An End Point-Specific Framework for Read-Across Analog Selection for Human Health Effects.

Integrating computational chemistry and toxicology can improve the read-across analog approach to fill data gaps in chemical safety assessment. In read-across, structure-related parameters are compared between a target chemical with insufficient test data and one or more materials with sufficient data. Recent advances have focused on enhancing the grouping or clustering of chemicals to facilitate toxicity prediction via read-across. Analog selection ascertains relevant features, such as physical-chemical properties, toxicokinetic-related properties (bioavailability, metabolism, and degradation pathways), and toxicodynamic properties of chemicals with an emphasis on mechanisms or modes of action. However, each human health end point (genotoxicity, skin sensitization, phototoxicity, repeated dose toxicity, reproductive toxicity, and local respiratory toxicity) provides a different critical context for analog selection. Here six end point-specific, rule-based schemes are described. Each scheme creates an end point-specific workflow for filling the target material data gap by read-across. These schemes are intended to create a transparent rationale that supports the selected read-across analog(s) for the specific end point under study. This framework can systematically drive the selection of read-across analogs for each end point, thereby accelerating the safety assessment process.

The Path to UVCB Ecological Risk Assessment: Grappling with Substance Characterization.

Substances of unknown or variable composition, complex reaction products, and biological materials (UVCBs) pose a unique challenge to regulators and to product registrants, who are required to characterize their fate, exposure, hazard, and potential risks to human health and the environment. To address these challenges and ensure an efficient and fit-for-purpose process, it is proposed that the ecological risks of UVCBs be assessed following a tiered strategy. The development of this approach required exploring how substance composition ties into hazard and exposure information and determining the extent to which a UVCB needs to be characterized to ensure a robust risk assessment. The present study highlights the key aspects of this new method. It presents how a tiered substance characterization approach can be integrated into broader UVCB risk-assessment schemes to encourage an examination of data needs before a full substance characterization is performed. The first tier of the characterization process, Tier 0, is a fundamental step that includes data from basic, lower-resolution compositional analyses. Tier 0 assessments can be used to inform hazard and exposure for any substance of interest. The need for more sophisticated, higher-tier characterization is determined by the level of uncertainty of the risk assessment. The next step will integrate a tiered exposure assessment into the characterization scheme featured in the present study, to create a more complete risk-assessment framework. Environ Toxicol Chem 2022;41:2649-2657. © 2022 Her Majesty the Queen in Right of Canada, Health and Environmental Sciences Institute and The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC. Reproduced with the permission of the Minister of Environment and Climate Change Canada.

Improving the Environmental Risk Assessment of Substances of Unknown or Variable Composition, Complex Reaction Products, or Biological Materials.

Substances of unknown or variable composition, complex reaction products, or biological materials (UVCBs) pose unique risk assessment challenges to regulators and to product registrants. These substances can contain many constituents, sometimes partially unknown and/or variable, depending on fluctuations in their source material and/or manufacturing process. International regulatory agencies have highlighted the difficulties in characterizing UVCBs and assessing their toxicity and environmental fate. Several industrial sectors have attempted to address these issues by developing frameworks and characterization methods. Based on the output of a 2016 workshop, this critical review examines current practices for UVCB risk assessment and reveals a need for a multipronged and transparent approach integrating whole-substance and constituent-based information. In silico tools or empirical measurements can provide information on discrete and/or blocks of UVCB constituents with similar hazard properties. Read-across and/or whole-substance toxicity and fate testing using adapted emerging methods can provide whole-substance information. Continued collaboration of stakeholders representing government, industry, and academia will facilitate the development of practical testing strategies and guidelines for addressing regulatory requirements for UVCBs. Environ Toxicol Chem 2020;39:2097-2108. © 2020 Health and Environmental Sciences Institute. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.

Clustering a Chemical Inventory for Safety Assessment of Fragrance Ingredients: Identifying Read-Across Analogs to Address Data Gaps.

A valuable approach to chemical safety assessment is the use of read-across chemicals to provide safety data to support the assessment of structurally similar chemicals. An inventory of over 6000 discrete organic chemicals used as fragrance materials in consumer products has been clustered into chemical class-based groups for efficient search of read-across sources. We developed a robust, tiered system for chemical classification based on (1) organic functional group, (2) structural similarity and reactivity features of the hydrocarbon skeletons, (3) predicted or experimentally verified Phase I and Phase II metabolism, and (4) expert pruning to consider these variables in the context of specific toxicity end points. The systematic combination of these data yielded clusters, which may be visualized as a top-down hierarchical clustering tree. In this tree, chemical classes are formed at the highest level according to organic functional groups. Each subsequent subcluster stemming from classes in this hierarchy of the cluster is a chemical cluster defined by common organic functional groups and close similarity in the hydrocarbon skeleton. By examining the available experimental data for a toxicological endpoint within each cluster, users can better identify potential read-across chemicals to support safety assessments.

Benthic invertebrate and microbial biodiversity in sub-tropical urban rivers: Correlations with environmental variables and emerging chemicals.

Urban rivers often function as sinks for various contaminants potentially placing the benthic communities at risk of exposure. We performed a comprehensive biological survey of the benthic macroinvertebrate and bacterial community compositions in six rivers from the suburb to the central urban area of Guangzhou city (South China), and evaluated their correlations with emerging organic contaminants, heavy metals and nutrients. Overall, the benthic macroinvertebrate community shifted from molluscs to oligochaete from the suburban to the central urban rivers that receive treated and untreated sewage. An exception was the site in the Sha River where chironomids were most abundant. The differences in macroinvertebrate community assemblages were significantly associated with chromium, total phosphorus, galaxolide, triclosan and sand content in the sediment. There was no significant difference in benthic macroinvertebrate composition between the dry and wet season. As assessed by double constrained ordination, sexual reproduction was the only trait of benthic macroinvertebrates that showed a significant correlation with pollution variables, as it was significantly positively correlated with chromium and total phosphorus. This suggests that r-strategist occurs in polluted sampling sites. The benthic bacterial community composition showed a significant difference between seasons and among the Liuxi River, Zhujiang River and central urban rivers. The differences in community composition of the benthic bacteria were significantly correlated with galaxolide, total phosphorus, lead and triclosan. These results suggest that input of treated and untreated sewage significantly altered the benthic macroinvertebrate and bacterial community compositions in urban rivers.

Response of sediment bacterial community to triclosan in subtropical freshwater benthic microcosms.

The response of sediment bacterial communities in subtropical freshwater benthic microcosms to sediment-associated triclosan (TCS; 28 d exposure) was analysed using Illumina high-throughput sequencing. This study highlights the interactive effects of TCS and the presence of benthic macroinvertebrates (Limnodrilus hoffmeisteri and Viviparidae bellamya) on sediment bacterial communities. Our results show that TCS alone significantly altered the taxonomic composition and decreased alpha diversity of sediment bacterial communities at concentrations ≥80 µg TCS/g dry weight (dw) sediment (sed). Regarding dominant phyla, TCS significantly reduced the relative abundance of Bacteroidetes and Firmicutes at these concentrations, whereas the relative abundance of Chloroflexi and Cyanobacteria increased. In the presence of benthic macroinvertebrates, the sediment bacterial community was affected by 8 µg TCS/g dw sed as well. However, the presence of benthic macroinvertebrates did not cause measurable changes to bacterial community in unspiked (i.e., control) sediment. These results indicate that TCS alone would not alter the sediment bacterial community at environmentally relevant concentrations (up till 8 µg/g dw sed), but may have an effect in combination with the presence of benthic macroinvertebrates. Therefore, we recommend to include benthic macroinvertebrates when assessing the response of sediment bacterial communities during exposure to environmental stress such as organic contaminants.

Fate and effects of sediment-associated polycyclic musk HHCB in subtropical freshwater microcosms.

Galaxolide (HHCB) is used as a fragrance ingredient in household and personal care products, and has been ubiquitously detected in the environment. Here we investigated the fate of HHCB in subtropical freshwater microcosms, and evaluated effects of sediment-associated HHCB on a biological community consisting of algae, Daphnia, benthic macroinvertebrates and bacteria. The concentrations of sediment-associated HHCB did not change significantly during a 28 days exposure period, but HHCB accumulated in worms with biota-sediment accumulation-factor (BSAF) values in the range of 0.29-0.66 for Branchiura sowerbyi and 0.94-2.11 for Limnodrilus hoffmeisteri. There was no significant effects of HHCB (30 µg/g dry weight (dw) sediment) on chlorophyll-a content, sediment bacterial community composition, and survival and growth of benthic macroinvertebrates. However, the presence of benthic macroinvertebrates altered the sediment bacterial community structure relative to microcosms without introduced organisms. The findings of this study suggest that a single high-dose of HHCB, over 28 days, at environmentally relevant concentrations would not impose direct toxicological risks to aquatic organisms such as benthic macroinvertebrates.

Fate and effects of sediment-associated triclosan in subtropical freshwater microcosms.

Triclosan (TCS) is an antibacterial agent that is commonly used in personal care products. Because of its sediment-binding properties, TCS exposure presents a potential threat to sediment-dwelling aquatic organisms. Currently our knowledge of the fate and effects of sediment-associated TCS in aquatic systems is limited. To understand the impact of sediment-associated TCS, we used microcosms to assess effects of TCS exposure on a diverse range of organisms selected to mimic a subtropical community, with an exposure period of 28 days. We included the oligochaete freshwater worm Limnodrilus hoffmeisteri to evaluate the interaction between sediment-associated TCS and sediment-dwelling organisms, including potential loss of TCS from the sediment due to biological activity and bioaccumulation. Benthic macroinvertebrate presence significantly increased the TCS levels from 0.013 ± 0.007 µg/L to 0.613 ± 0.030 µg/L in the overlying water through biological activity, posing a potential additional risk to pelagic species, but it did not result in a significant reduction of the sediment concentration. Furthermore, worms accumulated TCS with estimated Biota-Sediment-Accumulation-Factors (BSAFs) ranging between 0.38-3.55. Other than for algae, TCS at environmental concentrations did not affect the survival of the introduced organisms, including the L. hoffmeisteri. Our results demonstrate that, although TCS at currently detected maximum concentration may not have observable toxic effects on the benthic macroinvertebrates in the short term, it can lead to bioaccumulation in worms.

Bioaccumulation and Biotransformation of Triclosan and Galaxolide in the Freshwater Oligochaete Limnodrilus hoffmeisteri in a Water/Sediment Microcosm.

Personal care products are widely used in our daily life in considerable quantities and discharged via the down-the-drain route to aquatic environments, resulting in potential risks to aquatic organisms. We investigated bioaccumulation and biotransformation of two widely used personal care products, triclosan (TCS) and galaxolide (HHCB) spiked to sediment, in the oligochaete worm Limnodrilus hoffmeisteri in water/sediment microcosms. After 7 days of sediment exposure to 3.1 µg of TCS or HHCB/g of dry weight sediment, the accumulation of TCS and HHCB in L. hoffmeisteri reached equilibrium, at which point the biota-sediment accumulation factors (BSAFs) were 2.07 and 2.50 for TCS and HHCB, respectively. The presence of L. hoffmeisteri significantly accelerated the dissipation of the levels of TCS and HHCB in the microcosms, with approximately 9.03 and 2.90% of TCS and HHCB, respectively, eliminated from the water/sediment systems after exposure for 14 days in the presence of worms. Two biotransformation products, methyl triclosan and triclosan O-sulfate, were identified for TCS in worm tissue, whereas only methyl triclosan was identified in the sediment. Unlike TCS, no evidence of biotransformation products was found for HHCB in either worm tissue or sediment. These experiments demonstrate that L. hoffmeisteri biotransformed TCS through methylation and sulfation, whereas HHCB biotransformation was undetectable.

Occurrence and ecological risk assessment of emerging organic chemicals in urban rivers: Guangzhou as a case study in China.

Urban rivers may receive contamination from various sources including point sources like domestic sewage and nonpoint sources (e.g., runoff), resulting in contamination with various chemicals. This study investigated the occurrence of emerging organic contaminants (3 endocrine disrupting compounds (EDCs), and 17 pharmaceuticals and personal care products (PPCPs)) in six urban rivers of a representative subtropical city, Guangzhou (southern China). Our results showed that EDCs and personal care products were frequently detected in the water phase and sediment phase. 4-nonylphenol (4-NP) was the most predominant compound with the highest concentration of 5050ng/L in the water phase and 14,400ng/g dry weight (dw) in the sediment. Generally, higher total concentrations of EDCs and PPCPs were detected in the four urban streams compared to the main stream Zhujiang River and the Liuxi River at the suburb area. A screening-level risk assessment showed that 4-nonylphenol and triclosan (TCS) pose potential risks to aquatic organisms in most sampling sites. For individual taxa, 4-NP may pose risks to various groups of aquatic organisms, while TCS only might pose high risks to algae. CAPSULE: Higher contamination of EDCs and PPCPs was observed in rivers in urban area; 4-nonylphenol and triclosan showed RQs>1 in >70% of the reported area.

Probabilistic determination of the ecological risk from OTNE in aquatic and terrestrial compartments based on US-wide monitoring data.

OTNE [1-(1,2,3,4,5,6,7,8-octahydro-2,3,8,8-tetramethyl-2-naphthyl)ethan-1-one; trade name Iso E Super] is a fragrance ingredient commonly used in consumer products which are disposed down the drain. This research measured effluent and sludge concentrations of OTNE at 44 US wastewater treatment plants (WWTP). The mean effluent and sludge concentrations were 0.69 ± 0.65 µg/L and 20.6 ± 33.8 mg/kg dw respectively. Distribution of OTNE effluent concentrations and dilution factors were used to predict surface water and sediment concentrations and distributions of OTNE sludge concentrations and loading rates were used to predict terrestrial concentrations. The 90th percentile concentration of OTNE in US WWTP mixing zones was predicted to be 0.04 and 0.85 µg/L under mean and 7Q10 low flow (lowest river flow occurring over a 7 day period every 10 years) conditions respectively. The 90th percentile sediment concentrations under mean and 7Q10 low flow conditions were predicted to be 0.081 and 1.6 mg/kg dw respectively. Based on current US sludge application practices, the 90th percentile OTNE terrestrial concentration was 1.38 mg/kg dw. The probability of OTNE concentrations being below the predicted no effect concentration (PNEC) for the aquatic and sediment compartments was greater than 99%. For the terrestrial compartment, the probability of OTNE concentrations being lower than the PNEC was 97% for current US sludge application practices. Based on the results of this study, OTNE concentrations in US WWTP effluent and sludge do not pose an ecological risk to aquatic, sediment and terrestrial organisms.

Fate and effects of acetyl cedrene in sediments inhabited by different densities of the deposit feeder, Capitella teleta.

Fragrance materials, such as acetyl cedrene (AC), are of environmental concern because they are continuously released to aquatic systems down the drain. In the present study, Capitella teleta (formerly Capitella capitata species I) was exposed to AC-amended sediment at two population densities corresponding to 44,000 and 88,000 worms/m(2). The fate of AC in systems with worms was compared to that in identical systems without worms. We examined the toxicity of AC on worm survival, growth, and feeding rate, and quantified the fate of AC in exposure systems by mass balance. Worm survival was close to 100% in all treatments. Acetyl cedrene had some positive effects on worm growth, but not feeding, whereas density had negative effects on both growth and feeding rates. After 14 d, the sediment concentration of AC was reduced by 88 to 99% in the presence of worms, whereas sediment AC concentration was reduced by 13 to 31% or less in the absence of worms. Acetyl cedrene was detected in fecal pellets, at low concentrations compared to the initial concentration in the sediment, but not in worm tissue, suggesting that ingested AC is bioavailable to Capitella teleta and that worms can biotransform sediment-associated AC effectively.

Explaining differences between bioaccumulation measurements in laboratory and field data through use of a probabilistic modeling approach.

In the regulatory context, bioaccumulation assessment is often hampered by substantial data uncertainty as well as by the poorly understood differences often observed between results from laboratory and field bioaccumulation studies. Bioaccumulation is a complex, multifaceted process, which calls for accurate error analysis. Yet, attempts to quantify and compare propagation of error in bioaccumulation metrics across species and chemicals are rare. Here, we quantitatively assessed the combined influence of physicochemical, physiological, ecological, and environmental parameters known to affect bioaccumulation for 4 species and 2 chemicals, to assess whether uncertainty in these factors can explain the observed differences among laboratory and field studies. The organisms evaluated in simulations including mayfly larvae, deposit-feeding polychaetes, yellow perch, and little owl represented a range of ecological conditions and biotransformation capacity. The chemicals, pyrene and the polychlorinated biphenyl congener PCB-153, represented medium and highly hydrophobic chemicals with different susceptibilities to biotransformation. An existing state of the art probabilistic bioaccumulation model was improved by accounting for bioavailability and absorption efficiency limitations, due to the presence of black carbon in sediment, and was used for probabilistic modeling of variability and propagation of error. Results showed that at lower trophic levels (mayfly and polychaete), variability in bioaccumulation was mainly driven by sediment exposure, sediment composition and chemical partitioning to sediment components, which was in turn dominated by the influence of black carbon. At higher trophic levels (yellow perch and the little owl), food web structure (i.e., diet composition and abundance) and chemical concentration in the diet became more important particularly for the most persistent compound, PCB-153. These results suggest that variation in bioaccumulation assessment is reduced most by improved identification of food sources as well as by accounting for the chemical bioavailability in food components. Improvements in the accuracy of aqueous exposure appear to be less relevant when applied to moderate to highly hydrophobic compounds, because this route contributes only marginally to total uptake. The determination of chemical bioavailability and the increase in understanding and qualifying the role of sediment components (black carbon, labile organic matter, and the like) on chemical absorption efficiencies has been identified as a key next steps.

Macrocyclic fragrance materials--a screening-level environmental assessment using chemical categorization.

A screening-level aquatic environmental risk assessment for macrocyclic fragrance materials using a "group approach" is presented using data for 30 macrocyclic fragrance ingredients. In this group approach, conservative estimates of environmental exposure and ecotoxicological effects thresholds for compounds within two subgroups (15 macrocyclic ketones and 15 macrocyclic lactones/lactides) were used to estimate the aquatic ecological risk potential for these subgroups. It is reasonable to separate these fragrance materials into the two subgroups based on the likely metabolic pathway required for biodegradation and on expected different ecotoxicological modes of action. The current volumes of use for the macrocyclic ketones in both Europe and North America ranges from <1 (low kg quantities) to no greater than 50 metric tonnes in either region and for macrocyclic lactones/lactides the volume of use range for both regions is <1 to no greater than 1000 metric tonnes in any one region. Based on these regional tonnages, biodegradability of these two subgroups of materials, and minimal in stream dilution (3:1), the conservatively predicted exposure concentrations for macrocyclic ketones would range from <0.01 to 0.05 µg/L in Europe and from <0.01 to 0.03 µg/L in North America. For macrocyclic lactones/lactides, the concentration within the mixing zone would range from <0.01 to 0.7 µg/L in Europe and from <0.01 to 1.0 µg/L in North America. The PNECs derived for the macrocyclic ketones is 0.22 µg/L and for macrocyclic lactones/lactides is 2.7 µg/L. The results of this screening-level aquatic ecological risk assessment indicate that at their current tonnage, often referred to as volumes of use, macrocyclic fragrance materials in Europe and North America, pose a negligible risk to aquatic biota; with no PEC/PNEC ratio exceeding 1 for any material in any subgroup.

Investigation of the fate and effects of acetyl cedrene on Capitella teleta and sediment bacterial community.

The fate of the fragrance material, acetyl cedrene (AC), in sediment was examined in a 16 day laboratory experiment using the sediment microbial community subjected to the following treatments: AC (nominal concentration; 0 and 50 microg g(-1) dw sediment) and macrofaunal worms (with/without Capitella teleta (formerly Capitella sp. I)). Furthermore effects of AC on microbial respiration in the system were determined by examining CO(2) flux. T-RFLP (terminal restriction fragment length polymorphism) was used to analyze PCR (polymerase chain reaction) amplified 16S DNA gene fragments from the sediments to detect changes in the structure and diversity of the bacterial community. In addition, survival of C. teleta in sediment was determined. Lastly, we examined how the interactions between microbes and C. teleta in the sediment affected the above-mentioned parameters. The results showed that there was an interaction between worm treatment and time of sampling on the loss of AC from the sediment. This was caused by AC loss initially being fastest in the sediment with C. teleta present, but at experimental termination there was no significant difference between the two treatments (i.e., with/without worms) in the amount of AC remaining in the sediment. Survival of C. teleta was significantly reduced by AC at experimental termination, but neither microbial respiration nor structure and diversity of the bacterial community were significantly affected.

Individual- and population-level effects of the synthetic musk, HHCB, on the deposit-feeding polychaete, Capitella sp. I.

A life table response experiment lasting 120 d was used to investigate the effects of the synthetic polycyclic musk HHCB (1,3,4,6,7,8-hexahydro-4,6,6,7,8-hexamethylcyclopenta-gamma-2-benzopyrane; 0, 1.5, 26, 123, and 168 mg/kg dry wt sediment) on the life history of the infaunal polychaete Capitella species I. The HHCB exposure showed no detectable effects on adult survival, age at first reproduction, length of the reproductive period, number of broods, individual worm body volumes, or body size-specific egestion rates. In contrast, HHCB significantly affected juvenile survival (>or=123 mg/kg), maturation time (168 mg/kg), total number of eggs produced (>or=26 mg/kg), and brood size (>or=123 mg/kg) and marginally increased time between breeding attempts (>or=26 mg/kg). A declining trend was observed for population growth rate with increasing HHCB concentrations, but differences between the control and exposed groups were not significant. Thus, despite detectable effects of HHCB on individual life-history traits, the results suggest that environmentally realistic concentrations of HHCB are not likely to reduce the growth rate of Capitella sp. I populations.

Effects of the polycyclic musk HHCB on individual- and population-level endpoints in Potamopyrgus antipodarum.

Although the polycyclic musk 1,3,4,6,7,8-hexahydro-4,6,6,7,8,8-hexamethylcyclopenta[gamma]-2-benzopyran (HHCB) is frequently detected in aquatic sediments, very little is known about its effects on sediment-feeding organisms. Effects of sediment-associated HHCB on growth, feeding rate, survival and reproduction in the gastropod Potamopyrgus antipodarum were measured in the laboratory. Snails were exposed to six nominal HHCB concentrations: 0, 0.1, 1, 10, 30 and 100microg g(-1) dry weight (dw) sediment. Adult survival and growth were not affected by HHCB. However, juvenile growth and survival, reproduction, time to first reproduction and adult feeding rate were more sensitive endpoints and declined with increasing HHCB concentration. Individual-level endpoints for P. antipodarum were integrated into a population model to investigate the effects of HHCB on population growth rate. Under otherwise favorable laboratory conditions, population growth rate was slightly (by ca. 2%), but not significantly, reduced with increasing HHCB exposure concentration. Model simulations were performed to explore the consequences of HHCB exposure under more ecologically realistic conditions (i.e., survival and reproduction of unexposed snails were markedly reduced relative to the laboratory). The results suggest that despite detectable effects of HHCB on individual-level endpoints measured in the laboratory, impacts on population dynamics of this deposit feeder are not likely to occur at environmentally relevant exposure concentrations.