Nickel compounds are Group 1 carcinogens and possibly cancer-causing in the pancreas. We examined the toxicity of nickel in both 2-D and 3-D pancreatic cell cultures, to determine the LD50 for organic and inorganic nickel in normal and cancerous cells. Assays with cadmium chloride were performed to be a comparison to potential nickel-induced toxicity. Cells were exposed to twelve concentrations of NiCl2 or Ni-(Ac)2 for 48h (2-D), or six concentrations for 48 hours (3-D). There was a significant (P=0.0016) difference between HPNE and AsPC-1 LD50 values after cadmium exposure, at 69.9 µM and 29.2 µM, respectively. Neither form of nickel exhibited toxicity in 2-D or 3-D cultures, but after 48h, changes in spheroid morphology were observed. The inability of Ni to reduce viable cell numbers suggests a toxic mechanism that differs from cadmium, also a Group 1 carcinogen. The cell microenvironment was not a factor in nickel toxicity with no changes in viable cells in either 2-D or 3-D cultures. These studies only examined cytotoxicity, and not genotoxicity, a potential mechanism of nickel carcinogenicity. Alterations in DNA function or the expression of apoptotic proteins/processes would take longer to manifest. Current work focuses on cellular changes following extended nickel exposure.

This paper aims to present the importance of the benchmark dose (BMD) as a point of departure (the lowest dose or concentration in the experiment that deviates from the response that differs from the normal response) in toxicological risk assessment, as well as to present commonly used software for its calculation (BMDS and PROAST). Benchmark dose is defined as a statistical lower confidence limit of a dose that results in a small change in effect (5-10%) in comparison with the control value. The BMD approach is considered a substitution for the NOAEL approach, which uses the highest observed no-effect level (NOAEL) to obtain the reference dose. The BMD approach is a methodically more forward-thinking technique than the NOAEL approach because it has statistical power and provides a wide range of dose-response relationships and allows the determination of their uncertainty and variability. Moreover, the BMD approach contributes to the reduction of experimental animals in toxicity studies. Therefore, the European Food Safety Authority (EFSA) recommends the use of BMDL10 values for quantal and BMDL05 for continuous data.

Cadmium (Cd), one of the most abundant environmental pollutants, is considered to have endocrine disrupting properties. However, data on the dose-response relationship between Cd dose and levels of hormones have been insufficiently studied, especially in human data sets. Thus, the aim of this study was to determine the possibility of analyzing data obtained from a case-control study in female patients with benign/malignant breast tumors, using the Benchmark dose (BMD) concept. The collected data on Cd levels in breast tissue and estrogen serum levels were processed in PROAST software using different variables. The dose-response relationship between the internal dose of Cd and estradiol levels in the serum was investigated and BMD intervals were calculated. The dose-response relationship between the Cd concentration in breast tissue and the estradiol serum level was shown, indicating lower estradiol serum levels as a consequence of higher Cd concentrations in breast tissue. As one of the few studies analyzing human data using the BMD approach, these findings could have a pivotal role in dose response analysis of data collected from human studies.

Perand poly-fluorinated alkyl substances (PFAS) have been used for decades in a great variety of processes and products by virtue of their exceptional properties, versatility and chemical stability. Nevertheless, it is increasingly recognized that these substances can represent a serious hazard to human health and living organisms due to their persistence, long-range transport potential and tendency to accumulate in biota. For this reason, some efforts have been made across the EU to identify alternative molecules, with a shorter carbon chain and theoretically safer profile, that might replace the previous generation of legacy PFAS. Unfortunately, this strategy has not been entirely successful and serious concerns are still posed by PFAS in different human populations. Among others, an emerging aspect is represented by the adverse effects that both legacy and alternative PFAS can exert on the human endocrine system, with respect to vulnerable target subpopulations. In this review we will briefly summarize PFAS properties, uses and environmental fate, focusing on their effects on human reproductive capacity and fertility, body weight control and obesity as well as thyroid function.

Mercury (Hg) is one of the most important environmental pollutants with endocrinedisrupting properties. There is little data from epidemiological studies describing the doseresponse relationship between toxic metal levels and hormone levels. The aim of this study was to use the nearest neighbor matching analysis to determine the difference in Hg concentration in healthy/sick subjects with thyroid disease and to use Benchmark modeling to determine the doseresponse relationship between Hg levels in the blood and thyroid-stimulating hormone (TSH) and thyroid hormones in serum. Blood samples were collected and used for Hg measurement using the ICP-MS method, and separated serum was used for hormone analysis. The study showed the existence of a statistically significant difference in Hg levels measured in healthy and sick subjects and the existence of a dose-response relationship between Hg and all measured hormones, with a narrow interval obtained for the Hg-TSH pair. The results of this research support the use of the Benchmark dose approach for the purpose of analyzing data from human studies, and our further research will be focused on examining the impact of low doses on animal models in order to determine more precise effects of low doses on the organism.