There is increasing interest in the use of tiered approaches in risk assessment of mixtures or co-exposures to chemicals for prioritization. One possible screening-level risk assessment approach is the threshold of toxicological concern (TTC). To date, default assumptions of dose or response additivity have been used to characterize the toxicity of chemical mixtures. Before a screening-level approach could be used, it is essential to know whether synergistic interactions can occur at low, environmentally relevant exposure levels. Studies demonstrating synergism in mammalian test systems were identified from the literature, with emphasis on studies performed at doses close to the points of departure (PODs) for individual chemicals. This search identified 90 studies on mixtures. Few included quantitative estimates of low-dose synergy; calculations of the magnitude of interaction were included in only 11 papers. Quantitative methodology varied across studies in terms of the null hypothesis, response measured, POD used to test for synergy, and consideration of the slope of the dose-response curve. It was concluded that consistent approaches should be applied for quantification of synergy, including that synergy be defined in terms of departure from dose additivity; uniform procedures be developed for assessing synergy at low exposures; and the method for determining the POD for calculating synergy be standardized. After evaluation of the six studies that provided useful quantitative estimates of synergy, the magnitude of synergy at low doses did not exceed the levels predicted by additive models by more than a factor of 4.

Quantifying the transfer of organic chemicals from the environment into terrestrial plants is essential for assessing human and ecological risks, using plants as environmental contamination biomonitors, and predicting phytoremediation effectiveness. Experimental data describing chemical uptake by plants are often expressed as ratios of chemical concentrations in the plant compartments of interest (e.g., leaves, shoots, roots, xylem sap) to those in the exposure medium (e.g., soil, soil porewater, hydroponic solution, air). These ratios are generally referred to as "bioconcentration factors" but have also been named for the specific plant compartment sampled, such as "root concentration factors," "leaf concentration factors," or "transpiration stream (xylem sap) concentrations factors." We reviewed over 350 articles to develop a database with 7049 entries of measured bioaccumulation data for 310 organic chemicals and 112 terrestrial plant species. Various experimental approaches have been used; therefore, interstudy comparisons and data-quality evaluations are difficult. Key exposure and plant growth conditions were often missing, and units were often unclear or not reported. The lack of comparable high-confidence data also limits model evaluation and development. Standard test protocols or, at a minimum, standard reporting guidelines for the measurement of plant uptake data are recommended to generate comparable, high-quality data that will improve mechanistic understanding of organic chemical uptake by plants. Environ Toxicol Chem 2018;37:21-33. C 2017 SETAC

As regulatory initiatives increasingly call for an understanding of the cumulative risks from chemical mixtures, evaluating exposure data from large biomonitoring programs, which may inform these cumulative risk assessments, will improve the understanding of occurrence and patterns of coexposures. Here we have analyzed the urinary metabolite data for six phthalates (di-butyl phthalate; di-isobutyl phthalate; butyl-benzyl phthalate; bis(2-ethylhexyl) phthalate; di-isononyl phthalate; and di-isodecyl phthalate) in the 2007/2008 National Health and Nutrition Examination Survey (NHANES) data set. For the total data set (N=2604), the co-occurrence of multiple phthalates at the upper percentile of exposure was infrequent. There were no individuals in the NHANES sample who were exposed to >95th percentiles for all six phthalates. For 75% of individuals, none of the six phthalates were above the 95th percentile of their respective exposure distributions. These data suggest that high exposure to multiple phthalates is infrequent in the NHANES population. This analysis solely focused on the pattern of contribution of individual phthalates to total exposure. It did not address the pattern of contribution to potential risk. The approach presented could potentially be used to provide insight into understanding the coexposure patterns for other chemicals.

Background: The Life Cycle Initiative, hosted at the United Nations Environment Programme, selected human toxicity impacts from exposure to chemical substances as an impact category that requires global guidance to overcome current assessment challenges. The initiative leadership established the Human Toxicity Task Force to develop guidance on assessing human exposure and toxicity impacts. Based on input gathered at three workshops addressing the main current scientific challenges and questions, the task force built a roadmap for advancing human toxicity characterization, primarily for use in life cycle impact assessment (LCIA). Objectives: The present paper aims at reporting on the outcomes of the task force workshops along with interpretation of how these outcomes will impact the practice and reliability of toxicity characterization. The task force thereby focuses on two major issues that emerged from the workshops, namely considering near-field exposures and improving dose–response modeling. Discussion: The task force recommended approaches to improve the assessment of human exposure, including capturing missing exposure settings and human receptor pathways by coupling additional fate and exposure processes in consumer and occupational environments (near field) with existing processes in outdoor environments (far field). To quantify overall aggregate exposure, the task force suggested that environments be coupled using a consistent set of quantified chemical mass fractions transferred among environmental compartments. With respect to dose–response, the task force was concerned about the way LCIA currently characterizes human toxicity effects, and discussed several potential solutions. A specific concern is the use of a (linear) dose–response extrapolation to zero. Another concern addresses the challenge of identifying a metric for human toxicity impacts that is aligned with the spatiotemporal resolution of present LCIA methodology, yet is adequate to indicate health impact potential. Conclusions: Further research efforts are required based on our proposed set of recommendations for improving the characterization of human exposure and toxicity impacts in LCIA and other comparative assessment frameworks. https://doi.org/10.1289/EHP3871

The Risk Assessment IDentification And Ranking (RAIDAR) model is refined to calculate relative human exposures as expressed by total intake, intake fraction (iF), and total body burden (TBB) metrics. The RAIDAR model is applied to three persistent organic pollutants (POPs) and six petrochemicals using four mode-of-entry emission scenarios to evaluate the effect of metabolic biotransformation estimates on human exposure calculations. When biotransformation rates are assumed to be negligible, daily intake and iFs for the nine substances ranged over six orders of magnitude and TBBs ranged over 10 orders of magnitude. Including biotransformation estimates for fish, birds, and mammals reduced substance-specific daily intake and iF by up to 4.5 orders of magnitude and TBB by more than eight orders of magnitude. The RAIDAR iF calculations are compared to the European Union System for the Evaluation of Substances (EUSES) model iF calculations and differences are discussed, especially the treatment of food web bioaccumulation. Model selection and application assumptions result in different rankings of human exposure potential. These results suggest a need to critically consider model selection and to include reliable biotransformation rate estimates when assessing relative human exposure and ranking substances for priority setting. Recommendations for further model evaluations and revisions are discussed.

European exposure factor data have been collected in one centrally available, freely accessible site on the Internet: the ExpoFacts database (http://www.ktl.fi/expofacts/). The process of compiling the database required locating the exposure factor data and evaluating its general applicability and public availability. The scope of the ExpoFacts database covers 30 European countries, often each with its own approach for data generation and publication. The database includes information on food intake, time use, physiology, housing, and demographic parameters, as available. Information included in the database, as well as the challenges in collecting and compiling this information, are summarized. Data were found to be unavailable for ExpoFacts for a number of reasons: (1) data have not been collected, (2) collected data are not published, (3) the publishing format or language makes the data hard to locate and use, (4) copyright restrictions prevent presenting the data in an open access website, or (5) data exist, but are too expensive to acquire. Improving accessibility and harmonization of existing data would enhance the information base for exposure and risk assessments. In addition, the ExpoFacts project demonstrates a successful process for acquiring, storing, and sharing exposure factors data.

The European Solvents Industry Group (ESIG) Generic Exposure Scenario (GES) Risk and Exposure Tool (EGRET) was developed to facilitate the safety evaluation of consumer uses of solvents, as required by the European Union Registration, Evaluation and Authorization of Chemicals (REACH) Regulation. This exposure-based risk assessment tool provides estimates of both exposure and risk characterization ratios for consumer uses. It builds upon the consumer portion of the European Center for Ecotoxicology and Toxicology of Chemicals (ECETOC) Targeted Risk Assessment (TRA) tool by implementing refinements described in ECETOC TR107. Technical enhancements included the use of additional data to refine scenario defaults and the ability to include additional parameters in exposure calculations. Scenarios were also added to cover all frequently encountered consumer uses of solvents. The TRA tool structure was modified to automatically determine conditions necessary for safe use. EGRET reports results using specific standard phrases in a format consistent with REACH exposure scenario guidance, in order that the outputs can be readily assimilated within safety data sheets and similar information technology systems. Evaluation of tool predictions for a range of commonly encountered consumer uses of solvents found it provides reasonable yet still conservative exposure estimates.

As the general public and retailers ask for disclosure of chemical ingredients in the marketplace, a number of hazard screening tools were developed to evaluate the so-called "greenness" of individual chemical ingredients and/or formulations. The majority of these tools focus only on hazard, often using chemical lists, ignoring the other part of the risk equation: exposure. Using a hazard-only focus can result in regrettable substitutions, changing 1 chemical ingredient for another that turns out to be more hazardous or shifts the toxicity burden to others. To minimize the incidents of regrettable substitutions, BizNGO describes "Common Principles" to frame a process for informed substitution. Two of these 6 principles are: "reduce hazard" and "minimize exposure." A number of frameworks have emerged to evaluate and assess alternatives. One framework developed by leading experts under the auspices of the US National Academy of Sciences recommended that hazard and exposure be specifically addressed in the same step when assessing candidate alternatives. For the alternative assessment community, this article serves as an informational resource for considering exposure in an alternatives assessment using elements of problem formulation; product identity, use, and composition; hazard analysis; exposure analysis; and risk characterization. These conceptual elements build on practices from government, academia, and industry and are exemplified through 2 hypothetical case studies demonstrating the questions asked and decisions faced in new product development. These 2 case studies-inhalation exposure to a generic paint product and environmental exposure to a shampoo rinsed down the drain-demonstrate the criteria, considerations, and methods required to combine exposure models addressing human health and environmental impacts to provide a screening level hazard and exposure (risk) analysis. This article informs practices for these elements within a comparative risk context to improve alternatives assessment evaluation and decision making. Integr Environ Assess Manag