Purpose Reducing chemical pressure on human and environmental health is an integral part of the global sustainability agenda. Guidelines for deriving globally applicable, life cycle–based indicators are required to consistently quantify toxicity impacts from chemical emissions as well as from chemicals in consumer products. In response, we elaborate the methodological framework and present recommendations for advancing near-field/far-field exposure and toxicity characterization, and for implementing these recommendations into the scientific consensus model USEtox. Methods An expert taskforce was convened by the Life Cycle Initiative hosted by UN Environment to expand existing guidance for evaluating human toxicity impacts from exposure to chemical substances. This taskforce evaluated scientific advances since the original release of USEtox and identified two major aspects that required refinement, namely integrating near-field and far-field exposure, and improving human dose-response modeling. Dedicated efforts have led to a set of recommendations to address these aspects in an update of USEtox, while ensuring consistency with the boundary conditions for characterizing life cycle toxicity impacts and being aligned with recommendations from agencies that regulate chemical exposure. The proposed updated USEtox framework was tested in an illustrative rice production and consumption case study. Results and discussion On the exposure side, a matrix system is proposed and recommended to integrate far-field exposure from environmental emissions with near-field exposure from chemicals in various consumer product types. Consumer exposure is addressed via sub-models for each product type to account for product type-specific characteristics and exposure settings. Case study results illustrate that product use–related exposure dominates overall life cycle exposure. On the effect side, a probabilistic dose-response approach combined with a decision tree for identifying reliable points of departure is proposed for non-cancer effects, following recent guidance from the World Health Organization. This approach allows for explicitly considering both uncertainty and human variability in toxicity effect factors. Factors reflecting disease severity are proposed to distinguish cancer from non-cancer effects and within the latter to discriminate reproductive/developmental and other non-cancer effects. All proposed aspects have been consistently implemented into the original USEtox framework. Conclusions The recommended methodological advancements address several key limitations in earlier approaches. Next steps are to test the new characterization framework in additional case studies and to close remaining research gaps. Our framework is applicable for evaluating chemical emissions and product-related exposure in life cycle assessment, chemical alternatives assessment and chemical substitution, consumer exposure and risk screening, and high-throughput chemical prioritization.
Background: Regulatory toxicity values used to assess and manage chemical risks rely on the determination of the point of departure (POD) for a critical effect, which results from a comprehensive and systematic assessment of available toxicity studies. However, regulatory assessments are only available for a small fraction of chemicals. Objectives: Using in vivo experimental animal data from the U.S. Environmental Protection Agency’s Toxicity Value Database, we developed a semiautomated approach to determine surrogate oral route PODs, and corresponding toxicity values where regulatory assessments are unavailable. Methods: We developed a curated data set restricted to effect levels, exposure routes, study designs, and species relevant for deriving toxicity values. Effect levels were adjusted to chronic human equivalent benchmark doses ( ). We hypothesized that a quantile of the distribution could serve as a surrogate POD and determined the appropriate quantile by calibration to regulatory PODs. Finally, we characterized uncertainties around the surrogate PODs from intra- and interstudy variability and derived probabilistic toxicity values using a standardized workflow. Results: The distribution for each chemical was adequately fit by a lognormal distribution, and the 25th percentile best predicted the available regulatory PODs [ , units]. We derived surrogate PODs for 10,145 chemicals from the curated data set, differentiating between general noncancer and reproductive/developmental effects, with typical uncertainties (at 95% confidence) of a factor of 10 and 12, respectively. From these PODs, probabilistic reference doses (1% incidence at 95% confidence), as well as human population effect doses (10% incidence), were derived. Discussion: In providing surrogate PODs calibrated to regulatory values and deriving corresponding toxicity values, we have substantially expanded the coverage of chemicals from 744 to 8,023 for general noncancer effects, and from 41 to 6,697 for reproductive/developmental effects. These results can be used across various risk assessment and risk management contexts, from hazardous site and life cycle impact assessments to chemical prioritization and substitution. https://doi.org/10.1289/EHP11524
Human cell-based population-wide in vitro models have been proposed as a strategy to derive chemical-specific estimates of inter-individual variability; however, the utility of this approach has not yet been tested for cumulative exposures in mixtures. This study aimed to test defined mixtures and their individual components and determine whether adverse effects of the mixtures were likely to be more variable in a population than those of the individual chemicals. The in vitro model comprised 146 human lymphoblastoid cell lines from four diverse subpopulations of European and African descent. Cells were exposed, in concentration–response, to 42 chemicals from diverse classes of environmental pollutants; in addition, eight defined mixtures were prepared from these chemicals using several exposure- or hazard-based scenarios. Points of departure for cytotoxicity were derived using Bayesian concentration–response modeling and population variability was quantified in the form of a toxicodynamic variability factor (TDVF). We found that 28 chemicals and all mixtures exhibited concentration–response cytotoxicity, enabling calculation of the TDVF. The median TDVF across test substances, for both individual chemicals or defined mixtures, ranged from a default assumption (101/2) of toxicodynamic variability in human population to >10. The data also provide a proof of principle for single-variant genome-wide association mapping for toxicity of the chemicals and mixtures, although replication would be necessary due to statistical power limitations with the current sample size. This study demonstrates the feasibility of using a set of human lymphoblastoid cell lines as an in vitro model to quantify the extent of inter-individual variability in hazardous properties of both individual chemicals and mixtures. The data show that population variability of the mixtures is unlikely to exceed that of the most variable component, and that similarity in genome-wide associations among components may be used to accrue additional evidence for grouping of constituents in a mixture for cumulative assessments.
Background: The fire at the Intercontinental Terminals Company (ITC, Deer Park, La Porte, TX, USA) from March 17-20, 2019 resulted in substantial releases of chemical contaminants to the environment, including the surface waters of the Houston Ship Channel. Objective: To characterize spatial and temporal trends, as well as potential human health risks, from these releases. Methods: Out of 433 substances with available data, seven were selected for analysis: benzene, toluene, ethylbenzene, xylenes, oil & grease, suspended solids, and total petroleum hydrocarbons. Spatial and temporal concentration trends were characterized, and hazard quotients and cancer risks were calculated to estimate the potential for human health impacts from these contaminants. Results: Temporal analysis showed presence of these chemical contaminants in water immediately after the event; their concentrations dissipated substantially within 4 weeks. The spatial distribution of contaminants indicated the highest concentrations in the waterways within about 1km of the ITC. The greatest potential human health risks stemmed from presence of benzene. Significance: A short-term but substantial spike in the concentrations of a number of hazardous contaminants occurred near the incident, with concentrations returning to apparent baseline levels within one month likely due to a combination of volatization, dilution and degradation.
Natural and anthropogenic disasters may be associated with redistribution of chemical contaminants in the environment; however, current methods for assessing hazards and risks of complex mixtures are not suitable for disaster response. This study investigated the suitability of in vitro toxicity testing methods as a rapid means of identifying areas of potential human health concern. We used sediment samples (n = 46) from Galveston Bay and the Houston Ship Channel (GB/HSC) areas after hurricane Harvey, a disaster event that led to broad redistribution of chemically-contaminated sediments, including deposition of the sediment on shore due to flooding. Samples were extracted with cyclohexane and dimethyl sulfoxide and screened in a compendium of human primary or induced pluripotent stem cell (iPSC)-derived cell lines from different tissues (hepatocytes, neuronal, cardiomyocytes, and endothelial) to test for concentration-dependent effects on various functional and cytotoxicity phenotypes (n = 34). Bioactivity data were used to map areas of potential concern and the results compared to the data on concentrations of polycyclic aromatic hydrocarbons (PAHs) in the same samples. We found that setting remediation goals based on reducing bioactivity is protective of both “known” risks associated with PAHs and “unknown” risks associated with bioactivity, but the converse was not true for remediation based on PAH risks alone. Overall, we found that in vitro bioactivity can be used as a comprehensive indicator of potential hazards and is an example of a new approach method (NAM) to inform risk management decisions on site cleanup.
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