Beyond the cancer slope factor: Broad application of Bayesian and probabilistic approaches for cancer dose-response assessment.

Traditional cancer slope factors derived from linear low-dose extrapolation give little consideration to uncertainties in dose-response model choice, interspecies extrapolation, and human variability. As noted previously by the National Academies, probabilistic methods can address these limitations, but have only been demonstrated in a few case studies. Here, we applied probabilistic approaches for Bayesian Model Averaging (BMA), interspecies extrapolation, and human variability distributions to 255 animal cancer bioassay datasets previously used by governmental agencies. We then derived predictions for both population cancer incidence and individual cancer risk. For model uncertainty, we found that lower confidence limits from BMA and from U.S. Environmental Protection Agency (EPA)'s Benchmark Dose Software (BMDS) correlated highly, with 86% differing by <10-fold. Incorporating other uncertainties and human variability, the lower confidence limits of the probabilistic risk-specific dose (RSD) at 10-6 population incidence were typically 3- to 30-fold lower than traditional slope factors. However, in a small (<7%) number of cases of highly non-linear experimental dose-response, the probabilistic RSDs were >10-fold less stringent. Probabilistic RSDs were also protective of individual risks of 10-4 in >99% of the population. We conclude that implementing Bayesian and probabilistic methods provides a more scientifically rigorous basis for cancer dose-response assessment and thereby improves overall cancer risk characterization.

Probabilistic Points of Departure and Reference Doses for Characterizing Human Noncancer and Developmental/Reproductive Effects for 10,145 Chemicals.

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 (BMDh). We hypothesized that a quantile of the BMDh 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 BMDh distribution for each chemical was adequately fit by a lognormal distribution, and the 25th percentile best predicted the available regulatory PODs [R2≥0.78, residual standard error (RSE)≤0.53 log10 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.

Unseen Risk: Mapping Contamination Hazards to Enhance Risk Perception in Galena Park, Texas.

As extreme weather events have become more frequently observed in recent decades, concerns about exposure to potential flood risk have increased, especially in underserved and socially vulnerable communities. Galena Park, Texas, is a socially vulnerable community that also confronts escalated physical vulnerabilities due to existing flood risks from Buffalo Bayou and the Houston Ship Channel as well as proximity to industrial facilities that emit chemical pollution. To better understand the underlying risks that Galena Park is facing, this research assesses and visualizes the existing contamination hazards associated with the chemical facilities within Galena Park. Through this process, we (1) compute the environmental, health, and physical hazards associated with industrial facilities, (2) spatially geocode the points of contamination sources and flood exposure, and (3) increase awareness of existing risk by visualizing and distributing related information using an ArcGIS Dashboard. The results indicate that there are 169 points of location from 127 industrial facilities, and 24 points were inducing potential chemicals. In total, 126 chemicals have potential physical, health, and environmental hazards. On average, each facility has 2.4 chemicals that could cause potential hazards with a range of zero to 57 chemicals. When examining the specific physical, health, and environmental risks associated with the chemicals, on average each facility has 14.6 types of risks associated with it. This includes, on average, 9.8 types of health hazards, 1.53 physical hazards, and 2.3 environmental hazards per facility. When analyzing the spatial relationship between the chemical exposure and the current flood risk using the Dashboard, it is noticeable that most of the industrial facilities are located in the south of Galena Park, near Buffalo Bayou, where a variety of industrial facilities are clustered. Through this study, we spatially mapped the existing risks in Galena Park that are not readily available to the community and risks that are not currently tangible or visible. The utility of ArcGIS Dashboards affords the opportunity to translate massive databases into digestible knowledge that can be shared and utilized within the community. This study also takes another step toward building community resilience by providing knowledge that can be used to prepare for and respond to disasters. Visualizing unseen risks and promoting awareness can enhance risk perception when supported by scientific knowledge. Further investigation is necessary to enhance preparedness behaviors, identify proper evacuation techniques and routes, and build community networks to comprehensively promote resilience to multi-hazard circumstances.

Cumulative Risk Meets Inter-Individual Variability: Probabilistic Concentration Addition of Complex Mixture Exposures in a Population-Based Human In Vitro Model.

Although humans are continuously exposed to complex chemical mixtures in the environment, it has been extremely challenging to investigate the resulting cumulative risks and impacts. Recent studies proposed the use of "new approach methods," in particular in vitro assays, for hazard and dose−response evaluation of mixtures. We previously found, using five human cell-based assays, that concentration addition (CA), the usual default approach to calculate cumulative risk, is mostly accurate to within an order of magnitude. Here, we extend these findings to further investigate how cell-based data can be used to quantify inter-individual variability in CA. Utilizing data from testing 42 Superfund priority chemicals separately and in 8 defined mixtures in a human cell-based population-wide in vitro model, we applied CA to predict effective concentrations for cytotoxicity for each individual, for "typical" (median) and "sensitive" (first percentile) members of the population, and for the median-to-sensitive individual ratio (defined as the toxicodynamic variability factor, TDVF). We quantified the accuracy of CA with the Loewe Additivity Index (LAI). We found that LAI varies more between different mixtures than between different individuals, and that predictions of the population median are generally more accurate than predictions for the "sensitive" individual or the TDVF. Moreover, LAI values were generally <1, indicating that the mixtures were more potent than predicted by CA. Together with our previous studies, we posit that new approach methods data from human cell-based in vitro assays, including multiple phenotypes in diverse cell types and studies in a population-wide model, can fill critical data gaps in cumulative risk assessment, but more sophisticated models of in vitro mixture additivity and bioavailability may be needed. In the meantime, because simple CA models may underestimate potency by an order of magnitude or more, either whole-mixture testing in vitro or, alternatively, more stringent benchmarks of cumulative risk indices (e.g., lower hazard index) may be needed to ensure public health protection.

A Population-Based Human In Vitro Approach to Quantify Inter-Individual Variability in Responses to Chemical Mixtures.

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.

Potential Human Health Hazard of Post-Hurricane Harvey Sediments in Galveston Bay and Houston Ship Channel: A Case Study of Using In Vitro Bioactivity Data to Inform Risk Management Decisions.

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.

Exposure and Toxicity Characterization of Chemical Emissions and Chemicals in Products: Global Recommendations and Implementation in USEtox.

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 in 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 advances since the original release of USEtox. Based on these advances, the taskforce 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 framework was finally 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 submodels for each product type to account for product 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 effect factors. Factors reflecting disease severity are proposed to distinguish cancer from non-cancer effects, and within the latter 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.

Spatial and temporal distribution of surface water contaminants in the Houston Ship Channel after the Intercontinental Terminal Company Fire.

BACKGROUND: The fire at the Intercontinental Terminals Company (ITC, Deer Park, La Porte, TX, USA) from March 17 to 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 and 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 1 km 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 1 month likely due to a combination of volatization, dilution and degradation.

Comprehensive analysis to determine the differences of solar salt produced in South Korea and China.

Food fraud, including adulteration, addition, tampering, and misrepresentation of food ingredients and packaging for improper economic profit, has been global concerns affecting public health and safety. In South Korea, counterfeit expression of solar salt has been a problem causing improper economic profit, especially for those products produced from China, but labeled as 'domestics'. In this study, we were tried to discriminate geographical origins of solar salt between South Korea and China through various analytical techniques, the determination of moisture and sodium chloride contents, multi-elemental analysis, and isotope analysis. With the application of a statistical analysis, more than 93.3% of discrimination capability of positive classification was achieved in this study.