A quantitative screening-level approach to incorporate chemical exposure and risk into alternative assessment evaluations.

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 2017;13:1007-1022. © 2017 The Authors. Integrated Environmental Assessment and Management published by Wiley Periodicals, Inc. on behalf of Society of Environmental Toxicology & Chemistry (SETAC).

Improving the scientific foundation for mixtures joint toxicity and risk assessment: contributions from the SOT mixtures project--introduction.

Risk assessments are enhanced when policy and other decision-makers have access to experimental science designed to specifically inform key policy questions. Currently, our scientific understanding and science policy for environmental mixtures are based largely on extrapolating from and combining data in the observable range of single chemical toxicity to lower environmental concentrations and composition, i.e., using higher dose data to extrapolate and predict lower dose toxicity. There is a growing consensus that the default assumptions underlying those mixtures risk assessments that are conducted in the absence of actual mixtures data rest on an inadequate scientific database. Future scientific research should both build upon the current science and advance toxicology into largely uncharted territory. More precise approaches to better characterize toxicity of mixtures are needed. The Society of Toxicology (SOT) sponsored a series of panels, seminars, and workshops to help catalyze and improve the design and conduct of experimental toxicological research to better inform risk assessors and decision makers. This paper summarizes the activities of the SOT Mixtures Program and serves as the introductory paper to a series of articles in this issue, which hope to inspire innovative research and challenge the status quo.

Hershey Medical Center Technical Workshop Report: optimizing the design and interpretation of epidemiologic studies for assessing neurodevelopmental effects from in utero chemical exposure.

Neurodevelopmental disabilities affect 3-8% of the 4 million babies born each year in the U.S. alone, with known etiology for less than 25% of those disabilities. Numerous investigations have sought to determine the role of environmental exposures in the etiology of a variety of human neurodevelopmental disorders (e.g., learning disabilities, attention deficit-hyperactivity disorder, intellectual disabilities) that are manifested in childhood, adolescence, and young adulthood. A comprehensive critical examination and discussion of the various methodologies commonly used in investigations is needed. The Hershey Medical Center Technical Workshop: Optimizing the design and interpretation of epidemiologic studies for assessing neurodevelopmental effects from in utero chemical exposure provided such a forum for examining these methodologies. The objective of the Workshop was to develop scientific consensus on the key principles and considerations for optimizing the design and interpretation of epidemiologic studies of in utero exposure to environmental chemicals and subsequent neurodevelopmental effects. (The Panel recognized that the nervous system develops post-natally and that critical periods of exposure can span several developmental life stages.) Discussions from the Workshop Panel generated 17 summary points representing key tenets of work in this field. These points stressed the importance of: a well-defined, biologically plausible hypothesis as the foundation of in utero studies for assessing neurodevelopmental outcomes; understanding of the exposure to the environmental chemical(s) of interest, underlying mechanisms of toxicity, and anticipated outcomes; the use of a prospective, longitudinal cohort design that, when possible, runs for periods of 2-5 years, and possibly even longer, in an effort to assess functions at key developmental epochs; measuring potentially confounding variables at regular, fixed time intervals; including measures of specific cognitive and social-emotional domains along with non-cognitive competence in young children, as well as comprehensive measures of health; consistency of research design protocols across studies (i.e., tests, covariates, and analysis styles) in an effort to improve interstudy comparisons; emphasis on design features that minimize introduction of systematic error at all stages of investigation: participant selection, data collection and analysis, and interpretation of results; these would include (but not be limited to) reducing selection bias, using double-blind designs, and avoiding post hoc formulation of hypotheses; a priori data analysis strategies tied to hypotheses and the overall research design, particularly for methods used to characterize and address confounders in any neurodevelopmental study; actual quantitative measurements of exposure, even if indirect, rather than methods based on subject recall; careful examination of standard test batteries to ensure that the battery is tailored to the age group as well as what is known about the specific neurotoxic effects on the developing nervous system; establishment of a system for neurodevelopmental surveillance for tracking the outcomes from in utero exposure across early developmental time periods to determine whether central nervous system injuries may be lying silent until developmentally challenged; ongoing exploration of computerized measures that are culturally and linguistically sensitive, and span the age range from birth into the adolescent years; routine incorporation of narrative in manuscripts concerning the possibility of spurious (i.e., false positive and false negative) test results in all research reportage (this can be facilitated by detailed, transparent reporting of design, covariates, and analyses so that others can attempt to replicate the study); forthright, disciplined, and intellectually honest treatment of the extent to which results of any study are conclusive--that is, how generalizable the results of the study are in terms of the implications for the individual study participants, the community studied, and human health overall; confinement of reporting to the actual research questions, how they were tested, and what the study found, and avoiding, or at least keeping to a minimum, any opinions or speculation concerning public health implications; education of clinicians and policymakers to critically read scientific reports, and to interpret study findings and conclusions appropriately; and recognition by investigators of their ethical duty to report negative as well as positive findings, and the importance of neither minimizing nor exaggerating these findings.

Use of a physiologically based pharmacokinetic model to identify exposures consistent with human biomonitoring data for chloroform.

Biomonitoring data provide evidence of human exposure to environmental chemicals by quantifying the chemical or its metabolite in a biological matrix. To better understand the correlation between biomonitoring data and environmental exposure, physiologically based pharmacokinetic (PBPK) modeling can be of use. The objective of this study was to use a combined PBPK model with an exposure model for showering to estimate the intake concentrations of chloroform based on measured blood and exhaled breath concentrations of chloroform. First, the predictive ability of the combined model was evaluated with three published studies describing exhaled breath and blood concentrations in people exposed to chloroform under controlled showering events. Following that, a plausible exposure regimen was defined combining inhalation, ingestion, and dermal exposures associated with residential use of water containing typical concentrations of chloroform to simulate blood and exhaled breath concentrations of chloroform. Simulation results showed that inhalation and dermal exposure could contribute substantially to total chloroform exposure. Next, sensitivity analysis and Monte Carlo analysis were performed to investigate the sources of variability in model output. The variability in exposure conditions (e.g., shower duration) was shown to contribute more than the variability in pharmacokinetics (e.g., body weight) to the predicted variability in blood and exhaled breath concentrations of chloroform. Lastly, the model was used in a reverse dosimetry approach to estimate distributions of exposure consistent with concentrations of chloroform measured in human blood and exhaled breath.

Can mode of action predict mixture toxicity for risk assessment?

Recent regulatory guidance for mixture risk assessments and for regulating pesticide chemicals recommends using information about the "mode" or "mechanism" of action of individual chemicals to predict dose response characteristics of mixtures. Dose addition is assumed for mixtures of chemicals that have similar mechanisms and response addition for those with dissimilar mechanisms. Three different sets of criteria have been formulated to guide the selection of an appropriate data set for characterizing a chemical's mode of action, but the sufficiency of those criteria to predict dose addition for a mixture has not been validated experimentally. Several examples from the pharmacological and toxicological literature challenge the premise that dose response characteristics of a mixture can be predicted from the modes of action of its components. Detoxification pathways may need to be understood before dose addition in the observable effect range can be extrapolated to mixture concentrations below the no observable effect levels of the mixture components. Because elucidating discreet mechanisms of action may be possible only for chemicals that exhibit a high degree of biological specificity and dose sensitivity, practical limitations on the approach must be defined. To reduce the large uncertainties inherent in the recommended approach, future research should be focused on defining the mechanistic features that predict dose additive toxicity in mixtures. A detailed characterization of pharmacodynamics, pharmacokinetics, and slope of dose response curves may be necessary to evaluate whether the toxicity of a mixture can be predicted by the mode of action of its component chemicals.