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Proctor D.M.,ToxStrategies Inc. | Suh M.,ToxStrategies Inc. | Campleman S.L.,Oakland University | Thompson C.M.,ToxStrategies Inc.
Toxicology | Year: 2014

Inhalation of hexavalent chromium [Cr(VI)] is associated with increased lung cancer risk among workers in several industries, most notably chromate production workers exposed to high concentrations of Cr(VI) (≥100μg/m3), for which clear exposure-response relationships and respiratory irritation and tissue damage have been reported. Data from this industry are used to assess lung cancer risk associated with environmental and current occupational exposures, occurring at concentrations that are significantly lower. There is considerable uncertainty in the low dose extrapolation of historical occupational epidemiology data to assess risk at current exposures because no published or well recognized mode of action (MOA) for Cr(VI)-induced lung tumors exists. We conducted a MOA analysis for Cr(VI)-induced lung cancer evaluating toxicokinetic and toxicological data in humans and rodents and mechanistic data to assess plausibility, dose-response, and temporal concordance for potential MOAs. Toxicokinetic data support that extracellular reduction of Cr(VI), which limits intracellular absorption of Cr(VI) and Cr(VI)-induced toxicity, can be overwhelmed at high exposure levels. In vivo genotoxicity and mutagenicity data are mostly negative and do not support a mutagenic MOA. Further, both chronic bioassays and the epidemiologic literature support that lung cancer occurs at exposures that cause tissue damage. Based on this MOA analysis, the overall weight of evidence supports a MOA involving deposition and accumulation of particulate chromium in the bifurcations of the lung resulting in exceedance of clearance mechanisms and cellular absorption of Cr(VI). Once inside the cell, reduction of Cr(VI) results in oxidative stress and the formation of Cr ligands. Subsequent protein and DNA damage lead to tissue irritation, inflammation, and cytotoxicity. These effects, concomitant with increased cell proliferation, result in changes to DNA sequences and/or methylation status that can lead to tumorigenesis. This MOA supports the use of non-linear approaches when extrapolating lung cancer risk occurring at high concentration occupational exposures to environmentally-relevant exposures. © 2014 Elsevier Ireland Ltd.

Berman D.W.,Aeolus Inc. | Brorby G.P.,ToxStrategies Inc. | Sheehan P.J.,Exponent, Inc. | Bogen K.T.,Exponent, Inc. | Holm S.E.,Georgia Pacific LLC
Annals of Occupational Hygiene | Year: 2012

An ongoing research effort designed to reconstruct the character of historical exposures associated with use of chrysotile-containing joint compounds naturally raised questions concerning how the character (e.g. particle size distributions) of dusts generated from use of recreated materials compares to dusts from similar materials manufactured historically. This also provided an opportunity to further explore the relative degree that the characteristics of dusts generated from a bulk material are mediated by the properties of the bulk material versus the mechanical processes applied to the bulk material by which the dust is generated. In the current study, the characteristics of dusts generated from a recreated ready mix and recreated dry mix were compared to each other, to dusts from a historical dry mix, and to dusts from the commercial chrysotile fiber (JM 7RF3) used in the recreated materials. The effect of sanding on the character of dusts generated from these materials was also explored. Dusts from the dry materials studied were generated and captured for analysis in a dust generator-elutriator. The recreated and historical joint compounds were also prepared, applied to drywall, and sanded inside sealed bags so that the particles produced from sanding could be introduced into the elutriator and captured for analysis. Comparisons of fiber size distributions in dusts from these materials suggest that dust from commercial fiber is different from dusts generated from the joint compounds, which are mixtures, and the differences persist whether the materials are sanded or not. Differences were also observed between sanded recreated ready mix and either the recreated dry mix or a historical dry mix, again whether sanded or not. In all cases, however, such differences disappeared when variances obtained from surrogate data were used to better represent the 'irreducible variation' of these materials. Even using the smaller study-specific variances, no differences were observed between the recreated dry mix and the historical dry mix, indicating that chrysotile-containing joint compounds can be recreated using historical formulations such that the characteristics of the modern material reasonably mimic those of a corresponding historical material. Similarly, no significant differences were observed between dusts from sanded and unsanded versions of similar materials, suggesting (as in previous studies) that the characteristics of asbestos-containing dusts are mediated primarily by the properties of the bulk material from which they are derived. © 2012 The Author.

Urban J.D.,ToxStrategies Inc. | Carakostas M.C.,ToxStrategies Inc. | Taylor S.L.,University of Nebraska - Lincoln
Food and Chemical Toxicology | Year: 2015

Steviol glycoside sweeteners are extracted from the plant Stevia rebaudiana (Bertoni), a member of the Asteraceae (Compositae) family. Many plants from this family can induce hypersensitivity reactions via multiple routes of exposure (e.g., ragweed, goldenrod, chrysanthemum, echinacea, chamomile, lettuce, sunflower and chicory). Based on this common taxonomy, some popular media reports and resources have issued food warnings alleging the potential for stevia allergy. To determine if such allergy warnings are warranted on stevia-based sweeteners, a comprehensive literature search was conducted to identify all available data related to allergic responses following the consumption of stevia extracts or highly purified steviol glycosides. Hypersensitivity reactions to stevia in any form are rare. The few cases documented in the peer-reviewed literature were reported prior to the introduction of high-purity products to the market in 2008 when many global regulatory authorities began to affirm the safety of steviol glycosides. Neither stevia manufacturers nor food allergy networks have reported significant numbers of any adverse events related to ingestion of stevia-based sweeteners, and there have been no reports of stevia-related allergy in the literature since 2008. Therefore, there is little substantiated scientific evidence to support warning statements to consumers about allergy to highly purified stevia extracts. © 2014 Elsevier Ltd.

Gatto N.M.,ToxStrategies Inc. | Kelsh M.A.,Exponent, Inc. | Mai D.H.,Exponent, Inc. | Suh M.,Exponent, Inc. | Proctor D.M.,ToxStrategies Inc.
Cancer Epidemiology | Year: 2010

Introduction: We conducted a systematic literature review and meta-analysis of oral cavity, esophageal, stomach, small intestine, colon, and rectal cancers among workers occupationally exposed to Cr(VI). Methods: Using PubMed, studies published from 1950 to 2009 evaluating the relationship between Cr(VI) exposure and GI cancers were identified. Measures of effect and variability were extracted from 32 studies meeting specific inclusion criteria, and meta-analysis summary relative risk measures were calculated using random effects models and inverse variance weighting methods. Results: Meta-standardized mortality ratios (SMRs) were, for cancer of the: oral cavity [1.02 (95% CI=0.77-1.34)]; esophagus [1.17 (95% CI=0.90-1.51)]; stomach [1.09 (95% CI=0.93-1.28)]; colon [0.89 (95% CI=0.70-1.12)]; and rectum [1.17 (95% CI=0.98-1.39)]. Analyses of more highly exposed subgroups included in the studies or subgroups based on geographic region or by industry with recognized Cr(VI) exposures (welding, chrome plating, chromate production, and pigment production) did not result in elevated meta-SMRs except for esophageal cancer among US cohorts [meta-SMR=1.49 (95% CI=1.06-2.09)]. However, that finding was based on a subgroup of only four studies, one of which was a PMR study. Potential confounding by socioeconomic status (SES), diet and/or smoking, or limitations due to the healthy-worker effect (HWE) were evaluated, and while smoking, diet and SES may be important factors that may have upwardly biased the meta-SMRs, HWE is not likely to have significantly affected the summary results. None of three studies reporting small intestine cancers observed a statistically significant increased risk. Discussion: These meta-analyses and literature review indicate that Cr(VI)-exposed workers are not at a greater risk of GI cancers than the general population. © 2010 Elsevier Ltd.

Urban J.D.,ToxStrategies Inc. | Wikoff D.S.,ToxStrategies Inc. | Bunch A.T.G.,ToxStrategies Inc. | Harris M.A.,ToxStrategies Inc. | Haws L.C.,ToxStrategies Inc.
Science of the Total Environment | Year: 2014

Over the last several decades, dioxin releases have decreased >90%, leading to a corresponding decrease in human body burdens. In addition, the weight-of-evidence indicates that soil exposures have little impact on human body burdens of dioxin-like compounds (DLCs), with dietary sources being the greatest contributor. In spite of this, USEPA recently proposed substantially lower preliminary remediation goals (PRGs) for soil based on their new oral reference dose (RfD) for dioxin. As such, it is important to understand how these lower soil PRGs compare to background concentrations in urban/suburban and rural soils. The objective of this evaluation was to conduct a comprehensive review of available data concerning background levels of DLCs in U.S. soils. There was substantial variability in how the soil dioxin data were presented (e.g., raw vs. summary data, congener vs. toxic equivalency [TEQ] concentration, number of DLC congeners reported, etc.). In cases where TEQ estimates were based on outdated TEFs and congener-specific data was provided, TEQ concentrations were recalculated using the current WHO2006 TEFs. The data available for rural soils were generally more robust than for urban/suburban soils. Not surprisingly, background levels of DLCs in urban/suburban soils were higher and more variable than in rural soils: 0.1-186 vs. 0.1-22.9ng/kg TEQ, respectively. In several cases, incomplete soil DLC data were available (e.g., DL-PCBs not included) and, as such, calculated TEQ concentrations likely underestimate actual background levels. Though the current data are somewhat limited, these findings indicate that background DLC concentrations in urban/suburban soils may exceed the USEPA's updated PRGs based on the oral RfD, and are expected to substantially exceed future PRGs to be developed based on the forthcoming dioxin cancer slope factor. This demonstrates a need to characterize anthropogenic background DLCs in non-rural areas across the US to avoid establishing soil screening levels and PRGs that are lower than background concentrations. © 2013 Elsevier B.V.

Lansita J.A.,ToxStrategies Inc. | Mounho-Zamora B.,Century Inc.
Current Pain and Headache Reports | Year: 2015

Monoclonal antibodies (mAbs) represent a class of biotechnology-derived therapeutics for use in the treatment of various disease indications such as oncology, autoimmune, cardiovascular, and metabolic disorders. Monoclonal antibodies are immunoglobulin (Ig) proteins engineered to bind to specific antigens with high specificity. The concepts reviewed in this paper include 1) the regulatory procedures and guidelines that apply to mAbs, 2) the types of toxicology studies applicable to mAbs, and 3) the scientific challenges, such as the selection of a relevant animal species and the development of anti-drug antibodies, that can arise due to the unique properties of mAbs. © 2015, Springer Science+Business Media New York.

Mahadevan B.,Abbott Laboratories | Thorsrud B.A.,MPI Research Inc. | Brorby G.P.,ToxStrategies Inc. | Ferguson H.E.,Abbott Laboratories
Food and Chemical Toxicology | Year: 2014

Octenyl succinic anhydride (OSA)-modified starch functions as both an emulsifier and emulsion stabilizer in foods, and is intended for use in infant formula, follow-on formula, and formulae for special medical purposes. These formulae predominantly include extensively hydrolyzed protein or free amino acids, rather than intact protein, which otherwise would provide emulsifying functionality. The study objectives were to evaluate (1) the safety of OSA-modified starch after three weeks of administration to neonatal farm piglets, beginning 2. days after birth and (2) the impact of OSA-modified starch on piglet growth. OSA-modified starch was added to formula at concentrations of 2, 4, and 20. g/L. The vehicle control, low-dose, and mid-dose diets were supplemented with Amioca™ Powder to balance the nutritional profiles of all formulations. There were no test article-related effects of any diet containing OSA-modified starch on piglet growth and development (clinical observations, body weight, feed consumption), or clinical pathology parameters (hematology, clinical chemistry, coagulation, urinalysis). In addition, there were no adverse effects at terminal necropsy (macro- and microscopic pathology evaluations). Therefore, dietary exposure to OSA-modified starch at concentrations up to 20. g/L was well tolerated by neonatal farm piglets and did not result in adverse health effects or impact piglet growth. © 2014 Elsevier Ltd.

Suh M.,ToxStrategies Inc. | Abraham L.,ToxStrategies Inc. | Hixon J.G.,ToxStrategies Inc. | Proctor D.M.,ToxStrategies Inc.
Journal of Exposure Science and Environmental Epidemiology | Year: 2014

Among women with urinary iodine concentration <100 μg/l i. The 2001-2002 National Health and Nutrition Examination Survey (NHANES), urinary perchlorate was associated with significant changes in thyroid stimulating hormone and total thyroxine (T4). Although perchlorate, nitrate, and thiocyanate all potentially act to inhibit iodide uptake, free T4 was not found to be associated with exposure to these chemicals i. The same data. Fetuses of pregnant mothers with iodine deficiency are thought to be a sensitive subpopulation for perchlorate exposure, bu. The potential associations between free T4 and exposure to these chemicals among pregnant mothers in NHANES 2001-2002 and 2007-2008 have not been specifically evaluated to date. This study investigate. The potential associations between urinary perchlorate, nitrate, and thiocyanate and serum free T4 in individuals with low urinary iodine levels and pregnant women. Multivariate regression models of free T4 were conducted and included urinary perchlorate, nitrate, thiocyanate, and covariates known to have an impact o. The thyroid (anti-thyroid peroxidase (TPO) antibodies, age, race/ethnicity, body mass index, and hours of fasting). Meta-analyses were also conducted on non-pregnant and on pregnant women fro. The two survey cycles. Urinary nitrate was associated with serum free T4 in non-pregnant women of NHANES 2001-2002 who had urinary iodine ≥100 μg/l. I. The meta-analysis, urinary perchlorate, nitrate, and thiocyanate were significant predictors of serum free T4 in non-pregnant women. No association was found in men and pregnant women. TPO antibodies were significant predictors of free T4 among non-pregnant women only whe. The models included urinary perchlorate, nitrate, or thiocyanate. Risk assessment for perchlorate exposure should consider co-exposure to nitrate and thiocyanate. © 2014 Nature America, Inc. All rights reserved.

Lansita J.A.,ToxStrategies Inc | Mounho-Zamora B.,Century Inc.
Current Pain and Headache Reports | Year: 2015

Monoclonal antibodies (mAbs) represent a class of biotechnology-derived therapeutics for use in the treatment of various disease indications such as oncology, autoimmune, cardiovascular, and metabolic disorders. Monoclonal antibodies are immunoglobulin (Ig) proteins engineered to bind to specific antigens with high specificity. The concepts reviewed in this paper include 1) the regulatory procedures and guidelines that apply to mAbs, 2) the types of toxicology studies applicable to mAbs, and 3) the scientific challenges, such as the selection of a relevant animal species and the development of anti-drug antibodies, that can arise due to the unique properties of mAbs. © 2015, Springer Science+Business Media New York.

Urban J.D.,ToxStrategies Inc. | Carakostas M.C.,ToxStrategies Inc. | Brusick D.J.,Brusick Consultancy
Food and Chemical Toxicology | Year: 2013

The safety of steviol glycoside sweeteners has been extensively reviewed in the literature. National and international food safety agencies and approximately 20 expert panels have concluded that steviol glycosides, including the widely used sweeteners stevioside and rebaudioside A, are not genotoxic. However, concern has been expressed in recent publications that steviol glycosides may be mutagenic based on select studies representing a small fraction of the overall database, and it has been suggested that further in vivo genotoxicity studies are required to complete their safety profiles. To address the utility of conducting additional in vivo genotoxicity studies, this review evaluates the specific genotoxicity studies that are the sources of concern, and evaluates the adequacy of the database including more recent genotoxicity data not mentioned in those publications. The current database of in vitro and in vivo studies for steviol glycosides is robust and does not indicate that either stevioside or rebaudioside A are genotoxic. This, combined with a lack of evidence for neoplasm development in rat bioassays, establish the safety of all steviol glycosides with respect to their genotoxic/carcinogenic potential. © 2012 Elsevier Ltd.

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