Potential implications of new information concerning manganese Ohio community health effects studies.

Several epidemiology studies have been conducted in Ohio communities where industrial facilities with manganese emissions are located. New information not addressed in the published papers for this research has been disclosed by U.S. federal agencies pursuant to the Freedom of Information Act. This paper describes the newly available information, presents statistical analyses of the new summary data, and explores how this information potentially impacts the conclusions of the published research. Based on a statistical analysis of the newly available data, we found very few, and no consistent, statistical differences for various illnesses, self-reported symptoms, and neuropsychological/neuromotor test results between one community with a manganese emission source and a control town that were part of the initial research. Further, we determined that the distribution of total suspended particulate manganese air concentrations did not correlate with the distribution of the more biologically relevant respirable manganese concentrations when data from two communities with potential manganese emissions were combined. These results are important, particularly in determining whether the studies should influence regulatory reference values related to manganese. We recommend that the full health effects data set associated with the published research be made available and re-evaluated to address the issues identified in this paper.

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.

Electricians' chrysotile asbestos exposure from electrical products and risks of mesothelioma and lung cancer.

Both mechanistic and epidemiology studies indicate chrysotile asbestos has a threshold below which it does not cause mesothelioma or lung cancer. We conducted a critical review to determine whether electricians are at increased risk for these cancers and, if so, whether their exposure to chrysotile in electrical products could be responsible. We found that most, but not all, epidemiology studies indicate electricians are at increased risk for both cancers. Studies that evaluated electricians' exposure to asbestos during normal work tasks have generally reported low concentrations in air; an experimental study showed that grinding or drilling products containing encapsulated chrysotile resulted in exposures to chrysotile fibers far below the OSHA permissible exposure limit and the cancer no observed adverse effect level. Studies of other craftsmen who often work in the vicinity of electricians, such as insulators, reported asbestos (including amphibole) exposures that were relatively high. Overall, the evidence does not indicate that exposure to chrysotile in electrical products causes mesothelioma or lung cancer in electricians. Rather, the most likely cause of lung cancer in electricians is smoking, and the most likely cause of mesothelioma is exposure to amphibole asbestos as a result of renovation/demolition work or working in the proximity of other skilled craftsmen.

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.

Hypothesis-Based Weight-of-Evidence evaluation of methanol as a human carcinogen.

Recent scientific debate has focused on the potential for exposure to methanol to cause lymphomas in humans. The concern stems from a few animal studies reporting an association, although evidence suggests the studies may have been confounded by chronic respiratory infection. Although the toxicological evidence for methanol carcinogenesis is weak, two modes of action have been put forth, one involving metabolism of methanol to formaldehyde, followed by formaldehyde induction of lymphoma, and another involving oxidative stress caused by hydrogen peroxide release during catalase-induced metabolism of methanol to formaldehyde. In this article, we apply our Hypothesis-Based Weight-of-Evidence (HBWoE) approach to evaluate the evidence regarding methanol exposure and lymphoma, attending to how human, animal, and mode-of-action results inform one another, tracing the logic of inference within and across all studies, and articulating how one could account for the suite of available observations. Upon comparison of alternative proposals regarding what causal processes may have led to the array of observations as we see them, we conclude that the apparent association between methanol exposure and lymphoma in some animal studies is weak and strains biological plausibility, and is better interpreted as due to confounding or to a mechanism not relevant in humans.

Is exposure to formaldehyde in air causally associated with leukemia?--A hypothesis-based weight-of-evidence analysis.

Recent scientific debate has focused on the potential for inhaled formaldehyde to cause lymphohematopoietic cancers, particularly leukemias, in humans. The concern stems from certain epidemiology studies reporting an association, although particulars of endpoints and dosimetry are inconsistent across studies and several other studies show no such effects. Animal studies generally report neither hematotoxicity nor leukemia associated with formaldehyde inhalation, and hematotoxicity studies in humans are inconsistent. Formaldehyde's reactivity has been thought to preclude systemic exposure following inhalation, and its apparent inability to reach and affect the target tissues attacked by known leukemogens has, heretofore, led to skepticism regarding its potential to cause human lymphohematopoietic cancers. Recently, however, potential modes of action for formaldehyde leukemogenesis have been hypothesized, and it has been suggested that formaldehyde be identified as a known human leukemogen. In this article, we apply our hypothesis-based weight-of-evidence (HBWoE) approach to evaluate the large body of evidence regarding formaldehyde and leukemogenesis, attending to how human, animal, and mode-of-action results inform one another. We trace the logic of inference within and across all studies, and articulate how one could account for the suite of available observations under the various proposed hypotheses. Upon comparison of alternative proposals regarding what causal processes may have led to the array of observations as we see them, we conclude that the case for a causal association is weak and strains biological plausibility. Instead, apparent association between formaldehyde inhalation and leukemia in some human studies is better interpreted as due to chance or confounding.

Hypothesis-based weight-of-evidence evaluation of the neurodevelopmental effects of chlorpyrifos.

We used a hypothesis-based weight-of-evidence (HBWoE) approach to analyze the evidence regarding the hypothesis that chlorpyrifos can cause neurodevelopmental effects below the threshold for inhibition of acetylcholinesterase activity in the nervous system, which is an established mode of action for chlorpyrifos neurotoxicity. The epidemiology data do not consistently demonstrate associations between chlorpyrifos exposure and neurodevelopmental toxicity, and the animal toxicity data do not provide clear evidence that neurodevelopmental effects occur at doses below the threshold for acetylcholinesterase inhibition. The alternative mechanisms proposed to underlie potential neurodevelopmental effects in humans have been observed in the absence of acetylcholinesterase inhibition in a few in vitro studies but not in the developing brain in vivo. We provide perspective on the HBWoE approach compared with frameworks developed by the United States Environmental Protection Agency and the European Center for Ecotoxicology and Toxicology of Chemicals. We suggest that our HBWoE approach offers advantages over these frameworks in providing a better perspective on how to integrate all of the relevant data and how to use each line of evidence to inform the integration of other kinds of data or compare alternative hypotheses. Based on an HBWoE analysis, we conclude that a causal association between chlorpyrifos exposure and neurodevelopmental effects in the absence of acetylcholinesterase inhibition in the brain is not plausible in humans, and the few positive associations observed in epidemiology studies are most likely attributable to alternative explanations.

Hypothesis-based weight of evidence: a tool for evaluating and communicating uncertainties and inconsistencies in the large body of evidence in proposing a carcinogenic mode of action--naphthalene as an example.

Human health risk assessment consists of bringing to bear a large body of in vitro, animal, and epidemiologic studies on the question of whether environmental exposures to a substance are a potential risk to humans. The body of scientific information is typically less than definitive and often contains apparent contradictions. Often various possible conclusions about potential human risks may be drawn from the data and these may vary from very strong to tenuous. The task, therefore, is to communicate the uncertainties in the inferences from the data effectively, giving proper consideration to contrary data and alternative scientifically plausible interpretations. We propose an approach, Hypothesis-Based Weight of Evidence (HBWoE), to organize, evaluate, and communicate the large body of available relevant data on a given chemical, using naphthalene as an example. The goal for our use of the term "weight of evidence" (WoE) is broad in that we express the relative degrees of credence that should be placed in alternative possible interpretations of the naphthalene data and hypothesized carcinogenic modes of action (MoAs), expressed in a way that shows how such credence is tied to specific scientific interpretations, considering consistencies, inconsistencies, and contradictions within the data set.

A framework for assessing causality and adverse effects in humans with a case study of sulfur dioxide.

Following exposure to a substance, several biological events can occur that may eventually, depending on the exposure dose and duration, lead to adverse effects. We developed a framework to evaluate whether an exposure is causally related to an effect and whether that effect is adverse. An exposure is not likely to be causal if an effect is: not statistically significantly different in exposed and non-exposed study subjects; isolated or independent; secondary; observed because of study limitations; or unrelated to the apical effect and not associated with functional impairment. Adaptive effects are not adverse and, although effects that overwhelm homeostasis often are, this may not be the case if they are transient, early precursors of an apical effect, reversible, or of low severity. We applied the framework to a case study of sulfur dioxide (SO(2)) and conclude that the available evidence supports a short-term exposure threshold of 400 ppb SO(2) for adverse effects on lung function in sensitive individuals. At this concentration, effects are transient, reversible, and of low severity. Below this concentration, effects are isolated or independent and not statistically different in exposed and unexposed subjects in clinical trials, and study limitations affect interpretation of observational studies.

Incorporating ToxCast™ data into naphthalene human health risk assessment.

Chronic inhalation of naphthalene causes nasal olfactory epithelial tumors in rats and benign lung adenomas in mice. The available human data do not establish an association between naphthalene and increased respiratory cancer risk. Therefore, cancer risk assessment of naphthalene in humans depends predominantly on experimental evidence from rodents. The United States Environmental Protection Agency's (US EPA) Toxicity Forecaster (ToxCast™) database contains data from 710 in vitro assays for naphthalene, the majority of which were conducted in human cells. Of these assays, only 18 were active for naphthalene, and all were in human liver cells. No assays were active in human bronchial epithelial cells. In our analysis, all of the active naphthalene ToxCast assay data were reviewed and used to: 1) determine naphthalene human inhalation concentrations corresponding to relevant activity concentrations for all active naphthalene assays, using a physiologically based pharmacokinetic (PBPK) model; and 2) evaluate the transcriptional responses for active assays in the context of consistency with the larger naphthalene data set and proposed modes of action (MoAs) for naphthalene toxicity and carcinogenicity. The transcriptional responses in liver cells largely reflect cellular activities related to oxidative stress and chronic inflammation. Overall, the results from our analysis of the active ToxCast assays for naphthalene are consistent with conclusions from our earlier weight-of-evidence evaluation for naphthalene carcinogenesis.

Proposal for a revised Reference Concentration (RfC) for manganese based on recent epidemiological studies.

In 1993, based on observations of subclinical neurological effects in workers, the United States Environmental Protection Agency (US EPA) published a Reference Concentration (RfC) of 0.05 microg/m(3) for manganese (Mn). The geometric mean exposure concentration, 150 microg/m(3) respirable Mn, was considered the lowest observable adverse effect level (LOAEL), and uncertainty factors (UFs) were applied to account for sensitive populations, database limitations, a LOAEL, subchronic exposure, and potential differences in toxicity of different forms of Mn. Based on a review of more recent literature, we propose two alternate Mn RfCs. Of 12 more recent occupational studies of eight cohorts with chronic exposure durations, examining subclinical neurobehavioral effects, predominantly on the motor system, three were considered appropriate for development of an RfC. All three studies yielded no observable adverse effect levels (NOAELs) of approximately 60 microg/m(3) respirable Mn. Converting the occupational NOAEL to a human equivalent concentration (HEC) of 21microg/m(3) (for continuous exposure) and applying a UF of 10 to account for intraspecies variability yielded an RfC of 2microg/m(3). We also derived a similar RfC (7 microg/m(3)) using an Mn benchmark dose (BMD) as the point of departure. Overall confidence in both RfCs is medium.

Derivation of an occupational exposure level for manganese in welding fumes.

Exposure to high levels of manganese (Mn) in occupational settings is known to lead to adverse neurological effects. Since Mn is an essential nutrient, there are mechanisms that maintain its homeostatic control in the body, and there is some level of Mn in air that does not perturb Mn homeostasis. However, the Mn exposure concentrations at which no adverse effects are expected in occupational settings vary considerably across regulatory agencies. We set out to derive a Mn Occupational Exposure Level (OEL) for welders based on a review of studies that evaluated Mn exposure concentrations from welding fumes and: (1) neurological effects in welders; (2) levels of Mn in the brains of welders (via pallidal index [PI] estimated from magnetic resonance imaging [MRI]); (3) other biomarkers of Mn exposure in welders (i.e., blood and urine); and (4) Mn brain concentrations, PI, and corresponding neurological effects in non-human primates. Our analysis suggests uncertainty in quantifying dose-response associations for Mn from many of the occupational welding studies. The few welding studies that adequately estimate exposure suggest a possible OEL of 100-140µg/m3 for respirable Mn. This range is consistent with other epidemiology studies, studies of biomarkers of Mn exposure in welders, and with studies in non-human primates, though future studies could provide a stronger basis for deriving a Mn occupational guideline for welders.