Refined reference doses and new procedures for phthalate mixture risk assessment focused on male developmental toxicity

New procedures for phthalate mixture risk assessments (MRAs) focused on male developmental toxicity (anti-androgenicity) are overdue. Previous efforts suffer from several shortcomings: There is a lack of consistency in terms of the phthalates entered into the assessments, and in the choice of tolerable intakes. Many of these values do not reflect new evidence about low dose male developmental effects. Nearly all previous mixture risk assessments have focused solely on phthalates, with no regard for exposures to other chemicals that also induce male developmental toxicity, leading to underestimations of risks. Here, we address these weaknesses and inconsistencies by proposing criteria for the selection of phthalates for MRA based on structure-activity relationships. We suggest new reference doses for phthalates for use in MRA, as follows: DBP 6.7 μg/kg/d, DIBP 100 μg/kg/d, BBP 10 μg/kg/d, DEHP 10 μg/kg/d, DINP 59 μg/kg/d. We conclude that the fixation on the Hazard Index (HI) = 1 as signalling acceptable combined phthalate exposures is misguided as it ignores co-exposure to other anti-androgenic chemicals that also contribute to male developmental risks. Until more comprehensive assessments of phthalates in combination with other anti-androgens become feasible, we propose the use of a HI of 0.1–0.2 as a benchmark for interpreting phthalate mixture risk assessments

Application of the linear network model of finding the shortest way of evacuation of the population

The report considers an algorithm for solving the problem of advance evacuation of the population, which is formulated as finding the shortest path in a linear network model representing the routes of movement along the existing transport network of roads with a cycle. The starting point is the prefabricated evacuation point, and the final one is the receiving evacuation point, the numbers on the edges are the length of the path between the intermediate points

Effect of Physisporinus vitreus on wood properties of Norway spruce. Part 1: Aspects of delignification and surface hardness

The white rot fungus Physisporinus vitreus is currently tested for several biotechnological applications such as permeability improvement of refractory wood species or the optimization of the acoustic properties of wood for violins. The enzymatic activity of P. vitreus results in the degradation of pit membranes and simultaneous alterations of the tracheid cell wall structure in wood of Norway spruce [Picea abies (L.) Karst]. By this means, selective delignification and simultaneous degradation occur in the latewood tracheids at short incubation times. To study the delignification of individual cell wall layers in latewood tracheids, cellular UV-microspectrophotometry was applied to wood of Norway spruce that had been incubated for between 3 and 9weeks. By means of this technique, the progressing delignification was demonstrated in the latewood tracheid secondary walls. Moreover, local delignification in close proximity to hyphal tunneling, cavities, and notches was evident. Additionally, the mechanical changes were measured (a) at the macroscopic level by Brinell hardness test and (b) at the cellular level by nanoindentation. Brinell hardness was significantly reduced with increasing incubation time which was attributed to the partial delignification. Unlike Brinell tests, results from nanoindentation tests did not show a clear effect of fungal activity because of the material heterogeneity and the high spatial resolution of this technique. The present study provides methodological approaches for the investigation of wood-fungus interactions and contributes to a better understanding of the characteristics of wood decay at the subcellular level caused by the white rot fungus P. vitreus. Moreover, it establishes the basis for a subsequent chemical analysis, for which the results will be the topic of a second paper in this serie

Intravitreal treatment in patients with exudative age-related macular degeneration and visual acuity ≤ 0.05

Background: To investigate intravitreal treatment efficiencies in patients suffering from exudative ARMD with a BCVA ≤ 0.05. Methods: Retrospective analysis: Analysis parameters were lesion type, BCVA at baseline and at follow-up, the intravitreal drug used, and its application frequency. Patients were divided into: 1) following injections of bevacizumab, triamcinolone, their combination, or ranibizumab regardless of their lesion subtype, 2) or by lesion subtype. Statistical tests were performed using Wilcoxon signed-rank tests, Kruskal-Wallis tests and multivariable logistic regressions. Results: Seventy four eyes of 74 patients were analyzed. Follow-up was at 12.0 to 15.7 weeks. Median difference of BCVA (logMAR) between baseline and follow-up was 0.000 (−0.030, 0.175) in classic (p = 0.105), 0.000 (−1.15, 0.20) in occult (p = 0.005), −0.200 (−1.20, 0.60) in cases with subretinal fluid (p = 0.207), 0.000 (-0.60, 0.30) in pigment epithelial detachment (p = 0.813), and 0.050 (−0.40, 0.70) in Junius Kuhnt maculopathy (p = 0.344). BCVA increased ≥ 0.2 logMAR in 4 (24 %) classic, 9 (47 %) occult, 6 (33 %) pigment epithelial detachment, 6 (55 %) subretinal fluid, in 29 (39 %) eyes regardless of the lesion type, and reached a BCVA ≥ 0.05 in 7 (9 %) of those with a baseline BCVA <0.05. Conclusions: Results indicate that in patients with ARMD and a BCVA lower 0.05, intravitreal treatment may improve visual acuity, most probably in cases with occult lesions.<br

Role of clothing in both accelerating and impeding dermal absorption of airborne SVOCs

To assess the influence of clothing on dermal uptake of semi-volatile organic compounds (SVOCs), we measured uptake of selected airborne phthalates for an individual wearing clean clothes or air-exposed clothes and compared these results with dermal uptake for bare-skinned individuals under otherwise identical experimental conditions. Using a breathing hood to isolate dermal from inhalation uptake, we measured urinary metabolites of diethylphthalate (DEP) and di-n-butylphthalate (DnBP) from an individual exposed to known concentrations of these compounds for 6 h in an experimental chamber. The individual wore either clean (fresh) cotton clothes or cotton clothes that had been exposed to the same chamber air concentrations for 9 days. For a 6-h exposure, the net amounts of DEP and DnBP absorbed when wearing fresh clothes were, respectively, 0.017 and 0.007 μg/kg/(μg/m3); for exposed clothes the results were 0.178 and 0.261 μg/kg/(μg/m3), respectively (values normalized by air concentration and body mass). When compared against the average results for bare-skinned participants, clean clothes were protective, whereas exposed clothes increased dermal uptake for DEP and DnBP by factors of 3.3 and 6.5, respectively. Even for non-occupational environments, wearing clothing that has adsorbed/absorbed indoor air pollutants can increase dermal uptake of SVOCs by substantial amounts relative to bare skin

Is bisphenol-A exposure during pregnancy associated with blood glucose levels or diagnosis of gestational diabetes?

Recent epidemiological studies indicate bisphenol A (BPA), an estrogenic chemical used in production of epoxy, polycarbonate, and plastic may increase risk of insulin resistance and type 2 diabetes. Exposure to BPA during pregnancy may contribute to development of gestational diabetes mellitus (GDM), a precursor to type 2 diabetes in women. This pilot study examined the association between BPA exposure, fasting blood glucose levels (FBG), and GDM diagnosis during pregnancy. Banked urine samples from 22 cases of GDM and 72 controls were analyzed for total (free BPA + conjugates) urinary BPA concentrations (μg/L). FBG levels (mg/dl) were obtained from 1-h 50-g glucose tolerance tests (GTT) that women underwent for routine GDM screening (mean gestational age = 26.6 weeks, SD = 3.8). Those with an initial screening value ≥ 135 mg/dl underwent 3-h 100 g oral GTT. GDM diagnoses were made when the initial screening value was ≥ 200 mg/dl or when values at ≥ 2 time points exceeded 3-h oral GTT thresholds. Among controls, median FBG levels (mg/dL) did not differ across exposure tertiles, defined according to the distribution of total specific-gravity-adjusted urinary BPA concentrations. Logistic regression models controlling for race/ethnicity did not provide evidence of association between BPA exposure and case status across increasing tertiles of BPA exposure (number of GDM cases/controls in tertile1: 13/24; in tertile 2: 6/24; in tertile 3: 3/24). Findings do not support a relationship between total urinary BPA concentrations and altered glucose metabolism during pregnancy. However, due to study limitations, findings need to be interpreted with caution

Obesity or diet? Levels and determinants of phthalate body burden – A case study on Portuguese children

In this study we analyzed one of the most comprehensive sets of 21 urinary phthalate metabolites representing exposure to 11 parent phthalates (DEP, DMP, DiBP, DnBP, BBzP, DEHP, DiNP, DiDP, DCHP, DnPeP, DnOP) in first morning urine samples of 112 Portuguese children (4-18 years) sampled in 2014/15. The study population consisted of two groups: group 1 with normal weight/underweight children (N = 43) following their regular diet and group 2 with obese/overweight children (N = 69) following a healthy diet (with nutritional counselling). Most of the metabolites were above the limits quantification (81-100%) except for MCHP, MnPEP and MnOP. Metabolite levels were generally comparable to other recent child and general populations sampled worldwide, confirming the steady decline in exposures to most phthalates. Compared to Portuguese children sampled in 2011/2012, median urinary metabolite levels decreased by approximately 50% for DEHP, DnBP, DiBP and BBzP. Risk assessments for individual phthalates and the sum of the anti-androgenic phthalates did not indicate to attributable health risks, also at the upper percentiles of exposure. In the healthy diet group the median concentration of the DEHP metabolites was significant lower, while all phthalate metabolites except MEP tended to be lower compared to the regular diet group. Multiple log-linear regression analyses revealed significantly lower daily intakes (DIs) for all phthalates in the healthy diet group compared to the regular diet group (geometric mean ratios (gMR) between 0.510-0.618; p ≤ 0.05), except for DEP (gMR: 0.811; p = 0.273). The same analyses with the continuous variable body mass index instead of the diet groups also showed effects on the DIs (gMRs between 0.926-0.951; p ≤ 0.05), however much smaller than the effects of the diet. The results indicate that obese children following a healthy diet composed of fresh and less packaged/processed food can considerably reduce their intake for most phthalates and can have lower phthalate intakes than regular weight/regular diet children.Luísa Correia-Sá is grateful to Fundação para a Ciência e a Tecnologia (FCT) by the grant (SFRH/BD/87019/2012), financed by POCH, subsidized by Fundo Social Europeu and Ministério da Ciência, Tecnologia e Ensino Superior. The authors are thankful to the project Qualidade e Segurança Alimentar – uma abordagem (nano)tecnológica, reference NORTE-01-0145-FEDER-000011.info:eu-repo/semantics/publishedVersio

Hexamoll(R) DINCH and DPHP metabolites in urine of children and adolescents in Germany: Human biomonitoring results of the German Environmental Survey GerES V, 2014-2017

The production and use of the plasticisers Hexamoll(R) DINCH (di-(iso-nonyl)-cyclohexane-1,2-dicarboxylate) and DPHP (di-(2-propylheptyl) phthalate) have increased after both chemicals were introduced into the market in the early 2000s as substitutes for restricted high molecular weight phthalates. During the population representative German Environmental Survey (GerES) of Children and Adolescents (GerES V, 2014–2017), we collected urine samples and measured the concentrations of DINCH and DPHP metabolites in 2228 and in a subsample of 516 participants, respectively. We detected DINCH and DPHP metabolites in 100% and 62% of the 3-17 years old children and adolescents, respectively. Geometric means of DINCH metabolites were 2.27 μg/L for OH-MINCH, 0.93 μg/L for oxo-MINCH, 1.14 μg/L for cx-MINCH and 3.47 μg/L for DINCH (Σ of OH-MINCH + cx-MINCH). Geometric means of DPHP metabolites were 0.30 μg/L for OH-MPHP, 0.32 µg/L for oxo-MPHP and 0.64 μg/L for DPHP (Σ of OH-MPHP + oxo-MPHP). The 3-5 years old children had almost 3-fold higher DINCH biomarkers levels than adolescents (14-17 years). Higher concentrations of DPHP biomarkers among young children only became apparent after creatinine adjustment. Urinary levels of DINCH but not of DPHP biomarkers were associated with the levels of the respective plasticisers in house dust. When compared to HBM health-based guidance values, we observed no exceedance of the HBM-I value of 1 mg/L for DPHP (Σ of OH-MPHP + oxo-MPHP). However, 0.04% of the children exceeded the health based guidance value HBM-I of 3 mg/L for DINCH (Σ of OH-MINCH + cx-MINCH). This finding shows that even a less toxic replacement of restricted chemicals can reach exposures in some individuals, at which, according to current knowledge, health impacts cannot be excluded with sufficient certainty. In conclusion, we provide representative data on DINCH and DPHP exposure of children and adolescents in Germany. Further surveillance is warranted to assess the substitution process of plasticisers, and to advise exposure reduction measures, especially for highly exposed children and adolescents. Providing the results to the European HBM Initiative HBM4EU will support risk assessment and risk management not only in Germany but also in Europe

Transdermal uptake of diethyl phthalate and di(n-butyl) phthalate directly from air: Experimental verification

Background: Fundamental considerations indicate that, for certain phthalate esters, dermal absorption from air is an uptake pathway that is comparable to or larger than inhalation. Yet this pathway has not been experimentally evaluated and has been largely overlooked when assessing uptake of phthalate esters. Objectives: This study investigated transdermal uptake, directly from air, of diethyl phthalate (DEP) and di(n-butyl) phthalate (DnBP) in humans. Methods: In a series of experiments, six human participants were exposed for six hours in a chamber containing deliberately elevated air concentrations of DEP and DnBP. The participants either wore a hood and breathed air with phthalate concentrations substantially below those in the chamber or did not wear a hood and breathed chamber air. All urinations were collected from initiation of exposure until 54 hours later. Metabolites of DEP and DnBP were measured in these samples and extrapolated to parent phthalate intakes, corrected for background and hood air exposures. Results: For DEP the median dermal uptake directly from air was 4.0 µg/(µg/m3 in air) compared with an inhalation intake of 3.8 µg/(µg/m3 in air). For DnBP the median dermal uptake from air was 3.1 µg/(µg/m3 in air) compared with an inhalation intake of 3.9 µg/(µg/m3 in air). Conclusions: This study shows that dermal uptake directly from air can be a meaningful exposure pathway for DEP and DnBP. For other semivolatile organic compounds (SVOCs) whose molecular weight and Kow are in the appropriate range, direct absorption from air is also anticipated to be significant