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Michael Dourson - One of the best experts on this subject based on the ideXlab platform.
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A review of the Reference Dose for chlorpyrifos.
Regulatory toxicology and pharmacology : RTP, 2005Co-Authors: Qiyu Zhao, Michael Dourson, Bernard GadagbuiAbstract:Chlorpyrifos is an inhibitor of cholinesterase (ChE) and inhibition of ChE is believed to be the most sensitive effect in all animal species evaluated and in humans from previous evaluations. Recent literature, in particular epidemiology studies reporting associations between chlorpyrifos levels and fetal birth weight decreases, suggest the need to reevaluate the basis of the Reference Dose (RfD) for chlorpyrifos, however. In this paper, we evaluated newly available publications regarding chlorpyrifos toxicity and discuss the choice of critical effect--whether cholinesterase inhibition or developmental effect, the choice of appropriate species and study, the appropriate point of departure, and choice of uncertainty factors--including a discussion of the FQPA safety factor. We conclude that RBC cholinesterase inhibition is the critical effect, that human studies form the best choice of species--supported by a wealth of experimental animal data, that a NOAEL of 0.1 mg/kg/day is the most appropriate point of departure, and that a 10-fold factor for within human variability is sufficient to characterize the overall uncertainty in this rather large database. The resulting RfD is 0.01 mg/kg/day.
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Reference Dose for perchlorate based on thyroid hormone change in pregnant women as the critical effect.
Regulatory toxicology and pharmacology : RTP, 2004Co-Authors: Joan Strawson, Qiyu Zhao, Michael DoursonAbstract:Abstract The most relevant data for developing a Reference Dose (RfD) for perchlorate exposures comes from human epidemiology and clinical studies, supplemented with available and extensive information on experimental animals. Specifically, serum T4 decrease is the critical effect of perchlorate, based on a mode-of-action analysis and the evidence provided by the body of rodent studies on perchlorate. However, no T4 decreases have been observed in human populations following perchlorate exposure at non-therapeutic Doses. An RfD of 0.002 mg/kg-day can be derived using an epidemiology study. A freestanding NOAEL of 0.006 mg/kg-day for T4 decrease was identified in children from the epidemiology study. The use of this NOAEL has the advantage of a being identified in a sensitive subgroup, neonates and children. Data are sufficient to estimate an overall uncertainty factor of 3-fold with this NOAEL based on expected differences in toxicokinetics and toxicodynamics between children, and pregnant women and their fetuses, the second identified sensitive subgroup for perchlorate, and concerns about the over-iodination of this population. This RfD is supported by a human clinical study using inhibition of iodine uptake in adults as a measurable surrogate for the critical effect of T4 decrease in humans. However, although this latter study has a well-established Dose–response curve for inhibition of iodine uptake, even perchlorate Doses that result in a 70% inhibition of iodine uptake have no apparent effect on human T4 levels. Thus, the use of this study as the primary basis of the RfD is problematic. Nevertheless, a benchmark Dose of 0.01 mg/kg-day was identified in this clinical study, which supports a threshold value of 0.006 mg/kg-day identified by its authors and the RfD of 0.002 mg/kg-day estimated in this paper.
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Uncertainties in the Reference Dose for methylmercury.
Neurotoxicology, 2001Co-Authors: Michael Dourson, Andrea E. Wullenweber, Kenneth A. PoirierAbstract:This paper critically examines the National Academy of Sciences and the National Research Council report on the toxicological effects of methyl mercury and the recently published US Environmental Protection Agency Reference Dose (RfD) for Methylmercury. Particular scrutiny is placed on the choice of the critical study and the underlining assumptions utilized in the selection of specific uncertainty factors (UFs) and the rationale for using a less-than-default factor of 10. The UFs that were utilized or considered by other agencies and organizations are also critically examined, explained and compared to one another. Based on these analyses, the authors suggest research that could be performed that would ameliorate the uncertainty of choosing a more precise partial UF or that may even provide completeness of database to allow for selecting of a UF for unity, thus improving the precision of the current published RfD.
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Use of human data for the derivation of a Reference Dose for chlorpyrifos.
Regulatory toxicology and pharmacology : RTP, 2001Co-Authors: Marcia Van Gemert, Michael Dourson, Angelo Moretto, Michael WatsonAbstract:Abstract In 1998 a panel of experts met to discuss the data available on chlorpyrifos, both human and animal, and to determine the most appropriate endpoints to be used for the derivation of the Reference Dose (RfD). Since that time, additional data have become available on chlorpyrifos from an experimental study involving humans. Moreover, Food Quality Protection Act (FQPA) considerations need to be addressed, and the appropriate cholinesterase endpoint, whether plasma, red blood cell, peripheral nerve, or brain, has become highly debated. Therefore, Dow AgroSciences, one of the manufacturers of chlorpyrifos, convened a second panel of toxicology and medical experts on June 21, 1999, to consider the presently available scientific literature both published and unpublished on chlorpyrifos and to determine the acute and chronic toxicological RfDs for chlorpyrifos. Four questions were posed to this second panel of experts concerning the available data on chlorpyrifos. (1) Should the RfD for chlorpyrifos be based on acetylcholinesterase (AChE) inhibition or butyrylcholinesterase (BuChE) inhibition as an endpoint for adverse effect? (2) Should the RfDs for chlorpyrifos be based on the data set from three human studies, which are supported by animal data? (3) Should the FQPA safety factor be reduced to 1×based on animal studies of pre- or postnatal toxicity? (4) If an RfD for chlorpyrifos were to be based on animal data, then is a 10-fold interspecies uncertainty factor necessary? The panel of experts concluded that: (1) inhibition of BuChE is not an adverse effect, and the RfD for chlorpyrifos should be based on AChE inhibition; (2) the RfD for chlorpyrifos should be based on the three available human studies, which are also supported by animal data; (3) the extra FQPA safety factor should be reduced to 1×, because chlorpyrifos shows no pre- or postnatal toxicity of concern at relevant human exposure conditions; and (4) the extra 10-fold safety factor for interspecies variation appears overly cons ervative because no differences in species sensitivity to chlorpyrifos is evident.
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Health Risk above the Reference Dose for Multiple Chemicals
Regulatory Toxicology and Pharmacology, 1999Co-Authors: Linda K. Teuschler, Michael Dourson, William Stiteler, Peter Mcclure, Heather TullyAbstract:Recent work indicates that the regression of toxicity data viewed as categories of pathological staging is useful for exploring the likely health risk at Doses above a Reference Dose (RfD), which is an estimate (with uncertainty spanning perhaps an order of magnitude) of a daily exposure to the human population (including sensitive subgroups) that is likely to be without an appreciable risk of deleterious effects during a lifetime. Toxic effects, which may include both quantal and continuous data, are classified into ordered categories of total toxic severity (e.g., none, mild, adverse, severe). These severity categories are regressed on explanatory variables, such as Dose or exposure duration, to estimate the probability of observing an adverse or severe effect. In this paper, categorical regression has been expanded to compare the likely risks across multiple chemicals when exposures are above their RfDs. Existing health risk data for diazinon, disulfoton, S-ethyl dipropylthiocarbamate, fenamiphos, and lindane were analyzed. As expected, the estimated risks of adverse effects above the RfD varied among the chemicals. For example, at 10-fold above the RfD these risks were modeled to be 0.002, 0.0001, 0.0007, 0.002, and 0.02, respectively. The results and impacts of this analysis indicate that categorical regression is a useful screening tool to analyze risks above the RfD for specific chemicals and suggest its application in evaluating comparative risks where multiple chemical exposures exist.
Alan H. Stern - One of the best experts on this subject based on the ideXlab platform.
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The derivation of a Reference Dose (RfD) for perfluorooctane sulfonate (PFOS) based on immune suppression.
Environmental research, 2018Co-Authors: Brian Pachkowski, Gloria B. Post, Alan H. SternAbstract:Abstract Exposure to perfluorooctane sulfonate (PFOS) is ubiquitous in populations and environments worldwide. Its long half-life in humans, indefinite persistence in the environment, and awareness of its widespread presence in drinking water make the human health assessment of PFOS a priority. While developmental, endocrine, and hepatic effects, and increased serum cholesterol are among the outcomes resulting from PFOS exposure, immunosuppression has also consistently emerged as an adverse effect. An in-depth review of the relevant scientific literature on the toxicology of PFOS has identified immunosuppression as a sensitive endpoint for PFOS toxicity. Here, we focus specifically on that endpoint and provide a detailed derivation of a Reference Dose (RfD) of 1.8 × 10−6 mg/kg/day for chronic human exposure to PFOS. This RfD is based on decreased plaque-forming cell (PFC) response in mice, an endpoint that reflects suppression of the immune response to a foreign antigen. We additionally identify two endpoints in the epidemiology literature, decreased vaccine response and increased incidence of childhood infections, that are associated with PFOS exposure and that are consistent with and support the decreased PFC response endpoint from animal studies. We provide a weight of evidence analysis integrating the evidence from animal and epidemiology endpoints. Finally, we compare this RfD to the PFOS RfD derived by the United States Environmental Protection Agency (USEPA) Office of Water based on a developmental endpoint. Based on this comparison, and given our assessment, the USEPA RfD does not provide sufficient protection against the adverse health effects of PFOS. The RfD derived herein is intended to be public health protective and appropriately minimizes PFOS exposure based on available evidence.
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Estimation of the interindividual variability in the one-compartment pharmacokinetic model for methylmercury: implications for the derivation of a Reference Dose.
Regulatory toxicology and pharmacology : RTP, 1997Co-Authors: Alan H. SternAbstract:A critical step in the U.S. EPA's derivation of an Reference Dose (RfD) for methylmercury is conversion of the maternal hair Hg concentration of 11 ppm to average daily intake using the one-compartment pharmacokinetic model. A default uncertainty factor (UF) adjustment of 3 for interindividual variability was then applied to this conversion. A probabilistic (Monte Carlo) analysis is presented estimating the interindividual variability inherent in this Dose conversion for women 18-40 years old based on data in the scientific literature. The Dose of 1.1 micrograms/kg/day, calculated by the U.S. EPA to correspond to 11 ppm Hg in hair, is estimated in this analysis to be larger than 94-99% of corresponding Doses. The application of a UF of 3 to this U.S. EPA value gives a Dose which is estimated to be larger than 28-73% of corresponding Doses. This analysis suggests that if the Dose conversion in the RfD is intended to be inclusive of 95-99% of women 18-40, the daily intake should be set at 0.1-0.3 microgram/kg/day. The RfD of 0.03-0.1 microgram/kg/day, derived from this Dose by the U.S. EPA's application of an additional UF of 3 for additional toxicologic concerns, is somewhat smaller than the current RfD of 0.1 microgram/kg/day.
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Re-evaluation of the Reference Dose for Methylmercury and Assessment of Current Exposure Levels
Risk analysis : an official publication of the Society for Risk Analysis, 1993Co-Authors: Alan H. SternAbstract:Methylmercury (Me-Hg) is widely distributed through freshwater and saltwater food chains and human consumption of fish and shellfish has lead to widespread exposure. Both the US EPA Reference Dose (0.3 [mu]g/kg/day) and the FAO/WHO Permissible Tolerable Weekly Intake (3.3 [mu]g/kg/week) are currently based on the prevention of paraesthesia in adult and older children. However, Me-Hg exposure in utero is known to result in a range of developmental neurologic effects including clinical CNS symptoms and delayed onset of walking. Based on a critical review of development toxicity data from human and animal studies, it is concluded that current guidelines for the prevention of paraesthesia are not adequate to address developmental effects. A Dose of 0.07 [mu]g/kg/day is suggested as the best estimate of a potential Reference Dose for developmental effects. Data on nationwide fish consumption rates and Me-Hg levels in fish/seafood weighted by proportion of the catch intended for human consumption are analyzed in a Monte Carlo simulation to derive a probability distribution of background Me-Hg exposure. While various uncertainties in the toxicologic and exposure data limit the precision with which health risk can be estimated, this analysis suggests that at current levels of Me-Hg exposure, a significant fraction of womenmore » of childbearing age have exposures above this suggested Reference Dose.« less
Albin Fredriksson - One of the best experts on this subject based on the ideXlab platform.
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automated robust proton planning using Dose volume histogram based mimicking of the photon Reference Dose and reducing organ at risk Dose optimization
International Journal of Radiation Oncology Biology Physics, 2019Co-Authors: Roel G J Kierkels, Albin Fredriksson, Stefan Both, Johannes A Langendijk, D Scandurra, Erik W KorevaarAbstract:Purpose: Patient selection for proton therapy is increasingly based on proton to photon plan comparisons. To improve efficient decision making, we developed a Dose mimicking and reducing (DMR) algorithm to automatically generate a robust proton plan from a Reference photon Dose, as well as target and organ at risk (OAR) delineations. Methods and Materials: The DMR algorithm was evaluated in 40 patients with head and neck cancer. The first step of the DMR algorithm comprises Dose-volume histogram-based mimicking of the photon Dose distribution in the clinical target volumes and OARs. Target robustness is included by mimicking the nominal photon Dose in 21 perturbed scenarios. The second step of the optimization aims to reduce the OAR Doses while retaining the robust target coverage as achieved in the first step. We evaluated each DMR plan against the manually robustly optimized Reference proton plan in terms of plan robustness (voxel-wise minimum Dose). Furthermore, the DMR plans were evaluated against the Reference photon plan using normal tissue complication probability (NTCP) models of xerostomia, dysphagia, and tube feeding dependence. Consequently, Delta NTCPs were defined as the difference between the NTCPs of the photon and proton plans. Results: The Dose distributions of the DMR and Reference proton plans were very similar in terms of target robustness and OAR Dose values. Regardless of proton planning technique (ie, DMR or Reference proton plan), the same treatment modality was selected in 80% (32 of 40) of cases based on the Sigma Delta NTCPs. In 15% (6 of 40) of cases, a conflicting decision was made based on relatively small Dose differences to the OARs ( Conclusions: The DMR algorithm automatically optimized robust proton plans from a photon Reference Dose that were comparable to the dosimetrist-optimized proton plans in patients with head and neck cancer. This algorithm has been successfully embedded into a framework to automatically select patients for proton therapy based on NTCPs. (C) 2018 Elsevier Inc. All rights reserved.
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Automated improvement of radiation therapy treatment plans by optimization under Reference Dose constraints
Physics in medicine and biology, 2012Co-Authors: Albin FredrikssonAbstract:A method is presented that automatically improves upon previous treatment plans by optimization under Reference Dose constraints. In such an optimization, a previous plan is taken as Reference and a new optimization is performed toward some goal, such as minimization of the Doses to healthy structures under the constraint that no structure can become worse off than in the Reference plan. Two types of constraints that enforce this are discussed: either each voxel or each Dose–volume histogram of the improved plan must be at least as good as in the Reference plan. These constraints ensure that the quality of the Dose distribution cannot deteriorate, something that constraints on conventional physical penalty functions do not. To avoid discontinuous gradients, which may restrain gradient-based optimization algorithms, the positive part operators that constitute the optimization functions are regularized. The method was applied to a previously optimized plan for a C-shaped phantom and the effects of the choice of regularization parameter were studied. The method resulted in reduced integral Dose and reduced Doses to the organ at risk while maintaining target homogeneity. It could be used to improve upon treatment plans directly or as a means of quality control of plans.
Greg Paoli - One of the best experts on this subject based on the ideXlab platform.
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Beyond the RfD: Broad Application of a Probabilistic Approach to Improve Chemical Dose-Response Assessments for Noncancer Effects.
Environmental health perspectives, 2018Co-Authors: Weihsueh A. Chiu, Daniel A. Axelrad, Chimeddulam Dalaijamts, Chris Dockins, Kan Shao, Andrew J. Shapiro, Greg PaoliAbstract:Background: The National Academies recommended risk assessments redefine the traditional noncancer Reference Dose (RfD) as a probabilistically derived risk-specific Dose, a framework for which was ...
Clifton J Mclellan - One of the best experts on this subject based on the ideXlab platform.
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derivation of a bisphenol a oral Reference Dose rfd and drinking water equivalent concentration
Journal of Toxicology and Environmental Health-part B-critical Reviews, 2008Co-Authors: Calvin C Willhite, Gwendolyn L Ball, Clifton J MclellanAbstract:Human exposure to bisphenol A (BPA) is due to that found in the diet, and BPA and its metabolites were detected at parts per billion (or less) concentrations in human urine, milk, saliva, serum, plasma, ovarian follicular fluid, and amniotic fluid. Adverse health effects in mice and rats may be induced after parenteral injection or after massive oral Doses. Controlled ingestion trials in healthy adult volunteers with 5 mg d16-BPA were unable to detect parent BPA in plasma despite exquisitely sensitive (limit of detection = 6 nM) methods, but by 96 h 100% of the administered Dose was recovered in urine as the glucuronide. The extensive BPA glucuronidation following ingestion is not seen after parenteral injection; only the parent BPA binds plasma proteins and estrogen receptors (ER). The hypothesis that BPA Dose-response may be described by a J- or U-shape curve was not supported by toxicogenomic data collected in fetal rat testes and epididymes (after repeated parenteral exposure at 2-400,000 microg/kg-d), where a clear monotonic Dose-response both in the numbers of genes and magnitude of individual gene expression was evident. There is no clear indication from available data that the BPA Doses normally consumed by humans pose an increased risk for immunologic or neurologic disease. There is no evidence that BPA poses a genotoxic or carcinogenic risk and clinical evaluations of 205 men and women with high-performance liquid chromatography (HPLC)-verified serum or urinary BPA conjugates showed (1) no objective signs, (2) no changes in reproductive hormones or clinical chemistry parameters, and (3) no alterations in the number of children or sons:daughters ratio. Results of benchmark Dose (BMD10 and BMDL10) calculations and no-observed-adverse-effect level (NOAEL) inspections of all available and reproducible rodent studies with oral BPA found BMD and NOAEL values all greater than the 5 mg/kg-d NOAELs from mouse and rat multigeneration reproduction toxicity studies. While allometric and physiologically based pharmacokinetic (PBPK) models were constructed for interspecies scaling of BPA and its interaction with ER, multigeneration feeding studies with BPA at Doses spanning 5 orders of magnitude failed to identify signs of developmental toxicity or adverse changes in reproductive tract tissues; the 5-mg/kg-d NOAELs identified for systemic toxicity in rats and mice were less than the oral NOAELs for reproductive toxicity. Thus, it is the generalized systemic toxicity of ingested BPA rather than reproductive, immunologic, neurobehavioral, or genotoxic hazard that represents the point of departure. Using U.S. Environmental Protection Agency (EPA) uncertainty factor guidance and application of a threefold database uncertainty factor (to account for the fact that the carcinogenic potential of transplacental BPA exposure has yet to be fully defined and comprehensive neurobehavioral and immunotoxicologic evaluations of BPA by relevant routes and at relevant Doses have yet to be completed) to the administered Dose NOAEL results in an oral RfD of 0.016 mg/kg-d. Assuming the 70-kg adult consumes 2 L of water each day and adopting the default 20% U.S. EPA drinking water relative source contribution yields a 100 microg/L BPA total allowable concentration (TAC).
