Data For Risk Assessment Purposes Research Articles

Genotoxicity assessment of titanium dioxide nanoparticles using a standard battery of in vivo assays

As one representative of nanometal oxides, titanium dioxide nanoparticles (TiO2-NPs) have been widely used, particularly in the food industry. The genotoxicity of TiO2-NPs has attracted great attention over the years. This study was undertaken to investigate the chromosome and DNA damage effects of TiO2-NPs (0, 50, 150, and 500 mg/kg BW) using rodent models. After a comprehensive characterization, we conducted a standard battery of in vivo genotoxicity tests, including the chromosomal aberration test (CA), micronucleus (MN) test, and the comet test. The results of all these tests were negative. There were no structural or numerical chromosomal abnormalities in mice bone marrow cells, no increase in the frequency of micronucleated polychromatic erythrocytes in mice bone marrow cells, and no elevation in % tail DNA in rat hepatocytes. This indicated that TiO2-NPs did not cause chromosomal damage or have a direct impact on DNA. These findings suggested that TiO2-NPs did not exhibit genotoxicity and provided valuable data for risk assessment purposes.

Textual data transformations using natural language processing for risk assessment.

Underlying information about failure, including observations made in free text, can be a good source for understanding, analyzing, and extracting meaningful information for determining causation. The unstructured nature of natural language expression demands advanced methodology to identify its underlying features. There is no available solution to utilize unstructured data for risk assessment purposes. Due to the scarcity of relevant data, textual data can be a vital learning source for developing a risk assessment methodology. This work addresses the knowledge gap in extracting relevant features from textual data to develop cause-effect scenarios with minimal manual interpretation. This study applies natural language processing and text-mining techniques to extract features from past accident reports. The extracted features are transformed into parametric form with the help of fuzzy set theory and utilized in Bayesian networks as prior probabilities for risk assessment. An application of the proposed methodology is shown in microbiologically influenced corrosion-related incident reports available from the Pipeline and Hazardous Material Safety Administration database. In addition, the trained named entity recognition (NER) model is verified on eight incidents, showing a promising preliminary result for identifying all relevant features from textual data and demonstrating the robustness and applicability of the NER method. The proposed methodology can be used in domain-specific risk assessment to analyze, predict, and prevent future mishaps, ameliorating overall process safety.

Examination of Seafood Intake Using Online 24hr Recall Tool for Use in Risk Assessment Analysis

AbstractIntroductionHealthy eating recommendations advise eating two portions of fish per week. Although seafood consumption has doubled globally over the last 50 years there is currently very little data on seafood consumption in Ireland. It is important to know what is being consumed by a population for nutritional and food safety purposes. The aim of this study is to collect reported dietary intake data from Irish seafood consumers, using an online dietary intake assessment tool, to determine habitual intakes of seafood for use in risk assessment.Materials and MethodsFoodbook24 is a self-administered, online 24hr recall tool developed for the purpose of nutritional surveillance in Ireland. For the purpose of this study it was further developed to include a detailed list of seafood regularly consumed in Ireland. Foods were selected using established food databases (Langual, FoodEx2 and BIM Seafood Handbook). Food composition was determined using McCance and Widdowson (7th Ed.) and portion sizes were based on NANS, published portion size books and recipes. Participants will be recruited using commonly used approaches; radio adverts & face-to-face recruitment. Seafood consumers (n = 1000), balanced for gender, age and urban/rural location, will be targeted. Participants will complete 2×24hr recalls, over 2 weeks, and complete an accompanying food frequency questionnaire. Demographic and lifestyle data will also be collected.ResultsIn the development of the tool, a total of 246 foods were added to Foodbook24, including 38 species of fish, with approximately 2–25 fish dishes for each fish. The composition of 156 foods were a direct match to McCance and Widdowson, 36 were similar and 24 used a combination of foods. For fish meals and recipes, 17 meals had a direct match in McCance and Widdowson and 10 were obtained using the average of 3 recipes. Foodbook24 contained a large proportion (92%) of the relevant portion sizes, others came from relevant books and recipes.DiscussionData collection is currently ongoing, but it is expected that the study will represent a significant step forward in public health policy contribution by characterising the likelihood of illness within a population on an annual basis. Furthermore, it will demonstrate the use of novel intake assessment technologies for fast and cost-effective collection of data for risk assessment purposes, reducing the time and cost required for data collection.

Occurrence of fatty acid esters of 3-MCPD, 2-MCPD and glycidol in infant formula

The discovery of fatty acid esters of monochloropropanediol (MCPD) and glycidol generated during the refinement process in vegetable fats and oils caused concerns about possible adverse health effects. As these fats are components of infant formula, the current investigation of the MCPD and glycidyl ester contents in infant formula was necessary to update the data for risk assessment purposes. For the analysis of 3-MCPD, 2-MCPD and glycidyl esters in infant formula, an existing method for fats and oils had to be modified and validated. The fat fraction containing MCPD and glycidyl esters was extracted from infant formula by accelerated solvent extraction (ASE). The extracted fat was then analysed according to an established method for fats and oils. Glycidyl esters are converted to monobrompropanediol (3-MBPD) esters, MCPD and 3-MBPD esters hydrolysed subsequently and after derivatisation detected by GC-MS. Seven different products of infant formula, covering two types and five lots each, altogether 70 samples, were bought in retail markets and analysed. In all samples, 3-MCPD and glycidyl esters could be detected. Both 3-MCPD and glycidyl esters’ concentration levels were found to be lower in comparison with earlier investigations described in the literature. The occurrence of 2-MCPD esters in infant formula was investigated for the first time and revealed concentrations about half of 3-MCPD ester concentrations.

Mind the gap: Concerns using endpoints from endocrine screening assays in risk assessment

Endocrine screening assays not only provide mechanistic information on the potential of a substance to interact with the endocrine system, but also data potentially relevant for risk assessment. However, these screening assays have a number of limitations that should be considered before the direct use of such data for risk assessment purposes. This paper discusses the limitations that should be considered for both human and environmental risk assessment. A proposal is made to provide an objective and transparent process in order to consider which endpoint(s) might be incorporated into a risk assessment, and when more definitive studies may be of value. The proposal is complemented with an easy-to-follow flowchart to aid industry scientists and regulators when evaluating the relevance of these data. Such an approach is necessary to ensure the appropriate use of screening data to further our understanding of the eco/toxicological profile of substances undergoing screening.

The long and winding road of progress in the use of in vitro data for risk assessment purposes: From "carnation test" to integrated testing strategies.

This paper introduces the special issue on quantitative in vitro-in vivo extrapolations (QIVIVE). It highlights important issues in the development of in vitro toxicology towards its implementation in toxicological risk assessment.

Application of toxicokinetics to improve chemical risk assessment: Implications for the use of animals

While toxicokinetics has become an integral part of pharmaceutical safety assessment over the last two decades, its use in the chemical industry is relatively new. However, it is recognised as a potentially important tool in human health risk assessment and recent initiatives have advocated greater application of toxicokinetics as part of an improved assessment strategy for crop protection chemicals that could offer greater efficiency, use fewer animals and provide better data for risk assessment purposes. To explore the potential scientific and animal welfare benefits of increased use of toxicokinetic data across the chemical industry, an international workshop was held in 2008. Experts from a wide range of chemical industry sectors, including industrial chemicals, agrochemicals and consumer products, participated in the meeting as well as representatives from relevant regulatory authorities. Pharmaceutical industry experts were also invited, in order to share experiences from the extensive use of toxicokinetics in drug development. Given that increased generation of toxicokinetic data could potentially result in an increased number of animals undergoing testing, technologies and strategies to reduce and refine animal use for this purpose were also considered. This paper outlines and expands upon the key themes that emerged from the workshop.

Toxicological Responses of Red-Backed Salamanders (Plethodon cinereus) to Soil Exposures of Copper

Copper (Cu) has widespread military use in munitions and small arms, particularly as a protective jacket for lead projectiles. The distribution of Cu at many US military sites is substantial and sites of contamination include habitats in and around military storage facilities, manufacturing, load and packing plants, open burning/open detonation areas, and firing ranges. Some of these areas include habitat for amphibian species, which generally lack toxicity data for risk assessment purposes. In an effort to ascertain Cu concentrations in soil that are toxic to terrestrial amphibians, 100 red-backed salamanders (Plethodon cinereus) were randomly sorted by weight, assigned to either a control soil or one of four treatments amended with copper acetate in soil, and exposed for 28 days. Analytical mean soil concentrations were 18, 283, 803, 1333, and 2700 mg Cu/kg soil dry weight. Food consisted of uncontaminated flightless Drosophila melanogaster. Survival was reduced in salamanders exposed to 1333 and 2700 mg/kg by 55% and 100%, respectively. Mortality/morbidity occurred within the first 4 days of exposure. These data suggest that a Cu soil concentration of and exceeding 1333.3 +/- 120.2 mg/kg results in reduced survival, whereas hematology analyses suggest that a concentration of and exceeding 803.3 +/- 98.4 mg/kg might result in reduced total white blood cell count. No effects were observed at 283.3 +/- 36.7 mg/kg.

What influences a health risk assessment?

In this paper it is claimed that the health risk assessment process is influenced by (at least) four general factors, namely: the regulatory framework, the quality and availability of scientific data, general risk assessment principles, and case-by-case assumptions. Furthermore, the scientific basis of risk assessment relies on three overall types of methods for data generation: standardized animal experiments, epidemiology, and non-standardized mechanism data. In this paper, the use of the different types of data for risk assessment purposes are analyzed in the light of the factors claimed to influence the risk assessment process. It is concluded that the availability of pre-defined criteria for the interpretation and evaluation of data for regulatory health risk assessment purposes need to be further developed. Especially with the implementation of the new European chemicals legislation REACH.

Regulatory developmental neurotoxicology testing: data evaluation for risk assessment purposes

The recent emphasis on children's health has led to new requirements in developmental neurotoxicity testing and evolving new approaches to children's risk assessment. As more regulatory DNT studies are being submitted and used for children's risk assessment, appropriate data interpretation of developmental neurotoxicity studies is an important step to improving the scientific basis for children's risk assessments. Preweaning motor activity testing is used to illustrate the types of issues important to appropriate data analysis and evaluation. The EPA guidelines require that motor activity be tested at PND 13, 17, 21 and 60. Total activity at each time point and activity levels at each intrasession interval must be reported. Consequently, one common method for analyzing this data is to evaluate total activity levels at each time point or activity level in each intrasession time interval as independent measurements. Review of the scientific literature indicates that data evaluation for motor activity during development should focus primarily on the overall inverted U-shaped pattern of total activity over PND 13, 17 and 21 and secondarily on the development of intrasession response decrement. The interpretation of the data for risk assessment purposes needs to be guided by our understanding of the strengths and limitations of our knowledge of the biologic basis for these tests.

Comparison of Measured Dermal Dust Exposures with Predicted Exposures Given by the EASE Expert System

Estimation and Assessment of Substance Exposure (EASE) is a rule-based computer expert system used by regulatory authorities within the European Union to assist in assessing exposure for both new and existing substances. It can provide estimates of both inhalation exposure levels and dermal exposure levels to the hands and forearms. This article describes the results of a study in which measurements of workplace dermal zinc exposures were collected for an industry-wide risk assessment and also compared with the levels predicted by EASE. Measurements were obtained from subjects in seven different workplaces that were producing or working with zinc metal or zinc compounds. The work activities were grouped a priori into one of three categories used by EASE for dermal exposure assessment: 'non-dispersive use with intermittent direct handling', 'wide dispersive use with intermittent direct handling' and 'wide dispersive use with extensive direct handling'. The predicted exposure ranges for these categories are 0.1-1, 1-5 and 5-15 mg cm(-2) day(-1). Although the average measured exposure levels for each of the categories increased in line with the predictions from EASE, the model overestimated dermal exposure to the hands by a factor of approximately 50 when the mid-point of the EASE range was compared with the measured mean exposure. Furthermore, a significant additional exposure was found on other parts of the workers' bodies for which EASE does not provide any estimates. Interpretation of the dermal exposure data was complicated by the use of protective gloves, which might have limited the amount of zinc dust adhering to the workers' skin. However, observation of the work activities suggested that the pattern of glove use was such that they would not provide a consistent level of protection. This study provided an opportunity to collect a large amount of dermal zinc exposure data for risk assessment purposes and also enabled a dermal sampling method to be developed and assessed. There is no standard method for dermal dust exposure measurement, and the choice of method was a key factor in the exposure estimation process. With regard to comparison with the EASE predictions, it is possible that EASE could appear to perform more accurately if its predictions were compared with measurements obtained using surrogate skin sampling methods. However, we believe that such sampling can provide a gross overestimate of the dust on the skin surface. We suggest that further development of the EASE system is necessary to ensure that it better reflects whole-body dermal exposures to dusts.

Dose–response modeling of in vivo genotoxicity data for use in risk assessment: some approaches illustrated by an analysis of acrylamide

Methods for dose–response modeling of in vivo genotoxicity data are introduced and applied to a case study of acrylamide. Genetic toxicity results are typically summarized as being either positive or negative, with no further consideration of the dose–response patterns that can be estimated from such studies. This analysis explores the use of three modeling approaches: Poisson regression of counts of genetic effects per cell; dynamic modeling of the time-course of micronucleus production and loss as a function of exposure; and categorical regression of sets of genetic toxicity experiments, the results of which are recoded in terms of severities of response. Estimates derived from these models (benchmark doses and predictions of response rates for predetermined doses of interest) are then used to assess the relevance and role of the genetic toxicity results in a risk assessment. With respect to the acrylamide data base, the results suggest that the genetic damage studies do not appear to be consistent or congruent with the thyroid tumor endpoints observed in two long-term bioassays in rats. This suggests that acrylamide’s mechanism of action with respect to production of such tumors may not be genotoxic, and that a cancer risk assessment that applied a linear, no-threshold approach to such endpoints might be inappropriate. Benchmark doses derived from the genetic toxicity data base do not appear to be the critical ones for acrylamide risk assessment. Dose metric and modeling issues associated with the proposed dose–response approach to evaluation of genetic toxicity data are explored, and it is recommended that further advancements of the methodology be developed and employed for optimal use of such data for risk assessment purposes.

(Q)SARS: gatekeepers against risk on chemicals?

ECOSAR and DEREKfW predictions for the (eco)toxicological effects of circa 70 substances were compared with experimental data for risk assessment purposes. These and other (quantitative) structure–activity relationships ((Q)SARs) programs will play an important role in future chemical policies, such as in the European Union and The Netherlands, to reduce animal testing and costs and to speed up the number of risk assessments for hazardous chemicals. The two programs, ECOSAR and DEREKfW, were selected because they are easy to use and transparent in their predictions. They predict to which chemical class a substance belongs and also predict some (eco)toxicological properties. ECOSAR categorised 87% of the chemicals correctly in chemical classes. With regard to predicting ecotoxicity, criteria were drawn up for the reliability of the QSARs provided by ECOSAR. Application of these criteria had the result that half of the regression lines from ECOSAR were considered unreliable beforehand. It turned out, however, that the “unreliable” regression lines predicted similar accurately as the “reliable” lines, although much less chemicals were available for validating the “unreliable” QSARs. The overall accurate prediction of toxicity by ECOSAR was 67%. DEREKfW categorised 90% of the chemicals correctly in chemical classes, while 10% of the structural fragments needed a more detailed description. The accuracy of prediction was around 60% for sensitisation, 75% for genotoxicity and carcinogenicity for a limited number of chemicals. Irritation and reproductive toxicity were predicted poorly. Finally, it should be stressed that regulators and industries need to agree on the acceptability criteria relating to false negative and false positive (Q)SAR predictions. This to prevent unnecessary animal testing when regulators do not sufficiently rely on (Q)SAR predictions or to prevent too much faith in (Q)SAR predictions which will then may cause an insufficient protection of man and the environment. Therefore, if the regulatory trend is that (Q)SARs have to be applied more and more systematically in the risk assessment process, their validity and the available tools have to be explored further.

Freshwater to saltwater toxicity extrapolation using species sensitivity distributions

There is generally a lack of saltwater ecotoxicity data for risk assessment purposes, leaving an unknown margin of uncertainty in saltwater assessments that utilize surrogate freshwater data. Consequently, a need for sound scientific advice on the suitability of using freshwater data to extrapolate to saltwater effects exists. Here we use species sensitivity distributions to determine if freshwater datasets are adequately protective of saltwater species assemblages for 21 chemical substances. For ammonia and the metal compounds among these data, freshwater data were generally protective because freshwater organisms tended to be more sensitive. In contrast, for pesticide and narcotic compounds, saltwater species tended to be more sensitive and a suitable uncertainty factor would need to be applied to surrogate freshwater data. Biological and physicochemical factors contribute to such differences in freshwater and saltwater species sensitivities, but the species compositions of datasets used are also important.

The Use and Evaluation of Primary Data in 29 Trichloroethylene Carcinogen Risk Assessments

This paper reports the results from a detailed study on how risk assessments of chemicals are actually made. The study is performed by comparing 29 cancer risk assessments made of one and the same chemical substance, namely, trichloroethylene. In this paper, the conclusions that are drawn in these risk assessment documents are described, and differences between the conclusions are explored. This is made within the framework of a proposed cancer risk assessment index. The selection of scientific data for risk assessment purposes is analyzed and the different risk assessors' interpretations and evaluations of individual primary data are compared. It is concluded that the data sets utilized by the trichloroethylene risk assessors are surprisingly incomplete and that biased data selection may have influenced some of the risk assessors' conclusions. Different risk assessors often interpret and evaluate one and the same study in different ways. There are also indications of both interpretation bias and evaluation bias for some of the risk assessors.

Endocrine disruptors: a critical review of in vitro and in vivo testing strategies for assessing their toxic hazard to humans.

Currently, there is much concern that a wide range of both synthetic and naturally occurring environmental chemicals can act as endocrine disruptors (EDs), and can adversely affect humans and wildlife. Many in vivo and in vitro tests have been proposed for screening EDs, and several regulatory agencies, including the US Environmental Protection Agency (EPA), have recommended tier-testing schemes. Unfortunately, most of the proposed toxicity tests have substantial problems, including non-specificity and lack of reproducibility. There is also uncertainty concerning their relevance for generating useful hazard data for risk assessment purposes, in view of the diversity of the possible ED mechanisms of action (for example, receptor binding, steroidogenesis and modulation of the homeostatic processes which regulate endogenous responses to hormones). Moreover, most of the suggested test methods have yet to be validated according to internationally accepted criteria, although the OECD and the US EPA have defined tests for validation, and an interlaboratory "prevalidation" exercise has been initiated by the OECD. All this is compounded by the lack of information regarding human exposure levels to EDs, and a lack of direct evidence for a causal link between exposure and the development of adverse human health effects. In addition, the regulatory testing of EDs has important negative implications for animal welfare, as some of the proposed in vivo tests require large group sizes of animals and stressful procedures. From a detailed analysis of the available published literature, it is concluded that it is impossible to assess the relative values of currently available in vitro and in vivo toxicity tests for EDs, or to recommend any test or test battery. Any plans for the widespread testing of EDs are therefore premature and might be unnecessary, at least for detecting possible human effects. Several recommendations are made for rectifying this unsatisfactory situation, including the postponement of screening programmes pending: a) more information on human exposure; b) further details of the mechanisms of action of EDs; and c) the development of improved tests, followed by their proper scientific validation.

Risk Assessment of Thyroid Follicular Cell Tumors

Thyroid follicular cell tumors arise in rodents from mutations, perturbations of thyroid and pituitary hormone status with increased stimulation of thyroid cell growth by thyroid-stimulating hormone (TSH), or a combination of the two. The only known human thyroid carcinogen is ionizing radiation. It is not known for certain whether chemicals that affect thyroid cell growth lead to human thyroid cancer. The U.S. Environmental Protection Agency applies the following science policy positions: 1) chemically induced rodent thyroid tumors are presumed to be relevant to humans; 2) when interspecies information is lacking, the default is to assume comparable carcinogenic sensitivity in rodents and humans; 3) adverse rodent noncancer thyroid effects due to chemically induced thyroid-pituitary disruption are presumed to be relevant to humans; 4) linear dose-response considerations are applied to thyroid cancer induced by chemical substances that either do not disrupt thyroid functioning or lack mode of action information; 5) nonlinear thyroid cancer dose-response considerations are applied to chemicals that reduce thyroid hormone levels, increase TSH and thyroid cell division, and are judged to lack mutagenic activity; and 6) nonlinear considerations may be applied in thyroid cancer dose-response assessments on a case-by-case basis for chemicals that disrupt thyroid-pituitary functioning and demonstrate some mutagenic activity. Required data for risk assessment purposes is mode of action information on mutagenicity, increases in follicular cell growth (cell size and number) and thyroid gland weight, thyroid-pituitary hormones, site of action, correlations between doses producing thyroid effects and cancer, and reversibility of effects when dosing ceases.

What Can Be Done to Ensure the Usefulness of Epidemiologic Data for Risk Assessment Purposes?

Epidemiologic studies can play a central role in risk assessments. They are used in all risk assessment phases: hazard identification, dose-response, and exposure assessment. Epidemiologic studies have often been the first to show that a particular environmental exposure is a hazard to health. They have numerous advantages with respect to other sources of data which are used in risk assessments, the most important being that they do not require the assumption that they are generalizable to humans. For this reason, fewer and lower uncertainty factors may be appropriate in risk characterization based on epidemiologic studies. Unfortunately, epidemiologic studies have numerous problems, the most important being that the exposures are often not precisely measured. This article presents in detail the advantages of and problems with epidemiologic studies. It discusses two approaches to ensure their usefulness, biomarkers and an ordinance which requires baseline and subsequent surveillance of possible exposures and health effects from newly sited potentially polluting facilities. Biomarkers are biochemical measures of exposure, susceptibility factors, or preclinical pathological changes. Biomarkers are a way of dealing with the problems of poor measures, differential susceptibility and lack of early measures of disease occurrence that inherent in many environmental epidemiologic studies. The advantages of biomarkers is they can provide objective information on exposure days, months or even years later and evidence of pathology perhaps years earlier. The ordinance makes possible the use of a powerful epidemiologic study design, the prospective cohort study, where confounder(s) are best measured, and exposures, pathological changes, and health effects can be detected as soon as possible.