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Charlottesville, VA, United States
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Yamada T.,Sumitomo Chemical | Kondo M.,Sumitomo Chemical | Miyata K.,Sumitomo Chemical | Ogata K.,Sumitomo Chemical | And 6 more authors.
Toxicological Sciences | Year: 2017

Permethrin increased the incidence of bronchiolo-alveolar adenomas in female mice but not male mice or female or male rats. Studies were conducted to determine whether permethrin has mitogenic activity in Club cells in mouse lung as the basis for the mode of action (MOA) for the lung adenoma induction. Several short-term experiments focusing on timecourse, dose-response, reversibility, sex difference, strain difference, and species difference were evaluated for Club cell proliferation and morphology. The findings demonstrated that permethrin slightly and continuously enhanced Club cell proliferation at tumor-associated dose levels in female mice, but did not increase proliferation in male mice or in female rats. Electron microscopic examination demonstrated that permethrin produced morphological alterations in Club cells prior to increasing the Club cell proliferation. There was no evidence of increased cell death. These alterations in Club cells were also observed with a close structural analog cypermethrin. Taken together, the present studies provide evidence that the MOA for induction of mouse lung adenomas by permethrin involves slight morphological effects on Club cells, sustained Club cell proliferation, and eventually hyperplasia and bronchiolo-alveolar adenoma in susceptible mice. The potential human carcinogenic hazard of permethrin based on the tumorigenic MOA for lung tumors in mice was evaluated using the International Programme on Chemical Safety Human Relevance Framework. As humans are quantitatively much less sensitive to agents that increase Club cell proliferation and tumor formation in mice, it is not likely permethrin will lead to an increase in susceptibility to lung tumor development in humans. Epidemiological data for permethrin strongly supports this conclusion. © The Author 2017. Published by Oxford University Press on behalf of the Society of Toxicology.


Osimitz T.G.,Science Strategies LLC | Murphy J.V.,Neurology Section Childrens Mercy Hospital | Fell L.A.,Arcadis | Page B.,SALt Inc
Regulatory Toxicology and Pharmacology | Year: 2010

DEET is the major component of most topically applied insect repellents used in the US. The DEET Registry is a post-marketing surveillance system to provide systematic and detailed information about medical events temporally associated with DEET use.From 1995 to 2001, 296 moderate and major severity cases were included in the DEET Registry. Of these, 36 (14.5%) cases were deemed to be probably and 157 (65%) cases possibly related to DEET exposure. Insufficient data prevented determination of causality in the remaining 49 (20.2%) cases. Forty-one percent of the cases were in children 19 or younger. Forty-two percent of children experienced a seizure of moderate or major severity.The widely variable spectrum of other neurological symptoms reported in the Registry makes it unlikely they were due to one agent. People with an underlying neurological disorder were not disproportionately represented in the DEET Registry. Data showed no clear relationship between case severity and DEET concentration or concurrent use of common medicines.Recognizing the extensive use of DEET in the US and considering the information about the more serious adverse events described in the Registry, the risk of serious neurological events following the use of DEET repellents is quite low. © 2009 Elsevier Inc.


Osimitz T.G.,Science Strategies LLC | Droege W.,Science Strategies LLC | Boobis A.R.,Imperial College London | Lake B.G.,University of Surrey
Food and Chemical Toxicology | Year: 2013

Limited testing resources, the need to limit animal use, and the demand for better knowledge about carcinogenic hazards require that the carcinogenicity testing paradigm based on lifetime cancer bioassays in rats and mice should be as efficient and reliable as possible. We have therefore reevaluated the rodent bioassay, particularly for nongenotoxic chemicals and conducted a rigorous examination of the 710 substances listed in the Carcinogenic Potency Database (CPDB) that were tested in both mice and rats. The CPDB is a web-based database that provides access to the literature and the results of 6540 bioassays on 1547 chemicals that have been published in the general literature through 2001 and by the National Cancer Institute/National Toxicology Program through 2004. Only three chemicals ( o-benzyl- p-chlorophenol, Elmiron®, p-tolylurea) were identified as unequivocally non-genotoxic, mouse non-liver carcinogens. A careful analysis showed that their carcinogenicity in mice is irrelevant for assessment of human cancer hazards. This is consistent with data showing, with a few well-known exceptions, that non-genotoxic carcinogens in rodents are considered to be non-carcinogenic to humans. As a result, we propose that the inclusion of the mouse bioassay in the standard assessment scheme for non-genotoxic chemicals is no longer necessary. © 2013 .


Lake B.G.,University of Surrey | Price R.J.,University of Surrey | Osimitz T.G.,Science Strategies LLC
Pest Management Science | Year: 2015

A number of non-genotoxic chemicals, including some pesticides, have been shown to increase the incidence of liver tumours in rats and/or mice. Frameworks for analysing the modes of action (MOAs) by which chemicals produce liver tumours in rodents and the relevance of such tumour data for human risk assessment have now been established. One common MOA for rodent liver tumour formation by non-genotoxic chemicals involves activation of the constitutive androstane receptor (CAR). Key and associative events for a CAR-activation MOA include receptor activation, liver hypertrophy, induction of cytochrome P450 enzyme activities, increased replicative DNA synthesis, altered hepatic foci and liver tumours. While some effects of rodent CAR activators can be observed in human liver, a major species difference is that, unlike rodents, CAR activators do not increase replicative DNA synthesis in human hepatocytes. The CAR-activation MOA for rodent liver tumour formation is thus not plausible for humans, and hence such compounds do not pose a hepatocarcinogenic hazard for humans. © 2014 Society of Chemical Industry.


Osimitz T.G.,Science Strategies LLC | Eldridge M.L.,University of Tennessee at Knoxville | Sloter E.,WIL Research Laboratories LLC | Welsh W.,UMDNJ Robert Wood Johnson Medical School | And 5 more authors.
Food and Chemical Toxicology | Year: 2012

Eastman Tritan™ copolyester, a novel plastic from Eastman is manufactured utilizing three monomers, di-methylterephthalate (DMT), 1,4-cyclohexanedimethanol (CHDM), and 2,2,4,4-tetramethyl-1,3-cyclobutanediol (TMCD) in various ratios. As with most any polymer, the monomers along with the high molecular weight oligomers, whose toxicity is most commonly represented by the monomers, make up the predominate amount of free chemicals available for leaching into the environment and/or foods. In light of the high level of public concern about the presence of endocrine (primarily estrogenic) activity ascribed to certain plastics and chemicals in the environment, Tritan's™ monomers were evaluated using QSAR for binding to the androgen receptor and estrogen receptors (alpha and beta) as well as a battery of in vitro and in vivo techniques to determine their potential androgenicity or estrogenicity. The findings were universally negative. When these data are coupled with other in vivo data developed to assess systemic toxicity and developmental and reproductive toxicity, the data clearly indicate that these monomers do not pose an androgenic or estrogenic risk to humans. Additional data presented also support such a conclusion for terephthalic acid (TPA). TPA is also a common polyester monomer and is the main mammalian metabolite formed from DMT. © 2012 Elsevier Ltd.


PubMed | Science Strategies LLC, CeeTox Inc. and UMDNJ Robert Wood Johnson Medical School
Type: | Journal: Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association | Year: 2015

The paper presents results from the screening of seven monomers used by Eastman Chemical to make various polymers. Ethylene glycol, diethylene glycol, polytetramethylene glycol, isophthalic acid, monosodium-5-sulfoisophthalic acid, 1,4-cyclohexanedicarboxylic acid, and dimethylcyclohexanedicarboxylate were screened for potential androgenicity or estrogenicity. The following studies were conducted: QSAR for binding to the AR and ER, in vitro Androgen Receptor Binding Assay, in vitro Estrogen Receptor Binding Assays (alpha and beta isoforms), in vitro Androgen Receptor Transactivation Assay in human cells, and in vitro Estrogen Receptor Transactivation Assay in human cells. None of the QSAR models predicted that any of the monomers possessed appreciable binding affinity for either AR or ER. Binding assays showed no evidence of interaction with either the AR or the alpha or beta ER receptors. Similarly, the AR and ER transactivation assays were negative. Moreover, six of the seven monomers have been subjected to 13-week and developmental toxicity studies in rats with no androgen- or estrogen-related effects being noted. Given the negative results of the in vitro screening assays (except PMG which demonstrated cytotoxicity) as well as available repeated dose and developmental and reproductive studies, the data suggest that none of the monomers tested exhibit androgenic or estrogenic hazards.


Driver J.,Infoscientific.com Inc. | Ross J.,Risksciences.net LLC | Pandian M.,Infoscientific.com Inc. | Assaf N.,Valent BioSciences Corporation | And 2 more authors.
Journal of Toxicology and Environmental Health - Part A: Current Issues | Year: 2013

Postapplication exposure assessment related to indoor residential application of pesticide products requires consideration of product use information, application methods, chemical-specific deposition, time-dependent availability and transferability of surface residues, reentry time, and temporal location and macro-and microactivity/behavior patterns (Baker et al., 2000). Children's mouthing behavior results in potential postapplication exposure to available pesticides in treated microenvironments through the nondietary ingestion route, in addition to the dermal or inhalation routes. Children's activities and associated behaviors may result in multiple or repeat contact of dermal areas (clothed and unclothed body areas and hands) with treated surfaces, or surfaces that may have indirect sources of residues. Further, some surfaces contacted may have transferable pesticide residues and others may not. Transfer of residues from the indoor residential environment to the dermal surface (e.g., hands) of an individual has been assumed to be linear as a function of time and number of contacts. However, studies suggest that this transfer process to the hands and other body areas may be rapidly saturable. In the most recent U.S. Environmental Protection Agency (EPA), Office of Pesticide Programs (OPP) "Residential Exposure Assessment Standard Operating Procedures" (U.S. EPA, 2012), the input variable for the number of dermal contacts (with treated surfaces) is an exponent, making the relationship nonlinear. Further, removal processes such as hand washing and transfer to untreated surfaces are important to consider. Predictive algorithms for estimating children's hand-to-mouth-related incidental ingestion exposures post pesticide application have been developed by the EPA/OPP and incorporated into probabilistic models. A review of literature addressing variables used to estimate potential incidental ingestion exposure is presented. Data relevant to input variables for predictive algorithms are discussed, including the results of a multiyear, pesticide transferable residue measurement program conducted by the Non-Dietary Exposure Task Force (NDETF) and the associated distributional characterization for this key variable. Sources of conservative bias in current hand-to-mouth, incidental ingestion exposure estimation and the role of biomonitoring to evaluate predicted exposures are discussed. © 2013 Taylor and Francis Group, LLC.


Voutchkova A.M.,Yale University | Osimitz T.G.,Science Strategies LLC | Anastas P.T.,Yale University
Chemical Reviews | Year: 2010

A study was conducted to demonstrate a comprehensive molecular design framework for reduced hazard. The study aimed at providing a relatively detailed understanding to chemists untrained in toxicology the current state of knowledge of the relationships between physical-chemical properties and toxicological hazard of chemicals. It informed about the available tools hat needed to be used by these chemists to define such relationships that guided the design of safer chemicals. Another significant objective of the investigations was to reduce the hazard or intrinsic toxicity of chemicals to humans and the environment. Mechanistic toxicology was demonstrated as another field of research that aimed at understanding and identifying the molecular events that led from initial exposure to the chemical to the ultimate manifestation of toxic injury to the organism.


Osimitz T.G.,Science Strategies LLC | Droege W.,Science Strategies LLC | Hayes A.W.,Harvard University
Human and Experimental Toxicology | Year: 2016

Tetrabromobisphenol A (TBBPA) is used to protect a wide range of electrical and electronic equipment, consumer electronics and office and communication equipment from catching fire. TBBPA reacts covalently with other monomers becoming an integral part of the cross-linked molecular structure. This study was conducted to evaluate the subchronic toxicity of TBBPA administered by gavage daily for 13 weeks at 0, 100, 300, and 1000 mg/kg/day in male and female CD® rats. A 6-week post-treatment control and 1000 mg/kg/day recovery groups were included. TBBPA exerted no marked effect on the rate of mortality, clinical signs, body or organ weights, feed consumption, histopathology, urinalysis, ophthalmology, and neurological outcomes in a functional observation battery, motor activity, serum thyroid stimulating hormone, serum triiodothyronine, or other serum chemistries. Although differences were observed for bilirubin and alkaline phosphatase, the observed alterations were within the normal range and thus were neither biologically or toxicologically meaningful. The single thyroid-related parameter affected by TBBPA was a reduction in serum thyroxine levels, but the decrease was not of sufficient magnitude to induce other more sensitive indicators of thyroid perturbation. The No Observed Adverse Effect Level was at least 1000 mg/kg/day, the highest dose tested. Based on an upper bound aggregate exposure for adults estimated by the European Union, the margin of exposure is approximately 5000, suggesting that, for the endpoints examined in this study, exposure to TBBPA presents a reasonable certainty of no harm. © The Author(s) 2016.


Osimitz T.G.,Science Strategies LLC | Droege W.,Science Strategies LLC | Driver J.H.,riskSciences.net
Human and Ecological Risk Assessment | Year: 2015

ABSTRACT: This article presents a risk assessment for human exposure to nonylphenol(NP). We critically reviewed and assessed all relevant full-text publications based on a variety of data quality attributes. Two categories of data,environmental monitoring and biomonitoring from exposed individuals,were used to estimate human exposure to NP. Environmental monitoring data included the measurement of NP in food,water,air,and dust. From these data and estimates of human intake rates for the sources,exposures were estimated from each source and source-specific Margins of Exposure(MOEs) calculated. However,the nature of the populations studied prevented the calculation of aggregate exposure calculations from these data. Rather,the most reliable estimates of aggregate exposure to NP were those derived from biomonitoring studies in exposed individuals. Using the daily absorbed dose estimates for NP,MOEs were calculated for these populations. The MOEs were based on the use of a No-Observed-Adverse-Effect-Level(NOAEL) for sensitive toxicological endpoints of interest,that is,systemic and reproductive toxicity from continuous-feeding more than 3.5 generations(13 mg/kg/day). The MOEs were all greater than 1000(ranging from 2863 to 8.4 × 107),clearly indicating reasonable certainty of no harm for source-specific and aggregate(based on biomonitoring) exposures to NP. © 2015,Copyright © Taylor & Francis Group,LLC.

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