The reference values in the interpretation of toxicological data

The worldwide gradual expansion of industrialization has led to a dramatic increase in the production and use of chemical substances. This has resulted in a greater dispersion of these elements in the environment and in an increased exposure of the general population and workers. In this scenario, a thorough knowledge of exposure levels is needed in order to assess chemical risks in environmental and occupational settings. Biological monitoring is among the most useful tools for assessing exposure. However, in order to provide really effective guidance in the application/implementation of risk management measures, biomonitoring results need to be compared with appropriate references. Reference values (RVs) are an excellent resource since useful information for a correct interpretation of toxicological data can be obtained by comparing them with biomonitoring results. In the field of public health, this may enable us to identify potential sources of exposure, define the principal and most frequently exploited routes of exposure, and outline chemical absorption. Similarly, in occupational medicine, RVs can be used to give meaning to biomonitoring findings, especially when a biological limit value is not available for the chemical in question. Furthermore, these values are a valid tool for assessing exposure to chemical carcinogens. Therefore, by integrating reference values in an appropriate and complete system of guide values that also includes action levels and biological limit values, we could obtain both an adequate assessment of exposure and a better understanding of toxicological data.Key words: Biological limit values, biological monitoring, chemical risk, exposure assessment, reference values     

Structure and Properties of Cast Ti-Al-Si Alloys

Intermetallic compounds based on Ti-Al- (Si) are attractive materials with good thermal stability and low density. However, the production of these materials is quite complicated. Partially modified conventional methods of melting metallurgy are most often used due to availability, possible high productivity, and relatively low production costs. Therefore, some technologies for the production of intermetallics based on Ti-Al are currently available, but with certain disadvantages, which are caused by poor casting properties or extreme reactivity of the melt with crucibles. Some shortcomings can be eliminated by modifying the melting technology, which contributes to increasing the cost of the process. The work deals with the preparation of Ti-Al-Si intermetallic compounds with different contents of aluminum and silicon, which were produced by centrifugal casting in an induction vacuum furnace Linn Supercast-Titan. This process could contribute to the commercial use of these alloys in the future. For this research, the TiAl15Si15(in wt.%) alloy was selected, which represents a balanced ratio of aluminides and silicides in its structure, and the TiAl35Si5 alloy, which due to the lower silicon content allows better melting conditions, especially with regard to the melting temperature. This alloy was also investigated after HIP (“Hot Isostatic Pressing”) treatment.     

Pharmacokinetics of Piperaquine Transfer into the Breast Milk of Melanesian Mothers

Transfer of piperaquine (PQ) into breast milk was examined in 27 Papua New Guinean women given a 3-day course of dihydroartemisinin-PQ or sulfadoxine-pyrimethamine-PQ during the second/third trimester. Breast milk was sampled on days 1, 2, 3 to 5, 7 to 11, and 14 to 17 postdelivery, a median of 70 days postdose (range, 6 to 145 days). A blood sample was taken at delivery, and additional serial samples were available from 9 women who delivered within 42 days of dosing. Milk and plasma PQ were assayed by high-performance liquid chromatography. A population-based approach was used to model the log_e(plasma) and milk concentration-time data. A sigmoid E_max model best described PQ breast milk transfer. The population average milk:plasma PQ ratio was 0.58, with a peak of 2.5 at delivery. The model-derived maximum milk intake (148 ml/kg of body weight/day) was similar to the accepted value of 150 ml/kg/day. The median estimated absolute and relative cumulative infant PQ doses were 22 μg and 0.07%, respectively, corresponding to absolute and relative daily doses of 0.41 μg/kg and 0.004%. Model-based simulations for PQ treatment regimens given at birth, 1 week postdelivery, and 6 weeks postdelivery showed that the highest median estimated relative total infant dose (0.36%; median absolute total dose of 101 μg/kg) was seen after maternal PQ treatment 6 weeks postpartum. The maximum simulated relative total and daily doses from any scenario were 4.3% and 2.5%, respectively, which were lower than the recommended 10% upper limit. Piperaquine is transferred into breast milk after maternal treatment doses, but PQ exposure for suckling infants appears safe.     

Fetal Size in a Rural Melanesian Population with Minimal Risk Factors for Growth Restriction: An Observational Ultrasound Study from Papua New Guinea

We conducted a prospective longitudinal study of fetal size in rural Papua New Guinea (PNG) involving 439 ultrasound-dated singleton pregnancies with no obvious risk factors for growth restriction. Sonographically estimated fetal weights (EFWs; N = 788) and birth weights (N = 376) were included in a second-order polynomial regression model (optimal fit) to generate fetal weight centiles. Means for specific fetal biometric measurements were also estimated. Fetal weight centiles from a healthy PNG cohort were consistently lower than those derived from Caucasian and Congolese populations, which overestimated the proportion of fetuses measuring small for gestational age (SGA; < 10th centile). Tanzanian and global reference centiles (Caucasian weight reference adapted to our PNG cohort) were more similar to those observed in our cohort, but the global reference underestimated SGA. Individual biometric measurements did not differ significantly from other cohorts. In rural PNG, a locally derived nomogram may be most appropriate for detection of SGA fetuses.     

Calibration and validation of toxicokinetic-toxicodynamic models for three neonicotinoids and some aquatic macroinvertebrates

Ecotoxicology - Exposure patterns in ecotoxicological experiments often do not match the exposure profiles for which a risk assessment needs to be performed. This limitation can be overcome by...     

The impact of descriptive norms on motivation to participate in cancer screening – Evidence from online experiments

ObjectiveThe current study tested in two online experiments whether manipulating normative beliefs about cancer screening uptake increases intention to attend colorectal screening among previously disinclined individuals.Methods2461 men and women from an Internet panel (Experiment 1 N = 1032; Experiment 2, N = 1423) who initially stated that they did not intend to take up screening were asked to guess how many men and women they believe to get screened for colorectal cancer. Across participants, we varied the presence/absence of feedback on the participant’s estimate, as well as the stated proportion of men and women doing the screening test.ResultsAcross the two experiments, we found that receiving one of the experimental messages stating that uptake is higher than estimated significantly increased the proportion of disinclined men and women becoming intenders. While, we found a positive relationship between the communicated uptake and screening intentions, we did not find evidence that providing feedback on the estimate has an added benefit.ConclusionScreening intention can be effectively manipulated through a high uptake message.Practice implicationsCommunication of high screening uptake is an easy and effective way to motivate disinclined individuals to engage in colorectal cancer screening.     

ER stress abrogates the immunosuppressive effect of IL-10 on human macrophages through inhibition of STAT3 activation

Inflammation Research - To determine whether ER stress affects the inhibitory pathways of the human immune system, particularly the immunosuppressive effect of IL-10 on macrophages. In vitro...     

Predisposing germline mutations in high hyperdiploid acute lymphoblastic leukemia in children

High hyperdiploidy (HD) is the most common cytogenetic subtype of childhood acute lymphoblastic leukemia (ALL), and a higher incidence of HD has been reported in ALL patients with congenital cancer syndromes. We assessed the frequency of predisposing germline mutations in 57 HD‐ALL patients from the California Childhood Leukemia Study via targeted sequencing of cancer‐relevant genes. Three out of 57 patients (5.3%) harbored confirmed germline mutations that were likely causal, in NBN, ETV6, and FLT3, with an additional six patients (10.5%) harboring putative predisposing mutations that were rare in unselected individuals (<0.01% allele frequency in the Exome Aggregation Consortium, ExAC) and predicted functional (scaled CADD score ≥ 20) in known or potential ALL predisposition genes (SH2B3, CREBBP, PMS2, MLL, ABL1, and MYH9). Three additional patients carried rare and predicted damaging germline mutations in GAB2, a known activator of the ERK/MAPK and PI3K/AKT pathways and binding partner of PTPN11‐encoded SHP2. The frequency of rare and predicted functional germline GAB2 mutations was significantly higher in our patients (2.6%) than in ExAC (0.28%, P = 4.4 × 10^?3), an observation that was replicated in ALL patients from the TARGET project (P = .034). We cloned patient GAB2 mutations and expressed mutant proteins in HEK293 cells and found that frameshift mutation P621fs led to reduced SHP2 binding and ERK1/2 phosphorylation but significantly increased AKT phosphorylation, suggesting possible RAS‐independent leukemogenic effects. Our results support a significant contribution of rare, high penetrance germline mutations to HD‐ALL etiology, and pinpoint GAB2 as a putative novel ALL predisposition gene.