونیست های AR همیشه شاخص مطمئنی برای رد خطرات مربوط به این دسته از مواد شیمیایی نیستند. کارها و تلاش های  جدید برای بررسی انتاگونیست های AR در بافت های انسانی به منظور ارزیابی خطر پذیری تجمعی نیاز  خواهد بود.

عنوان انگلیسی:Mixture effects at very low doses with combinations of anti-androgenic pesticides, antioxidants, industrial pollutant and chemicals used in personal care products~~en~~

Introduction Cryptorchidisms and hypospadias are the most frequent congenital malformations in boys. Although there are marked differences in regional prevalence, several countries have experienced increases in the incidence of cryptorchidisms (reviewed in: Main et al., 2010) and hypospadias (Boisen et al., 2004; Nassar et al., 2007; Nelson et al., 2005; Pierik et al., 2004). Alcohol consumption, low birth weight, premature birth and diets lacking in protein (Pierik et al., 2004) are well recognised risk factors, but these alone cannot explain the continuing rises in inci dence. Skakkebaek et al. (2001) have proposed that cryptorchidism and hypospadias are part of the testicular dysgenesis syndrome, hypothesised to arise from insufficient androgen action in foetal life, and that exposures to anti androgenic chemicals are an etiological factor. Although evidence for links between exposure to specific chemicals and testicular dysgenesis syndrome in humans is currently limited (reviewed in: WHO, 2012), support for the plausibility of an involvement of androgen receptor (AR) antagonists comes from experimental studies using a developmental toxicity model in the rat. In foetal life, steroidal androgens are key drivers of the differentiation of the Wolffian duct system into the vas deferens, epididymis, seminal vesicles and external genitalia. Exposure of male rats to AR antagonists and other anti androgens in foetal life leads to incomplete masculinisation and severe malformations of the reproductive organs, similar to some of the disorders seen in humans such as cryptorchidisms and hypospadias (e.g. Gray et al., 1999; Hass et al., 2007). These observations have provided the stimulus to assess human health risks associated with AR antagonists. The realisation that humans are typically exposed to numerous antiandrogens simultaneously (Schlumpf et al., 2010;Woodruff et al., 2011) has motivated the consideration of possible combination effects. In animal experiments, anti-androgens are known to produce combination effects (Christiansen et al., 2009, 2012; Hass et al., 2007; Metzdorff et al., 2007; Rider et al., 2008), but there are obvious limitations to studying the joint effects of larger numbers of agents in vivo, even though such information is essential for risk assessment. However, to predict the effects of large multi-component mixtures on the basis of the toxicity of its components will stretch the resources for in vivo studies. Such resource limitations do not come into play with in vitro assays with AR responsive reporter gene constructs and their use has considerably advanced our knowledge about the ways in which AR antagonists can act together (Birkhoj et al., 2004; Ermler et al., 2011; Kjrstad et al., 2010; Orton et al., 2012). The experimental results with anti-androgen mixtures have stimulated interest in cumulative risk assessment for these chemicals (NRC, 2008). Cumulative risk assessment cannot proceed without addressing which chemicals should be considered together, and which criteria should be used to build common assessment groups. In the USA, chemicals with similar structures have been grouped together (USEPA, 2006a, 2006b, 2006c, 2007, 2011), but more recently, alternative approaches which place an emphasis on common adverse outcomes have been suggested (EFSA, 2013; NRC, 2008). Although the data published in the literature show that combination effects can arise from quite diverse AR antagonists (Ermler et al., 2010; Orton et al., 2012), the development of common assessment groups for these agents will also require evidence that chemicals from a range of sources and exposure routes can together antagonise the AR. A combination of 30 AR antagonists was selected for testing, which comprised 13 pesticides (herbicides, insecticides, fungicides) and 17 non-pesticides (antioxidants, parabens, UV-filters, synthetic musks, bisphenol A (BPA), benzo(a)pyrene (BaP), perfluorooctane sulfonate (PFOS) and pentabromodiphenyl ether (BDE100)). While human exposure to the 13 selected pesticides was inferred from their wide use in the EU (no biomonitoring data available: Orton et al., 2011), the 17 non-pesticides were selected based on their high levels in human tissues (Ermler et al., 2011). These chemicals together covered a wide range of sources and exposures routes, including oral (pesticides, antioxidants: McKinlay et al., 2008; BPA: Geens et al., 2012), dermal (UV filters: Giokas et al., 2007; synthetic musks: Roosens et al., 2007; parabens: Darbre and Harvey, 2008; brominated flame retardants: Buttke et al., 2013) and inhalation (BaP: Ravindra et al., 2008). The large number of chemicals included in our mixtures provided the opportunity to assess the combined effects of AR antagonists at low concentrations, particularly at concentrations where the effects of the single components are below the detection limit of the assay. Such data is important to contribute to future efforts of modelling the effects of untested mixtures composed of xenobiotics with known anti-androgenicity at relevant concentrations. We used a fixed-mixture ratio experimental design, in which we employed two common concepts for predicting the (additive) effects of mixtures: concentration addition (CA, also called dose addition) and independent action (IA, also called response addition). CA assumes that all compounds have a similar mechanism of action (e.g., binding to the same receptor), whereas IA presumes that all mixture components affect the same endpoint via different sites or modes of action (dissimilar action). Both additivity models assume that there is no interaction between the compounds, neither on a physico-chemical level nor in their toxicokinetics and toxicodynamics.

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