PCB 180 is a persistent non-dioxin-like polychlorinated biphenyl (NDL-PCB) abundantly present in food and the environment. Risk characterization of NDL-PCBs is confounded by the presence of highly potent dioxin-like impurities. We used ultrapure PCB 180 to characterize its toxicity profile in a 28-day repeat dose toxicity study in young adult rats extended to cover endocrine and behavioral effects. Using a loading dose/maintenance dose regimen, groups of 5 males and 5 females were given total doses of 0, 3, 10, 30, 100, 300, 1000 or 1700 mg PCB 180/kg body weight by gavage. Dose-responses were analyzed using benchmark dose modeling based on dose and adipose tissue PCB concentrations. Body weight gain was retarded at 1700 mg/kg during loading dosing, but recovered thereafter. The most sensitive endpoint of toxicity that was used for risk characterization was altered open field behavior in females; i.e. increased activity and distance moved in the inner zone of an open field suggesting altered emotional responses to unfamiliar environment and impaired behavioral inhibition. Other dose-dependent changes included decreased serum thyroid hormones with associated histopathological changes, altered tissue retinoid levels, decreased hematocrit and hemoglobin, decreased follicle stimulating hormone and luteinizing hormone levels in males and increased expression of DNA damage markers in liver of females. Dose-dependent hypertrophy of zona fasciculata cells was observed in adrenals suggesting activation of cortex. There were gender differences in sensitivity and toxicity profiles were partly different in males and females. PCB 180 adipose tissue concentrations were clearly above the general human population levels, but close to the levels in highly exposed populations. The results demonstrate a distinct toxicological profile of PCB 180 with lack of dioxin-like properties required for assignment of WHO toxic equivalency factor. However, PCB 180 shares several toxicological targets with dioxin-like compounds emphasizing the potential for interactions.

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39Convergent evidence associates endocrine disrupting chemicals (EDCs) with major, 40 increasingly-prevalent human disorders. Regulation requires elucidation of EDC-41 triggered molecular events causally linked to adverse health outcomes, but two factors 42 limit their identification. First, experiments frequently use individual chemicals, whereas 43 real life entails simultaneous exposure to multiple EDCs. Second, experimental studies are seldom integrated. This drawback was exacerbated until 45 recently by lack of physiopathologically meaningful human experimental systems that 46 link epidemiological data with results from model organisms. 47 We developed a novel approach, integrating epidemiological with experimental 48 evidence. Starting from 1,874 mother-child pairs we identified mixtures of chemicals, 49 measured during early pregnancy, associated with language delay or low-birth weight in 50 offspring. These mixtures were then tested on multiple complementary in vitro and in 51 vivo models. We demonstrate that each EDC mixture, at levels found in pregnant 52 women, disrupts hormone-regulated and disease-relevant gene regulatory networks at 53 both the cellular and organismal scale. . CC-BY-NC-ND 4.0 International license It is made available under a (which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint . http://dx.doi.org/10.1101/206664 doi: bioRxiv preprint first posted online Oct. 23, 2017; Results 70 An integrated epidemiological-experimental design assessing the impact of EDC mixtures on human health and development 72To assess health outcomes of real-life EDC exposures we harnessed: i) the power of a (which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint . http://dx.doi.org/10.1101/206664 doi: bioRxiv preprint first posted online Oct. 23, 2017; 5 these EDC mixtures in concentrations corresponding to human exposure ( Figure 1b); iii) 79 paradigmatic in vivo models to determine the physiological impact of key affected 80 pathways (Figure 1c (Table 1a), assessed for their urinary or serum EDC 94 levels around the 10 th week of gestation (Table 1b). Specifically, we profiled urine levels 95 of 10 metabolites of 5 phthalates, bisphenol A (BPA) and triclosan (TCS), as well as 96 serum levels of 8 perfluorinated alkyl acids (PFAAs). 97Specific mixtures (in terms of both composition and dose) were associated with the two 98 health outcomes in a three-step procedure ( Figure 1a). First, we identified the prenatal 99 exposure to EDCs, hereafter "bad actors", that was associated with lower birth weight or 100 language delay in children by using weighted quantile sum (WQS) regression 7 . Next, we 101 . CC-BY-NC-ND 4.0 International license It is made available under a (which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to...

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Neuropeptide Y (NPY) is an abundant neuropeptide in the mammalian brain important for behavioural consequences of stress and energy metabolism. We have addressed possible effects of the phthalate DiNP on NPY expression in human SH-SY5Y cells, a neuronal in vitro differentiation model. Pico- to nanomolar doses of DiNP and its metabolite MiNP resulted in decreased NPY mRNA and peptide expression in retinoid-differentiated cells. Thus, dys-regulated NPY may be an adverse outcome for exposure to low doses of DiNP in human beings.