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1.
Sulfosulfuron is a low-use rate sulfonylurea herbicide. A review of the toxicity database for sulfosulfuron indicates that the molecule has a low order of acute toxicity. It is not genotoxic and is not a reproductive, developmental, or nervous system toxicant. There were no indications of endocrine disruption in any study performed with the molecule. The only findings considered to be an adverse effect in mammalian laboratory animals following prolonged subchronic or chronic exposure to sulfosulfuron were isolated to the urinary tract. These findings occurred in conjunction with findings of urolith formation following high-level chemical dosing, resulting in epithelial hyperplasia that, in a few cases, progressed to tumor formation. Mode-of-action information supports the conclusion that these tumors result from a non-genotoxic, threshold-based process that is well established and widely considered to be not relevant to humans. Based on its short-term, infrequent application pattern and very low use rate and crop residues, aggregate and cumulative risk assessments indicate that sulfosulfuron has substantial margins of exposure and does not represent a significant risk to human health. 相似文献
2.
Annie M. Jarabek Lynn H. Pottenger Larry S. Andrews Daniel Casciano Michelle R. Embry 《Critical reviews in toxicology》2013,43(8):659-678
The assessment of human cancer risk from chemical exposure requires the integration of diverse types of data. Such data involve effects at the cell and tissue levels. This report focuses on the specific utility of one type of data, namely DNA adducts. Emphasis is placed on the appreciation that such DNA adduct data cannot be used in isolation in the risk assessment process but must be used in an integrated fashion with other information. As emerging technologies provide even more sensitive quantitative measurements of DNA adducts, integration that establishes links between DNA adducts and accepted outcome measures becomes critical for risk assessment. The present report proposes an organizational approach for the assessment of DNA adduct data (e.g., type of adduct, frequency, persistence, type of repair process) in concert with other relevant data, such as dosimetry, toxicity, mutagenicity, genotoxicity, and tumor incidence, to inform characterization of the mode of action. DNA adducts are considered biomarkers of exposure, whereas gene mutations and chromosomal alterations are often biomarkers of early biological effects and also can be bioindicators of the carcinogenic process. 相似文献
3.
Local lymph node assay: use in hazard and risk assessment. 总被引:3,自引:0,他引:3
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Research strategies for safety evaluation of nanomaterials, part IV: risk assessment of nanoparticles. 总被引:7,自引:0,他引:7
Joyce S Tsuji Andrew D Maynard Paul C Howard John T James Chiu-Wing Lam David B Warheit Annette B Santamaria 《Toxicological sciences》2006,89(1):42-50
Nanoparticles are small-scale substances (<100 nm) with unique properties and, thus, complex exposure and health risk implications. This symposium review summarizes recent findings in exposure and toxicity of nanoparticles and their application for assessing human health risks. Characterization of airborne particles indicates that exposures will depend on particle behavior (e.g., disperse or aggregate) and that accurate, portable, and cost-effective measurement techniques are essential for understanding exposure. Under many conditions, dermal penetration of nanoparticles may be limited for consumer products such as sunscreens, although additional studies are needed on potential photooxidation products, experimental methods, and the effect of skin condition on penetration. Carbon nanotubes apparently have greater pulmonary toxicity (inflammation, granuloma) in mice than fine-scale carbon graphite, and their metal content may affect toxicity. Studies on TiO2 and quartz illustrate the complex relationship between toxicity and particle characteristics, including surface coatings, which make generalizations (e.g., smaller particles are always more toxic) incorrect for some substances. These recent toxicity and exposure data, combined with therapeutic and other related literature, are beginning to shape risk assessments that will be used to regulate the use of nanomaterials in consumer products. 相似文献
6.
L T Haber A Maier Q Zhao J S Dollarhide R E Savage M L Dourson 《Toxicological sciences》2001,61(1):32-39
Mechanistic data, when available, have long been considered in risk assessment, such as in the development of the nitrate RfD based on effects in a sensitive group (infants). Recent advances in biology and risk assessment methods have led to a tremendous increase in the use of mechanistic data in risk assessment. Toxicokinetic data can improve extrapolation from animals to humans and characterization of human variability. This is done by the development of improved tissue dosimetry, by the use of uncertainty factors based on chemical-specific data, and in the development of physiologically based pharmacokinetic (PBPK) models. The development of the boron RfD illustrates the use of chemical-specific data in the improved choice of uncertainty factors. The draft cancer guidelines of the U.S. Environmental Protection Agency emphasize the use of mode of action data. The first choice under the guidelines is to use a chemical-specific, biologically based dose-response (BBDR) model. In the absence of a BBDR model, mode of action data are used to determine whether low-dose extrapolation is done using a linear or nonlinear (margin of exposure) approach. Considerations involved in evaluating a hypothesized mode of action are illustrated using 1,3-dichloropropene, and use of a BBDR model is illustrated using formaldehyde. Recent developments in molecular biology, including transgenic animals, microarrays, and the characterization of genetic polymorphisms, have significant potential for improving risk assessments, although further methods development is needed. Overall, use of mechanistic data has significant potential for reducing the uncertainty in assessments, while at the same time highlighting the areas of uncertainty. 相似文献
7.
Matthew W. Himmelstein Peter J. Boogaard Jean Cadet Peter B. Farmer Elizabeth A. Martin 《Critical reviews in toxicology》2013,43(8):679-694
The formation of deoxyribonucleic acid (DNA) adducts can have important and adverse consequences for cellular and whole organism function. Available methods for identification of DNA damage and quantification of adducts are reviewed. Analyses can be performed on various samples including tissues, isolated cells, and intact or hydrolyzed (digested) DNA from a variety of biological samples of interest for monitoring in humans. Sensitivity and specificity are considered key factors for selecting the type of method for assessing DNA perturbation. The amount of DNA needed for analysis is dependent upon the method and ranges widely, from <1 μg to 3?mg. The methods discussed include the Comet assay, the ligation-mediated polymerase reaction, histochemical and immunologic methods, radiolabeled (14C- and 3H-) binding, 32P-postlabeling, and methods dependent on gas chromatography (GC) or high-performance liquid chromatography (HPLC) with detection by electron capture, electrochemical detection, single or tandem mass spectrometry, or accelerator mass spectrometry. Sensitivity is ranked, and ranges from ~1 adduct in 104 to 1012 nucleotides. A brief overview of oxidatively generated DNA damage is also presented. Assay limitations are discussed along with issues that may have impact on the reliability of results, such as sample collection, processing, and storage. Although certain methodologies are mature, improving technology will continue to enhance the specificity and sensitivity of adduct analysis. Because limited guidance and recommendations exist for adduct analysis, this effort supports the HESI Committee goal of developing a framework for use of DNA adduct data in risk assessment. 相似文献
8.
Georgia M Farris Glen K Miller Gordon K Wollenberg Sylvain Molon-Noblot Christine Chan Srinivasa Prahalada 《Toxicological sciences》2007,97(2):548-561
Recombinant rat growth hormone (rrGH) and recombinant mouse growth hormone (rmGH) were developed to evaluate the potential carcinogenicity of each biologically active growth hormone (GH) as assessed in the respective species. Biological activities of rrGH and rmGH were demonstrated by showing an increase in body weight gain and serum levels of insulin-like growth factor-1 (IGF-1) in hypophysectomized rats receiving daily sc injections for 6 days. With the exception of pharmacologically mediated weight gain, rrGH and rmGH had no adverse effects in 5-week oral toxicity studies and no production of anti-recombinant GH antibodies. The high doses selected for the carcinogenicity studies provided systemic exposures of GH up to approximately 10-fold over basal levels. In the 105-week mouse carcinogenicity study, daily sc injections of rmGH at 0.1, 0.2, or 0.5 mg/kg/day were well tolerated and had no effects on survival or incidence of tumors. In the 106-week rat carcinogenicity study, daily sc injections of rrGH at 0.2, 0.4, or 0.8 mg/kg/day had a favorable effect on longevity in female rats administered 0.4 or 0.8 mg/kg/day, an increased weight gain in females and males, and no increase in the incidence of tumors. The absence of carcinogenic effects of recombinant GH administered daily for 2 years to rodents was consistent with publications of clinical experience, indicating a lack of convincing evidence for an increased risk of cancer in children receiving human recombinant GH replacement therapy. 相似文献
9.
Thompson HM 《Ecotoxicology (London, England)》2003,12(1-4):317-330
This paper reviews a wide variety of behavioural effects that have been reported in bees following exposure to pesticides, primarily insecticides. These range from effects on odour discrimination in the individual to the loss of foraging bees due to disruption of their homing behaviour. Some of these effects have the potential to have a significant impact on the development and survival of colonies. However, there is currently little guidance available on the types of behavioural data which should be collected during laboratory, semi-field or field regulatory studies or how they should be included and interpreted in risk assessment. Further work is required to allow risk assessment to include significant behavioural effects and their longer term consequences on colony survival and development. Such an approach will require a larger base set of data to predict the longer-term consequences on colonies of short-term effects on individuals, e.g. through population modelling. 相似文献
10.
Chiu WA Barton HA DeWoskin RS Schlosser P Thompson CM Sonawane B Lipscomb JC Krishnan K 《Journal of applied toxicology : JAT》2007,27(3):218-237
Physiologically based pharmacokinetic (PBPK) models are sophisticated dosimetry models that offer great flexibility in modeling exposure scenarios for which there are limited data. This is particularly of relevance to assessing human exposure to environmental toxicants, which often requires a number of extrapolations across species, route, or dose levels. The continued development of PBPK models ensures that regulatory agencies will increasingly experience the need to evaluate available models for their application in risk assessment. To date, there are few published criteria or well-defined standards for evaluating these models. Herein, important considerations for evaluating such models are described. The evaluation of PBPK models intended for risk assessment applications should include a consideration of: model purpose, model structure, mathematical representation, parameter estimation, computer implementation, predictive capacity and statistical analyses. Model purpose and structure require qualitative checks on the biological plausibility of a model. Mathematical representation, parameter estimation, computer implementation involve an assessment of the coding of the model, as well as the selection and justification of the physical, physicochemical and biochemical parameters chosen to represent a biological organism. Finally, the predictive capacity and sensitivity, variability and uncertainty of the model are analysed so that the applicability of a model for risk assessment can be determined. Published in 2007 by John Wiley & Sons, Ltd. 相似文献
11.
Lavelle KS Robert Schnatter A Travis KZ Swaen GM Pallapies D Money C Priem P Vrijhof H 《Regulatory toxicology and pharmacology : RTP》2012,62(2):302-312
Although regulatory agencies formally encourage the integration of all available data in chemical risk assessment, consistent implementation of this practice has been constrained by the lack of a clear, systematic method for doing so. In this paper, we describe a methodology for evaluating, classifying and integrating human and animal data into the risk assessment process that incorporates: (1) a balanced appraisal of human and animal data, (2) relevance to different stages of the risk assessment process, and (3) accommodation for different data quality requirements. The proposed framework offers a flexible, step-wise approach for determining which set of available data best support the chemical risk assessment that involves the rating and relative ranking of human and animal data quality. The evaluation of human data incorporates seven data quality elements, nature and specificity of the lead effect; evaluation of animal data incorporates data quality and relevance to humans. Results of simulations with selected chemicals previously evaluated in a formal risk assessment generally agreed with existing regulatory guidance. Application of the proposed framework across a wider range of chemical agents will improve transparency of the risk assessment process and validity of results, while informing continuous refinements to this evolving methodology. 相似文献
12.
Moore MM Heflich RH Haber LT Allen BC Shipp AM Kodell RL 《Regulatory toxicology and pharmacology : RTP》2008,51(2):151-161
Under the new U.S. Environmental Protection Agency (EPA) Cancer Risk Assessment Guidelines [U.S. EPA, 2005. Guidelines for Carcinogen Risk Assessment. EPA/630/P-03/001B, March 2005], the quantitative model chosen for cancer risk assessment is based on the mode-of-action (MOA) of the chemical under consideration. In particular, the risk assessment model depends on whether or not the chemical causes tumors through a direct DNA-reactive mechanism. It is assumed that direct DNA-reactive carcinogens initiate carcinogenesis by inducing mutations and have low-dose linear dose-response curves, whereas carcinogens that operate through a nonmutagenic MOA may have nonlinear dose-responses. We are currently evaluating whether the analysis of in vivo gene mutation data can inform the risk assessment process by better defining the MOA for cancer and thus influencing the choice of the low-dose extrapolation model. This assessment includes both a temporal analysis of mutation induction and a dose-response concordance analysis of mutation with tumor incidence. Our analysis of published data on riddelliine in rats and dichloroacetic acid in mice indicates that our approach has merit. We propose an experimental design and graphical analysis that allow for assessing time-to-mutation and dose-response concordance, thereby optimizing the potential for in vivo mutation data to inform the choice of the quantitative model used in cancer risk assessment. 相似文献
13.
James T MacGregor 《Toxicological sciences》2003,73(2):207-208
The biotechnology revolution is impacting all of the biologicalsciences, and toxicology is no exception. Perusal of the abstractsof the Societys recent annual meetings confirms thatour field is already actively using the powerful new tools ofmolecular biology to identify and understand the mechanismsof toxic responses. Thus, the Workshop on Toxicogenomics andRisk Assessment sponsored by the Society and discussed in thisissue by Cunningham et al. was a timely undertaking. This was not the first workshop to focus on the applicationof genomic approaches to risk assessment, but it was uniquein a number of respects. First, it brought together thought 相似文献
14.
Facilitating the use of non‐standard in vivo studies in health risk assessment of chemicals: a proposal to improve evaluation criteria and reporting
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Anna Beronius Linda Molander Christina Rudén Annika Hanberg 《Journal of applied toxicology : JAT》2014,34(6):607-617
To improve data availability in health risk assessment of chemicals and fill information gaps there is a need to facilitate the use of non‐standard toxicity studies, i.e. studies not conducted according to any standardized toxicity test guidelines. The purpose of this work was to propose criteria and guidance for the evaluation of reliability and relevance of non‐standard in vivo studies, which could be used to facilitate systematic and transparent evaluation of such studies for health risk assessment. Another aim was to propose user friendly guidance for reporting of non‐standard studies intended to promote an improvement in reporting of studies that could be of use in risk assessment. Requirements and recommendations for the design and execution of in vivo toxicity studies were identified from The Organisation for Economic Co‐operation and Development (OECD) test guidelines, and served as basis for the data evaluation criteria and reporting guidelines. Feedback was also collected from experts within the field of toxicity testing and risk assessment and used to construct a two‐tiered framework for study evaluation, as well as refine the reporting guidelines. The proposed framework emphasizes the importance of study relevance and an important aspect is to not completely dismiss studies from health risk assessment based on very strict criteria for reliability. The suggested reporting guidelines provide researchers with a tool to fulfill reporting requirements as stated by regulatory agencies. Together, these resources provide an approach to include all relevant data that may fill information gaps and reduce scientific uncertainty in health risk assessment conclusions, and subsequently also in chemical policy decisions. Copyright © 2014 John Wiley & Sons, Ltd. 相似文献
15.
Recent risk assessments for 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and related compounds have focused on adverse effects observed in rodent offspring exposed while in utero during critical gestational periods as among the most sensitive adverse effects attributable to TCDD exposure. In addition, these risk assessments have converged on the use of body concentration (or "body burden") of TCDD as a dose metric superior to administered dose for cross-species comparisons and risk assessments, due to the interspecies differences in elimination kinetics and substantial persistence of these compounds. The detailed, although incomplete, data that are available on maternal-fetal distribution of TCDD and related compounds illustrate differences in distribution among these compounds that impact assessments on a body-burden basis. These data also demonstrate differences in distribution after subchronic or chronic administration compared to acute administration. Some data are now also available addressing inconsistencies that may arise from the use of TCDD toxic equivalency factors (TEFs), which were derived on an administered-dose basis, in evaluating responses to mixtures of dioxins on a body-burden basis in the context of chronic exposure situations. Finally, the use of body burden as a dose metric does not account for or eliminate the substantial differences in sensitivity to dioxin observed across species or between different strains of the same species and, thus, does not eliminate the need to consider the relative sensitivity of humans compared to laboratory animal models in risk assessments. Additional research areas that may increase the foundation for interspecies extrapolations are discussed. 相似文献
16.
The current state of knowledge on the use of the benchmark dose concept in risk assessment 总被引:1,自引:0,他引:1
This review deals with the current state of knowledge on the use of the benchmark dose (BMD) concept in health risk assessment of chemicals. The BMD method is an alternative to the traditional no-observed-adverse-effect level (NOAEL) and has been presented as a methodological improvement in the field of risk assessment. The BMD method has mostly been employed in the USA but is presently given higher attention also in Europe. The review presents a number of arguments in favor of the BMD, relative to the NOAEL. In addition, it gives a detailed overview of the several procedures that have been suggested and applied for BMD analysis, for quantal as well as continuous data. For quantal data the BMD is generally defined as corresponding to an additional or extra risk of 5% or 10%. For continuous endpoints it is suggested that the BMD is defined as corresponding to a percentage change in response relative to background or relative to the dynamic range of response. Under such definitions, a 5% or 10% change can be considered as default. Besides how to define the BMD and its lower bound, the BMDL, the question of how to select the dose-response model to be used in the BMD and BMDL determination is highlighted. Issues of study design and comparison of dose-response curves and BMDs are also covered. 相似文献
17.
Shah Jehan Seema Anjum Khattak Rafiq Ahmad Muhammad Farooq Sardar Khan 《Toxin reviews》2020,39(1):68-77
AbstractThis study aimed to determine the heavy metals (HMs) contaminations in soil of the Hattar industrial estate (HIE), Haripur, Khyber Pakhtunkhwa. For this purpose, various types of soils were collected in HIE and analyzed for the HMs concentrations. The HMs showed highest contamination levels in wastewater irrigated agriculture soil (WWIAS), followed by waste dump site soil (WDSS), and the lowest in range land soil (RLS). Determined HMs concentrations were used for pollution quantification factors, including contamination factors (CFs), pollution load index (PLI), ecological risk factor (ER), and potential health risk assessment, including chronic or non-cancer and cancer risk levels. 相似文献
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Risk assessment of xenobiotics is a qualitative and quantitative assessment of toxic properties conventionally based on data resulting from tests in animals exposed to the substance. The assessment of dose-effect relationship includes evaluation of exposure at the site of action. More recently, emphasis is put on understanding the relationship between exposure at the site of action and the resulting effect, i.e. toxicodynamic. In this respect, results from genotoxicity studies may be a measure for exposure and at the same time of an effect. Results of toxicodynamic endpoints such as binding to receptors or release of hormones have been used when replacing default values for interspecies extrapolation. It may also be envisaged to use toxicodynamic endpoints in order to get an estimate of intraspecies variability. It was demonstrated that this approach may be helpful only if the relationship between the toxicodynamic endpoint and the definite endpoint is known by using the example of bisphenol A. Whereas there are clear effects of bisphenol A in in vitro and ex vivo studies, the classical two generation study has not been able to detect an effect on reproduction and/or fertility. Looking in the future development of toxicodynamic endpoints, gene profiling and the analysis of proteins (‘proteomics’) may be helpful tools employed in screening and being related to the mode of action are explored for their suitability in terms of toxicodynamic endpoints. 相似文献
20.
Regulatory demands on data quality for the environmental risk assessment of pharmaceuticals 总被引:2,自引:0,他引:2
A. Küster J. Bachmann U. Brandt I. Ebert S. Hickmann J. Klein-Goedicke G. Maack S. Schmitz E. Thumm B. Rechenberg 《Regulatory toxicology and pharmacology : RTP》2009,55(3):276-280
The evaluation of the quality of data and their use within the review of environmental risk assessment of human as well as veterinary pharmaceuticals is described from a regulatory point of view. A definition and differentiation in three categories for the reliability of data are given. Existing criteria relating to international testing standards for categorising reliability are adopted for their use within the environmental risk assessment of pharmaceuticals. A systematic documentation of evaluating reliability for literature data as well as for experimental studies (effect and environmental fate studies) is proposed. The data quality criteria are defined in order to increase the transparency of the evaluation process in Germany and thus the quality of the environmental risk assessment of pharmaceuticals. 相似文献