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1.
Front Plant Sci ; 9: 1025, 2018.
Article in English | MEDLINE | ID: mdl-30083174

ABSTRACT

Soybean (Glycine max) is an important food stock, and also considered an allergenic food with at least eight well characterized allergens. However, it is a less prevalent allergen source than many other foods and is rarely life-threatening. Soybean is incorporated into commonly consumed foods, and therefore, the allergens pose a potential concern for individuals already sensitized. The protein profile of soybean can be affected by several factors including genetic and environmental. To investigate how soybean allergen content may be affected by genetics and/or environment, nine soy allergens were quantified from three commercial soybean varieties grown at nine locations in three states within a single climate zone in North America; Iowa, Illinois, and Indiana, United States. Quantitation was achieved using liquid chromatography-selected reaction monitoring (LC-SRM) tandem mass spectrometry with AQUA peptide standards specific to the nine target allergens. Quantitation of allergen concentration indicated that both genetics and location affected specific allergen content. Seven of the nine allergens were significantly influenced by genetics, with the exceptions of glycinin G4 and KTI 3. The allergens P34, Gly m Bd 28k, glycinin G3, and KTI 1 showed statistically significant impact from location as well, but at a lower threshold of significance compared with genetics (cultivar/variety). This dataset contributes to our understanding of the natural variation of endogenous allergens, as it represents a sampling of soybeans grown in a controlled, distributed plot design under agronomic conditions common for commercial soybean food and feed production. The aim was to build upon our recent understanding of how allergens are expressed as part of the overall soybean proteome.

2.
Biosci Biotechnol Biochem ; 80(11): 2198-2207, 2016 Nov.
Article in English | MEDLINE | ID: mdl-27399872

ABSTRACT

In rice, several allergens have been identified such as the non-specific lipid transfer protein-1, the α-amylase/trypsin-inhibitors, the α-globulin, the 33 kDa glyoxalase I (Gly I), the 52-63 kDa globulin, and the granule-bound starch synthetase. The goal of the present study was to define optimal rice extraction and detection methods that would allow a sensitive and reproducible measure of several classes of known rice allergens. In a three-laboratory ring-trial experiment, several protein extraction methods were first compared and analyzed by 1D multiplexed SDS-PAGE. In a second phase, an inter-laboratory validation of 2D-DIGE analysis was conducted in five independent laboratories, focusing on three rice allergens (52 kDa globulin, 33 kDa glyoxalase I, and 14-16 kDa α-amylase/trypsin inhibitor family members). The results of the present study indicate that a combination of 1D multiplexed SDS-PAGE and 2D-DIGE methods would be recommended to quantify the various rice allergens.

3.
Regul Toxicol Pharmacol ; 79: 149-155, 2016 Aug.
Article in English | MEDLINE | ID: mdl-27105772

ABSTRACT

Genetically modified (GM) crops have achieved success in the marketplace and their benefits extend beyond the overall increase in harvest yields to include lowered use of insecticides and decreased carbon dioxide emissions. The most widely grown GM crops contain gene/s for targeted insect protection, herbicide tolerance, or both. Plant expression of Bacillus thuringiensis (Bt) crystal (Cry) insecticidal proteins have been the primary way to impart insect resistance in GM crops. Although deemed safe by regulatory agencies globally, previous studies have been the basis for discussions around the potential immuno-adjuvant effects of Cry proteins. These studies had limitations in study design. The studies used animal models with extremely high doses of Cry proteins, which when given using the ig route were co-administered with an adjuvant. Although the presumption exists that Cry proteins may have immunostimulatory activity and therefore an adjuvanticity risk, the evidence shows that Cry proteins are expressed at very low levels in GM crops and are unlikely to function as adjuvants. This conclusion is based on critical review of the published literature on the effects of immunomodulation by Cry proteins, the history of safe use of Cry proteins in foods, safety of the Bt donor organisms, and pre-market weight-of-evidence-based safety assessments for GM crops.


Subject(s)
Bacterial Proteins/genetics , Consumer Product Safety , Crops, Agricultural/genetics , Endotoxins/genetics , Food Safety , Hemolysin Proteins/genetics , Insecta/growth & development , Pest Control, Biological/methods , Plants, Genetically Modified/genetics , Animals , Bacillus thuringiensis Toxins , Bacterial Proteins/immunology , Bacterial Proteins/metabolism , Crops, Agricultural/immunology , Crops, Agricultural/metabolism , Crops, Agricultural/parasitology , Endotoxins/immunology , Endotoxins/metabolism , Gene Expression Regulation, Plant , Genotype , Hemolysin Proteins/immunology , Hemolysin Proteins/metabolism , Host-Parasite Interactions , Humans , Insecta/metabolism , Phenotype , Plants, Genetically Modified/immunology , Plants, Genetically Modified/metabolism , Plants, Genetically Modified/parasitology , Risk Assessment
4.
Crit Rev Toxicol ; 46(1): 54-73, 2016.
Article in English | MEDLINE | ID: mdl-26517449

ABSTRACT

The HESI-coordinated RISK21 roadmap and matrix are tools that provide a transparent method to compare exposure and toxicity information and assess whether additional refinement is required to obtain the necessary precision level for a decision regarding safety. A case study of the use of a pyrethroid, "pseudomethrin," in bed netting to control malaria is presented to demonstrate the application of the roadmap and matrix. The evaluation began with a problem formulation step. The first assessment utilized existing information pertaining to the use and the class of chemistry. At each stage of the step-wise approach, the precision of the toxicity and exposure estimates were refined as necessary by obtaining key data which enabled a decision on safety to be made efficiently and with confidence. The evaluation demonstrated the concept of using existing information within the RISK21 matrix to drive the generation of additional data using a value-of-information approach. The use of the matrix highlighted whether exposure or toxicity required further investigation and emphasized the need to address the default uncertainty factor of 100 at the highest tier of the evaluation. It also showed how new methodology such as the use of in vitro studies and assays could be used to answer the specific questions which arise through the use of the matrix. The matrix also serves as a useful means to communicate progress to stakeholders during an assessment of chemical use.


Subject(s)
Environmental Exposure/adverse effects , Insecticide-Treated Bednets/adverse effects , Pyrethrins/toxicity , Animals , Decision Making , Environmental Exposure/analysis , Humans , Models, Animal , Risk Assessment , Toxicity Tests , United States , United States Environmental Protection Agency
5.
Transgenic Res ; 24(4): 587-603, 2015 Aug.
Article in English | MEDLINE | ID: mdl-25716164

ABSTRACT

In January 2014, an international meeting sponsored by the International Life Sciences Institute/Health and Environmental Sciences Institute and the Canadian Food Inspection Agency titled "Genetic Basis of Unintended Effects in Modified Plants" was held in Ottawa, Canada, bringing together over 75 scientists from academia, government, and the agro-biotech industry. The objectives of the meeting were to explore current knowledge and identify areas requiring further study on unintended effects in plants and to discuss how this information can inform and improve genetically modified (GM) crop risk assessments. The meeting featured presentations on the molecular basis of plant genome variability in general, unintended changes at the molecular and phenotypic levels, and the development and use of hypothesis-driven evaluations of unintended effects in assessing conventional and GM crops. The development and role of emerging "omics" technologies in the assessment of unintended effects was also discussed. Several themes recurred in a number of talks; for example, a common observation was that no system for genetic modification, including conventional methods of plant breeding, is without unintended effects. Another common observation was that "unintended" does not necessarily mean "harmful". This paper summarizes key points from the information presented at the meeting to provide readers with current viewpoints on these topics.


Subject(s)
Crops, Agricultural/genetics , Food, Genetically Modified , Plants, Genetically Modified/genetics , Consumer Product Safety , Humans , Risk Assessment
6.
Toxicol Sci ; 143(2): 256-67, 2015 Feb.
Article in English | MEDLINE | ID: mdl-25628403

ABSTRACT

FutureTox II, a Society of Toxicology Contemporary Concepts in Toxicology workshop, was held in January, 2014. The meeting goals were to review and discuss the state of the science in toxicology in the context of implementing the NRC 21st century vision of predicting in vivo responses from in vitro and in silico data, and to define the goals for the future. Presentations and discussions were held on priority concerns such as predicting and modeling of metabolism, cell growth and differentiation, effects on sensitive subpopulations, and integrating data into risk assessment. Emerging trends in technologies such as stem cell-derived human cells, 3D organotypic culture models, mathematical modeling of cellular processes and morphogenesis, adverse outcome pathway development, and high-content imaging of in vivo systems were discussed. Although advances in moving towards an in vitro/in silico based risk assessment paradigm were apparent, knowledge gaps in these areas and limitations of technologies were identified. Specific recommendations were made for future directions and research needs in the areas of hepatotoxicity, cancer prediction, developmental toxicity, and regulatory toxicology.


Subject(s)
Computer Simulation , In Vitro Techniques , Toxicology/methods , Toxicology/trends , Congresses as Topic , Predictive Value of Tests , Societies, Scientific , United States
7.
Crit Rev Toxicol ; 44 Suppl 3: 1-5, 2014 Aug.
Article in English | MEDLINE | ID: mdl-25070413

ABSTRACT

The Health and Environmental Sciences Institute (HESI)-coordinated Risk Assessment in the 21st Century (RISK21) project was initiated to develop a scientific, transparent, and efficient approach to the evolving world of human health risk assessment, and involved over 120 participants from 12 countries, 15 government institutions, 20 universities, 2 non-governmental organizations, and 12 corporations. This paper provides a brief overview of the tiered RISK21 framework called the roadmap and risk visualization matrix, and articulates the core principles derived by RISK21 participants that guided its development. Subsequent papers describe the roadmap and matrix in greater detail. RISK21 principles include focusing on problem formulation, utilizing existing information, starting with exposure assessment (rather than toxicity), and using a tiered process for data development. Bringing estimates of exposure and toxicity together on a two-dimensional matrix provides a clear rendition of human safety and risk. The value of the roadmap is its capacity to chronicle the stepwise acquisition of scientific information and display it in a clear and concise fashion. Furthermore, the tiered approach and transparent display of information will contribute to greater efficiencies by calling for data only as needed (enough precision to make a decision), thus conserving animals and other resources.


Subject(s)
Environmental Exposure , Health Status , Public Health , Risk Assessment/methods , Decision Making , Environmental Exposure/adverse effects , Environmental Exposure/prevention & control , Humans , National Academy of Sciences, U.S. , Public Health/methods , Public Health/trends , Safety , United Kingdom , United States
8.
Crit Rev Toxicol ; 44 Suppl 3: 6-16, 2014 Aug.
Article in English | MEDLINE | ID: mdl-25070414

ABSTRACT

Abstract The RISK21 integrated evaluation strategy is a problem formulation-based exposure-driven risk assessment roadmap that takes advantage of existing information to graphically represent the intersection of exposure and toxicity data on a highly visual matrix. This paper describes in detail the process for using the roadmap and matrix. The purpose of this methodology is to optimize the use of prior information and testing resources (animals, time, facilities, and personnel) to efficiently and transparently reach a risk and/or safety determination. Based on the particular problem, exposure and toxicity data should have sufficient precision to make such a decision. Estimates of exposure and toxicity, bounded by variability and/or uncertainty, are plotted on the X- and Y-axes of the RISK21 matrix, respectively. The resulting intersection is a highly visual representation of estimated risk. Decisions can then be made to increase precision in the exposure or toxicity estimates or declare that the available information is sufficient. RISK21 represents a step forward in the goal to introduce new methodologies into 21st century risk assessment. Indeed, because of its transparent and visual process, RISK21 has the potential to widen the scope of risk communication beyond those with technical expertise.


Subject(s)
Environmental Exposure , Hazardous Substances/toxicity , Risk Assessment/methods , Decision Making , Environmental Exposure/adverse effects , Environmental Exposure/prevention & control , Hazardous Substances/chemistry , Humans , Models, Theoretical , Probability , Quantitative Structure-Activity Relationship , Safety , United Kingdom , United States , United States Environmental Protection Agency
9.
Crit Rev Toxicol ; 44 Suppl 3: 17-43, 2014 Aug.
Article in English | MEDLINE | ID: mdl-25070415

ABSTRACT

The HESI RISK21 project formed the Dose-Response/Mode-of-Action Subteam to develop strategies for using all available data (in vitro, in vivo, and in silico) to advance the next-generation of chemical risk assessments. A goal of the Subteam is to enhance the existing Mode of Action/Human Relevance Framework and Key Events/Dose Response Framework (KEDRF) to make the best use of quantitative dose-response and timing information for Key Events (KEs). The resulting Quantitative Key Events/Dose-Response Framework (Q-KEDRF) provides a structured quantitative approach for systematic examination of the dose-response and timing of KEs resulting from a dose of a bioactive agent that causes a potential adverse outcome. Two concepts are described as aids to increasing the understanding of mode of action-Associative Events and Modulating Factors. These concepts are illustrated in two case studies; 1) cholinesterase inhibition by the pesticide chlorpyrifos, which illustrates the necessity of considering quantitative dose-response information when assessing the effect of a Modulating Factor, that is, enzyme polymorphisms in humans, and 2) estrogen-induced uterotrophic responses in rodents, which demonstrate how quantitative dose-response modeling for KE, the understanding of temporal relationships between KEs and a counterfactual examination of hypothesized KEs can determine whether they are Associative Events or true KEs.


Subject(s)
Carcinogens/toxicity , Models, Theoretical , Risk Assessment/methods , Toxicology/methods , Animals , Carcinogens/chemistry , Carcinogens/metabolism , Dose-Response Relationship, Drug , Humans , Species Specificity , United States , United States Environmental Protection Agency
10.
Clin Transl Allergy ; 4(1): 10, 2014 Apr 15.
Article in English | MEDLINE | ID: mdl-24735755

ABSTRACT

The scope of allergy risk is diverse considering the myriad ways in which protein allergenicity is affected by physiochemical characteristics of proteins. The complexity created by the matrices of foods and the variability of the human immune system add additional challenges to understanding the relationship between sensitization potential and allergy disease. To address these and other issues, an April 2012 international symposium was held in Prague, Czech Republic, to review and discuss the state-of-the-science of sensitizing properties of protein allergens. The symposium, organized by the Protein Allergenicity Technical Committee of the International Life Sciences Institute's Health and Environmental Sciences Institute, featured presentations on current methods, test systems, research trends, and unanswered questions in the field of protein sensitization. A diverse group of over 70 interdisciplinary scientists from academia, government, and industry participated in the symposium. Experts provided overviews on known mechanisms by which proteins in food may cause sensitization, discussed experimental models to predict protein sensitizing potential, and explored whether such experimental techniques may be applicable in regulatory settings. Three accompanying reviews address critical factors and methods for assessing allergic sensitization: 1) food-and protein-related factors; 2) host-specific factors and 3) screening methods, i.e., the ability of experimental models to predict the sensitizing potential of proteins and whether such models are applicable within regulatory settings.

11.
Toxicol Sci ; 126(2): 291-7, 2012 Apr.
Article in English | MEDLINE | ID: mdl-22262567

ABSTRACT

The practice of toxicology is changing rapidly, as demonstrated by the response to the 2007 NRC report on "Toxicity Testing in the 21(st) Century." New assays are being developed to replace animal testing; yet the use of data from these assays in decision making is not clear. A Health and Environmental Sciences Institute committee held a May 2011 workshop to discuss approaches to identifying adverse effects in the context of the NRC report. Scientists from industry, government, academia, and NGOs discussed two case studies and explored how information from new, high data content assays developed for screening can be used to differentiate adverse effects from adaptive responses. The terms "adverse effect" and "adaptive response" were defined, as well as two new terms, the relevant pathways of toxicological concern (RPTCs) and relevant responses for regulation (RRRs). RPTCs are biochemical pathways associated with adverse events and need to be elucidated before they are used in regulatory decision making. RRRs are endpoints that are the basis for risk assessment and may or may not be at the level of pathways. Workshop participants discussed the criteria for determining whether, at the RPTC level, an effect is potentially adverse or potentially indicative of adaptability, and how the use of prototypical, data-rich compounds could lead to a greater understanding of RPTCs and their use as RRRs. Also discussed was the use of RPTCs in a weight-of-evidence approach to risk assessment. Inclusion of data at this level could decrease uncertainty in risk assessments but will require the use of detailed dosimetry and consideration of exposure context and the time and dose continuum to yield scientifically based decisions. The results of this project point to the need for an extensive effort to characterize RPTCs and their use in risk assessment to make the vision of the 2007 NRC report a reality.


Subject(s)
Toxicology , History, 21st Century , Risk Assessment , Toxicity Tests
12.
Crit Rev Toxicol ; 41(6): 507-44, 2011 Jul.
Article in English | MEDLINE | ID: mdl-21591905

ABSTRACT

Quantitative methods for estimation of cancer risk have been developed for daily, lifetime human exposures. There are a variety of studies or methodologies available to address less-than-lifetime exposures. However, a common framework for evaluating risk from less-than-lifetime exposures (including short-term and/or intermittent exposures) does not exist, which could result in inconsistencies in risk assessment practice. To address this risk assessment need, a committee of the International Life Sciences Institute (ILSI) Health and Environmental Sciences Institute conducted a multisector workshop in late 2009 to discuss available literature, different methodologies, and a proposed framework. The proposed framework provides a decision tree and guidance for cancer risk assessments for less-than-lifetime exposures based on current knowledge of mode of action and dose-response. Available data from rodent studies and epidemiological studies involving less-than-lifetime exposures are considered, in addition to statistical approaches described in the literature for evaluating the impact of changing the dose rate and exposure duration for exposure to carcinogens. The decision tree also provides for scenarios in which an assumption of potential carcinogenicity is appropriate (e.g., based on structural alerts or genotoxicity data), but bioassay or other data are lacking from which a chemical-specific cancer potency can be determined. This paper presents an overview of the rationale for the workshop, reviews historical background, describes the proposed framework for assessing less-than-lifetime exposures to potential human carcinogens, and suggests next steps.


Subject(s)
Carcinogens/toxicity , Environmental Exposure/standards , Mutagens/toxicity , Biological Assay/methods , Carcinogens/administration & dosage , Databases, Factual , Decision Trees , Dose-Response Relationship, Drug , Endpoint Determination , Food Contamination/analysis , Guidelines as Topic , Household Products/adverse effects , Humans , Mutagens/administration & dosage , National Institute of Environmental Health Sciences (U.S.) , Neoplasms/chemically induced , Pesticides/adverse effects , Risk Assessment , Time Factors , United States , United States Environmental Protection Agency , United States Food and Drug Administration
13.
Crit Rev Toxicol ; 40(10): 893-911, 2010 Nov.
Article in English | MEDLINE | ID: mdl-20854192

ABSTRACT

The public health and environmental communities will face many challenges during the next decade. To identify significant issues that might be addressed as part of the International Life Sciences Institute (ILSI) Health and Environmental Sciences Institute (HESI) scientific portfolio, an expert group of key government, academic, and industry scientists from around the world were assembled in 2009 to map the current and future landscape of scientific and regulatory challenges. The value of the scientific mapping exercise was the development of a tool which HESI, individual companies, research institutions, government agencies, and regulatory authorities can use to anticipate key challenges, place them into context, and thus strategically refine and expand scientific project portfolios into the future.


Subject(s)
Environmental Health/legislation & jurisprudence , Health Planning Guidelines , Health Priorities/trends , Public Health/trends , Toxicology/trends , Academies and Institutes , Government , Humans , Industry , Risk Assessment/trends
14.
Regul Toxicol Pharmacol ; 58(3 Suppl): S2-7, 2010 Dec.
Article in English | MEDLINE | ID: mdl-20615445

ABSTRACT

The International Life Sciences Institute Health and Environmental Sciences Institute Protein Allergenicity Technical Committee hosted an international workshop November 16-17, 2009, in Paris, France, with over 60 participants from academia, government, and industry to review and discuss the potential utility of "-omics" technologies for assessing the variability in plant gene, protein, and metabolite expression. The goal of the workshop was to illustrate how a plant's constituent makeup and phenotypic processes can be surveyed analytically. Presentations on the "-omics" techniques (i.e., genomics, proteomics, and metabolomics) highlighted the workshop, and summaries of these presentations are published separately in this supplemental issue. This paper summarizes key messages, as well as the consensus points reached, in a roundtable discussion on eight specific questions posed during the final session of the workshop. The workshop established some common, though not unique, challenges for all "-omics" techniques, and include (a) standardization of separation/extraction and analytical techniques; (b) difficulty in associating environmental impacts (e.g., planting, soil texture, location, climate, stress) with potential alterations in plants at genomic, proteomic, and metabolomic levels; (c) many independent analytical measurements, but few replicates/subjects--poorly defined accuracy and precision; and (d) bias--a lack of hypothesis-driven science. Information on natural plant variation is critical in establishing the utility of new technologies due to the variability in specific analytes that may result from genetic differences (crop genotype), different crop management practices (conventional high input, low input, organic), interaction between genotype and environment, and the use of different breeding methods. For example, variations of several classes of proteins were reported among different soybean, rice, or wheat varieties or varieties grown at different locations. Data on the variability of allergenic proteins are important in defining the risk of potential allergenicity. Once established as a standardized assay, survey approaches such as the "-omics" techniques can be considered in a hypothesis-driven analysis of plants, such as determining unintended effects in genetically modified (GM) crops. However, the analysis should include both the GM and control varieties that have the same breeding history and exposure to the same environmental conditions. Importantly, the biological relevance and safety significance of changes in "-omic" data are still unknown. Furthermore, the current compositional assessment for evaluating the substantial equivalence of GM crops is robust, comprehensive, and a good tool for food safety assessments. The overall consensus of the workshop participants was that many "-omics" techniques are extremely useful in the discovery and research phases of biotechnology, and are valuable for hypothesis generation. However, there are many methodological shortcomings identified with "-omics" approaches, a paucity of reference materials, and a lack of focused strategy for their use that currently make them not conducive for the safety assessment of GM crops.


Subject(s)
Biotechnology/methods , Crops, Agricultural/chemistry , Plants, Genetically Modified/chemistry , Animals , Crops, Agricultural/genetics , Genes, Plant , Genetic Variation , Genomics/methods , Humans , Metabolomics/methods , Plants, Genetically Modified/genetics , Proteomics/methods , Research Design
15.
Toxicol Sci ; 113(1): 4-26, 2010 Jan.
Article in English | MEDLINE | ID: mdl-19770482

ABSTRACT

Assessing the risk profiles of potentially sensitive populations requires a "tool chest" of methodological approaches to adequately characterize and evaluate these populations. At present, there is an extensive body of literature on methodologies that apply to the evaluation of the pediatric population. The Health and Environmental Sciences Institute Subcommittee on Risk Assessment of Sensitive Populations evaluated key references in the area of pediatric risk to identify a spectrum of methodological approaches. These approaches are considered in this article for their potential to be extrapolated for the identification and assessment of other sensitive populations. Recommendations as to future research needs and/or alternate methodological considerations are also made.


Subject(s)
Models, Biological , Public Health/methods , Toxicity Tests/methods , Adolescent , Adult , Age Factors , Biomarkers/metabolism , Child , Child, Preschool , Dose-Response Relationship, Drug , Environmental Exposure , Environmental Monitoring , Genetic Predisposition to Disease , Government Regulation , Health Policy , Humans , Infant , Infant, Newborn , Pharmacokinetics , Public Health/legislation & jurisprudence , Risk Assessment , Risk Factors
16.
Toxicol Pathol ; 37(6): 714-32, 2009 Oct.
Article in English | MEDLINE | ID: mdl-19700658

ABSTRACT

The two-year cancer bioassay in rodents remains the primary testing strategy for in-life screening of compounds that might pose a potential cancer hazard. Yet experimental evidence shows that cancer is often secondary to a biological precursor effect, the mode of action is sometimes not relevant to humans, and key events leading to cancer in rodents from nongenotoxic agents usually occur well before tumorigenesis and at the same or lower doses than those producing tumors. The International Life Sciences Institute (ILSI) Health and Environmental Sciences Institute (HESI) hypothesized that the signals of importance for human cancer hazard identification can be detected in shorter-term studies. Using the National Toxicology Program (NTP) database, a retrospective analysis was conducted on sixteen chemicals with liver, lung, or kidney tumors in two-year rodent cancer bioassays, and for which short-term data were also available. For nongenotoxic compounds, results showed that cellular changes indicative of a tumorigenic endpoint can be identified for many, but not all, of the chemicals producing tumors in two-year studies after thirteen weeks utilizing conventional endpoints. Additional endpoints are needed to identify some signals not detected with routine evaluation. This effort defined critical questions that should be explored to improve the predictivity of human carcinogenic risk.


Subject(s)
Carcinogenicity Tests/methods , Carcinogens/toxicity , Databases, Factual , Neoplasms, Experimental/chemically induced , Animals , Female , Humans , Immune System Phenomena/drug effects , Male , Mice , Neoplasms, Experimental/immunology , Neoplasms, Experimental/pathology , Neoplasms, Experimental/prevention & control , Rats , Rats, Inbred F344 , Risk Assessment/methods
17.
Toxicol Sci ; 111(1): 4-18, 2009 Sep.
Article in English | MEDLINE | ID: mdl-19525443

ABSTRACT

Although rarely occurring in humans, hemangiosarcomas (HS) have become important in evaluating the potential human risk of several chemicals, including industrial, agricultural, and pharmaceutical agents. Spontaneous HS arise frequently in mice, less commonly in rats, and frequently in numerous breeds of dogs. This review explores knowledge gaps and uncertainties related to the mode of action (MOA) for the induction of HS in rodents, and evaluates the potential relevance for human risk. For genotoxic chemicals (vinyl chloride and thorotrast), significant information is available concerning the MOA. In contrast, numerous chemicals produce HS in rodents by nongenotoxic, proliferative mechanisms. An overall framework is presented, including direct and indirect actions on endothelial cells, paracrine effects in local tissues, activation of bone marrow endothelial precursor cells, and tissue hypoxia. Numerous obstacles are identified in investigations into the MOA for mouse HS and the relevance of the mouse tumors to humans, including lack of identifiable precursor lesions, usually late occurrence of the tumors, and complexities of endothelial biology. This review proposes a working MOA for HS induced by nongenotoxic compounds that can guide future research in this area. Importantly, a common MOA appears to exist for the nongenotoxic induction of HS, where there appears to be a convergence of multiple initiating events (e.g., hemolysis, decreased respiration, adipocyte growth) leading to either dysregulated angiogenesis and/or erythropoiesis that results from hypoxia and macrophage activation. These later events lead to the release of angiogenic growth factors and cytokines that stimulate endothelial cell proliferation, which, if sustained, provide the milieu that can lead to HS formation.


Subject(s)
Hemangiosarcoma/pathology , Animals , Carcinogens/toxicity , DNA/drug effects , Dogs , Hemangiosarcoma/chemically induced , Hemangiosarcoma/epidemiology , Humans , Mice , Neovascularization, Pathologic/pathology , Neovascularization, Physiologic/physiology , Peroxisome Proliferator-Activated Receptors/agonists , Rats , Risk Assessment , Species Specificity , Vinyl Chloride/toxicity
18.
Crit Rev Toxicol ; 38(10): 817-45, 2008.
Article in English | MEDLINE | ID: mdl-18853291

ABSTRACT

To predict important strategic issues in product safety during the next 10 years, the Health and Environmental Sciences Institute (HESI) of the International Life Sciences Institute initiated a mapping exercise to evaluate which issues are likely to be of societal, scientific, and regulatory importance to regulatory authorities, the HESI membership, and the scientific community at large. Scientists representing government, academia, and industry participated in the exercise. Societal issues identified include sensitive populations, alternative therapies, public education on the precautionary principle, obesity, and aging world populations. Scientific issues identified include cancer testing, children's health, mixtures and co-exposures, sensitive populations, idiosyncratic reactions, "omics" or bioinformatics, and environmental toxicology. Regulatory issues identified include national and regional legislation on chemical safety, exposure inputs, new technologies, transitioning new science into regulations and guidelines, conservative default factors, data quality, and sensitive populations. Because some issues were identified as important in all three areas (e.g. sensitive populations), a comprehensive approach to assessment and management is needed to ensure consideration of societal, scientific, and regulatory implications. The resulting HESI Combined Challenges Map is not intended to offer a universal description of challenges in safety assessment, nor is it intended to address, advocate, or manage the prioritized issues. Rather, the map focuses on and predicts issues likely to be central to the strategic agendas of individual companies and regulatory authorities in the developed world. Many of these issues will become increasingly important in the future in rapidly developing economies, such as India and China. The scientific mapping exercise has particular value to the toxicology community because it represents the contributions of key scientists from around the world from government, academia, and industry.


Subject(s)
Ecology/methods , Environmental Health/methods , Environmental Monitoring , Public Health/trends , Risk Assessment/methods , Ecology/legislation & jurisprudence , Ecology/trends , Environmental Exposure/prevention & control , Environmental Health/legislation & jurisprudence , Environmental Health/trends , Humans , Risk Assessment/legislation & jurisprudence , Risk Assessment/trends
19.
Int J Hyg Environ Health ; 210(3-4): 247-51, 2007 May.
Article in English | MEDLINE | ID: mdl-17321214

ABSTRACT

The International Life Sciences Institute (ILSI) Health and Environmental Sciences Institute (HESI) established a Biomonitoring Technical Committee in 2002 to define and characterize appropriate scientific use(s) of biomonitoring tools and/or biomonitoring data needed to characterize exposure to chemicals, and to explore mechanisms for integrating biomonitoring exposure data and toxicology data into a robust risk assessment process. This paper summarizes the Technical Committee's initiatives and perspectives on improving the quality, value, application, and interpretation of human biomonitoring data for exposure and risk assessment purposes. Scientific outreach, collaborative partners, and new projects are described.


Subject(s)
Biomarkers/analysis , Environmental Monitoring/methods , Consensus Development Conferences as Topic , Environmental Monitoring/standards , Global Health , Humans , Internationality , Quality Control , Risk Assessment/methods
20.
Environ Health Perspect ; 114(11): 1755-62, 2006 Nov.
Article in English | MEDLINE | ID: mdl-17107864

ABSTRACT

Biomonitoring uses analytic methods that permit the accurate measurement of low levels of environmental chemicals in human tissues. However, depending on the intended use, biomonitoring, like all exposure tools, may not be a stand-alone exposure assessment tool for some of its environmental public health uses. Although biomonitoring data demonstrate that many environmental chemicals are absorbed in human tissues, uncertainty exists regarding if and at what concentrations many of these chemicals cause adverse health outcomes. Moreover, without exposure pathway information, it is difficult to relate biomonitoring results to sources and routes of exposure and develop effective health risk management strategies. In September 2004, the Health and Environmental Sciences Institute, U.S. Environmental Protection Agency, Centers for Disease Control and Prevention, Agency for Toxic Substances and Disease Registry, and International Council of Chemical Associations co-sponsored the International Biomonitoring Workshop, which explored the processes and information needed for placing biomonitoring data into perspective for risk assessment purposes, with special emphasis on integrating biomarker measurements of exposure, internal dose, and potential health outcome. Scientists from international governments, academia, and industry recommended criteria for applying biomonitoring data for various uses. Six case studies, which are part of this mini-monograph, were examined: inorganic arsenic, methyl eugenol, organophosphorus pesticides, perfluorooctanesulfonate, phthalates, and polybrominated diphenyl ethers. Based on the workshop and follow-up discussions, this overview article summarizes lessons learned, identifies data gaps, outlines research needs, and offers guidance for designing and conducting biomonitoring studies, as well as interpreting biomonitoring data in the context of risk assessment and risk management.


Subject(s)
Environmental Monitoring , Environmental Pollutants/toxicity , Environmental Exposure/adverse effects , Environmental Exposure/analysis , Environmental Pollutants/analysis , Epidemiologic Studies , Humans , Risk Assessment
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