Using membrane-water partition coefficients in a critical membrane burden approach to aid the identification of neutral and ionizable chemicals that induce acute toxicity below narcosis levels.

The risk assessment of thousands of chemicals used in our society benefits from adequate grouping of chemicals based on the mode and mechanism of toxic action (MoA). We measure the phospholipid membrane-water distribution ratio (DMLW) using a chromatographic assay (IAM-HPLC) for 121 neutral and ionized organic chemicals and screen other methods to derive DMLW. We use IAM-HPLC based DMLW as a chemical property to distinguish between baseline narcosis and specific MoA, for reported acute toxicity endpoints on two separate sets of chemicals. The first set comprised 94 chemicals of US EPA's acute fish toxicity database: 47 categorized as narcosis MoA, 27 with specific MoA, and 20 predominantly ionic chemicals with mostly unknown MoA. The narcosis MoA chemicals clustered around the median narcosis critical membrane burden (CMBnarc) of 140 mmol kg-1 lipid, with a lower limit of 14 mmol kg-1 lipid, including all chemicals labelled Narcosis_I and Narcosis_II. This maximum 'toxic ratio' (TR) between CMBnarc and the lower limit narcosis endpoint is thus 10. For 23/28 specific MoA chemicals a TR >10 was derived, indicative of a specific adverse effect pathway related to acute toxicity. For 10/12 cations categorized as "unsure amines", the TR <10 suggests that these affect fish via narcosis MoA. The second set comprised 29 herbicides, including 17 dissociated acids, and evaluated the TR for acute toxic effect concentrations to likely sensitive aquatic plant species (green algae and macrophytes Lemna and Myriophyllum), and non-target animal species (invertebrates and fish). For 21/29 herbicides, a TR >10 indicated a specific toxic mode of action other than narcosis for at least one of these aquatic primary producers. Fish and invertebrate TRs were mostly <10, particularly for neutral herbicides, but for acidic herbicides a TR >10 indicated specific adverse effects in non-target animals. The established critical membrane approach to derive the TR provides for useful contribution to the weight of evidence to bin a chemical as having a narcosis MoA or less likely to have acute toxicity caused by a more specific adverse effect pathway. After proper calibration, the chromatographic assay provides consistent and efficient experimental input for both neutral and ionizable chemicals to this approach.

Construction of an In Silico Structural Profiling Tool Facilitating Mechanistically Grounded Classification of Aquatic Toxicants.

The performance of chemical safety assessment within the domain of environmental toxicology is often impeded by a shortfall of appropriate experimental data describing potential hazards across the many compounds in regular industrial use. In silico schemes for assigning aquatic-relevant modes or mechanisms of toxic action to substances, based solely on consideration of chemical structure, have seen widespread employment─including those of Verhaar, Russom, and later Bauer (MechoA). Recently, development of a further system was reported by Sapounidou, which, in common with MechoA, seeks to ground its classifications in understanding and appreciation of molecular initiating events. Until now, this Sapounidou scheme has not seen implementation as a tool for practical screening use. Accordingly, the primary purpose of this study was to create such a resource─in the form of a computational workflow. This exercise was facilitated through the formulation of 183 structural alerts/rules describing molecular features associated with narcosis, chemical reactivity, and specific mechanisms of action. Output was subsequently compared relative to that of the three aforementioned alternative systems to identify strengths and shortcomings as regards coverage of chemical space.

Remote-delivered cardiac rehabilitation during COVID-19: a prospective cohort comparison of health-related quality of life outcomes and patient experiences.

AIMS: Enforced suspension and reduction of in-person cardiac rehabilitation (CR) services during the coronavirus disease-19 (COVID-19) pandemic restrictions required rapid implementation of remote delivery methods, thus enabling a cohort comparison of in-person vs. remote-delivered CR participants. This study aimed to examine the health-related quality of life (HRQL) outcomes and patient experiences comparing these delivery modes. METHODS AND RESULTS: Participants across four metropolitan CR sites receiving in-person (December 2019 to March 2020) or remote-delivered (April to October 2020) programmes were assessed for HRQL (Short Form-12) at CR entry and completion. A General Linear Model was used to adjust for baseline group differences and qualitative interviews to explore patient experiences. Participants (n = 194) had a mean age of 65.94 (SD 10.45) years, 80.9% males. Diagnoses included elective percutaneous coronary intervention (40.2%), myocardial infarction (33.5%), and coronary artery bypass grafting (26.3%). Remote-delivered CR wait times were shorter than in-person [median 14 (interquartile range, IQR 10-21) vs. 25 (IQR 16-38) days, P < 0.001], but participation by ethnic minorities was lower (13.6% vs. 35.2%, P < 0.001). Remote-delivered CR participants had equivalent benefits to in-person in all HRQL domains but more improvements than in-person in Mental Health, both domain [mean difference (MD) 3.56, 95% confidence interval (CI) 1.28, 5.82] and composite (MD 2.37, 95% CI 0.15, 4.58). From qualitative interviews (n = 16), patients valued in-person CR for direct exercise supervision and group interactions, and remote-delivered for convenience and flexibility (negotiable contact times). CONCLUSION: Remote-delivered CR implemented during COVID-19 had equivalent, sometimes better, HRQL outcomes than in-person, and shorter wait times. Participation by minority groups in remote-delivered modes are lower. Further research is needed to evaluate other patient outcomes.

Development of an Enhanced Mechanistically Driven Mode of Action Classification Scheme for Adverse Effects on Environmental Species.

This study developed a novel classification scheme to assign chemicals to a verifiable mechanism of (eco-)toxicological action to allow for grouping, read-across, and in silico model generation. The new classification scheme unifies and extends existing schemes and has, at its heart, direct reference to molecular initiating events (MIEs) promoting adverse outcomes. The scheme is based on three broad domains of toxic action representing nonspecific toxicity (e.g., narcosis), reactive mechanisms (e.g., electrophilicity and free radical action), and specific mechanisms (e.g., associated with enzyme inhibition). The scheme is organized at three further levels of detail beyond broad domains to separate out the mechanistic group, specific mechanism, and the MIEs responsible. The novelty of this approach comes from the reference to taxonomic diversity within the classification, transparency, quality of supporting evidence relating to MIEs, and that it can be updated readily.

Equine Calming Products: A Short Survey Into Their Use, Effect, and Knowledge Using a Small Sample of Horse Owners in the North of Scotland, UK.

Equine calming products (ECPs) are often used by horse owners to alter or mitigate unwanted or dangerous behaviors in various situations. Little scientific research to date examines horse owners' knowledge surrounding these products. The objective of this pilot survey was to determine horse owners' use and perceptions of ECPs. For convenience, a survey was distributed to riding club members, livery yards, and riding instructors in the North of Scotland, UK, to ascertain the following information; the number of horse owners and caretakers who use an ECP, whether the product was considered to be effective, reasons for use and identification of the effective ingredient. Total response rate was 63% (n = 58); correctly completed questionnaires were received. Of the total respondents, 69% (n = 40) confirmed the use of an ECP and 82% would use them again, and 45% reporting regular use. Over half (59%) thought the calming effect was induced by magnesium, 9% thought the calming effect was induced by herbs, valerian, or tryptophan, and 32% did not know what ingredient had a possible calming effect. Of those using or having used an ECP, 40% felt that there was some positive effect, 30% were unsure as to whether there was any difference or not, 25% felt there was no difference, and 5% felt there was a negative effect on horse's behavior. A variety of reasons were given for using an ECP. The results suggest that horse owners are willing to use ECPs without underpinning knowledge of ingredients or scientific evidence of efficacy.

Ecotoxicological thresholds-practical application to an industrial inventory.

The concept of thresholds of toxicological concern as a potentially useful tool in environmental risk assessment has been applied to the inventory of a home and personal care products company to derive a series of chemical class-based ecotoxicological threshold of concern (ecoTTC) values. Cationic chemicals of various types show notably higher toxicity than other classes and should be treated separately. Despite this, the ecoTTC for the full data set in the present study is only slightly lower than that derived previously for chemicals causing toxicity via Verhaar modes of action (MoAs) 1 to 3. Exclusion of cationic chemicals resulted in an ecoTTC value slightly higher than the MoA 1 to 3 value. These observations indicate that such data sets contain few specifically acting chemicals. The applicability of threshold approaches in environmental risk assessment has been extended to include a limited number of inorganic/organometallic chemicals, polymers, and all classes of surfactants. The use of such ecoTTC values in conjunction with mode of action-based quantitative structure-activity relationships will allow the efficient screening and prioritization of large inventories of heterogeneous chemicals, focusing resources on those chemicals that require additional information to better understand any potential risk.

Accounting for dissociation and photolysis: a review of the algal toxicity of triclosan.

Triclosan, an antimicrobial agent commonly used in down-the-drain consumer products, is toxic to freshwater microalgae. However, the rapid photolysis and pH-dependent dissociation of this compound may give rise to uncertainty in growth inhibition tests with freshwater microalgae, if these are not well characterized. Methods are presented to minimize these uncertainties by stabilizing pH with an organic buffering agent (Bis-Tris) and by the application of ultraviolet (UV) covers to remove UV wavelengths. Toxicity tests with these methods were in compliance with the validity criteria of the Organisation for Economic Co-operation and Development test 201, and no negative effects were seen in controls relative to the unmodified method. The methods were used for toxicity tests with triclosan at pH levels of 7.0, 8.0, and 8.5, yielding effective concentration, 10% values of 0.5 µg/L, 0.6 µg/L, and 12.1 µg/L, respectively. The observed change in toxicity with pH was proportional to the change in bioconcentration factor (BCF) as calculated using the cell model (a dynamic flux model based on the Fick-Nernst-Planck equations, in this case parameterized for an algal cell). Effect concentrations produced with the methods presented in the present study offer robust data on which to base risk assessment, and it is suggested that similar approaches be used to minimize uncertainty when other compounds that dissociate and photolyse are tested.

Toxicity of haloacetic acids to freshwater algae.

Haloacetic acids (HAA), such as trichloroacetic acid (TCA), are commonly occurring by-products from disinfection and bleaching processes using sodium hypochlorite. Currently, the lowest no observed effect concentration (NOEC) for TCA is reported to be 8.7microgL(-1), which was derived from a toxicity study conducted in 1981 on Chlorella pyrenoidosa. The purity of the test material was not documented and it is unknown if other halogenated impurities or co-formulants were present. However, this NOEC is used to derive a predicted no effect concentration, which is used in various regulatory risk assessments. We present a range of algal toxicity studies conducted on five different algal species and two HAAs and observed no toxicity of TCA to C. pyrenoidosa at 115mgL(-1). The most sensitive species to TCA (NOEC, 3mgL(-1)) were Pseudokirchneriella subcapitata and Scenedesmus subspicatus, demonstrating that the toxicity of TCA to algae is over two orders of magnitude less sensitive than previously reported.

Aquatic toxicity of ethoxylated and propoxylated alcohols to daphnia magna.

Ethoxylated alcohols, which are used as nonionic surfactants, are known to act as general narcotics in acute aquatic toxicity; that is, they behave in the same way as nonsurfactant unreactive organic chemicals. The toxicity of such chemicals is well predicted by quantitative structure-activity relationships based solely on the logarithm of the octanol/water partition coefficient (log P), which can be calculated from structure. In the present study, we have shown, using experimental results, that a similar approach can be used to determine the toxicity of ethoxylate/propoxylate alcohols (i.e., containing propoxy [PO] and ethoxy [EO] units). Our calculations indicate that use of the Roberts position-dependent branching factor in calculating the PO group contribution is more appropriate than the Leo and Hansch branch factor. The resulting log P value for a PO group is 0.01; that is, the overall contribution to the final log P value is close to zero. On this basis, it is predicted that nonionic surfactants containing both EO and PO groups should have the same molar toxicity as surfactants based on the same parent alcohol and with the same number of EO groups but with no PO groups. This prediction has been confirmed in Daphnia acute toxicity tests. Furthermore, both EO/PO and EO-only nonionics are found to fit the same linear relationship between log P and toxicity.