Principles of environmentally-sustainable anaesthesia: a global consensus statement from the World Federation of Societies of Anaesthesiologists.

The Earth's mean surface temperature is already approximately 1.1°C higher than pre-industrial levels. Exceeding a mean 1.5°C rise by 2050 will make global adaptation to the consequences of climate change less possible. To protect public health, anaesthesia providers need to reduce the contribution their practice makes to global warming. We convened a Working Group of 45 anaesthesia providers with a recognised interest in sustainability, and used a three-stage modified Delphi consensus process to agree on principles of environmentally sustainable anaesthesia that are achievable worldwide. The Working Group agreed on the following three important underlying statements: patient safety should not be compromised by sustainable anaesthetic practices; high-, middle- and low-income countries should support each other appropriately in delivering sustainable healthcare (including anaesthesia); and healthcare systems should be mandated to reduce their contribution to global warming. We set out seven fundamental principles to guide anaesthesia providers in the move to environmentally sustainable practice, including: choice of medications and equipment; minimising waste and overuse of resources; and addressing environmental sustainability in anaesthetists' education, research, quality improvement and local healthcare leadership activities. These changes are achievable with minimal material resource and financial investment, and should undergo re-evaluation and updates as better evidence is published. This paper discusses each principle individually, and directs readers towards further important references.

Incidence, mortality and survival in malignant pleural mesothelioma before and after asbestos in Denmark, Finland, Norway and Sweden.

BACKGROUND: Malignant pleural mesothelioma (MPM) is a rare but fatal cancer, which is largely caused by exposure to asbestos. Reliable information about the incidence of MPM prior the influence of asbestos is lacking. The nationwide regional incidence trends for MPM remain poorly characterized. We use nationwide MPM data for Denmark (DK), Finland (FI), Norway (NO) and Sweden (SE) to assess incidence, mortality and survival trends for MPM in these countries. METHODS: We use the NORDCAN database for the analyses: incidence data were available from 1943 in DK, 1953 in FI and NO and 1958 in SE, through 2016. Survival data were available from 1967 through 2016. World standard population was used in age standardization. RESULTS: The lowest incidence that we recorded for MPM was 0.02/100,000 for NO women and 0.05/100,000 for FI men in 1953-57, marking the incidence before the influence of asbestos. The highest rate of 1.9/100,000 was recorded for DK in 1997. Female incidence was much lower than male incidence. In each country, the male incidence trend for MPM culminated, first in SE around 1990. The regional incidence trends matched with earlier asbestos-related industrial activity, shipbuilding in FI and SE, cement manufacturing and shipbuilding in DK and seafaring in NO. Relative 1-year survival increased from about 20 to 50% but 5-year survival remained at or below 10%. CONCLUSION: In the Nordic countries, the male incidence trends for MPM climaxed and started to decrease, indicating that the prevention of exposure was beneficial. Survival in MPM has improved for both sexes but long-term survival remains dismal.

Inhalation cancer risk assessment for environmental exposure to hexavalent chromium: Comparison of margin-of-exposure and linear extrapolation approaches.

Hexavalent chromium [Cr(VI)] exists in the ambient air at low concentrations (average upperbound ~0.1 ng/m3) yet airborne concentrations typically exceed EPA's Regional Screening Level for residential exposure (0.012 ng/m3) and other similar benchmarks, which assume a mutagenic mode of action (MOA) and use low-dose linear risk assessment models. We reviewed Cr(VI) inhalation unit risk estimates developed by researchers and regulatory agencies for environmental and occupational exposures and the underlying epidemiologic data, updated a previously published MOA analysis, and conducted dose-response modeling of rodent carcinogenicity data to evaluate the need for alternative exposure-response data and risk assessment approaches. Current research supports the role of non-mutagenic key events in the MOA, with growing evidence for epigenetic modifiers. Animal data show a weak carcinogenic response, even at cytotoxic exposures, and highlight the uncertainties associated with the current epidemiological data used in risk assessment. Points of departure from occupational and animal studies were used to determine margins of exposure (MOEs). MOEs range from 1.5 E+3 to 3.3 E+6 with a median of 5 E+5, indicating that current environmental exposures to Cr(VI) in ambient air should be considered of low concern. In this comprehensive review, the divergent results from default linear and MOE assessments support the need for more relevant and robust epidemiologic data, additional mechanistic studies, and refined risk assessment strategies.

Deriving Compound-Specific Exposure Limits for Chemicals Used in Pharmaceutical Synthesis: Challenges in Expert Decision-Making Exemplified Through a Case Study-Based Workshop.

A workshop entitled "Deriving Compound-Specific Exposure Limits for Chemicals Used in Pharmaceutical Synthesis" was held at the 2018 Genetic Toxicology Association annual meeting. The objectives of the workshop were to provide an educational forum and use case studies and live multiple-choice polling to establish the degree of similarity/diversity in approach/opinion of the industry experts and other delegates present for some of the more challenging decision points that need to be considered when developing a compound-specific exposure limit (ie, acceptable intake or permissible or permitted daily exposure). Herein we summarize the relevant background and case study information for each decision point topic presented as well as highlight significant polling responses and discussion points. A common observation throughout was the requirement for expert judgment to be applied at each of the decision points presented which often results in different reasoning being applied by the risk assessor when deriving a compound-specific exposure limit. This supports the value of precompetitive cross-industry collaborations to develop compound-specific limits and harmonize the methodology applied, thus reducing the associated uncertainty inherent in the application of isolated expert judgment in this context. An overview of relevant precompetitive cross-industry collaborations working to achieve this goal is described.

Potential gains in life expectancy by attaining daily ambient fine particulate matter pollution standards in mainland China: A modeling study based on nationwide data.

BACKGROUND: Ambient fine particulate matter pollution (PM2.5) is one leading cause of disease burden, but no study has quantified the association between daily PM2.5 exposure and life expectancy. We aimed to assess the potential benefits in life expectancy by attaining the daily PM2.5 standards in 72 cities of China during 2013-2016. METHODS AND FINDINGS: We applied a two-stage approach for the analysis. At the first stage, we used a generalized additive model (GAM) with a Gaussian link to examine the city-specific short-term association between daily PM2.5 and years of life lost (YLL); at the second stage, a random-effects meta-analysis was used to generate the regional and national estimations. We further estimated the potential gains in life expectancy (PGLE) by assuming that ambient PM2.5 has met the Chinese National Ambient Air Quality Standard (NAAQS, 75 µg/m3) or the ambient air quality guideline (AQG) of the World Health Organization (WHO) (25 µg/m3). We also calculated the attributable fraction (AF), which denoted the proportion of YLL attributable to a higher-than-standards daily mean PM2.5 concentration. During the period from January 18, 2013 to December 31, 2016, we recorded 1,226,849 nonaccidental deaths in the study area. We observed significant associations between daily PM2.5 and YLL: each 10 µg/m3 increase in three-day-averaged (lag02) PM2.5 concentrations corresponded to an increment of 0.43 years of life lost (95% CI: 0.29-0.57). We estimated that 168,065.18 (95% CI: 114,144.91-221,985.45) and 68,684.95 (95% CI: 46,648.79-90,721.11) years of life lost can be avoided by achieving WHO's AQG and Chinese NAAQS in the study area, which corresponded to 0.14 (95% CI: 0.09-0.18) and 0.06 (95% CI: 0.04-0.07) years of gain in life expectancy for each death in these cities. We observed differential regional estimates across the 7 regions, with the highest gains in the Northwest region (0.28 years of gain [95% CI: 0.06-0.49]) and the lowest in the North region (0.08 [95% CI: 0.02-0.15]). Furthermore, using WHO's AQG and Chinese NAAQS as the references, we estimated that 1.00% (95% CI: 0.68%-1.32%) and 0.41% (95% CI: 0.28%-0.54%) of YLL could be attributable to the PM2.5 exposure at the national level. Findings from this study were mainly limited by the unavailability of data on individual PM2.5 exposure. CONCLUSIONS: This study indicates that significantly longer life expectancy could be achieved by a reduction in the ambient PM2.5 concentrations. It also highlights the need to formulate a stricter ambient PM2.5 standard at both national and regional levels of China to protect the population's health.

Air Pollution and Mortality in the Medicare Population.

BACKGROUND: Studies have shown that long-term exposure to air pollution increases mortality. However, evidence is limited for air-pollution levels below the most recent National Ambient Air Quality Standards. Previous studies involved predominantly urban populations and did not have the statistical power to estimate the health effects in underrepresented groups. METHODS: We constructed an open cohort of all Medicare beneficiaries (60,925,443 persons) in the continental United States from the years 2000 through 2012, with 460,310,521 person-years of follow-up. Annual averages of fine particulate matter (particles with a mass median aerodynamic diameter of less than 2.5 µm [PM2.5]) and ozone were estimated according to the ZIP Code of residence for each enrollee with the use of previously validated prediction models. We estimated the risk of death associated with exposure to increases of 10 µg per cubic meter for PM2.5 and 10 parts per billion (ppb) for ozone using a two-pollutant Cox proportional-hazards model that controlled for demographic characteristics, Medicaid eligibility, and area-level covariates. RESULTS: Increases of 10 µg per cubic meter in PM2.5 and of 10 ppb in ozone were associated with increases in all-cause mortality of 7.3% (95% confidence interval [CI], 7.1 to 7.5) and 1.1% (95% CI, 1.0 to 1.2), respectively. When the analysis was restricted to person-years with exposure to PM2.5 of less than 12 µg per cubic meter and ozone of less than 50 ppb, the same increases in PM2.5 and ozone were associated with increases in the risk of death of 13.6% (95% CI, 13.1 to 14.1) and 1.0% (95% CI, 0.9 to 1.1), respectively. For PM2.5, the risk of death among men, blacks, and people with Medicaid eligibility was higher than that in the rest of the population. CONCLUSIONS: In the entire Medicare population, there was significant evidence of adverse effects related to exposure to PM2.5 and ozone at concentrations below current national standards. This effect was most pronounced among self-identified racial minorities and people with low income. (Supported by the Health Effects Institute and others.).

Adverse Cardiovascular Effects of Traffic Noise with a Focus on Nighttime Noise and the New WHO Noise Guidelines.

Exposure to traffic noise is associated with stress and sleep disturbances. The World Health Organization (WHO) recently concluded that road traffic noise increases the risk for ischemic heart disease and potentially other cardiometabolic diseases, including stroke, obesity, and diabetes. The WHO report focused on whole-day noise exposure, but new epidemiological and translational field noise studies indicate that nighttime noise, in particular,is an important risk factor for cardiovascular disease (CVD) through increased levels of stress hormones and vascular oxidative stress, leading to endothelial dysfunction and subsequent development of various CVDs. Novel experimental studies found noise to be associated with oxidative stress-induced vascular and brain damage, mediated by activation of the NADPH oxidase, uncoupling of endothelial and neuronal nitric oxide synthase, and vascular/brain infiltration with inflammatory cells. Noise-induced pathophysiology was more pronounced in response to nighttime as compared with daytime noise. This review focuses on the consequences of nighttime noise.

Reflections on the OECD guidelines for in vitro skin absorption studies.

At the 8th conference of Occupational and Environmental Exposure of the Skin to Chemicals (OEESC) (16-18 September 2019) in Dublin, Ireland, several researchers performing skin permeation assays convened to discuss in vitro skin permeability experiments. We, along with other colleagues, all of us hands-on skin permeation researchers, present here the results from our discussions on the available OECD guidelines. The discussions were especially focused on three OECD skin absorption documents, including a recent revision of one: i) OECD Guidance Document 28 (GD28) for the conduct of skin absorption studies (OECD, 2004), ii) Test Guideline 428 (TGD428) for measuring skin absorption of chemical in vitro (OECD, 2004), and iii) OECD Guidance Notes 156 (GN156) on dermal absorption issued in 2011 (OECD, 2011). GN156 (OECD, 2019) is currently under review but not finalized. A mutual concern was that these guidance documents do not comprehensively address methodological issues or the performance of the test, which might be partially due to the years needed to finalize and update OECD documents with new skin research evidence. Here, we summarize the numerous factors that can influence skin permeation and its measurement, and where guidance on several of these are omitted and often not discussed in published articles. We propose several improvements of these guidelines, which would contribute in harmonizing future in vitro skin permeation experiments.

Too loud? Do powered hand dryers violate federal noise exposure standards?

OBJECTIVE: The aim of this study was to determine if high-powered air hand dryers produce sufficient noise to warrant concern over acoustic trauma as determined by federally established standards. STUDY DESIGN: Prospective observational field data collection SETTING: Urban and suburban community SUBJECTS AND METHODS: Using a NIOSH developed and calibrated soundmeter app, powered hand dryers were measured throughout two metropolitan areas. Ear level measurements were performed while drying wet hands. Recorded variables included average LAeq, Time-Weighted Average, Max and Peak Levels, Noise Dose, and Projected Dose according to NIOSH and OSHA standards, and all three major weighting networks (A, C, and Z). RESULTS: Fifty-four trials were performed at 27 locations. Average dryer run time was 28.9 s (range 14-45 s). Average LAeq (dBA), average maximum level (dBA), and average TWA (dBA) were 90.46 ± 5.32, 94.86 ± 5.73, 59.90 ± 6.80, respectively. The noise generated exceeded published manufacturer specifications. However, even with estimated cumulative daily exposure, the noise generated by these dryers did not exceed federal safety standards. CONCLUSIONS: Air-powered hand dryers produce noise output at a level that many would find subjectively uncomfortable with some brands/models consistently producing noise in excess of 90 dBA. Nonetheless, these dryers do not produce sound exceeding NIOSH standards for noise exposure.

Permitted Daily Exposure Values: Application Considerations in Toxicological Risk Assessments.

Permitted daily exposure (PDE) values are used by some toxicologists to support the safety qualification of various types of impurities found in a drug substance (DS) or drug product (DP). Permitted daily exposure values are important tools for the toxicologist, but one must be aware of their limitations to ensure that they are used appropriately and effectively in the risk assessment process. First, a toxicologist must always perform a comprehensive analysis of all available animal and human safety data for an impurity, including identifying any data gaps that may exist. Second, if adequate data are available and there are no genotoxicity concerns, an appropriate well-designed repeat-dose toxicity study in animals should be chosen to calculate the PDE. It is important to note that PDE values qualify general systemic toxicity and not necessarily local toleration end points such as irritation and sensitization that are more concentration than dose dependent. In addition, a PDE value calculated from a general toxicity study in animals may not necessarily qualify for reproductive toxicology end points. Lastly, PDE values should never be thought of as analytical limits for or acceptable levels of an impurity in a DS or DP, as this ignores quality considerations. Using safety information from several chemicals as proxy impurities, this article serves as an educational primer to facilitate a better understanding of the development and use of PDE values in the risk assessment process.

Carbon monoxide poisoning.

Despite established exposure limits and safety standards as well as the availability of carbon monoxide (CO) alarms, each year 50,000 people in the United States visit emergency departments for CO poisoning. Carbon monoxide poisoning can occur from brief exposures to high levels of CO or from longer exposures to lower levels. Common symptoms can include headaches, nausea and vomiting, dizziness, general malaise, and altered mental status. Some patients may have chest pain, shortness of breath, and myocardial ischemia, and may require mechanical ventilation and treatment of shock. Individuals poisoned by CO often develop brain injury manifested by neurological problems, including cognitive sequelae, anxiety and depression, persistent headaches, dizziness, sleep problems, motor weakness, vestibular and balance problems, gaze abnormalities, peripheral neuropathies, hearing loss, tinnitus, Parkinsonian-like syndrome, and other problems. In addition, some will have cardiac issues or other ailments. While breathing oxygen hastens the removal of carboxyhemoglobin (COHb), hyperbaric oxygen (HBO2) hastens COHb elimination and favorably modulates inflammatory processes instigated by CO poisoning, an effect not observed with breathing normobaric oxygen. Hyperbaric oxygen improves mitochondrial function, inhibits lipid peroxidation transiently, impairs leukocyte adhesion to injured microvasculature, and reduces brain inflammation caused by the CO-induced adduct formation of myelin basic protein. Based upon three supportive randomized clinical trials in humans and considerable evidence from animal studies, HBO2 should be considered for all cases of acute symptomatic CO poisoning. Hyperbaric oxygen is indicated for CO poisoning complicated by cyanide poisoning, often concomitantly with smoke inhalation.

Use of interaction matrices to formalise the development of conceptual models of contaminant transport in the biosphere and the translation of those conceptual models into mathematical models.

In developing models of the biosphere for use in assessing the impacts on human health and the environment of releases of contaminants from disposal facilities for solid radioactive wastes or from contaminated legacy sites, there is a need to demonstrate that the models adopted are both comprehensive and appropriate to the assessment context. To achieve this end, it is useful to develop a structured approach to conceptual model development and it is here proposed that interaction matrices (IMs) provide a suitable framework. This process can provide a conceptual model expressed in terms of either a single IM or a nested set of IMs. The focus of the work described herein is the development of a transparent approach to translating such a set of IMs into a mathematical model, which is typically expressed as a set of ordinary differential equations complemented by algebraic expressions. Some remarks are also made on appropriate approaches to obtaining numerical solutions of these equations in circumstances where simplifications of the general equations can be justified. Overall, the intent is to provide background and guidance by providing a formal basis for the process in generalised terms.

An updated evaluation of potential health hazards associated with exposures to asbestos-containing drywall accessory products.

Following a previously published (2012) evaluation of the potential health hazards related to the use of asbestos-containing drywall accessory products, additional information regarding asbestos exposures during the use of accessory products, as well as studies of chrysotile asbestos risk as a function of exposure, have been published in the peer-reviewed literature. The purpose of this analysis is to update the original evaluation with this new information. It was previously estimated that a professional drywaller performing joint compound-associated tasks could have a lifetime cumulative chrysotile exposure of 12-26 f/cc-year. Using conservative assumptions regarding airborne asbestos levels during different drywalling tasks, task duration, and job tenure, we found that a range of 4.3-36.3 f/cc-year is a plausible estimate of a career drywaller's cumulative asbestos exposure from historical joint compound use. The estimated range for bystander exposures would be below (sometimes significantly below) this range depending on the frequency and duration of work near drywallers. Further, the estimated drywaller and bystander total fiber exposures were well below a recently published "no-observed adverse effect level, best estimate" for predominately chrysotile exposures of 89-168 f/cc-year for lung cancer and 208-415 f/cc-year for mesothelioma. We also determined that, even if the chrysotile or possibly talc ingredients in the drywall products had contained asbestiform tremolite, the cumulative tremolite exposures would have been well below a recently published tremolite no-effect level of 0.5-2.6 f/cc-year. Based on our calculations, typical drywall work using asbestos-containing drywall accessory products is not expected to increase the risk of asbestos-related lung cancer or mesothelioma. These conclusions are consistent with the lack of epidemiological evidence that drywall work resulted in an increased incidence of asbestos-related disease in the drywall trades.

Urinary 1H NMR metabolomics profile of Italian citizens exposed to background levels of arsenic: a (pre)cautionary tale.

Objectives: Arsenic is a toxic metal ubiquitous in the environment and in daily life items. Long-term arsenic exposure is associated with severe adverse health effects involving various target organs. It would be useful to investigate the existence of metabolic alterations associated with lifestyle and/or with the environment. For this purpose, we studied the correlation between urinary arsenic levels and urinary proton nuclear magnetic resonance spectroscopy (1H NMR) metabolomics profiles in a non-occupationally nor environmentally arsenic exposed general population.Methods: Urine samples were collected from 86 healthy subjects. Total and non-alimentary urinary arsenic (U-naAs) levels, namely the sum of arsenite, arsenate, monomethylarsonate and dimethylarsinate, were measured and 1H NMR analysis was performed. Orthogonal Projection to Latent Structures was applied to explore the correlation between the metabolomics profiles and U-naAs levels.Results: Despite the extremely low U-naAs levels (mean value = 6.13 ± 3.17 µg/g creatinine) of our studied population a urinary metabolomics profile related to arsenic was identified.Conclusion: The identified profile could represent a fingerprint of early arsenic biological effect and could be used in further studies as an indicator of susceptibility, also in subjects exposed to a low arsenic dose, with implications in occupational health, toxicology, and public health.

Clinical standardization of two controlled allergen challenge facilities: The Environmental Exposure Unit and the Biogenics Research Chamber.

BACKGROUND: Controlled allergen challenge facilities (CACF), in disparate geographic regions with dissimilar engineering and base populations, have historically functioned as single, independent sites in clinical allergy trials. We aimed to demonstrate "between-unit reproducibility" to allow controlled challenge trials of participants using 2 CACFs. OBJECTIVE: To compare and standardize 2 CACFs located in Kingston, Ontario, Canada, and San Antonio, Texas, by examining participant-reported symptom severity during qualifying and treatment visits and evaluating response to treatment, while using the same allergen. METHODS: At 2 different CACFs, participants were enrolled in a double-blind, placebo-controlled, crossover intervention trial with cetirizine 10 mg. Different distribution devices delivered common short ragweed pollen via laminar air flow and maintained an airborne concentration of 3500 ± 700 grains/m3 in both facilities. A 1-hour "sham" run with no pollen release preceded a priming exposure of 3 hours and was followed 3 days later by a qualifying/treatment 5-hour exposure. At least 14 days later, another priming exposure was followed by the crossover exposure and treatment. RESULTS: Forty-eight and 43 subjects completed the study at Kingston and San Antonio, respectively. Demographics were similar. Fewer than 10% exhibited symptoms with sham exposure. No significant differences were found between the 2 facilities in maximal total rhinoconjunctivitis symptom score, total nasal symptom score, and total ocular symptom score, nor in areas under the curve. In both facilities, no significant effects of cetirizine 10 mg over placebo were detected. CONCLUSION: The results were equivalent, demonstrating that the 2 CACFs can be used together in dual-center clinical trials and show the possibility of multicenter trials involving multiple CACFs.

The derivation of a Reference Dose (RfD) for perfluorooctane sulfonate (PFOS) based on immune suppression.

Exposure to perfluorooctane sulfonate (PFOS) is ubiquitous in populations and environments worldwide. Its long half-life in humans, indefinite persistence in the environment, and awareness of its widespread presence in drinking water make the human health assessment of PFOS a priority. While developmental, endocrine, and hepatic effects, and increased serum cholesterol are among the outcomes resulting from PFOS exposure, immunosuppression has also consistently emerged as an adverse effect. An in-depth review of the relevant scientific literature on the toxicology of PFOS has identified immunosuppression as a sensitive endpoint for PFOS toxicity. Here, we focus specifically on that endpoint and provide a detailed derivation of a Reference Dose (RfD) of 1.8 × 10-6 mg/kg/day for chronic human exposure to PFOS. This RfD is based on decreased plaque-forming cell (PFC) response in mice, an endpoint that reflects suppression of the immune response to a foreign antigen. We additionally identify two endpoints in the epidemiology literature, decreased vaccine response and increased incidence of childhood infections, that are associated with PFOS exposure and that are consistent with and support the decreased PFC response endpoint from animal studies. We provide a weight of evidence analysis integrating the evidence from animal and epidemiology endpoints. Finally, we compare this RfD to the PFOS RfD derived by the United States Environmental Protection Agency (USEPA) Office of Water based on a developmental endpoint. Based on this comparison, and given our assessment, the USEPA RfD does not provide sufficient protection against the adverse health effects of PFOS. The RfD derived herein is intended to be public health protective and appropriately minimizes PFOS exposure based on available evidence.

Trans-1,1,1,4,4,4-hexafluoro-2-butene (HFO-1336mzz-E) (2018).

Trans-1,1,1,4,4,4-hexafluoro-2-butene (HFO-133mzz-E) is an odorless gas that finds uses as a foam transfer agent, heat transfer fluid, and specialty gas. The acute 4-h LC50 (in rats) for HFO-133mzz-E is > 17,000 ppm; it was not an eye or dermal irritant in 3- and 13-week repeated-dose inhalation studies in rats at concentrations up to 1.5% (15,000 ppm). HFO-133mzz-E was not a cardiac sensitizer at 70,000 ppm in a standard epinephrine challenge study in Beagle dogs. In a 3-week, repeated-dose (non-GLP) inhalation range-finding study in male and female rats, HFO-133mzz-E concentrations of 7500 and 15,000 ppm were determined to be well-tolerated. In the follow-up, GLP-compliant, 28-day repeated-dose inhalation study (as per OECD 412), male and female rats were exposed to 0, 1000, 10,000, or 15,000/20,000 ppm (20,000 ppm concentration was decreased to 15,000 ppm after week 1 because of deaths and body weight loss). The study no-observed-adverse-effect level (NOAEL) was established at 10,000 ppm based on reduced body weight gain and mortality observed at 15,000 ppm. In a 90-day GLP-compliant repeated-dose study (as per OECD 413), male and female rats were exposed to 0, 1000, 5000, 7500, or 15,000 ppm HFO-133mzz-E. Three male rats exposed to 15,000 ppm HFO-133mzz-E died during exposure; clinical signs such as restlessness, blepharospasm, and myoclonic jerks were also observed, during the first month of the study, at 15,000 ppm. There were no significant gross or histopathological organ/tissue lesions attributable to HFO-133mzz-E exposure. The study NOAEL was established at 7500 ppm. In a GLP prenatal developmental study (OECD 414), groups of time-mated nulliparous female rats were exposed via inhalation to 0, 1000, 5000, 7500, or 15,000 ppm HFO-1336mzz-E beginning on gestation day (GD) 6 up to and including GD 19. Under the conditions of this study, the NOAEL for maternal and fetal effects was established at 7500 ppm. HFO-1336mzz-E was not genotoxic in either in vitro or in vivo assays. Based on the results of the 90-day inhalation study, 7500 ppm was determined to be the NOAEL and was selected as the point of departure for the derivation of the 8-h time-weighted average (TWA), health-based workplace environmental exposure level (WEEL) value. This subchronic inhalation NOAEL was adjusted to account for duration of exposure, interindividual variability, and intraindividual variability. The resulting 8-h TWA WEEL value of 400 ppm is fully expected to provide a significant margin of safety against the production of any potential adverse health effects in workers following long-term inhalation exposure to HFO-1336mzz-E.

The reference value of blood lead level among the general adult population of eastern Iran.

The aim of this study to the estimate the lead concentrations in the blood of the adult population in South Khorasan Province, evaluate factors related to high lead blood concentrations and establish lead reference values (RVs) in our study population. In cross-sectional study, 400 people who lived in the province of South Khorasan in 2017 were selected. Demographic information was collected and clinical examinations were performed. As the geometric means, blood lead concentration (BLC) was expressed, 10th, 50th, 90th, and 95th percentiles, and 95% confidence intervals (CI) of the 95th percentile. The upper limits rounded values of the 95% CI with the 95th percentile were applied to calculate RVs. Mean BLC was 6.02 ± 7.41 µg dL-1, median of BLC was 4.4 µg dL-1 (IQR: 2.9-6.5; range 0.9-54.7 µg dL-1). One hundred and twenty-five (31.2%) participants had BLCs between 5 and 10.0 µg dL-1, 40 (10.0%) between 10 and 20.0 µg dL-1, and 15 (3.8%%) over 20 µg dL-1. The RVs for BLC for men and women were 16 [95% CI: 10.13-15.96] µg dL-1 and 15 [95% CI: 9.81-14.45] µg dL-1, respectively. Higher BLCs were significantly associated with age, gender, hemoglobin, white blood cell count, and serum phosphorus concentration. This bio-monitoring study of BLCs in the general population of South Khorasan Province offers important demographic and lifestyle factors-stratified reference data. It is essential to continue efforts to reduce lead exposure.

Spatial analysis of chromium in southwestern part of Iran: probabilistic health risk and multivariate global sensitivity analysis.

This study was concerned with chromium as a potential carcinogenic contaminant in 64 wells located in five aquifers, southwest of Iran. A probabilistic health risk assessment indicated a high risk to the local residents including adults and children in the study area. A sequential sensitivity analysis and a novel approach known as multivariate global sensitivity analysis using both principal component analysis and B-spline were applied to investigate the behavior of health risk model along time considering four independent input parameters in the risk equation. In this context, based on the results of sensitivity analysis, concentration of chromium in drinking water (Cw) and body weight (W) were the most influential parameters. Random forest (RF) was used as a variable selection method to choose the most influential parameters for the prediction of chromium. Five parameters, among 13 water quality variables, including phosphate, nitrate, fluoride, manganese and iron were selected by RF as the most important parameters for spatial prediction. Hybrid methods of RF and ordinary kriging (RFOK) and RF and inverse distance weighting (RFIDW) were then applied for spatial prediction of Cr using the secondary variables. The RFOK and RFIDW were more efficient than that of ordinary kriging (OK) with respect to a cross-validation algorithm. For instance, in terms of relative root mean squared error, the performance of OK was improved from 31.72 to 23.21 and 23.61 for RFOK and RFIDW, respectively.

Overview on legislation and scientific approaches for risk assessment of combined exposure to multiple chemicals: the potential EuroMix contribution.

This article reviews the current legislative requirements for risk assessment of combined exposure to multiple chemicals via multiple exposure routes, focusing on human health and particularly on food-related chemicals. The aim is to identify regulatory needs and current approaches for this type of risk assessment as well as challenges of the implementation of appropriate and harmonized guidance at international level. It provides an overview of the current legal requirements in the European Union (EU), the United States and Canada. Substantial differences were identified in the legal requirements for risk assessment of combined exposure to multiple chemicals and its implementation between EU and non-EU countries and across several regulatory sectors. Frameworks currently proposed and in use for assessing risks from combined exposure to multiple chemicals via multiple routes and different durations of exposure are summarized. In order to avoid significant discrepancies between regulatory sectors or countries, the approach for assessing risks of combined exposure should be based on similar principles for all types of chemicals. OECD and EFSA identified the development of harmonized methodologies for combined exposure to multiple chemicals as a key priority area. The Horizon 2020 project "EuroMix" aims to contribute to the further development of internationally harmonized approaches for such risk assessments by the development of an integrated test strategy using in vitro and in silico tests verified for chemical mixtures based on more appropriate data on potential combined effects. These approaches and testing strategies should be integrated in a scientifically based weight of evidence approach to account for complexity and uncertainty, to improve risk assessment.