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.

A comparison of hourly with annual air pollutant emissions: Implications for estimating acute exposure and public health risk.

Health risks from air pollutants are evaluated by comparing chronic (i.e., an average over 1 yr or greater) or acute (typically 1-hr) exposure estimates with chemical- and duration-specific reference values or standards. When estimating long-term pollutant concentrations via exposure modeling, facility-level annual average emission rates are readily available as model inputs for most air pollutants. In contrast, there are far fewer facility-level hour-by-hour emission rates available for many of these same pollutants. In this report, we first analyze hour-by-hour emission rates for total reduced sulfur (TRS) compounds from eight kraft pulp mill operations. This data set is used to demonstrate discrepancies between estimating exposure based on a single TRS emission rate that has been calculated as the mean of all operating hours of the year, as opposed to reported hourly emission rates. A similar analysis is then performed using reported hourly emission rates for sulfur dioxide (SO2) and oxides of nitrogen (NOx) from three power generating units from a U.S. power plant. Results demonstrate greater variability at kraft pulp mill operations, with ratios of reported hourly to average hourly TRS emissions ranging from less than 1 to greater than 160 during routine facility operations. Thus, if fluctuations in hourly emission rates are not accounted for, over- or underestimates of hourly exposure, and thus acute health risk, may occur. In addition to this analysis, we also demonstrate an additional challenge when assessing health risk based on hourly exposures: the lack of human health reference values based on 1-hr exposures. Implications: Largely due to the lack of reported hourly emission rate data for many air pollutants, an hourly average emission rate (calculated from an annual emission rate) is often used when modeling the potential for acute health risk. We calculated ratios between reported hourly and hourly average emission rates from pulp and paper mills and a U.S. power plant to demonstrate that if not considered, hourly fluctuations in emissions could result in an over- or underestimation of exposure and risk. We also demonstrate the lack of 1-hr human health reference values meant to be protective of the general population, including children.

Manganese testing under a clean air act test rule and the application of resultant data in risk assessments.

In the 1990's, the proposed use of methylcyclopentadienyl manganese tricarbonyl (MMT) as an octane-enhancing gasoline fuel additive led to concerns for potential public health consequences from exposure to manganese (Mn) combustion products in automotive exhaust. After a series of regulatory/legal actions and negotiations, the U.S. Environmental Protection Agency (EPA) issued under Clean Air Act (CAA) section 211(b) an Alternative Tier 2 Test Rule that required development of scientific information intended to help resolve uncertainties in exposure or health risk estimates associated with MMT use. Among the uncertainties identified were: the chemical forms of Mn emitted in automotive exhaust; the relative toxicity of different Mn species; the potential for exposure among sensitive subpopulations including females, the young and elderly; differences in sensitivity between test species and humans; differences between inhalation and oral exposures; and the influence of dose rate and exposure duration on tissue accumulation of Mn. It was anticipated that development of specific sets of pharmacokinetic (PK) information and models regarding Mn could help resolve many of the identified uncertainties and serve as the best foundation for available data integration. The results of the test program included development of several unique Mn datasets, and a series of increasingly sophisticated Mn physiologically-based pharmacokinetic (PBPK) models. These data and models have helped address each of the uncertainties originally identified in the Test Rule. The output from these PBPK models were used by the Agency for Toxic Substances and Disease Registry (ATSDR) in 2012 to inform the selection of uncertainty factors for deriving the manganese Minimum Risk Level (MRL) for chronic exposure durations. The EPA used the MRL in the Agency's 2015 evaluation of potential residual risks of airborne manganese released from ferroalloys production plants. This resultant set of scientific data and models likely would not exist without the CAA section 211(b) test rule regulatory procedure.

Interpreting Mobile and Handheld Air Sensor Readings in Relation to Air Quality Standards and Health Effect Reference Values: Tackling the Challenges.

The US Environmental Protection Agency (EPA) and other federal agencies face a number of challenges in interpreting and reconciling short-duration (seconds to minutes) readings from mobile and handheld air sensors with the longer duration averages (hours to days) associated with the National Ambient Air Quality Standards (NAAQS) for the criteria pollutants-particulate matter (PM), ozone, carbon monoxide, lead, nitrogen oxides, and sulfur oxides. Similar issues are equally relevant to the hazardous air pollutants (HAPs) where chemical-specific health effect reference values are the best indicators of exposure limits; values which are often based on a lifetime of continuous exposure. A multi-agency, staff-level Air Sensors Health Group (ASHG) was convened in 2013. ASHG represents a multi-institutional collaboration of Federal agencies devoted to discovery and discussion of sensor technologies, interpretation of sensor data, defining the state of sensor-related science across each institution, and provides consultation on how sensors might effectively be used to meet a wide range of research and decision support needs. ASHG focuses on several fronts: improving the understanding of what hand-held sensor technologies may be able to deliver; communicating what hand-held sensor readings can provide to a number of audiences; the challenges of how to integrate data generated by multiple entities using new and unproven technologies; and defining best practices in communicating health-related messages to various audiences. This review summarizes the challenges, successes, and promising tools of those initial ASHG efforts and Federal agency progress on crafting similar products for use with other NAAQS pollutants and the HAPs. NOTE: The opinions expressed are those of the authors and do not necessary represent the opinions of their Federal Agencies or the US Government. Mention of product names does not constitute endorsement.

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.

Summary of the workshop on the power of aggregated toxicity data.

In this workshop, ongoing federal agency (i.e., EPA, ATSDR, FDA, NIEHS and others) projects that employ toxicity data were discussed, as well as the possibility of innovative approaches for use of existing and new sources of information in risk assessment. Quantitative risk assessment relies upon having detailed exposure-response data, such as number of animals and incidence by exposure group in dichotomous measures and values by individual animal for continuous measures; this level of detail is often not reported in peer-reviewed studies. Additionally, biologically-based models (e.g., PBPK) are useful in risk assessment but require knowledge or collection of parameters as inputs (both chemical-specific and more general physiological parameters), and this information is not always readily available. Structure activity relationship information is also being called upon to help fill in knowledge gaps about specific chemicals where data from related chemicals may be available. Some existing data sources have been developed by various agencies for specific applications, such as those mentioned, and advantage should be taken of those existing resources; however, a great deal more is possible. The purpose of this workshop was to gather together many of the stakeholders using and developing shared toxicological information, determine the potential for greater collaboration, and determine the best course to facilitate the further development of joint information resources. A number of recommendations (development of a consensus toxicological review format, standardization of terminology and data sharing formats, and agreement on primary data elements) and topics for additional discussion were the major products of this workshop.

An exposure-response database for detailed toxicity data.

Risk assessment for human health effects often depends on evaluation of toxicological literature from a variety of sources. Risk assessors have limited resources for obtaining raw data, performing follow-on analyses or initiating new studies. These constraints must be balanced against a need to improve scientific credibility through improved statistical and analytical methods that optimize the use of available information. Computerized databases are used in toxicological risk assessment both for storing data and performing predictive analyses. Many systems provide primarily either bibliographic information or summary factual data from toxicological studies; few provide adequate information to allow application of dose-response models. The Exposure-Response database (ERDB) described here fills this gap by allowing entry of sufficiently detailed information on experimental design and results for each study, while limiting data entry to the most relevant. ERDB was designed to contain information from the open literature to support dose-response assessment and allow a high level of automation in performance of various types of dose-response analyses. Specifically, ERDB supports emerging analytical approaches for dose-response assessment, while accommodating the diverse nature of published literature. Exposure and response data are accessible in a relational multi-table design, with closely controlled standard fields for recording values and free-text fields to describe unique aspects of the study. Additional comparative analyses are made possible through summary tables and graphic representations of the data contained within ERDB.

The Air Toxics Health Effects Database (ATHED).

The Air Toxics Health Effects Database (ATHED) is currently used by the EPA's Office of Air Quality Planning and Standards (OAQPS) to support risk assessments for the Residual Risk Program. An assessment of the residual risk is required to be performed at a specified time (typically 8 years) following the promulgation of a technology-based Maximum Achievable Control Technologies (MACT) standard. The goal of the Residual Risk Program is to assure that the risk that remains after MACT standards are implemented (i.e., the "residual risk") is acceptable, and if not, to propose additional regulations to mitigate those risks. ATHED maintains all available reference values for each chemical as separate data records, and includes values for all exposure durations (acute, short-term, subchronic and chronic). These values are used as benchmarks to determine acceptable exposure levels to the hazardous air pollutants (HAPs) listed in Section 112 of the Clean Air Act. ATHED also provides useful background information on the uncertainty and/or modifying factors that were applied in the derivation of each reference value, as well as the point of departure and the critical study/studies. To facilitate comparisons across durations for a specific chemical, ATHED data can be graphically presented.

A review of the mutagenicity and rodent carcinogenicity of ambient air.

Although ambient air was first shown to be carcinogenic in 1947 and mutagenic in 1975, no overarching review of the subsequent literature has been produced. Recently, Claxton et al. [L.D. Claxton, P.P. Matthews, S.H. Warren, The genotoxicity of ambient outdoor air, a review: Salmonella mutagenicity, Mutat. Res./Rev. Mutat. Res. 567 (2004) 347-399] reviewed the literature on the mutagenicity of urban air in the Salmonella mutagenicity assay. Here, we review the literature on the mutagenicity of urban air in other test systems and review the carcinogenicity of urban air in experimental systems. Urban air was carcinogenic in most of the reports involving rodents. Studies ascribed carcinogenic activity primarily to PAHs, nitroarenes, and other aromatic compounds. Atmospheric conditions, along with the levels and types of pollutants, contributed to the variations in carcinogenic and mutagenic activity of air from different metropolitan areas. The majority of the mutagenesis literature was in the Salmonella assay (50%), with plant systems accounting for most of the rest (31%). The present data give little support to the use of plant systems to compare air mutagenicity among multiple sites or studies. Studies in mice have shown that particulate air pollution causes germ-cell mutations. Air sheds contain similar types and classes of mutagens; however, the levels of these compounds vary considerably among air sheds. Combustion emissions were associated with much of the mutagenicity and carcinogenicity of urban air. Most studies focused on the particulate fraction; thus, additional work is needed on the volatile and semi-volatile fractions, metals, and atmospheric transformation. Smaller particles have greater percentages of extractable organic material and are more mutagenic than larger particles. Although hundreds of genotoxic compounds have been identified in ambient air, only a few (<25) are routinely monitored, emphasizing the value of coupling bioassay with chemistry in the monitoring of air for carcinogenic and mutagenic activities and compounds.

Proceedings of the Hydrogen Sulfide Health Research and Risk Assessment Symposium October 31-November 2, 2000.

The Hydrogen Sulfide Health Research and Risk Assessment Symposium came about for several reasons: (1) increased interest by the U.S. Environmental Protection Agency (EPA) and several state agencies in regulating hydrogen sulfide (H2S); (2) uncertainty about ambient exposure to H2S; (3) confusion and disagreement in the literature about possible health effects at low-level exposures; and (4) presentation of results of a series of recent animal bioassays. The American Petroleum Institute (API) proposed this symposium and the EPA became an early co-sponsor, with the Chemical Industry Institute of Toxicology (CIIT) and the American Forest & Paper Association (AF&PA) contributing expertise and funding assistance. The topics covered in this symposium included Animal Research, Human Research, Mode-of-Action and Dosimetry Issues, Environmental Exposure and Monitoring, Assessment and Regulatory Issues, and closed with a panel discussion. The overall goals of the symposium were to: gather together experts in H2S health effects research and individuals from governmental agencies charged with protecting the public health, provide a venue for reporting of recent research findings, identify gaps in the current information, and outline new research directions and promote research collaboration. During the course of the symposium, presenters provided comprehensive reviews of the state of knowledge for each topic. Several new research proposals discussed at the symposium have subsequently been initiated. This report provides a summary of the talks, poster presentations, and panel discussions that occurred at the Hydrogen Sulfide Health and Risk Assessment Symposium.

Acute health reference values: overview, perspective, and current forecast of needs.

A number of organizations have developed acute inhalation health reference values, each with (1) a specific purpose, (2) populations to protect, (3) exposure scenarios (accidental releases, workplace, routine excursions of ambient levels), and (4) severity of adverse health effects considered in their development. The first section of this article reviews the existing values from different organizations and describes their purposes and method of development. The second part of the article provides a comparative review of how the values were derived, the critical endpoints considered for each value, the populations being protected by each value, and the potential for use outside of their intended purpose (e.g., Homeland Security, regulatory analysis, etc.). Additionally, an analysis of the acute inhalation reference values that was developed in support of the Office of Air and Radiation's residual risk assessment for hazardous air pollutants is presented and reviewed. The third and final part of the article focuses on the efforts of the U.S. Environmental Protection Agency (EPA) to develop a set of less-than-lifetime reference values, along with a discussion of how that effort fits with the existing sets of values described in the prior sections.