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Bailey L.A.,University of Cambridge | Prueitt R.L.,Gradient | Rhomberg L.R.,University of Cambridge
Regulatory Toxicology and Pharmacology | Year: 2012

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. © 2011 Elsevier Inc..

Rhomberg L.R.,University of Cambridge | Bailey L.A.,University of Cambridge | Goodman J.E.,University of Cambridge | Hamade A.K.,University of Cambridge | Mayfield D.,Gradient
Critical Reviews in Toxicology | Year: 2011

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. © 2011 Informa Healthcare USA, Inc.

Goodman J.E.,University of Cambridge | Prueitt R.L.,Gradient | Chandalia J.,University of Cambridge | Sax S.N.,University of Cambridge
Journal of Applied Toxicology | Year: 2014

The US EPA is evaluating controlled human ozone exposure studies to determine the adequacy of the current ozone National Ambient Air Quality Standard of 75 ppb. These studies have shown that ozone exposures of 80 ppb and greater are associated with lung function decrements. Here, we critically review studies with exposures below 80 ppb to determine the lowest ozone concentration at which decrements are causally associated with ozone exposure and could be considered adverse using the Adverse Effects/Causation Framework. Regarding causation, the framework includes consideration of whether exposure-related effects are primary or secondary, statistically significant, isolated or independent, or due to study limitations. Regarding adversity, the framework indicates one should consider whether effects are adaptive, compensatory, precursors to an apical effect, severe, transient and/or reversible. We found that, at exposures below 72 ppb ozone, lung function effects are primary effects, but are isolated, independent and not statistically different compared to effects observed during filtered air exposure, indicating a lack of causation. Up to 72 ppb, lung function effects may be precursors to an apical effect, but are not likely adverse because they are transient, reversible, of low severity, do not interfere with normal activity and do not result in permanent respiratory injury or progressive respiratory dysfunction. Overall, these studies do not demonstrate a causal association between ozone concentrations in the range of the current National Ambient Air Quality Standard and adverse effects on lung function. © 2013 John Wiley & Sons, Ltd.

Goodman J.E.,University of Cambridge | Dodge D.G.,Gradient | Bailey L.A.,University of Cambridge
Regulatory Toxicology and Pharmacology | Year: 2010

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 (SO2) and conclude that the available evidence supports a short-term exposure threshold of 400ppb SO2 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. © 2010 Elsevier Inc.

Lewandowski T.A.,Gradient
Human and Experimental Toxicology | Year: 2017

Carisoprodol is a widely prescribed muscle relaxant and is also a drug known to be a subject to abuse. Despite the fact that carisoprodol has been available for prescription since 1959, a number of gaps in our knowledge of the toxicokinetics of this common drug exist. For example, the volume of distribution (Vd) for carisoprodol in humans has not been reported. A two-compartment pharmacokinetic model describing carisoprodol metabolism and that of the primary metabolite, meprobamate, was developed to better understand the pharmacokinetics of this drug. The model accounts for first pass metabolism of carisoprodol and was able to replicate the data from several previously reported data sets. Based on an analysis of four different data sets, the Vd for carisoprodol ranged from 0.93 to 1.3 L/kg, while that for meprobamate ranged from 1.4 to 1.6 L/kg. The model was also used to estimate the probable dose of this drug in an individual where questions concerning the drug's role in her death had been posed. The model may, therefore, have significant utility for estimating doses of carisoprodol in medicolegal cases. © SAGE Publications.

Mayfield D.B.,Gradient | Fairbrother A.,Exponent, Inc.
Integrated Environmental Assessment and Management | Year: 2013

Wildlife toxicity reference values (TRVs) are routinely used during screening level and baseline ecological risk assessments (ERAs). Risk assessment professionals often adopt TRVs from published sources to expedite risk analyses. The US Environmental Protection Agency (USEPA) developed ecological soil screening levels (Eco-SSLs) to provide a source of TRVs that would improve consistency among risk assessments. We conducted a survey and evaluated more than 50 publicly available, large-scale ERAs published in the last decade to evaluate if USEPA's goal of uniformity in the use of wildlife TRVs has been met. In addition, these ERAs were reviewed to understand current practices for wildlife TRV use and development within the risk assessment community. The use of no observed and lowest observed adverse effect levels culled from published compendia was common practiceamong the majority of ERAs reviewed.We found increasing use over time of TRVs established in the Eco-SSL documents; however, Eco-SSL TRV values were not used in the majority of recent ERAs and there continues to be wide variation in TRVs for commonly studied contaminants (e.g., metals, pesticides, PAHs, and PCBs). Variability in the toxicity values was driven by differences in the key studies selected, dose estimation methods, and use of uncertainty factors. These differences result in TRVs that span multiple orders of magnitude for many of the chemicals examined. This lack of consistency in TRV development leads to highly variable results in ecological risk assessments conducted throughout the United States. © 2012 SETAC.

Mayfield D.B.,Gradient | Fairbrother A.,Exponent, Inc.
Chemosphere | Year: 2015

Rare earth elements (REEs or lanthanides) were measured in ten freshwater fish species from a reservoir in Washington State (United States). The REE distribution patterns were examined within fillet and whole body tissues for three size classes. Total concentrations (σREE) ranged from 0.014 to 3.0mgkg-1 (dry weight) and averaged 0.243mgkg-1 (dry weight). Tissue concentration patterns indicated that REEs accumulated to a greater extent in organs, viscera, and bone compared to muscle (fillet) tissues. Benthic feeding species (exposed to sediments) exhibited greater concentrations of REEs than pelagic omnivorous or piscivorous fish species. Decreasing REE concentrations were found with increasing age, total length or weight for largescale and longnose suckers, smallmouth bass, and walleye. Concentration patterns in this system were consistent with natural conditions without anthropogenic sources of REEs. These data provide additional reference information with regard to the fate and transport of REEs in freshwater fish tissues in a large aquatic system. © 2014 Elsevier Ltd.

Boroumand A.,Gradient | Abriola L.M.,Tufts University
Water Resources Research | Year: 2015

Analysis of partitioning tracer tests conducted in dense nonaqueous phase liquid (DNAPL) source zones relies on conceptual models that describe mass exchange between the DNAPL and aqueous phases. Such analysis, however, is complicated by the complex distribution of entrapped DNAPL mass and formation heterogeneity. Due to parameter uncertainty in heterogeneous regions and the desire to reduce model complexity, the effect of mass transfer limitations is often neglected, and an equilibrium-based model is typically used to interpret test results. This work explores the consequences of that simplifying assumption on test data interpretation and develops an alternative upscaled modeling approach to quantify effective mass transfer rates. To this end, a series of partitioning tracer tests is numerically simulated in heterogeneous two-dimensional PCE-DNAPL source zones, representative of a range of hydraulic conductivity and DNAPL mass distribution characteristics. The effective mass transfer coefficient corresponding to each test is determined by fitting an upscaled model to the simulated data, and regression analysis is performed to explore the correlation between various source zone metrics and the effective mass transfer coefficient. Results suggest that vertical DNAPL spreading, Reynolds number, pool fraction, and the effective organic phase saturation are the most significant parameters controlling tracer partitioning rates. Finally, a correlation for prediction of the effective (upscaled) mass transfer coefficient is proposed and verified using existing experimental data. The developed upscaled model incorporates the influence of physical heterogeneity on the rate of tracer partitioning and, thus, can be used for the estimation of source zone mass distribution characteristics from tracer test results. © 2015. American Geophysical Union. All Rights Reserved.

Lewandowski T.A.,Gradient | Peterson M.K.,Gradient | Charnley G.,HealthRisk Strategies LLC
Food and Chemical Toxicology | Year: 2015

Ensuring adequate iodine intake is important, particularly among women of reproductive age, because iodine is necessary for early life development. Biologically based dose-response modeling of the relationships among iodide status, perchlorate dose, and thyroid hormone production in pregnant women has indicated that iodide intake has a profound effect on the likelihood that exposure to goitrogens will produce hypothyroxinemia. We evaluated the possibility of increasing iodine intake to offset potential risks from perchlorate exposure. We also explored the effect of dietary exposures to nitrate and thiocyanate on iodine uptake and thyroid hormone production. Our modeling indicates that the level of thyroid hormone perturbation associated with perchlorate exposures in the range of current regulatory limits is extremely small and would be overwhelmed by other goitrogen exposures. Our analysis also shows that microgram levels of iodine supplementation would be sufficient to prevent the goitrogenic effects of perchlorate exposure at current regulatory limits among at risk individuals. The human health risks from supplementing drinking water with iodine are negligible; therefore, this approach is worthy of regulatory consideration. © 2015 The Authors.

Hughes M.F.,U.S. Environmental Protection Agency | Beck B.D.,Gradient | Chen Y.,New York University | Lewis A.S.,Gradient | Thomas D.J.,U.S. Environmental Protection Agency
Toxicological Sciences | Year: 2011

The metalloid arsenic is a natural environmental contaminant to which humans are routinely exposed in food, water, air, and soil. Arsenic has a long history of use as a homicidal agent, but in the past 100 years arsenic, has been used as a pesticide, a chemotherapeutic agent and a constituent of consumer products. In some areas of the world, high levels of arsenic are naturally present in drinking water and are a toxicological concern. There are several structural forms and oxidation states of arsenic because it forms alloys with metals and covalent bonds with hydrogen, oxygen, carbon, and other elements. Environmentally relevant forms of arsenic are inorganic and organic existing in the trivalent or pentavalent state. Metabolism of arsenic, catalyzed by arsenic (13 oxidation state) methyltransferase, is a sequential process of reduction from pentavalency to trivalency followed by oxidative methylation back to pentavalency. Trivalent arsenic is generally more toxicologically potent than pentavalent arsenic. Acute effects of arsenic range from gastrointestinal distress to death. Depending on the dose, chronic arsenic exposure may affect several major organ systems. A major concern of ingested arsenic is cancer, primarily of skin, bladder, and lung. The mode of action of arsenic for its disease endpoints is currently under study. Two key areas are the interaction of trivalent arsenicals with sulfur in proteins and the ability of arsenic to generate oxidative stress. With advances in technology and the recent development of animal models for arsenic carcinogenicity, understanding of the toxicology of arsenic will continue to improve.

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