Toxicology Excellence for Risk Assessment

Cincinnati, OH, United States

Toxicology Excellence for Risk Assessment

Cincinnati, OH, United States
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Kirman C.R.,Summit Toxicology | Kirman C.R.,Sapphire Group | Albertini R.J.,University of Vermont | Sweeney L.M.,Toxicology Excellence for Risk Assessment | And 3 more authors.
Critical Reviews in Toxicology | Year: 2010

1,3-Butadiene (BD) is a multisite carcinogen in laboratory rodents following lifetime exposure, with mice demonstrating greater sensitivity than rats. In epidemiology studies of men in the styrene-butadiene rubber industry, leukemia mortality is associated with butadiene exposure, and this association is most pronounced for high-intensity BD exposures. Metabolism is an important determinant of BD carcinogenicity. BD is metabolized to several electrophilic intermediates, including epoxybutene (EB), diepoxybutane (DEB), and epoxybutane diol (EBD), which differ considerably in their genotoxic potency (DEB >> EB > EBD). Important species differences exist with respect to the formation of reactive metabolites and their subsequent detoxification, which underlie observed species differences in sensitivity to the carcinogenic effects of BD. The modes of action for human leukemia and for the observed solid tumors in rodents are both likely related to the genotoxic potencies for one or more of these metabolites. A number of factors related to metabolism can also contribute to nonlinearity in the dose-response relationship, including enzyme induction and inhibition, depletion of tissue glutathione, and saturation of oxidative metabolism. A quantitative risk assessment of BD needs to reflect these species differences and sources of nonlinearity if it is to reflect the current understanding of the disposition of BD. © 2010 Informa Healthcare USA, Inc.


Moser V.C.,Health-U | Padilla S.,US Toxicology | Simmons J.E.,US Toxicology | Haber L.T.,Toxicology Excellence for Risk Assessment | Hertzberg R.C.,Biomathematics Consulting
Toxicological Sciences | Year: 2012

Statistical design and environmental relevance are important aspects of studies of chemical mixtures, such as pesticides. We used a dose-additivity model to test experimentally the default assumptions of dose additivity for two mixtures of seven N-methylcarbamates (carbaryl, carbofuran, formetanate, methomyl, methiocarb, oxamyl, and propoxur). The best-fitting models were selected for the single-chemical dose-response data and used to develop a combined prediction model, which was then compared with the experimental mixture data. We evaluated behavioral (motor activity) and cholinesterase (ChE)-inhibitory (brain, red blood cells) outcomes at the time of peak acute effects following oral gavage in adult and preweanling (17 days old) Long-Evans male rats. The mixtures varied only in their mixing ratios. In the relative potency mixture, proportions of each carbamate were set at equitoxic component doses. A California environmental mixture was based on the 2005 sales of each carbamate in California. In adult rats, the relative potency mixture showed dose additivity for red blood cell ChE and motor activity, and brain ChE inhibition showed a modest greater-than additive (synergistic) response, but only at a middle dose. In rat pups, the relative potency mixture was either dose-additive (brain ChE inhibition, motor activity) or slightly less-than additive (red blood cell ChE inhibition). On the other hand, at both ages, the environmental mixture showed greater-than additive responses on all three endpoints, with significant deviations from predicted at most to all doses tested. Thus, we observed different interactive properties for different mixing ratios of these chemicals. These approaches for studying pesticide mixtures can improve evaluations of potential toxicity under varying experimental conditions that may mimic human exposures. Published by Oxford University Press 2012.


Maier A.,Toxicology Excellence for Risk Assessment | Kohrman-Vincent M.,Toxicology Excellence for Risk Assessment | Parker A.,Toxicology Excellence for Risk Assessment | Haber L.T.,Toxicology Excellence for Risk Assessment
Regulatory Toxicology and Pharmacology | Year: 2010

The current emphasis on occupational exposures to diacetyl has led to new research on its effects. We evaluated whether the data are sufficient to support a transition from a hazard-based risk management approach to a quantitative occupational risk assessment approach, characterized by developing a health-based occupational exposure limit (OEL). Inhalation health effects data were evaluated and issues and uncertainties related to occupational risk assessment needs were identified. A systematic hazard characterization, supported by both the toxicology and epidemiology literature, showed that the respiratory tract effects of diacetyl are the primary end points of relevance for developing an OEL. In an effort to provide a systematic approach for the analysis of the issues that need to be considered in developing an occupational risk assessment for diacetyl, a potential OEL was derived. A concentration-response assessment was completed using tracheobronchial effects in mice as the critical effect. The resulting benchmark concentration (lower bound estimate or BMCL) was adjusted to a human equivalent concentration of 1.8 ppm. A composite uncertainty factor of 10 was recommended to account for extrapolation from an adjusted BMCL from an animal study and for human variability in sensitivity and taking into account other uncertainties in the overall database. The resulting OEL recommendation of 0.2 ppm as a time-weighted average (TWA) was supported by the current occupational epidemiology literature. This evaluation showed that a health-based OEL value can be derived for diacetyl with moderate to high confidence. © 2010 Elsevier Inc.


Cain W.S.,University of California at San Diego | Dourson M.L.,Toxicology Excellence for Risk Assessment | Kohrman-Vincent M.J.,Toxicology Excellence for Risk Assessment | Allen B.C.,Bruce Allen Consulting
Regulatory Toxicology and Pharmacology | Year: 2010

An unpublished laboratory study by Russell and Rush (1996) showed that human subjects sense the presence of methyl isothiocyanate (MITC) via the eyes at concentrations as low as hundreds of ppb in air, with dependence upon duration of exposure. The longer the stimulation, the lower the concentrations sensed. Application of benchmark concentration (BMC10) modeling indicated a best estimate of 330. ppb by the end of 4. h. With a confidence limit (BMCL) applied, the level dropped to 220. ppb, when employing a probit model. Receptors known as TRPA1 ion channels present in trigeminal and associated peripheral afferent nerves have shown particular sensitivity to isothiocyanates. Sensitivity to these electrophiles, which occur naturally in plants (e.g., capers and mustard greens), most likely derives from a mechanism of reversible covalent bonding. Such sensing can provide warning of potential damage rather than actual damage itself. Based upon its reputation as a lachrymator, Russell and Rush assumed that the eyes would sense MITC, before the upper airways, so gathered no data from the airways, except for odor. Field results from spills and results of acute exposures to animals covered in Dourson et al. (2010) add pertinent information on the matter. © 2010 Elsevier Inc.


Budinsky R.A.,Dow Chemical Company | Schrenk D.,University of Kaiserslautern | Simon T.,Ted Simon LLC | Van Den Berg M.,University Utrecht | And 10 more authors.
Critical Reviews in Toxicology | Year: 2014

Dioxins and dioxin-like compounds are tumor promoters that cause liver cancer in rats and mice. The aryl hydrocarbon receptor (AHR) has been implicated as a key component in this tumor promotion response. Despite extensive knowledge of the toxicology of dioxins, no mode of action (MOA) hypothesis for their tumorigenicity has been formally documented using the Human Relevance MOA framework developed by the International Programme on Chemical Safety (IPCS). To address this information gap, an expert panel was convened as part of a workshop on receptor-mediated liver tumorigenicity. Liver tumors induced by ligands of the AHR were assessed using data for dioxins and related chemicals as a case study. The panel proposed a MOA beginning with sustained AHR activation, eventually leading to liver tumors via a number of other processes, including increased cell proliferation of previously initiated altered hepatic foci, inhibition of intrafocal apoptosis and proliferation of oval cells. These processes have been identified and grouped as three key events within the hepatocarcinogenic MOA: (1) sustained AHR activation, (2) alterations in cellular growth and homeostasis and (3) pre-neoplastic tissue changes. These key events were identified through application of the Bradford-Hill considerations in terms of both their necessity for the apical event/adverse outcome and their human relevance. The panel identified data supporting the identification and dose-response behavior of key events, alteration of the dose-response by numerous modulating factors and data gaps that potentially impact the MOA. The current effort of applying the systematic frameworks for identifying key events and assessing human relevance to the AHR activation in the tumorigenicity of dioxins and related chemicals is novel at this time. The results should help direct future regulatory efforts and research activities aimed at better understanding the potential human cancer risks associated with dioxin exposure. © 2014 Informa Healthcare USA, Inc. All rights reserved: reproduction in whole or part not permitted.


Hasegawa R.,Japan National Institute of Health Sciences | Hirata-Koizumi M.,Japan National Institute of Health Sciences | Dourson M.L.,Toxicology Excellence for Risk Assessment | Parker A.,Toxicology Excellence for Risk Assessment | And 2 more authors.
Regulatory Toxicology and Pharmacology | Year: 2013

The available toxicity information for boron was reevaluated and four appropriate toxicity studies were selected in order to derive a tolerable daily intake (TDI) using newly proposed uncertainty factors (UFs) presented in Hasegawa et al. (2010). No observed adverse effect levels (NOAELs) of 17.5 and 8.8mgB/kg/day for the critical effect of testicular toxicity were found in 2-year rat and dog feeding studies. Also, the 95% lower confidence limit of the benchmark doses for 5% reduction of fetal body weight (BMDL05) was calculated as 44.9 and 10.3mgB/kg/day in mouse and rat developmental toxicity studies, respectively. Measured values available for differences in boron clearance between rats and humans and variability in the glomerular filtration rate (GFR) in pregnant women were used to derive chemical specific UFs. For the remaining uncertainty, newly proposed default UFs, which were derived from the latest applicable information with a probabilistic approach, and their subdivided factors for toxicokinetic and toxicodynamic variability were applied. Finally, overall UFs were calculated as 68 for rat testicular toxicity, 40 for dog testicular toxicity, 247 for mouse developmental toxicity and 78 for rat developmental toxicity. It is concluded that 0.13mgB/kg/day is the most appropriate TDI for boron, based on rat developmental toxicity. © 2012 Elsevier Inc.


Dourson M.,Toxicology Excellence for Risk Assessment | Becker R.A.,American Chemistry Council | Haber L.T.,Toxicology Excellence for Risk Assessment | Pottenger L.H.,Dow Chemical Company | And 2 more authors.
Critical Reviews in Toxicology | Year: 2013

Over the last dozen years, many national and international expert groups have considered specific improvements to risk assessment. Many of their stated recommendations are mutually supportive, but others appear conflicting, at least in an initial assessment. This review identifies areas of consensus and difference and recommends a practical, biology-centric course forward, which includes: (1) incorporating a clear problem formulation at the outset of the assessment with a level of complexity that is appropriate for informing the relevant risk management decision; (2) using toxicokinetics and toxicodynamic information to develop Chemical Specific Adjustment Factors (CSAF); (3) using mode of action (MOA) information and an understanding of the relevant biology as the key, central organizing principle for the risk assessment; (4) integrating MOA information into dose-response assessments using existing guidelines for non-cancer and cancer assessments; (5) using a tiered, iterative approach developed by the World Health Organization/International Programme on Chemical Safety (WHO/IPCS) as a scientifically robust, fit-for-purpose approach for risk assessment of combined exposures (chemical mixtures); and (6) applying all of this knowledge to enable interpretation of human biomonitoring data in a risk context. While scientifically based defaults will remain important and useful when data on CSAF or MOA to refine an assessment are absent or insufficient, assessments should always strive to use these data. The use of available 21st century knowledge of biological processes, clinical findings, chemical interactions, and dose-response at the molecular, cellular, organ and organism levels will minimize the need for extrapolation and reliance on default approaches. © 2013 Informa Healthcare USA, Inc. All rights reserved: reproduction in whole or part not permitted.


McAvoy D.C.,University of Cincinnati | Pittinger C.A.,Cincinnati Bell | Willis A.M.,Toxicology Excellence for Risk Assessment
Ecotoxicology and Environmental Safety | Year: 2015

The biotransformation of tetrabromobisphenol A (TBBPA) was evaluated in anaerobic digester sludge, soils, and freshwater sediments. In anaerobic digester sludge, TBBPA biotransformed rapidly with a 50% disappearance time (DT50) of 19 days, though little mineralization (1.1%) was observed. In aerobic soils, mineralization of TBBPA ranged from 17.5% to 21.6% with 55.3-83.6% of the TBBPA incorporated into the soils as a non-extractable bound residue. The DT50 for TBBPA in aerobic soils ranged from 5.3 to 7.7 days. In anaerobic soils, 48.3-100% of the TBBPA was incorporated into the soils as non-extractable bound residue with <4% mineralized. The soil fate studies demonstrated extensive incorporation of TBBPA into the solid matrix and this association was related to the amount of organic carbon in the soils (i.e., greater association of TBBPA with soil at higher organic carbon content). In anaerobic sediments the DT50 for TBBPA ranged from 28 to 42 days, whereas in aerobic sediments the DT50 for TBBPA ranged from 48 to 84 days and depended on the initial dose concentration. Most of the TBBPA in the sediment studies was incorporated as a non-extractable bound residue with little mineralization observed. Sediment extracts revealed three unknown biotransformation products and bisphenol A (BPA). These results were consistent with previously published studies where TBBPA biotransformed in anaerobic environments (digester sludge and sediments) by debromination and slowly mineralized in the test environments (anaerobic digester sludge, soils, and freshwater sediments). © 2015 Elsevier Inc.


Douron M.,Toxicology Excellence for Risk Assessment
Journal of Toxicology and Environmental Health - Part A: Current Issues | Year: 2010

The existing risk assessment and management model is a general framework that can incorporate the assessment of numerous types of chemicals, such as essential elements. The general nature of the framework, however, often precludes precise statements of risk and only gives assurances of accuracy by way of a judicious use of conservative assumptions. A mode-of-action framework may provide approaches that are both more precise and accurate, and that may be used for characterizing both risk and benefit of essential elements, but such a framework needs to address the differing severity of adverse effects. Current dose-response data gaps often hinder the evaluation of the risk and benefit of several essential elements; however, new modeling methods, such as categorical regression, need to be further explored. Finally, the essentiality of certain elements provides evidence that two thresholds likely exist in an individual for adverse effect, one at low doses for undernutrition, and another at high doses for toxicity, for the element of concern. This evidence may aid in the estimation of such thresholds in populations.


Maier A.,Toxicology Excellence for Risk Assessment | Kohrman-Vincent M.,Toxicology Excellence for Risk Assessment | Hertzberg R.,Emory University | Allen B.,NC Associates | And 2 more authors.
Food and Chemical Toxicology | Year: 2012

Previous risk assessment reviews analyzed the potential for dietary acrylamide to increase breast cancer risk. Here, we critically review acrylamide animal bioassay data on mammary tumors for human relevance. We applied a systematic evaluation using reasonable standards of scientific certainty and a systematic weight of evidence (WOE) approach to evaluate several hypothesized modes of action (MOA), including (1) genotoxicity related to glycidamide formation and oxidative stress, (2) endocrine effects due to age-related hyperprolactinemia or secondary to neurotoxicity, and (3) epigenetic effects. We conclude that the appropriate approach for low-dose extrapolation of the rat mammary tumors can be narrowed to two options: (1) linear low-dose extrapolation (i.e., based on a MOA of mutagenicity from direct DNA interaction) from a point of departure (POD) for the combined incidence of adenomas and adenocarcinomas, since these tumor types are related; or (2) non-linear extrapolation, using uncertainty factors to estimate a Reference Dose (RfD) from a POD for tumor promotion derived using the combined fibroadenoma, adenoma and adenocarcinoma data. Non-linear extrapolation is used in the latter approach because these combined tumor types are unlikely to be exclusively caused by mutagenicity. Comparison of the WOE for each alternative MOA indicates that a non-linear approach (option 2) is more appropriate for evaluation of acrylamide-induced mammary tumors; a linear approach (option 1) is shown for comparison. © 2012 Elsevier Ltd.

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