Finding toxicological information: An approach for occupational health professionals

<p>Abstract</p> <p>Background</p> <p>It can be difficult for occupational health professionals to assess which toxicological databases available on the Internet are the most useful for answering their questions. Therefore we evaluated toxicological databases for their ability to answer practical questions about exposure and prevention. We also propose recommended practices for searching for toxicological properties of chemicals.</p> <p>Methods</p> <p>We used a systematic search to find databases available on the Internet. Our criteria for the databases were the following: has a search engine, includes factual information on toxic and hazardous chemicals harmful for human health, and is free of charge. We developed both a qualitative and a quantitative rating method, which was used by four independent assessors to determine appropriateness, the quality of content, and ease of use of the database. Final ratings were based on a consensus of at least two evaluators.</p> <p>Results</p> <p>Out of 822 results we found 21 databases that met our inclusion criteria. Out of these 21 databases 14 are administered in the US, five in Europe, one in Australia, and one in Canada. Nine are administered by a governmental organization. No database achieved the maximum score of 27. The databases GESTIS, ESIS, Hazardous Substances Data Bank, TOXNET and NIOSH Pocket Guide to Chemical Hazards all scored more than 20 points. The following approach was developed for occupational health professionals searching for the toxicological properties of chemicals: start with the identity of the chemical; then search for health hazards, exposure route and measurement; next the limit values; and finally look for the preventive measures.</p> <p>Conclusion</p> <p>A rating system of toxicological databases to assess their value for occupational health professionals discriminated well between databases in terms of their appropriateness, quality of information, and ease of use. Several American and European databases yielded high scores and provide a valuable source for occupational health professionals.</p

Collection and Evaluation of (Q)SAR Models for Mutagenicity and Carcinogenicity

This evaluation of the non-commercial (Q)SARs for mutagenicity and carcinogenicity consisted of a preliminary survey (Phase I), and then of a more detailed analysis of short listed models (Phase II). In Phase I, the models were collected from the literature, and then assessed according to the OECD principles based on the information provided by the authors-. Phase I provided the support for short listing a number of promising models, that were analyzed more in depth in Phase II. In Phase II, the information provided by the authors was completed and complemented with a series of analyses aimed at generating an overall profile of each of the short listed models. The models can be divided into two families based on their target: a) congeneric; and b) non-congeneric sets of chemicals. The QSARs for congeneric chemicals include most of the chemical classes top ranking in the EU High Production Volume list, with the notable exception of the halogenated aliphatics. They almost exclusively aim at modeling Salmonella mutagenicity and rodent carcinogenicity, which are crucial toxicological endpoints in the regulatory context. The lack of models for in vivo genotoxicity should be remarked. Overall the short listed models can be interpreted mechanistically, and agree with, and/or support the available scientific knowledge, and most of the models have good statistics. Based on external prediction tests, the QSARs for the potency of congeneric chemicals are 30 to 70 % correct, whereas the models for discriminating between active and inactive chemicals have considerably higher accuracy (63 to 100 %), thus indicating that predicting intervals is more reliable than predicting individual data points. The internal validation procedures (e.g., cross-validation, etc...) did not seem to be a reliable measure of external predictivity. Among the non-local, or global approaches for non-congeneric data sets, four models based on the use of Structural Alerts (SA) were short listed and investigated in more depth. The four sets did not differ to a large extent in their performance. In the general databases of chemicals the SAs appear to agree around 65% with rodent carcinogenicity data, and 75% with Salmonella mutagenicity data. The SAs based models do not seem to work equally efficiently in the discrimination between active and inactive chemicals within individual chemical classes. Thus, their main role is that of preliminary, or large-scale screenings. A priority for future research on the SAs is their expansion to include alerts for nongenotoxic carcinogens. A general indication of this study, valid for both congeneric and noncongeneric models, is that there is uncertainty associated with (Q)SARs; the level of uncertainty has to be considered when using (Q)SAR in a regulatory context. However, (Q)SARs are not meant to be black-box machines for predictions, but have a much larger scope including organization and rationalization of data, contribution to highlight mechanisms of action, complementation of other data from different sources (e.g., experiments). Using only non-testing methods, the larger the evidence from QSARs (several different models, if available) and other approaches (e.g. chemical categories, read across) the higher the confidence in the prediction.JRC.I.3-Toxicology and chemical substance

Systematic Literature Review of Diffusion Coefficient Studies for Pharmaceutically-Active Compounds

Pharmaceutically-active compounds (PHACs) such as analgesics, antibiotics, hormones, and antiseptics have been proven beneficial to human life as they can cure illnesses and increase life expectancy. However, heightened usage has led to their emergence in various bodies of water. This has negatively impacted humankind and the environment due to these compounds’ toxicity levels and adverse health effects on living organisms. Therefore, this systematic literature review evaluated the existing literature on the diffusion coefficients of various PHACs. The diffusion coefficient of these compounds serves as a parameter that measures their transport through hydrological mediums and is inversely proportional to molecular size. This review focused on the prevalence of different types of PHACs, the methods used in these diffusion studies, and other affecting parameters. Upon conducting the review, it was determined that analgesics, followed by antibiotics, were the most frequently reported and studied PHACs found in bodies of water. Moreover, the Taylor Dispersion Method and molecular modeling were the most popular methods of diffusion coefficient. At the same time, measurements using electric conductivity were preferred mainly due to convenience in terms of simplicity and cost-effectiveness. Observations of related parameters, such as temperature and molecular size, mostly aligned with the previously established theory with diffusion coefficients of PHACs’ particles, have a direct relationship with temperature and an inverse relationship with molecular size

Complexity and Uncertainty in Human and Ecological Risk Assessment

Multiple interacting stressors in the environment present increasingly complex risks to human health. Too often, however, the data required for traditional risk assessment are either lacking or unavailable at the necessary spatial or temporal scale. In addition, assessment practices and management policies need to move away from single factor approaches in order to accommodate the reality of complex chemical mixtures and environmental stressors. Recent literature suggests that a paradigm shift is under way. This points to a need for the development of new techniques both for rapid data collection and flexible risk assessment strategies that can adapt to make use of readily available data. This dissertation presents two types of methods for improving the risk assessment process given these evolving challenges: predictive analytics and integrated effect-directed toxicity screening. The first technique addresses the characterization of environmental health using toxicological screening tools. Environmental influences on ecological and human health are often studied using indicators that represent important risk components such as chemical contamination, hazards, exposures, and biological stress. Unfortunately, studies are frequently constrained by the lack of calibrated indicators constructed from standardized metrics. The second technique is a novel method for population-level risk assessment that uses self-organizing feature maps (SOM) to generate multivariate clusters of cause-of-death and birth outcome metrics, in combination with the use of and supervised learning risk-propagation modelling to evaluate predictability of available indicators. I apply this method to identify exposure-outcome linkages at the county level for Wisconsin, USA and civil divisions in Dobrogea, Romania; thereby providing a dynamic visualization of public health risk relationships with behavioral risk factors (e.g. smoking, heavy drinking) and environmental factors (e.g. land cover, nitrates and faecal coliform in drinking water). These risk relationships do not demonstrate cause-effect, but provide guidance for targeted investigations and for risk-management prioritization. To investigate a unique way of measuring environmental health, a sediment contact assay using zebrafish (Danio rerio) embryos was adapted from Hollert et al. (2003) as an indicator of teratogenic stress within river sediments. Sediment samples were collected from Lake Michigan tributary watersheds. Sediment contact assay responses were then compared to prevalence of congenital heart disease (CHD) and vital statistic birth indicators aggregated from civil divisions associated with these same watersheds. Significant risk relationships were detected between variation in early life-stage (ELS) endpoints of zebrafish embryos 72 hour post-fertilization and the birth prevalence of human congenital heart disease and infant mortality. Examination of principal components of ELS endpoints suggests that variance related to zebrafish embryonic heart and circulatory malformations is most closely associated with human CHD prevalence. This study demonstrates a novel application of effect-based toxicity testing for ecological and human health risk assessments. These results support the hypothesis that bioassays normally used for ecological screening can be useful as indicators of environmental stress to humans so as to expand our understanding of environmental - human health linkages. Finally, next steps and new directions for these lines of thinking are discussed

The NORMAN Suspect List Exchange (NORMAN‑SLE): facilitating European and worldwide collaboration on suspect screening in high resolution mass spectrometry

Background: The NORMAN Association (https:// www. norman-​netwo rk. com/) initiated the NORMAN Suspect List Exchange (NORMAN-SLE; https:// www. norman-​netwo rk. com/ nds/ SLE/) in 2015, following the NORMAN collaborative trial on non-target screening of environmental water samples by mass spectrometry. Since then, this exchange of information on chemicals that are expected to occur in the environment, along with the accompanying expert knowledge and references, has become a valuable knowledge base for “suspect screening” lists. The NORMAN-SLE now serves as a FAIR (Findable, Accessible, Interoperable, Reusable) chemical information resource worldwide. Results: The NORMAN-SLE contains 99 separate suspect list collections (as of May 2022) from over 70 contributors around the world, totalling over 100,000 unique substances. The substance classes include per- and polyfluoroalkyl substances (PFAS), pharmaceuticals, pesticides, natural toxins, high production volume substances covered under the European REACH regulation (EC: 1272/2008), priority contaminants of emerging concern (CECs) and regulatory lists from NORMAN partners. Several lists focus on transformation products (TPs) and complex features detected in the environment with various levels of provenance and structural information. Each list is available for separate download. The merged, curated collection is also available as the NORMAN Substance Database (NORMAN SusDat). Both the NORMAN-SLE and NORMAN SusDat are integrated within the NORMAN Database System (NDS). The individual NORMAN-SLE lists receive digital object identifiers (DOIs) and traceable versioning via a Zenodo community (https:// zenodo. org/ commu nities/ norman-​sle), with a total of > 40,000 unique views, > 50,000 unique downloads and 40 citations (May 2022). NORMAN-SLE content is progressively integrated into large open chemical databases such as PubChem (https:// pubch em. ncbi. nlm. nih. gov/) and the US EPA’s CompTox Chemicals Dashboard (https:// compt ox. epa. gov/ dashb oard/), enabling further access to these lists, along with the additional functionality and calculated properties these resources offer. PubChem has also integrated significant annotation content from the NORMAN-SLE, including a classification browser (https:// pubch em. ncbi. nlm. nih. gov/ class ifica tion/# hid= 101). Conclusions: The NORMAN-SLE offers a specialized service for hosting suspect screening lists of relevance for the environmental community in an open, FAIR manner that allows integration with other major chemical resources. These efforts foster the exchange of information between scientists and regulators, supporting the paradigm shift to the “one substance, one assessment” approach. New submissions are welcome via the contacts provided on the NORMAN-SLE website (https:// www. norman-​netwo rk. com/ nds/ SLE/).NORMAN AssociationLuxembourg National Research Fund A18/BM/12341006European Union's Horizon 2020 research and innovation programme 101036756National Center for Biotechnology Information of the National Library of Medicine (NLM), National Institutes of Health (NIH)National Health and Medical Research Council (NHMRC) of Australia EL1 2009209Australian Research Council DP190102476 Queensland Department of HealthInstituto de Salud Carlos III European Commission CP19/00060 European Union through Fondo Europeo de Desarrollo Regional (FEDER)Federal Ministry of Education & Research (BMBF) FKz: 02WRS1495 A/B/EFWO 11G1821NNIH via grant NIH NIGMS R01GM092218 NIH via grant NIH NCI 1R03CA222452-01Vanderbilt Chemical Biology Interface training program 5T32GM065086-16Netherlands Organization for Scientific Research (NWO) 15747SOLUTIONS project (European Union's Seventh Framework Programme for research, technological development and demonstration) 603437HBM4EU (European Union's Horizon 2020 research and innovation programme 733032German Research Foundation (DFG) 441958208NaToxAq (European Union's Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie Grant 722493German Federal Ministry for the Environment, Nature Conservation and Nuclear Safety (BMU) (FKZ) 3716 67 416 0German Federal Ministry for the Environment, Nature Conservation, Nuclear Safety and Consumer Protection (BMUV) Project (FKZ) 3719 65 408 0EU Cohesion Funds within the project Monitoring and assessment of water body status 310011A366Swiss Federal Office for the Environment (FOEN)Canadian Institutes of Health Research (CIHR) Genome CanadaMAVA foundationValery FoundationNational Science Foundation (NSF) RUI-1306074 National Natural Science Foundation of China (NSFC) 22193051 21906177China Postdoctoral Science Foundation 2019M650863Environmental Protection Administration, Executive Yuan, R.O.C. Taiwan (Taiwan EPA) 108C002871Swiss Federal Office for the EnvironmentUnited States Environmental Protection AgencyCenter for Forestry Research & Experimentation (CIEF)European Commission 2019/040Marie Sklodowska-Curie grant 859891 European Commission European Commission Joint Research Centre 308610 289511Joint Programming Initiative FOODBALL 2014-17 MCIN/AEI RYC2020-028901-IESF investing in your futureAugust T Larsson Guest Researcher Programme from the Swedish University of Agricultural SciencesGerman Federal Ministry of Education and Research within the RiSKWa program 02WRS1273 02WRS1354RECETOX research infrastructure (the Czech Ministry of Education, Youth and Sports) LM2018121CETOCOEN PLUS project CZ.02.1.01/0.0/0.0/15_ 003/0000469 CETOCOEN EXCELLENCE Teaming 2 project - Czech ministry of Education, Youth and Sports CZ.02.1.01/0.0/0.0/1 7_043/000963

Integrated testing strategy for the study of the effects of the human pharmaceutical dutasteride on fish

This thesis was submitted for the degree of Doctor of Philosophy and awarded by Brunel University.In recent years, a growing number of human pharmaceuticals have been detected in the aquatic environment, generally at low concentrations (sub-ng/L to low μg/L). These compounds are characterised by highly specific mechanisms of action, high potency and prolonged activity in order to minimise dosing requirements and potential toxicity in patients. Among the various classes of pharmaceuticals, steroids and anti-steroids are widely used, as shown by the analysis of their clinical use carried out at the beginning of this Ph.D. project. Although the amounts used are much lower than the amounts of some other pharmaceuticals (e.g. analgesics), their ability to affect important physiological processes in fish (e.g. reproduction) at very low concentrations (ng/L) suggest that this class of compounds should represent a high priority for ecotoxicological research. In particular, this Ph.D. project addressed the question of whether or not dutasteride, a human pharmaceutical mainly used to treat benign prostatic hyperplasia, may cause adverse effects in the teleost fathead minnow (Pimephales promelas) by inhibiting the activity of both isoforms of 5α-reductase (5αR), the enzyme which convert testosterone into dihydrotestosterone (DHT). The theoretical framework used to guide the design of the experimental studies was based on the combination of several conceptual approaches, including the study of the evolutionary degree of conservation and functionality of the drug target in non-target species, and the cross-species extrapolation of pharmacological and toxicological information generated during pre-clinical and clinical studies in mammals during drug development. The results obtained during the first phase of this Ph.D. project strongly suggested that DHT has a physiological role in the fathead minnow. In fact, 5αRs are evolutionary conserved in this species, 5αRs genes are expressed in tissues such as the testis, and DHT circulates in fathead minnow plasma at concentrations similar to those detected in humans. These findings represented the rationale for testing the effects of dutasteride in the fathead minnow. Dutasteride caused significant adverse effects in all the in vivo studies performed in order to evaluate its potential toxicity on fish, including early life stage and short term reproduction studies, and all the tested life stages were sensitive to the inhibition of 5αRs activity; however, none of the observed adverse effects occurred at concentrations of exposure lower than 32 μg/L (measured concentration). The results also showed that female fish are highly sensitive to disruption of the androgenic pathways, highlighting their utility for the evaluation of potential adverse effects caused by anti-androgens on fish. In conclusion, the results presented in this Thesis suggest that, at present, the potential presence of dutasteride in the environment does not represent a risk to wild fish populations, due to the high concentrations required to elict significant adverse effect (LOEC = 32 μg/L) and the low volume of drug prescribed every year (5.07 kg in UK in 2006). However, the high bioaccumulation factor of dutasteride suggest that further studies should be conducted to elucidate the role played by the bioaccumulation process in the toxicity responses observed in fish.This work is funded by GlaxoSmithKlin

The NORMAN Suspect List Exchange (NORMAN-SLE): facilitating European and worldwide collaboration on suspect screening in high resolution mass spectrometry

Background The NORMAN Association (https://www.norman-network.com/) initiated the NORMAN Suspect List Exchange (NORMAN-SLE; https://www.norman-network.com/nds/SLE/) in 2015, following the NORMAN collaborative trial on non-target screening of environmental water samples by mass spectrometry. Since then, this exchange of information on chemicals that are expected to occur in the environment, along with the accompanying expert knowledge and references, has become a valuable knowledge base for “suspect screening” lists. The NORMAN-SLE now serves as a FAIR (Findable, Accessible, Interoperable, Reusable) chemical information resource worldwide. Results The NORMAN-SLE contains 99 separate suspect list collections (as of May 2022) from over 70 contributors around the world, totalling over 100,000 unique substances. The substance classes include per- and polyfluoroalkyl substances (PFAS), pharmaceuticals, pesticides, natural toxins, high production volume substances covered under the European REACH regulation (EC: 1272/2008), priority contaminants of emerging concern (CECs) and regulatory lists from NORMAN partners. Several lists focus on transformation products (TPs) and complex features detected in the environment with various levels of provenance and structural information. Each list is available for separate download. The merged, curated collection is also available as the NORMAN Substance Database (NORMAN SusDat). Both the NORMAN-SLE and NORMAN SusDat are integrated within the NORMAN Database System (NDS). The individual NORMAN-SLE lists receive digital object identifiers (DOIs) and traceable versioning via a Zenodo community (https://zenodo.org/communities/norman-sle), with a total of > 40,000 unique views, > 50,000 unique downloads and 40 citations (May 2022). NORMAN-SLE content is progressively integrated into large open chemical databases such as PubChem (https://pubchem.ncbi.nlm.nih.gov/) and the US EPA’s CompTox Chemicals Dashboard (https://comptox.epa.gov/dashboard/), enabling further access to these lists, along with the additional functionality and calculated properties these resources offer. PubChem has also integrated significant annotation content from the NORMAN-SLE, including a classification browser (https://pubchem.ncbi.nlm.nih.gov/classification/#hid=101). Conclusions The NORMAN-SLE offers a specialized service for hosting suspect screening lists of relevance for the environmental community in an open, FAIR manner that allows integration with other major chemical resources. These efforts foster the exchange of information between scientists and regulators, supporting the paradigm shift to the “one substance, one assessment” approach. New submissions are welcome via the contacts provided on the NORMAN-SLE website (https://www.norman-network.com/nds/SLE/)