Application of a unified probabilistic framework to the dose-response assessment of acrolein.

BACKGROUND: In quantitative chemical risk assessment, a reference value is an estimate of an exposure to a chemical that is "likely to be without appreciable risk." Because current "deterministic" approaches do not quantitatively characterize the likelihood or severity of harm, the National Academies has recommended using reference values derived from a risk-specific dose that are treated as random variables, with probability distributions characterizing uncertainty and variability. OBJECTIVES: In order to build familiarity and address issues needed for routine and standardized derivation of probabilistic risk-specific dose distributions, a case example applying the unified probabilistic framework presented in Chiu and Slob (2015) is developed for acrolein. This case study is based on an updated systematic evidence map of literature (Keshava et al., 2020) identifying nasal lesions reported in Dorman et al. (2008) as the most appropriate endpoint and study for reference value derivation. METHODS: The probability distribution was calculated for the risk-specific dose, which in this implementation of the approach was calculated for the dose at which 1% of the human population is estimated to experience minimal lesions, and a probabilistic reference value was computed as the 5th percentile of this distribution. A deterministic reference value was also derived for comparison, and a sensitivity analysis of the probabilistic reference value was conducted investigating alternative assumptions for the point of departure type and exposure duration. RESULTS: The probabilistic reference value of 6 × 10-4 mg/m3 was slightly lower than the deterministic reference value of 8 × 10-4 mg/m3, and the risk-specific dose distribution had an uncertainty spanning a factor of 137 (95th-5th percentile ratio). Sensitivity analysis yielded slightly higher probabilistic reference values ranging between 9 × 10-4 mg/m3 and 2 × 10-3 mg/m3. CONCLUSIONS: Using a probabilistic approach for deriving a reference value allows quantitative characterization of the severity, incidence, and uncertainty of effects at a given dose. The results can be used to inform risk management decisions and improve risk communication.

Application of systematic evidence mapping to assess the impact of new research when updating health reference values: A case example using acrolein.

BACKGROUND: The environmental health community needs transparent, methodologically rigorous, and rapid approaches for updating human health risk assessments. These assessments often contain reference values for cancer and/or noncancer effects. Increasingly, the use of systematic review methods are preferred when developing these assessments. Systematic evidence maps are a type of analysis that has the potential to be very helpful in the update process, especially when combined with machine-learning software advances designed to expedite the process of conducting a review. OBJECTIVES: To evaluate the applicability of evidence mapping to determine whether new evidence is likely to result in a change to an existing health reference value, using inhalation exposure to the air pollutant acrolein as a case example. METHODS: New literature published since the 2008 California Environmental Protection Agency's Office of Environmental Health Hazard Assessment (OEHHA) Reference Exposure Level (REL) for acrolein was assessed. Systematic review methods were used to search the literature and screening included the use of machine-learning software. The Populations, Exposures, Comparators and Outcomes (PECO) criteria were kept broad to identify studies that characterized acute and chronic exposure and could be informative for hazard characterization. Studies that met the PECO criteria after full-text review were briefly summarized before their suitability for chronic point of departure (POD) derivation and calculation of a reference value was considered. Studies considered potentially suitable underwent a targeted evaluation to determine their suitability for use in dose-response analysis. RESULTS: Over 15,000 studies were identified from scientific databases. Both machine-learning and manual screening processes were used to identify 60 studies considered PECO-relevant after full-text review. Most of these PECO-relevant studies were short-term exposure animal studies (acute or less than 1 month of exposure) and considered less suitable for deriving a chronic reference value when compared to the subchronic study in rats used in the 2008 OEHHA assessment. Thirteen epidemiological studies were identified but had limitations in the exposure assessment that made them less suitable for dose-response compared to the subchronic rat study. Among the 13 studies, there were four controlled trial studies that have the potential to be informative for future acute reference value derivation. Thus, the 2008 subchronic rat study used by OEHHA appears to still be the most appropriate study for chronic reference value derivation. In addition, advances in dosimetric modeling for gases, including new evidence pertinent to acrolein, could be considered when updating existing acrolein toxicity values. CONCLUSIONS: Evidence mapping is a very useful tool to assess the need for updating an assessment based on understanding the potential impact of new studies on revising an existing health reference value. In this case example, the focus was to identify studies suitable for chronic exposure dose-response analysis, while also identifying studies that may be important to consider for acute exposure scenarios, hazard identification, or for future research. This allows the evidence map to be a useful resource for a range of decision-making contexts. Specialized systematic review software increased the efficiency of the process in terms of human resources and time to conduct the analysis.

Systematic dose-response of environmental epidemiologic studies: Dose and response pre-analysis.

Meta-analysis approaches can be used to assess the human risks due to exposure to environmental chemicals when there are numerous high-quality epidemiologic studies of priority outcomes in a database. However, methodological issues related to how different studies report effect measures and incorporate exposure into their analyses arise that complicate the pooled analysis of multiple studies. As such, there are "pre-analysis" steps that are often necessary to prepare summary data reported in epidemiologic studies for dose-response analysis. This paper uses epidemiologic studies of arsenic-induced health effects as a case example and addresses the issues surrounding the estimation of mean doses from censored dose- or exposure-intervals reported in the literature (e.g., estimation of mean doses from high exposures that are only reported as an open-ended interval), calculation of a common dose metric for use in a dose-response meta-analysis (one that takes into consideration inter-individual variability), and calculation of response "effective counts" that inherently account for confounders. The methods herein may be generalizable to 1) the analysis of other environmental contaminants with a suitable database of epidemiologic studies, and 2) any meta-analytic approach used to pool information across studies. A second companion paper detailing the use of "pre-analyzed" data in a hierarchical Bayesian dose-response model and techniques for extrapolating risks to target populations follows.

BMDExpress 2: enhanced transcriptomic dose-response analysis workflow.

SUMMARY: A new version (version 2) of the genomic dose-response analysis software, BMDExpress, has been created. The software addresses the increasing use of transcriptomic dose-response data in toxicology, drug design, risk assessment and translational research. In this new version, we have implemented additional statistical filtering options (e.g. Williams' trend test), curve fitting models, Linux and Macintosh compatibility and support for additional transcriptomic platforms with up-to-date gene annotations. Furthermore, we have implemented extensive data visualizations, on-the-fly data filtering, and a batch-wise analysis workflow. We have also significantly re-engineered the code base to reflect contemporary software engineering practices and streamline future development. The first version of BMDExpress was developed in 2007 to meet an unmet demand for easy-to-use transcriptomic dose-response analysis software. Since its original release, however, transcriptomic platforms, technologies, pathway annotations and quantitative methods for data analysis have undergone a large change necessitating a significant re-development of BMDExpress. To that end, as of 2016, the National Toxicology Program assumed stewardship of BMDExpress. The result is a modernized and updated BMDExpress 2 that addresses the needs of the growing toxicogenomics user community. AVAILABILITY AND IMPLEMENTATION: BMDExpress 2 is available at https://github.com/auerbachs/BMDExpress-2/releases. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Sparking connections: toward better linkages between research and human health policy-an example with multiwalled carbon nanotubes.

Risk assessment and subsequent risk management of environmental contaminants can benefit from early collaboration among researchers, risk assessors, and risk managers. The benefits of collaboration in research planning are particularly evident in light of (1) increasing calls to expand upon the risk assessment paradigm to include a greater focus on problem formulation and consideration of potential tradeoffs between risk management options, and (2) decreasing research budgets. Strategically connecting research planning to future decision making may be most critical in areas of emerging science for which data are often insufficient to clearly direct targeted research to support future risk assessment and management efforts. This article illustrates an application of the comprehensive environmental assessment approach to inform research planning for future risk assessment and management of one emerging material, multiwalled carbon nanotubes (MWCNTs). High-priority research areas identified for MWCNTs in flame-retardant coatings applied to upholstery textiles included the following: release across the product life cycle; environmental transport, transformation and fate in air, wastewater and sediment; exposure in human occupational and consumer groups; kinetics in the human body; impacts on human health and aquatic populations; and impacts on economic, social, and environmental resources. This article focuses on specific research questions related to human health and how these may connect to future risk assessments and risk management efforts. Such connections will support more effective collaborations across the scientific community and may inform the prioritization of research funding opportunities for emerging materials like MWCNTs.

Air pollution toxicology--a brief review of the role of the science in shaping the current understanding of air pollution health risks.

Human and animal toxicology has had a profound impact on our historical and current understanding of air pollution health effects. Early animal toxicological studies of air pollution had distinctively military or workplace themes. With the discovery that ambient air pollution episodes led to excess illness and death, there became an emergence of toxicological studies that focused on industrial air pollution encountered by the general public. Not only did the pollutants investigated evolve from ambient mixtures to individual pollutants but also the endpoints and outcomes evaluated became more sophisticated, resulting in our present state of the science. Currently, a large toxicological database exists for the effects of particulate matter and ozone, and we provide a focused review of some of the major contributions to the biological understanding for these two "criteria" air pollutants. A limited discussion of the toxicological advancements in the scientific knowledge of two hazardous air pollutants, formaldehyde and phosgene, is also included. Moving forward, the future challenge of air pollution toxicology lies in the health assessment of complex mixtures and their interactions, given the projected impacts of climate change and altered emissions on ambient conditions. In the coming years, the toxicologist will need to be flexible and forward thinking in order to dissect the complexity of the biological system itself, as well as that of air pollution in all its varied forms.

The role of developmental toxicity studies in acute exposure assessments: analysis of single-day vs. multiple-day exposure regimens.

In accordance with most toxicity guidelines, developmental studies typically utilize repeated exposures, usually throughout gestation or during organogenesis in particular. However, it is known that developmental toxicity may occur in response to single exposures, especially during specific windows of susceptibility. An overview of the available literature gave sufficient evidence that for many agents, the same endpoints observed in repeated dose, multiple-day studies were also observed in single-day exposures, thus indicating the relevance of developmental toxicity to health assessments of acute exposures. Further, results of benchmark dose modeling of developmental endpoints indicated that for embryo lethality, single-day exposures required a two- to fourfold higher dose than the multiple-day exposures to produce the same level of response. For fused sternebrae, exposures on specific days produced equivalent levels of response at doses that were more similar to those utilized in the repeated exposures. Appreciable differences in biological half-life (and corresponding dose metrics) as well as specific windows of susceptibility may partially explain the observed multiple- vs. single-day exposure dose-response relationships. Our results highlight the need of a more thorough evaluation of outcomes from repeated dose developmental toxicity studies in regards to their importance to chronic and acute risk assessments.

Evaluation of evidence for infection as a mode of action for induction of rat lymphoma.

The European Food Safety Authority (EFSA) released a 2006 report questioning the relationship of aspartame exposure with increased incidence of lymphomas/leukemias in a European Ramazzini Foundation (ERF) rat study. The EFSA report suggested that the lymphoma/leukemia findings were most likely explained by infection in the rat colony. The ERF has also conducted the only available long-term oral study of methyl tertiary-butyl ether (MTBE). Thus, using the EFSA report as support, some have now raised questions about the human relevance of MTBE-associated hemolymphoreticular tumors reported by the ERF in female rats as well as whether their incidence was elevated above background levels. In this report, we discuss the hypothesized mode of action (MOA) of infection-induced lymphoma and its relevance to MTBE-associated lymphomas. We address the relationship of rat strain and study duration to lymphoma susceptibility and review evidence of low background rates of this tumor in control animals at the ERF, similar survival rates for female rats at the ERF and National Toxicology Program (NTP), and chemical- and gender-specificity of tumor induction for this type of tumor in studies at the ERF. We find that the background incidence of hemolymphoreticular tumors in female rats in the MTBE study is consistent with contemporaneous studies at the ERF and that there is an exposure-related effect, which is unlikely to be due to infections. We examine more recent tumor classification schemes for lymphomas, which support the combination of lymphoblastic leukemias and lymphomas reported by Belpoggi et al. ([1995] Toxicol Ind Health 11:119-149; [1998] Eur J Oncol 3:201-206).