The Conundrum of the PFOA human half-life, an international collaboration.

The Steering Committee of the Alliance for Risk Assessment (ARA) opened a call for scientists interested in resolving what appeared to be a conundrum in estimating of the half-life of perfluorooctanoate (PFOA) in humans. An Advisory Committee was formed from nominations received and a subsequent invitation led to the development of three small independent working groups to review appropriate information and attempt a resolution. Initial findings were shared among these groups and a conclusion developed from the ensuing discussions. Many human observational studies have estimated the PFOA half-life. Most of these studies note the likely occurrence of unmonitored PFOA exposures, which could inflate values of the estimated PFOA half-life. Also, few of these studies estimated the half-life of PFOA isomers, the branched chains of which likely have shorter half-lives. This could deflate values of the estimated linear PFOA half-life. Fortunately, several studies informed both of these potential problems. The majority opinion of this international collaboration is that the studies striking the best balance in addressing some of these uncertainties indicate the likely central tendency of the human PFOA half-life is less than 2 years. The single best value appears to be the geometric mean (GM) of 1.3 years (Zhang et al., 2013, Table 3), based on a GM = 1.7 years in young females (n = 20) and GM = 1.2 years in males of all ages and older females (n = 66). However, a combined median value from Zhang et al. (2013) of 1.8 years also adds value to this range of central tendency. While the Collaboration found this study to be the least encumbered with unmonitored PFOA exposures and branched isomers, more studies of similar design would be valuable. Also valuable would be clarification around background exposures in other existing studies in case adjustments to half-life estimates are attempted.

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.

Toxicological evaluation of carcinogenicity of the pyrethroid imiprothrin in rats and mice.

The carcinogenic potential of a non-genotoxic pyrethroid imiprothrin was examined in rats and mice. There was no carcinogenicity in rats up to a maximum dose of 5000 ppm of the diet. There was a higher (p = 0.03) incidence of lung adenocarcinomas at 7000 ppm in males, and females showed an increasing (p < 0.01) trend in the incidence of lung adenomas and combined lung adenoma/adenocarcinomas. Additional step sections of lung demonstrated no significant increases in any tumor at p < 0.05, although an increasing trend with dose was observed among females. We argue that, the 7000 ppm dose exceeded the Maximum Tolerated Dose (MTD) for both sexes, based on systemic toxicity as evidenced by body weight gain reduction (both sexes) and high mortality (females). If the 7000 ppm dose is therefore removed from consideration, there are not significant (p < 0.05) increases in tumor formation. Moreover, a consideration of multiple comparisons reveals that the lung tumor increases observed are totally consistent with what would be expected by chance alone. Based on high susceptibility of this mouse strain for the appearance of lung tumors and the lack of a statistically significant increase in tumors by appropriate analysis, the mouse study does not indicate a carcinogenic effect of imiprothrin, and thus no classification for carcinogenicity is warranted.

A bounding quantitative cancer risk assessment for occupational exposures to asphalt emissions during road paving operations.

The International Agency for Research on Cancer recently classified straight-run bitumens and associated emissions during road paving as possibly carcinogenic to humans (Group 2B), owing to potential exposures to polycyclic aromatic hydrocarbons. We examine existing chemistry, exposure, epidemiology, and animal toxicity data to explore quantitative cancer risk implications for paving workers exposed to asphalt emissions from the data used in identifying this qualitative hazard. Epidemiology studies show no consistent cancer risk elevation. One skin-painting mouse study of paving asphalt emission condensate found a single tumor at only the highest tested dose, as did one rat inhalation study. These studies were used to develop an upper bound on possible carcinogenic potency of emissions that are inhaled or dermally deposited. Extending earlier work on roofing asphalt, we conducted time-to-tumor modeling using the dose-time-response shape for several dose levels of benzo[a]pyrene (B[a]P) in concurrent bioassay controls to infer presumed parallel dose-time-response curves for paving-asphalt-emission condensate. In addition, we developed a scientific rationale, based on general scaling considerations and on dermal uptake, for the chosen means to scale observed dermal cancer potencies in mice to apply to dermal exposures in humans. The results indicate that paving asphalt emissions have a reduced dermal cancer potency compared to roofing asphalt, consistent with the lower levels of the multi-ringed PAHs implicated in cancer risks. Based on existing occupational exposure studies, cancer risks to pavers from both dermal and inhalation exposure to asphalt emissions is within a range typically acceptable within regulatory frameworks.

Hypothesis-based weight-of-evidence evaluation and risk assessment for naphthalene carcinogenesis.

Inhalation of naphthalene causes olfactory epithelial nasal tumors in rats (but not in mice) and benign lung adenomas in mice (but not in rats). The limited available human data have not identified an association between naphthalene exposure and increased respiratory cancer risk. Assessing naphthalene's carcinogenicity in humans, therefore, depends entirely on experimental evidence from rodents. We evaluated the respiratory carcinogenicity of naphthalene in rodents, and its potential relevance to humans, using our Hypothesis-Based Weight-of-Evidence (HBWoE) approach. We systematically and comparatively reviewed data relevant to key elements in the hypothesized modes of action (MoA) to determine which is best supported by the available data, allowing all of the data from each realm of investigation to inform interpretation of one another. Our analysis supports a mechanism that involves initial metabolism of naphthalene to the epoxide, followed by GSH depletion, cytotoxicity, chronic inflammation, regenerative hyperplasia, and tumor formation, with possible weak genotoxicity from downstream metabolites occurring only at high cytotoxic doses, strongly supporting a non-mutagenic threshold MoA in the rat nose. We also conducted a dose-response analysis, based on the likely MoA, which suggests that the rat nasal MoA is not relevant in human respiratory tissues at typical environmental exposures. Our analysis illustrates how a thorough WoE evaluation can be used to support a MoA, even when a mechanism of action cannot be fully elucidated. A non-mutagenic threshold MoA for naphthalene-induced rat nasal tumors should be considered as a basis to determine human relevance and to guide regulatory and risk-management decisions.

Systematic comparison of study quality criteria.

Approaches for the systematic review and evaluation of chemical toxicity are currently being reconsidered, with a specific focus on the evaluation of individual studies and their integration into the overall body of evidence. This renewed interest has arisen, in part, as a result of several prominent reviews of these approaches by special committees of the National Research Council (NRC), among others. We conducted a critical evaluation of several available frameworks for evaluating study quality. We assessed the criteria separately for human, animal, and in vitro studies as well as for systematic reviews. We then evaluated commonalities across disciplines. We also considered the potential implications of applying criteria frameworks and how they bear on fundamental risk assessment questions. We found that the available frameworks within each discipline differed in terms of their intended purpose and level of guidance for decision making. All the frameworks across disciplines shared common themes, however, including the adequate reporting of specific details of study conditions and design/protocol, selection and randomization of study groups (where applicable), outcome assessment methods and applicability (e.g., validity and reliability), avoidance of selective reporting, and the consideration of potential confounders or bias. We identified the most informative study quality considerations, which will enable researchers to implement more objective and standardized methods for evaluating studies and, ultimately, improve risk assessment methods.

Quantitative cancer risk assessment for occupational exposures to asphalt fumes during built-up roofing asphalt (BURA) operations.

The International Agency for Research on Cancer qualitatively characterized occupational exposure to oxidized bitumen emissions during roofing as probably carcinogenic to humans (Group 2A). We examine chemistry, exposure, epidemiology and animal toxicity data to explore quantitative risks for roofing workers applying built-up roofing asphalt (BURA). Epidemiology studies do not consistently report elevated risks, and generally do not have sufficient exposure information or adequately control for confounders, precluding their use for dose-response analysis. Dermal carcinogenicity bioassays using mice report increased tumor incidence with single high doses. In order to quantify potential cancer risks, we develop time-to-tumor model methods [consistent with U.S. Environmental Protection Agency (EPA) dose-response analysis and mixtures guidelines] using the dose-time-response shape of concurrent exposures to benzo[a]pyrene (B[a]P) as concurrent controls (which had several exposure levels) to infer presumed parallel dose-time-response curves for BURA-fume condensate. We compare EPA relative potency factor approaches, based on observed relative potency of BURA to B[a]P in similar experiments, and direct observation of the inferred BURA dose-time-response (scaled to humans) as means for characterizing a dermal unit risk factor. We apply similar approaches to limited data on asphalt-fume inhalation and respiratory cancers in rats. We also develop a method for adjusting potency estimates for asphalts that vary in composition using measured fluorescence. Overall, the various methods indicate that cancer risks to roofers from both dermal and inhalation exposure to BURA are within a range typically deemed acceptable within regulatory frameworks. The approaches developed may be useful in assessing carcinogenic potency of other complex mixtures of polycyclic aromatic compounds.

Are the elements of the proposed ozone National Ambient Air Quality Standards informed by the best available science?

The United States Environmental Protection Agency (US EPA) issues National Ambient Air Quality Standards (NAAQS) for six criteria pollutants, including ozone. Each standard has four elements: an indicator, level, averaging time, and form. Ozone levels (i.e., air concentrations) alone in scientific studies are not directly comparable to the "level" element of the NAAQS because the standard considers the level in the context of its relation to the remaining elements. Failure to appreciate this has led to misunderstandings regarding NAAQS that would be health-protective. This can be seen with controlled human ozone exposure studies, which often involved small numbers of people exercising quasi-continuously for a long duration at an intensity not common in the general population (and unlikely achievable by most sensitive individuals), under worst-case exposure profiles. In addition, epidemiology studies have used different averaging times and have had methodological limitations that may have biased results. Such considerations can make it difficult to compare ozone levels and results across studies and to appropriately apply them in a NAAQS evaluation. Relating patterns and circumstances of exposure, and exposure measurements, to all elements of the NAAQS can be challenging, but if US EPA fully undertook this, it would be evident that available evidence does not indicate that proposed lower ozone standards would be more health protective than the current one.

Comments on the opinions published by Bergman et al. (2015) on Critical Comments on the WHO-UNEP State of the Science of Endocrine Disrupting Chemicals (Lamb et al., 2014).

Recently Bergman et al. (2015) took issue with our comments (Lamb et al., 2014) on the WHO-UNEP(1) report entitled the "State of the Science of Endocrine Disrupting Chemicals - 2012" (WHO 2013a). We find several key differences between their view and ours regarding the selection of studies and presentation of data related to endocrine disrupting chemicals (EDCs) under the WHO-IPCS(2) definition (2002). In this response we address the factors that we think are most important: 1. the difference between hazard and risk; 2. the different approaches for hazard identification (weight of the evidence [WOE] vs. emphasizing positive findings over null results); and 3. the lack of a justification for conceptual or practical differences between EDCs and other groups of agents.

Hypothesis-Based Weight of Evidence: An Approach to Assessing Causation and its Application to Regulatory Toxicology.

Other papers in this symposium focus on combining direct observations or measurements of a phenomenon of interest. Here, I consider the distinct problem of integrating diverse kinds of data to address the scientific case for toxicological causation in view of information that usually contains gaps and outright contradictions. Existing weight-of-evidence approaches have been criticized as either too formulaic or too vague, simply calling for professional judgment that is hard to trace to its scientific basis. I discuss an approach-hypothesis-based weight of evidence-that emphasizes articulation of the hypothesized generalizations, their basis, and span of applicability. Hypothesized common processes should be expected to act elsewhere as well-in different species or different tissues-and so outcomes that ought to be affected become part of the evidence evaluation. A compelling hypothesis is one that provides a common unified explanation for observed results. Any apparent exceptions and failures to account for some data must be plausibly explained. Ad hoc additions to the explanations introduced to "save" hypotheses from apparent contradiction weaken the degree to which available data test causal propositions. In the end, we need an "account" of all the results at hand, specifying what is ascribed to hypothesized common causal processes and what to special exceptions, chance, or other factors. Evidence is weighed by considering comparative plausibility of an account including the proposed causal effect versus an alternative that explains all of the results at hand otherwise.

Improving weight of evidence approaches to chemical evaluations.

Federal and other regulatory agencies often use or claim to use a weight of evidence (WoE) approach in chemical evaluation. Their approaches to the use of WoE, however, differ significantly, rely heavily on subjective professional judgment, and merit improvement. We review uses of WoE approaches in key articles in the peer-reviewed scientific literature, and find significant variations. We find that a hypothesis-based WoE approach, developed by Lorenz Rhomberg et al., can provide a stronger scientific basis for chemical assessment while improving transparency and preserving the appropriate scope of professional judgment. Their approach, while still evolving, relies on the explicit specification of the hypothesized basis for using the information at hand to infer the ability of an agent to cause human health impacts or, more broadly, affect other endpoints of concern. We describe and endorse such a hypothesis-based WoE approach to chemical evaluation.

Mode of action framework analysis for receptor-mediated toxicity: The peroxisome proliferator-activated receptor alpha (PPARα) as a case study.

Several therapeutic agents and industrial chemicals induce liver tumors in rodents through the activation of the peroxisome proliferator-activated receptor alpha (PPARα). The cellular and molecular events by which PPARα activators induce rodent hepatocarcinogenesis has been extensively studied and elucidated. This review summarizes the weight of evidence relevant to the hypothesized mode of action (MOA) for PPARα activator-induced rodent hepatocarcinogenesis and identifies gaps in our knowledge of this MOA. Chemical-specific and mechanistic data support concordance of temporal and dose-response relationships for the key events associated with many PPARα activators including a phthalate ester plasticizer di(2-ethylhexyl) phthalate (DEHP) and the drug gemfibrozil. While biologically plausible in humans, the hypothesized key events in the rodent MOA, for PPARα activators, are unlikely to induce liver tumors in humans because of toxicodynamic and biological differences in responses. This conclusion is based on minimal or no effects observed on growth pathways, hepatocellular proliferation and liver tumors in humans and/or species (including hamsters, guinea pigs and cynomolgous monkeys) that are more appropriate human surrogates than mice and rats at overlapping dose levels. Overall, the panel concluded that significant quantitative differences in PPARα activator-induced effects related to liver cancer formation exist between rodents and humans. On the basis of these quantitative differences, most of the workgroup felt that the rodent MOA is "not relevant to humans" with the remaining members concluding that the MOA is "unlikely to be relevant to humans". The two groups differed in their level of confidence based on perceived limitations of the quantitative and mechanistic knowledge of the species differences, which for some panel members strongly supports but cannot preclude the absence of effects under unlikely exposure scenarios.

Strengthening the foundation of next generation risk assessment.

In a recent draft report, Next Generation Risk Assessment: Incorporation of Recent Advances in Molecular, Computational, and Systems Biology, the US Environmental Protection Agency presents valuable contributions to understanding the roles that evolving toxicity testing methods and associated interpretative techniques can play in assessing the risks associated with chemical exposures. However, the evaluations presented in the NexGen report would benefit from more thorough consideration of several essential components of a critical review of toxicity data, e.g., data quality, data relevance, and the extent to which the test endpoints reflect adverse effects. Such considerations are necessary to ensure that the NexGen report evaluations--and the resulting conclusions and recommendations--are grounded in scientifically sound, representative data reviews. We illustrate these concerns with a critique of the report's prototype ozone evaluation. Although substantial additional research is needed before new toxicity data types can be used reliably in rigorous risk assessment applications, they clearly offer exciting opportunities for advancing toxicological science and risk assessment. By explicitly identifying limitations still to be addressed and providing stronger guideposts for future research needs, the NexGen report could serve an influential role in achieving the promise of these new research approaches.

Critical comments on the WHO-UNEP State of the Science of Endocrine Disrupting Chemicals - 2012.

Early in 2013, the World Health Organization (WHO) released a 2012 update to the 2002 State of the Science of Endocrine Disrupting Chemicals. Several significant concerns have been identified that raise questions about conclusions reached in this report regarding endocrine disruption. First, the report is not a state-of-the-science review and does not follow the 2002 WHO recommended weight-of-evidence approach. Second, endocrine disruption is often presumed to occur based on exposure or a potential mechanism despite a lack of evidence to show that chemicals are causally established as endocrine disruptors. Additionally, causation is often inferred by the presentation of a series of unrelated facts, which collectively do not demonstrate causation. Third, trends in disease incidence or prevalence are discussed without regard to known causes or risk factors; endocrine disruption is implicated as the reason for such trends in the absence of evidence. Fourth, dose and potency are ignored for most chemicals discussed. Finally, controversial topics (i.e., low dose effects, non-monotonic dose response) are presented in a one-sided manner and these topics are important to understanding endocrine disruption. Overall, the 2012 report does not provide a balanced perspective, nor does it accurately reflect the state of the science on endocrine disruption.

Hypothesis-based weight-of-evidence evaluation of the human carcinogenicity of toluene diisocyanate.

Humans are exposed to toluene diisocyanate (TDI) primarily through inhalation in workplaces where TDI is produced or used. It is classified as a possible human carcinogen, based primarily on increased tumor incidences in rodents treated with TDI by oral gavage. We used the hypothesis-based weight-of-evidence (HBWoE) method to evaluate whether the available data support the hypothesis that TDI is a human carcinogen. The epidemiology data are not sufficiently robust to support TDI as a human carcinogen; the few positive associations are more likely attributable to alternative explanations than causation. The experimental animal studies indicate that inhalation exposure to TDI does not induce tumors in rats or mice. Tumors observed after oral gavage exposure are most likely due to the conversion of approximately 5% of the administered TDI to toluene diamine (TDA), a known rodent tumorigen. This contention is supported by the observations that TDA is rapidly formed from TDI during in vitro genotoxicity assays, the spectra of responses to TDA and TDI in these assays and in oral bioassays are essentially the same, and TDI is not genotoxic in rodents or humans in vivo after inhalation exposure, when TDA is not formed to a biologically significant degree. We conclude that the weight of the evidence indicates that the conversion of TDI to TDA does not occur in mammalian species under physiological exposure conditions (i.e. inhalation), but is necessary for carcinogenesis to occur. Thus, a causal association between TDI exposure and carcinogenic effects is not plausible in humans.

Evaluation of the causal framework used for setting national ambient air quality standards.

Abstract A scientifically sound assessment of the potential hazards associated with a substance requires a systematic, objective and transparent evaluation of the weight of evidence (WoE) for causality of health effects. We critically evaluated the current WoE framework for causal determination used in the United States Environmental Protection Agency's (EPA's) assessments of the scientific data on air pollutants for the National Ambient Air Quality Standards (NAAQS) review process, including its methods for literature searches; study selection, evaluation and integration; and causal judgments. The causal framework used in recent NAAQS evaluations has many valuable features, but it could be more explicit in some cases, and some features are missing that should be included in every WoE evaluation. Because of this, it has not always been applied consistently in evaluations of causality, leading to conclusions that are not always supported by the overall WoE, as we demonstrate using EPA's ozone Integrated Science Assessment as a case study. We propose additions to the NAAQS causal framework based on best practices gleaned from a previously conducted survey of available WoE frameworks. A revision of the NAAQS causal framework so that it more closely aligns with these best practices and the full and consistent application of the framework will improve future assessments of the potential health effects of criteria air pollutants by making the assessments more thorough, transparent, and scientifically sound.

A survey of frameworks for best practices in weight-of-evidence analyses.

The National Academy of Sciences (NAS) Review of the Environmental Protection Agency's Draft IRIS Assessment of Formaldehyde proposed a "roadmap" for reform and improvement of the Agency's risk assessment process. Specifically, it called for development of a transparent and defensible methodology for weight-of-evidence (WoE) assessments. To facilitate development of an improved process, we developed a white paper that reviewed approximately 50 existing WoE frameworks, seeking insights from their variations and nominating best practices for WoE analyses of causation of chemical risks. Four phases of WoE analysis were identified and evaluated in each framework: (1) defining the causal question and developing criteria for study selection, (2) developing and applying criteria for review of individual studies, (3) evaluating and integrating evidence and (4) drawing conclusions based on inferences. We circulated the draft white paper to stakeholders and then held a facilitated, multi-disciplinary invited stakeholder workshop to broaden and deepen the discussion on methods, rationales, utility and limitations among the surveyed WoE frameworks. The workshop developed recommendations for improving the conduct of WoE evaluations. Based on the analysis of the 50 frameworks and discussions at the workshop, best practices in conducting WoE analyses were identified for each of the four phases. Many of these best practices noted from the analysis and workshop could be implemented immediately, while others may require additional refinement as part of the ongoing discussions for improving the scientific basis of chemical risk assessments.

Hypothesis-based weight-of-evidence evaluation of methyl methacrylate olfactory effects in humans and derivation of an occupational exposure level.

Over 40 years of scientific evidence indicates that methyl methacrylate (MMA) causes olfactory effects in rodents that are relevant to humans. More recent scientific studies have focused on understanding the apparent lack of species concordance between the rodent and human studies. Toxicokinetic studies and a physiologically based pharmacokinetic (PBPK) model describing inhalation dosimetry of MMA in the upper respiratory tract (URT) of rats and humans point to differences in nasal morphology and biochemistry that could explain and reconcile these differences as species-specific manifestations of a common toxicological process. We have applied the hypothesis-based weight-of-evidence (HBWoE) approach to evaluate the concordance of the available data and the hypothesis that the observed difference in sensitivity between rats and humans may be the expected result of physiological and biochemical differences. Our WoE analysis indicates that when the several lines of evidence (i.e., animal, human, mode-of-action, and toxicokinetics data) are integrated, they inform interpretation of one another and, overall, support use of the human data for derivation of an MMA occupational exposure level (OEL) of 50 ppm.