Spatio-temporal trends in livestock exposure to per- and polyfluoroalkyl substances (PFAS) inform risk assessment and management measures.

The migration of per- and polyfluoroalkyl substances (PFAS) onto agricultural properties has resulted in the accumulation of PFAS in livestock. The environmental determinants of PFAS accumulation in livestock from the grazing environment are poorly understood, resulting in limited capacity to manage livestock exposure and subsequent transfer of PFAS through the food chain. Analytical- (n = 978 samples of soil, water, pasture, and serum matrices), farm management/practice- and livestock physiology data were collated and interrogated from environmental PFAS investigations across ten farms, from four agro-ecological regions of Victoria (Australia). Statistical analysis identified perfluorooctane sulfonate (PFOS) and perfluorohexane sulfonate (PFHxS) as key analytes of concern for livestock bioaccumulation. PFOS and PFHxS concentrations in livestock drinking water were positively correlated with serum concentrations while other intake pathways (pasture and soil) had weaker correlations. Seasonal trends in PFAS body burden (serum concentrations) were identified and suggested to be linked to seasonal grazing behaviours and physiological water requirements. The data showed for the first time that livestock exposure to PFAS is dynamic and with relatively short elimination half-lives, there is opportunity for exposure management. Meat from cattle, grazed on PFAS impacted sites, may exceed health-based guideline values for PFAS, especially for markets with low limits (like the European Commission Maximum Limits or EC MLs). This study found that sites with mean livestock drinking water concentrations as low as 0.003 µg PFOS/L may exceed the EC ML for PFOS in cattle meat. Risk assessment can be used to prioritise site cleanup and development of management plans to reduce PFAS body burden by considering timing of stock rotation and/or supplementation of primary exposure sources.

Export of virulence proteins by malaria-infected erythrocytes involves remodeling of host actin cytoskeleton.

Following invasion of human red blood cells (RBCs) by the malaria parasite, Plasmodium falciparum, a remarkable process of remodeling occurs in the host cell mediated by trafficking of several hundred effector proteins to the RBC compartment. The exported virulence protein, P falciparum erythrocyte membrane protein 1 (PfEMP1), is responsible for cytoadherence of infected cells to host endothelial receptors. Maurer clefts are organelles essential for protein trafficking, sorting, and assembly of protein complexes. Here we demonstrate that disruption of PfEMP1 trafficking protein 1 (PfPTP1) function leads to severe alterations in the architecture of Maurer's clefts. Furthermore, 2 major surface antigen families, PfEMP1 and STEVOR, are no longer displayed on the host cell surface leading to ablation of cytoadherence to host receptors. PfPTP1 functions in a large complex of proteins and is required for linking of Maurer's clefts to the host actin cytoskeleton.

Derivation of an occupational exposure limit for an inhalation analgesic methoxyflurane (Penthrox(®)).

Methoxyflurane (MOF) a haloether, is an inhalation analgesic agent for emergency relief of pain by self administration in conscious patients with trauma and associated pain. It is administered under supervision of personnel trained in its use. As a consequence of supervised use, intermittent occupational exposure can occur. An occupational exposure limit has not been established for methoxyflurane. Human clinical and toxicity data have been reviewed and used to derive an occupational exposure limit (referred to as a maximum exposure level, MEL) according to modern principles. The data set for methoxyflurane is complex given its historical use as anaesthetic. Distinguishing clinical investigations of adverse health effects following high and prolonged exposure during anaesthesia to assess relatively low and intermittent exposure during occupational exposure requires an evidence based approach to the toxicity assessment and determination of a critical effect and point of departure. The principal target organs are the kidney and the central nervous system and there have been rare reports of hepatotoxicity, too. Methoxyflurane is not genotoxic based on in vitro bacterial mutation and in vivo micronucleus tests and it is not classifiable (IARC) as a carcinogenic hazard to humans. The critical effect chosen for development of a MEL is kidney toxicity. The point of departure (POD) was derived from the concentration response relationship for kidney toxicity using the benchmark dose method. A MEL of 15 ppm (expressed as an 8 h time weighted average (TWA)) was derived. The derived MEL is at least 50 times higher than the mean observed TWA (0.23 ppm) for ambulance workers and medical staff involved in supervising use of Penthrox. In typical treatment environments (ambulances and treatment rooms) that meet ventilation requirements the derived MEL is at least 10 times higher than the modelled TWA (1.5 ppm or less) and the estimated short term peak concentrations are within the MEL. The odour threshold for MOF of 0.13-0.19 ppm indicates that the odour is detectable well below the MEL. Given the above considerations the proposed MEL is health protective.

Dynamic exposure and body burden models for per- and polyfluoroalkyl substances (PFAS) enable management of food safety risks in cattle.

With increasing global focus on planetary boundaries, food safety and quality, the presence of per- and polyfluoroalkyl substances (PFAS) in the food chain presents a challenge for the sustainable production and supply of quality assured food. Consumption of food is the primary PFAS exposure route for the general population. At contaminated sites, PFAS have been reported in a range of agricultural commodities including cattle. Consumer exposure assessments are complicated by the lack of validated modelling approaches to estimate PFAS bioaccumulation in cattle. Previous studies have shown that PFAS bioaccumulation in livestock is influenced by environmental, spatial and temporal factors that necessitate a dynamic modelling approach. This work presents an integrated exposure and population toxicokinetic (PopTK) model for cattle that estimates serum and tissue concentrations of PFAS over time. Daily exposures were estimated from intakes of water, pasture, and soil, and considered animal growth, seasonal variability (pasture moisture content and temperature) and variable PFAS concentrations across paddocks. Modelled serum and tissue estimates were validated against monitoring data from Australian and Swedish cattle farms. The models were also used to develop and test practical management options for reducing PFAS exposure and to prioritise remediation for farms. Model outputs for exposure management scenarios (testing cattle rotation and targeted supplementation of feed and water) showed potential for marked reductions in consumer exposures from cattle produce.

Suggestions for Improving the Characterization of Risk from Exposures to Per and Polyfluorinated Alkyl Substances.

Many state and federal environmental and health agencies have developed risk-based criteria for assessing the risk of adverse health effects of per- and polyfluorinated alkyl substances (PFAS) exposure to humans and the environment. However, the criteria that have been developed vary; drinking water criteria developed for perfluorooctanoic acid, for example, can vary by up to 750 fold. This is due to differences and variability in the data and information used, study/endpoint selection, assumptions and magnitude of uncertainty factors used in the absence and extrapolation of critical effect data, differences in underlying approaches to addressing exposure within criteria development, and/or policy decisions on levels of acceptable risk. We have critically evaluated the methods used to develop these criteria while focusing on derivation and application of drinking water criteria and discuss a range of improvements to risk-characterization practice recently presented at a Focused Topic Meeting on PFAS conducted by the Society of Environmental Toxicology and Chemistry in Durham, North Carolina, USA, 12 to 15 August 2019. We propose methods that consider maximizing the use of disparate data streams, seeking patterns, and proposing biologically based approaches to evidence integration toward informed criteria development. Environ Toxicol Chem 2021;40:883-898. © 2020 SETAC.

Environmental and anthropogenic influences on ambient background concentrations of fluoride in soil.

Excess exposure to fluoride causes substantive health burden in humans and livestock globally. However, few studies have assessed the distribution and controls of variability of ambient background concentrations of fluoride in soil. Ambient background concentrations of fluoride in soil were collated for Greater Melbourne, Greater Geelong, Ballarat and Mitchell in Victoria, Australia (n = 1005). Correlation analysis and machine learning techniques were used to identify environmental and anthropogenic influences of fluoride variability in soil. Sub-soils (>0.3 m deep), in some areas overlying siltstone and sandstone, and to a lesser extent, overlying basalt, were naturally enriched with fluoride at concentrations above ecological thresholds for grazing animals. Soil fluoride enrichment was predominantly influenced by parent material (mineralogy), precipitation (illuviation), leaching during palaeoclimates and marine inputs. Industrial air pollution did not significantly influence ambient background concentrations of fluoride at a regional scale. However, agricultural practices (potentially the use of phosphate fertilisers) were indicated to have resulted in added fluoride to surface soils overlying sediments. Geospatial variables alone were not sufficient to accurately model ambient background soil fluoride concentrations. A multiple regression model based on soil chemistry and parent material was shown to accurately predict ambient background fluoride concentrations in soils and support assessment of fluoride enrichment in the environment.

Extended-release methylphenidate for treatment of amphetamine/methamphetamine dependence: a randomized, double-blind, placebo-controlled trial.

AIMS: To assess the efficacy of methylphenidate as a substitution therapy for amphetamine/methamphetamine dependence in Finland and New Zealand. DESIGN: Parallel-group, double-blind, randomized placebo-controlled trial. SETTING: Out-patient care. PARTICIPANTS: Amphetamine-/methamphetamine-dependent, aged 16-65 years. MEASUREMENTS: The primary outcome measure was presence/absence of amphetamine/methamphetamine in urine samples collected twice weekly. Secondary measures included treatment adherence, alterations in craving scores and self-reported use. Primary analysis was by intention-to-treat (ITT). The study drug, methylphenidate (as Concerta(®) ), was up-titrated over 2 weeks to a maximum dose of 54 mg daily and continued for a further 20 weeks. Doses were given under daily supervision at the clinics. FINDINGS: Seventy-nine participants were randomized (40 methylphenidate; 39 placebo); 76 received allocated treatment and 27 completed the trial. ITT analysis (n = 78) showed no statistically significant difference in the percentage of positive urines between the methylphenidate and placebo arms (odds ratio: 0.95, 95% confidence interval: 0.83-1.08). However, there was a significant difference (P < 0.05) between the active and placebo arms in retention, the placebo arm displaying a significantly lower retention from 6 weeks that persisted until the end of the trial. CONCLUSIONS: The trial failed to replicate earlier findings suggesting that methylphenidate was superior to placebo. The low retention rate confounded the ability to draw firm conclusions about efficacy. The higher retention rate was observed in the methylphenidate arm. Any replication of this work would need to consider alternatives to the rigid clinic attendance criteria, and consider an increased dose.

Malaria parasite tyrosyl-tRNA synthetase secretion triggers pro-inflammatory responses.

Malaria infection triggers pro-inflammatory responses in humans that are detrimental to host health. Parasite-induced enhancement in cytokine levels correlate with malaria-associated pathologies. Here we show that parasite tyrosyl-tRNA synthetase (PfTyrRS), a housekeeping protein translation enzyme, induces pro-inflammatory responses from host immune cells. PfTyrRS exits from the parasite cytoplasm into the infected red blood cell (iRBC) cytoplasm, from where it is released into the extracellular medium on iRBC lysis. Using its ELR peptide motif, PfTyrRS specifically binds to and internalizes into host macrophages, leading to enhanced secretion of the pro-inflammatory cytokines TNF-α and IL-6. PfTyrRS-macrophage interaction also augments expression of adherence-linked host endothelial receptors ICAM-1 and VCAM-1. Our description of PfTyrRS as a parasite-secreted protein that triggers pro-inflammatory host responses, along with its atomic resolution crystal structure in complex with tyrosyl-adenylate, provides a novel platform for targeting PfTyrRS in anti-parasitic strategies.