Human exposure to toxic heavy metals is a global challenge. Concurrent exposure of heavy metals, such as lead (Pb), cadmium (Cd), arsenic (As) and methylmercury (MeHg) are particularly important due to their long lasting effects on the brain. The exact toxicological mechanisms invoked by exposure to mixtures of the metals Pb, Cd, As and MeHg are still unclear, however they share many common pathways for causing cognitive dysfunction. The combination of metals may produce additive/synergetic effects due to their common binding affinity with NMDA receptor (Pb, As, MeHg), Na - K ATP-ase pump (Cd, MeHg), biological Ca (Pb, Cd, MeHg), Glu neurotransmitter (Pb, MeHg), which can lead to imbalance between the pro-oxidant elements (ROS) and the antioxidants (reducing elements). In this process, ROS dominates the antioxidants factors such as GPx, GS, GSH, MT-III, Catalase, SOD, BDNF, and CERB, and finally leads to cognitive dysfunction. The present review illustrates an account of the current knowledge about the individual metal induced cognitive dysfunction mechanisms and analyse common Mode of Actions (MOAs) of quaternary metal mixture (Pb, Cd, As, MeHg). This review aims to help advancement in mixture toxicology and development of next generation predictive model (such as PBPK/PD) combining both kinetic and dynamic interactions of metals.

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Recent studies suggest universal fetal exposure to Bisphenol A (BPA) and its association with the adverse birth outcomes. Estimation of the fetal plasma BPA concentration from the maternal plasma BPA would be highly useful to predict its associated risk to this specific population. The objective of current work is to develop a pregnancy-physiologically based pharmacokinetic (P-PBPK) model to predict the toxicokinetic profile of BPA in the fetus during gestational growth, and to evaluate the developed model using biomonitoring data obtained from different pregnancy cohort studies. To achieve this objective, first, the adult PBPK model was developed and validated with the human BPA toxicokinetic data. This validated human PBPK model was extended to develop a P-PBPK model, which included the physiological changes during pregnancy and the fetus sub-model. The developed model would be able to predict the BPA pharmacokinetics (PKs) in both mother and fetus. Transplacental BPA kinetics parameters for this study were taken from the previous pregnant mice study. Both oral and dermal exposure routes were included into the model to simulate total BPA internal exposure. The impact of conjugation and deconjugation of the BPA and its metabolites on fetal PKs was investigated. The developed P-PBPK model was evaluated against the observed BPA concentrations in cord blood, fetus liver and amniotic fluid considering maternal blood concentration as an exposure source. A range of maternal exposure dose for the oral and dermal routes was estimated, so that simulation concentration matched the observed highest and lowest mother plasma concentration in different cohorts' studies. The developed model could be used to address the concerns regarding possible adverse health effects in the fetus being exposed to BPA and might be useful in identifying critical windows of exposure during pregnancy.

How the network around ROS protects against oxidative stress and Parkinson’s disease (PD), and how processes at the minutes timescale cause disease and aging after decades, remains enigmatic. Challenging whether the ROS network is as complex as it seems, we built a fairly comprehensive version thereof which we disentangled into a hierarchy of only five simpler subnetworks each delivering one type of robustness. The comprehensive dynamic model described in vitro data sets from two independent laboratories. Notwithstanding its five-fold robustness, it exhibited a relatively sudden breakdown, after some 80 years of virtually steady performance: it predicted aging. PD-related conditions such as lack of DJ-1 protein or increased α-synuclein accelerated the collapse, while antioxidants or caffeine retarded it. Introducing a new concept (aging-time-control coefficient), we found that as many as 25 out of 57 molecular processes controlled aging. We identified new targets for “life-extending interventions”: mitochondrial synthesis, KEAP1 degradation, and p62 metabolism.

In this paper we studied the exposure to three size fractions of outdoor particulate matter (PM10, PM2.5, and PM1) collected in an area influenced by a cement plant. For that purpose, three groups of population were evaluated (children, adults and retired) in two seasons (summer and winter). Outdoor measured PM concentrations, as well as physiological parameters and activity patterns of the three groups of population were used as input data in two different models. The first one was an indoor air quality model, used to elucidate indoor PM concentrations in different microenvironments. The second one was a dosimetry model, used to evaluate the internal exposure and the distribution of the different PM fractions in the respiratory tract. Results from the indoor air quality model showed that special attention must be paid to the finest particles, since they penetrate indoors in a greater degree. Highest pulmonary doses for the three PM sizes were reported for retired people, being this a result of the high amount of time in outdoor environments exercising lightly. For children, the exposure was mainly influenced by the time they also spend outdoors, but in this case due to heavy intensity activities. It was noticed that deposition of fine particles was more significant in the pulmonary regions of children and retired people in comparison with adults, which has implications in the expected adverse health effects for those vulnerable groups of population.

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17Ecosystem services provide multiple benefits to human wellbeing and are increasingly considered by 18 policy-makers in environmental management. However, the uncertainty related with the monetary 19 valuation of these benefits is not yet adequately defined or integrated by policy-makers. Given this 20 background, our aim was to quantify different sources of uncertainty when performing monetary 21 valuation of ecosystem services, in order to provide a series of guidelines to reduce them. With an 22 example of 4 ecosystem services (i.e., water provisioning, waste treatment, erosion protection, and 23 habitat for species) provided at the river basin scale, we quantified the uncertainty associated with 24 the following sources: (1) the number of services considered, (2) the number of benefits considered 25 for each service, (3) the valuation metrics (i.e. valuation methods) used to value benefits, and (4) the 26 uncertainty of the parameters included in the valuation metrics. Results indicate that the highest 27 uncertainty was caused by the number of services considered, as well as by the number of benefits 28 considered for each service, whereas the parametric uncertainty was similar to the one related to the 29 selection of valuation metric, thus suggesting that the parametric uncertainty, which is the only 30 uncertainty type commonly considered, was less critical than the structural uncertainty, which is in 31 turn mainly dependent on the decision-making context. Given the uncertainty associated to the 32 valuation structure, special attention should be given to the selection of services, benefits and 33 metrics according to a given context. 34

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