| 1. |
- Anderson, J. K., et al.
(författare)
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Grouping of PFAS for human health risk assessment : Findings from an independent panel of experts
- 2022
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Ingår i: Regulatory toxicology and pharmacology. - : Elsevier. - 0273-2300 .- 1096-0295. ; 134
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Tidskriftsartikel (refereegranskat)abstract
- An expert panel was convened to provide insight and guidance on per- and polyfluoroalkyl substances (PFAS) grouping for the purposes of protecting human health from drinking water exposures, and how risks to PFAS mixtures should be assessed. These questions were addressed through multiple rounds of blind, independent responses to charge questions, and review and comments on co-panelists responses. The experts agreed that the lack of consistent interpretations of human health risk for well-studied PFAS and the lack of information for the vast majority of PFAS present significant challenges for any mixtures risk assessment approach. Most experts agreed that "all PFAS" should not be grouped together, persistence alone is not sufficient for grouping PFAS for the purposes of assessing human health risk, and that the definition of appropriate subgroups can only be defined on a case-by-case manner. Most panelists agreed that it is inappropriate to assume equal toxicity/potency across the diverse class of PFAS. A tiered approach combining multiple lines of evidence was presented as a possible viable means for addressing PFAS that lack analytical and/or toxicological studies. Most PFAS risk assessments will need to employ assumptions that are more likely to overestimate risk than to underestimate risk, given the choice of assumptions regarding dose-response model, uncertainty factors, and exposure information.
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| 2. |
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| 3. |
- Bergman, Åke, et al.
(författare)
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Manufacturing doubt about endocrine disrupter science : A rebuttal of industry-sponsored critical comments on the UNEP/WHO report "State of the Science of Endocrine Disrupting Chemicals 2012"
- 2015
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Ingår i: Regulatory toxicology and pharmacology. - : Academic Press. - 0273-2300 .- 1096-0295. ; 73:3, s. 1007-1017
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Tidskriftsartikel (refereegranskat)abstract
- We present a detailed response to the critique of "State of the Science of Endocrine Disrupting Chemicals 2012" (UNEP/WHO, 2013) by financial stakeholders, authored by Lamb et al. (2014). Lamb et al.'s claim that UNEP/WHO (2013) does not provide a balanced perspective on endocrine disruption is based on incomplete and misleading quoting of the report through omission of qualifying statements and inaccurate description of study objectives, results and conclusions. Lamb et al. define extremely narrow standards for synthesizing evidence which are then used to dismiss the UNEP/WHO 2013 report as flawed. We show that Lamb et al. misuse conceptual frameworks for assessing causality, especially the Bradford-Hill criteria, by ignoring the fundamental problems that exist with inferring causality from empirical observations. We conclude that Lamb et al.'s attempt of deconstructing the UNEP/WHO (2013) report is not particularly erudite and that their critique is not intended to be convincing to the scientific community, but to confuse the scientific data. Consequently, it promotes misinterpretation of the UNEP/WHO (2013) report by non-specialists, bureaucrats, politicians and other decision makers not intimately familiar with the topic of endocrine disruption and therefore susceptible to false generalizations of bias and subjectivity.
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| 4. |
- Beronius, Anna, et al.
(författare)
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Health risk assessment procedures for endocrine disrupting compounds within different regulatory frameworks in the European Union
- 2009
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Ingår i: Regulatory toxicology and pharmacology. - : Elsevier BV. - 0273-2300 .- 1096-0295. ; 55:2, s. 111-122
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Tidskriftsartikel (refereegranskat)abstract
- In this study we have investigated how different regulatory frameworks in Europe cope with identification and risk assessment of endocrine disrupting compounds (EDCs). Four regulatory groups were selected for the investigation: existing industrial chemicals, environmental pollutants in food, pharmaceuticals and plant protection products. The legislation and guidelines for each of these groups were scrutinized and compared in detail. In addition, one recent European risk assessment document each for three identified EDCs, i.e. bisphenol A, dioxins and vinclozolin, were reviewed and compared. We found that the requirements for toxicity testing and availability and scope of risk assessment guidelines varied between the four regulatory frameworks. Also, the general principles regarding the human relevance of the mode of action identified in animal tests differed in the different risk assessments. In conclusion, there is little conformity in the risk assessment processes between these groups of chemicals. Because of the complicated nature of endocrine disruption, test methods, principles and criteria for data interpretation traditionally used might not be directly applicable to EDCs and further development of a transparent and reliable risk assessment process for this type of substances is needed.
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| 5. |
- Ding, Qian, et al.
(författare)
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Occupational exposure limits in Europe and Asia – Continued divergence or global harmonization?
- 2011
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Ingår i: Regulatory toxicology and pharmacology. - : Elsevier. - 0273-2300 .- 1096-0295. ; 61:3, s. 296-309
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Tidskriftsartikel (refereegranskat)abstract
- Occupational exposure limits (OELs) are used as a risk management tool aiming at protecting against negative health effects of occupational exposure to harmful substances. The systems of OEL development have not been standardized and divergent outcomes have been reported. However some harmonization processes have been initiated, primarily in Europe. This study investigates the state of harmonization in a global context. The OEL systems of eight Asian and seventeen European organizations are analyzed with respect to similarities and differences in: (1) the system for determining OELs, (2) the selection of substances, and (3) the levels of the OELs. The majority of the investigated organizations declare themselves to have been influenced by the American Conference of Governmental Industrial Hygienists (ACGIH), and in many cases this can be empirically confirmed. The EU harmonization process is reflected in trends towards convergence within the EU. However, comparisons of Asian and European organizations provide no obvious evidence that OELs are becoming globally harmonized.
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| 6. |
- Fick, Jerker, et al.
(författare)
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Predicted critical environmental concentrations for 500 pharmaceuticals
- 2010
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Ingår i: Regulatory toxicology and pharmacology. - : Elsevier. - 0273-2300 .- 1096-0295. ; 58:3, s. 516-23
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Tidskriftsartikel (refereegranskat)abstract
- A growing number of pharmaceuticals are found in surface waters worldwide, raising concerns about their effects on aquatic organisms and it is a major challenge to develop a rational strategy for prioritizing drugs on which to focus the most extensive environmental research efforts. However, in contrast to most other chemicals, very good understanding of the human potency of pharmaceuticals has been obtained through efficacy and safety testing. Assuming that a drug acts primarily through the same target(s) also in a non-target species, it would be possible to predict the likelihood for pharmacological interactions in wildlife. Among aquatic organisms, fish most often share drug targets with humans. In this study, we have calculated the predicted critical environmental concentration (CECs), i.e. the surface water concentration expected to cause a pharmacological effect in fish, for 500 pharmaceuticals, assuming equivalent pharmacological activity. The CECs are based on literature data on human potencies together with a predicted bioconcentration factor in fish for each drug based on lipophilicity. We propose that CECs could be used as preliminary indicators of specific drugs' potential to cause adverse pharmacological effects at specific water concentrations, used when selecting pharmaceuticals to include in screening campaigns and for assessing relevant detection limits.
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| 7. |
- Fu, Xin, et al.
(författare)
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Acute, subacute toxicity and genotoxic effect of Bio-Quinone (R) Q10 in mice and rats
- 2009
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Ingår i: Regulatory toxicology and pharmacology. - : Elsevier BV. - 0273-2300 .- 1096-0295. ; 53:1, s. 1-5
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Tidskriftsartikel (refereegranskat)abstract
- In the present study, the acute, subacute and genetic toxicity of Coenzyme Q10 (CoQ10) in the form of Bio-Quinone (R) (Pharma Nord, Denmark) was assessed. LD50 of CoQ10 by oral treatment was greater than 20 g/kg body weight in both female and male mice. Genotoxicity was assessed in mice by Ames test in Salmonella typhimurium strains TA97, TA98, TA100 and TA102, by bone marrow micronucleus test and sperm abnormality. Thirty-day subacute toxicity was conducted with oral daily dose at 0, 0.56, 1.13 and 2.25 g/kg body weight in rats. No significant changes in body weight, food intake, behavior, mortality, hematology, blood biochemistry, vital organ weight, sperm abnormality, mutagenicity and micro-nucleus formation were observed and no clinical signs or adverse effects were detected by administration of CoQ10. These results support the safety of CoQ10 for oral consumption.
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| 8. |
- Halamoda-Kenzaoui, Blanka, et al.
(författare)
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Bridging communities in the field of nanomedicine
- 2019
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Ingår i: Regulatory toxicology and pharmacology. - : Elsevier BV. - 0273-2300 .- 1096-0295. ; 106, s. 187-196
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Tidskriftsartikel (refereegranskat)abstract
- An early dialogue between nanomedicine developers and regulatory authorities are of utmost importance to anticipate quality and safety requirements for these innovative health products. In order to stimulate interactions between the various communities involved in a translation of nanomedicines to clinical applications, the European Commission's Joint Research Centre hosted a workshop titled "Bridging communities in the field of Nanomedicine" in Ispra/Italy on the 27th -28th September 2017. Experts from regulatory bodies, research institutions and industry came together to discuss the next generation of nanomedicines and their needs to obtain regulatory approval. The workshop participants came up with recommendations highlighting methodological gaps that should be addressed in ongoing projects addressing the regulatory science of nanomedicines. In addition, individual opinions of experts relevant to progress of the regulatory science in the field of nanomedicine were summarised in the format of a survey.
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| 9. |
- Hansson, Sven Ove, et al.
(författare)
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The substitution principle
- 2011
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Ingår i: Regulatory toxicology and pharmacology. - : Elsevier BV. - 0273-2300 .- 1096-0295. ; 59:3, s. 454-460
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Tidskriftsartikel (refereegranskat)abstract
- According to the substitution principle, hazardous chemicals should be replaced by less hazardous alternatives. In this paper, the major issues concerning the more precise definition of the principle are analyzed, and a general purpose definition is proposed. It is claimed that the priority between reducing hazard, functionality and economical considerations in the application of the substitution principle is a matter for adjustment in each particular case that cannot be settled beforehand. None of these objectives can have absolute priority over the others, but the substitution principle is aimed at increasing the priority given to the reduction of hazards to human health and the environment. Major methods to promote and implement the principle are summarized, current legislative approaches are discussed, and proposals for efficient implementation are made. It is emphasized that the primary responsibility for avoiding hazardous substances and processes rests with industry.
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| 10. |
- Hansson, Sven Ove, et al.
(författare)
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Towards, a theory of tiered testing
- 2007
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Ingår i: Regulatory toxicology and pharmacology. - : Elsevier BV. - 0273-2300 .- 1096-0295. ; 48:1, s. 35-44
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Tidskriftsartikel (refereegranskat)abstract
- Tiered testing is an essential part of any resource-efficient strategy for the toxicity testing of a large number of chemicals, which is required for instance in the risk management of general (industrial) chemicals, In spite of this, no general theory seems to be available for the combination of single tests into efficient tiered testing systems. A first outline of such a theory is developed. It is argued that chemical, toxicological, and decision-theoretical knowledge should be combined in the construction of such a theory. A decision-theoretical approach for the optimization of test systems is introduced. It is based on expected utility maximization with simplified assumptions covering factual and value-related information that is usually missing in the development of test systems.
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| 11. |
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| 12. |
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| 13. |
- Hedberg, Yolanda, et al.
(författare)
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Surface passivity largely governs the bioaccessibility of nickel-based powder particles at human exposure conditions
- 2016
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Ingår i: Regulatory toxicology and pharmacology. - : Elsevier BV. - 0273-2300 .- 1096-0295. ; 81, s. 162-170
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Tidskriftsartikel (refereegranskat)abstract
- The European chemical framework REACH requires that hazards and risks posed by chemicals, including alloys and metals, are identified and proven safe for humans and the environment. Therefore, differences in bioaccessibility in terms of released metals in synthetic biological fluids (different pH (1.5-7.4) and composition) that are relevant for different human exposure routes (inhalation, ingestion, and dermal contact) have been assessed for powder particles of an alloy containing high levels of nickel (Inconel 718, 57 wt% nickel). This powder is compared with the bioaccessibility of two nickel-containing stainless steel powders (AISI 316L, 10-12% nickel) and with powders representing their main pure alloy constituents: two nickel metal powders (100% nickel), two iron metal powders and two chromium metal powders. Xray photoelectron spectroscopy, microscopy, light scattering, and nitrogen absorption were employed for the particle and surface oxide characterization. Atomic absorption spectroscopy was used to quantify released amounts of metals in solution. Cytotoxicity (Alamar blue assay) and DNA damage (comet assay) of the Inconel powder were assessed following exposure of the human lung cell line A549, as well as its ability to generate reactive oxygen species (DCFH-DA assay). Despite its high nickel content, the Inconel alloy powder did not release any significant amounts of metals and did not induce any toxic response. It is concluded, that this is related to the high surface passivity of the Inconel powder governed by its chromium-rich surface oxide. Read-across from the pure metal constituents is hence not recommended either for this or any other passive alloy.
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| 14. |
- Henderson, Rayetta G., et al.
(författare)
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Inter-laboratory validation of bioaccessibility testing for metals
- 2014
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Ingår i: Regulatory toxicology and pharmacology. - : Elsevier BV. - 0273-2300 .- 1096-0295. ; 70:1, s. 170-181
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Tidskriftsartikel (refereegranskat)abstract
- Bioelution assays are fast, simple alternatives to in vivo testing. In this study, the intra- and inter-laboratory variability in bioaccessibility data generated by bioelution tests were evaluated in synthetic fluids relevant to oral, inhalation, and dermal exposure. Using one defined protocol, five laboratories measured metal release from cobalt oxide, cobalt powder, copper concentrate, Inconel alloy, leaded brass alloy, and nickel sulfate hexahydrate. Standard deviations of repeatability (S-r) and reproducibility (S-R) were used to evaluate the intra- and inter-laboratory variability, respectively. Examination of the s(R):s(r) ratios demonstrated that, while gastric and lysosomal fluids had reasonably good reproducibility, other fluids did not show as good concordance between laboratories. Relative standard deviation (RSD) analysis showed more favorable reproducibility outcomes for some data sets; overall results varied more between- than within-laboratories. RSD analysis of s(r) showed good within-laboratory variability for all conditions except some metals in interstitial fluid. In general, these findings indicate that absolute bioaccessibility results in some biological fluids may vary between different laboratories. However, for most applications, measures of relative bioaccessibility are needed, diminishing the requirement for high inter-laboratory reproducibility in absolute metal releases. The inter-laboratory exercise suggests that the degrees of freedom within the protocol need to be addressed.
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| 15. |
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| 16. |
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| 17. |
- Johnson, Candice, et al.
(författare)
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Skin sensitization in silico protocol
- 2020
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Ingår i: Regulatory toxicology and pharmacology. - : Elsevier BV. - 0273-2300 .- 1096-0295. ; 116
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Tidskriftsartikel (refereegranskat)abstract
- The assessment of skin sensitization has evolved over the past few years to include in vitro assessments of key events along the adverse outcome pathway and opportunistically capitalize on the strengths of in silico methods to support a weight of evidence assessment without conducing a test in animals. While in silico methods vary greatly in their purpose and format; there is a need to standardize the underlying principles on which such models are developed and to make transparent the implications for the uncertainty in the overall assessment. In this contribution, the relationship between skin sensitization relevant effects, mechanisms, and endpoints are built into a hazard assessment framework. Based on the relevance of the mechanisms and effects as well as the strengths and limitations of the experimental systems used to identify them, rules and principles are defined for deriving skin sensitization in silico assessments. Further, the assignments of reliability and confidence scores that reflect the overall strength of the assessment are discussed. This skin sensitization protocol supports the implementation and acceptance of in silico approaches for the prediction of skin sensitization.
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| 18. |
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| 19. |
- Karlsson, Mikael
(författare)
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Science and norms in policies for sustainable development: Assessing and managing risks of chemical substances and genetically modifed organisms in the European Union
- 2006
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Ingår i: Regulatory Toxicology and Pharmacology 44, 49-56. - : Elsevier BV. ; 44:1, s. 49-56
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Tidskriftsartikel (refereegranskat)abstract
- Use of chemical substances and genetically modifed organisms cause complex problems characterised by scientifc uncertainty and controversies. Aiming at sustainable development, policies for assessment, and management of risks in the two areas are under development in the European Union. The article points out that both science and norms play a central role in risk assessment as well as risk management and suggests that the precautionary principle, the principle of public participation, and the polluter pays principle, all adopted in the European Union, offer a way to operationalise the concept of sustainable development. It is shown, however, that a number of steps ought to be taken to better implement the principles through different policy measures. In doing so, and by recognising the role of both science and norms, the decision-making on risks related to the use of chemicals or genetically modifed organisms can be improved to better promote sustainable development
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| 20. |
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| 21. |
- Larsson, D. G. Joakim, 1969, et al.
(författare)
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Transparency throughout the production chain : a way to reduce pollution from the manufacturing of pharmaceuticals?
- 2009
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Ingår i: Regulatory toxicology and pharmacology. - : Elsevier BV. - 0273-2300 .- 1096-0295. ; 53:3, s. 161-163
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Tidskriftsartikel (refereegranskat)abstract
- Recent findings have shown that wastewater from bulk drug production can be a source of very high environmental concentrations of drugs in certain locations. The release of active ingredients is often not specifically regulated, and thus rapid initiatives from the industries themselves are warranted. Possible ways to stimulate action include changes in local and international regulations, including the implementation of appropriate environmental standards within existing industry guidelines as well as demands from prescribers and consumers of medicines. The lack of readily available information regarding the origin of drugs and the environmental impact of the production, however, prevents consumers from making informed decisions. Here, we investigated the origin of active pharmaceutical ingredients (APIs) in 242 selected products on the Swedish market. By comparing registers from Sweden and India we found that the APIs in 71 products (31%) originated from Indian manufacturers sending their waste to a treatment plant where unprecedented amount of environmental pollution with broad spectrum antibiotics and other drugs recently has been documented. We propose that increased transparency throughout the production chain would be one of several important steps to reducing pollution from the manufacturing of drugs.
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| 22. |
- Levin, Rikard, et al.
(författare)
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Indicators of uncertainty in chemical risk assessments
- 2004
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Ingår i: Regulatory toxicology and pharmacology. - : Elsevier BV. - 0273-2300 .- 1096-0295. ; 39:1, s. 33-43
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Tidskriftsartikel (refereegranskat)abstract
- For most of the chemical substances that are subject to regulatory and industrial decision making, important toxicological data are missing. The available dataset is often difficult to interpret, and the differences between alternative, scientifically reasonable interpretations may have major impact on decision making. Since such uncertainties are an important factor in decision making it is essential that they be reported in a transparent and understandable way. In order to clarify how toxicologists report uncertainties, 30 risk assessments for one and the same substance (trichloroethylene) from the years 1973-2001 were searched for phrases indicating uncertainty. These phrases can be divided between four categories: contentual, epistemic, conditionalising, and inferential uncertainty indicators. A typology of uncertainty indicators, based on these categories, is proposed. It is concluded that the use of uncertainty indicators in these texts is not transparent and that the development of standardised uncertainty indicators should significantly improve communications both within the scientific community and between scientists and policymakers.
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| 23. |
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| 24. |
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| 25. |
- Mazinanian, Neda, et al.
(författare)
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Nickel release and surface characteristics of fine powders of nickel metal and nickel oxide in media of relevance for inhalation and dermal contact
- 2013
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Ingår i: Regulatory toxicology and pharmacology. - : Elsevier BV. - 0273-2300 .- 1096-0295. ; 65:1, s. 135-146
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Tidskriftsartikel (refereegranskat)abstract
- Differences in surface oxide characteristics and extent of nickel release have been investigated in two thoroughly characterized micron-sized (mainly <4 mu m) nickel metal powders and a nickel oxide bulk powder when immersed in two different synthetic fluids, artificial sweat (ASW-pH 6.5) and artificial lysosomal fluid (ALF-pH 4.5) for time periods up to 24 h. The investigation shows significantly more nickel released from the nickel metal powders (<88%) compared to the NiO powder (<0.1%), attributed to differences in surface properties. Significantly more nickel was released from the nickel metal powder with a thin surface oxide predominantly composed of non-stoichiometric nickel oxide (probably Ni2O3), compared to the release from the nickel metal powder with a thicker surface oxide predominantly composed of NiO and to a lesser extent Ni2O3 (88% and 25% release after 24 h in ALF, respectively). Significantly lower amounts of nickel were released from the nickel metal powders in ASW (2.2% and <1%, respectively). The importance of particle and surface characteristics for any reliable risk assessment is discussed, and generated data compared with literature findings on bioaccessibility (released fraction) of nickel from powders of nickel metal and nickel oxide, and massive forms of nickel metal and nickel-containing alloys.
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| 26. |
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| 27. |
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| 28. |
- Molander, Linda, 1984-, et al.
(författare)
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Narrow-and-sharp or broad-and-blunt - Regulations of hazardous chemicals in consumer products in the European Union
- 2012
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Ingår i: Regulatory toxicology and pharmacology. - : Elsevier BV. - 0273-2300 .- 1096-0295. ; 62:3, s. 523-531
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Tidskriftsartikel (refereegranskat)abstract
- Chemicals are incorporated into a vast number of consumer products, and it has been recognized that considerable exposures of humans and the environment to chemicals are due to diffuse emissions from everyday products. Different approaches to the management of risks concerning chemicals in products are discussed on the international arena, but no general strategy has yet been adopted. The aim of this study is to investigate how health and environmental risks associated with chemicals in consumer products are currently managed in European Union legislations, mainly by the Toys Directive, the RoHS Directive, and REACH. Significant differences were found between the risk reduction strategies in these legislations, including substance prioritization, type of restrictions and requirements, and information dissemination to consumers. REACH regulates chemicals in products to a limited extent, and via quite complicated processes. Product-specific rules are therefore useful supplements to REACH for regulating chemicals in products. The combined effects of the RoHS and WEEE directives seem to be effective in promoting substitution of substances identified as problematic in electrical and electronic equipment, and it is recommended that the possibility to develop similar systems should be considered also for other product categories.
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| 29. |
- Molander, Linda, et al.
(författare)
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WikiPharma - A freely available, easily accessible, interactive and comprehensive database for environmental effect data for pharmaceuticals
- 2009
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Ingår i: Regulatory toxicology and pharmacology. - : Elsevier BV. - 0273-2300 .- 1096-0295. ; 55:3, s. 367-371
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Tidskriftsartikel (refereegranskat)abstract
- A significant number of Active Pharmaceutical Ingredients (APIs) have been identified in the environment and in surface waters. Data on the environmental hazards associated with these substances are emerging but are still scarce. We have compiled publicly available ecotoxicity data for APIs into a database called WikiPharma. The use of the database is free of charge. It can be accessed and updated continuously as a "wiki". The aim of WikiPharma is to provide an easily accessible, comprehensive and up-to-date overview of effects caused by pharmaceuticals on non-target organisms. The database currently contains basic information, i.e. substance name, ATC code(s) and pharmaceutical group(s), for 831 APIs representing 35 different drug classes. Effect data have been identified and included for 116 of these substances. These ecotoxicity test data have been extracted from 156 different sources. The development of a comprehensive database on ecological hazard of APIs can facilitate identification of data gaps and promote environmental risk assessment of these substances. The database is available at www.wikipharma.org.
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| 30. |
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| 31. |
- Mörsdorf, Alexander, et al.
(författare)
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Bioaccessibility of micron-sized powder particles of molybdenum metal, iron metal, molybdenum oxides and ferromolybdenum - Importance of surface oxides
- 2015
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Ingår i: Regulatory toxicology and pharmacology. - : Elsevier BV. - 0273-2300 .- 1096-0295. ; 72:3, s. 447-457
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Tidskriftsartikel (refereegranskat)abstract
- The European chemical framework REACH requires that hazards and risks posed by chemicals, including alloys and metals, that are manufactured, imported or used in different products (substances or articles) are identified and proven safe for humans and the environment. Metals and alloys need hence to be investigated on their extent of released metals (bioaccessibility) in biologically relevant environments. Read-across from available studies may be used for similar materials. This study investigates the release of molybdenum and iron from powder particles of molybdenum metal (Mo), a ferromolybdenum alloy (FeMo), an iron metal powder (Fe), MoO2, and MoO3 in different synthetic body fluids of pH ranging from 1.5 to 7.4 and of different composition. Spectroscopic tools and cyclic voltammetry have been employed to characterize surface oxides, microscopy, light scattering and nitrogen absorption for particle characterization, and atomic absorption spectroscopy to quantify released amounts of metals. The release of molybdenum from the Mo powder generally increased with pH and was influenced by the fluid composition. The mixed iron and molybdenum surface oxide of the FeMo powder acted as a barrier both at acidic and weakly alkaline conditions. These findings underline the importance of the surface oxide characteristics for the bioaccessibility of metal alloys.
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| 32. |
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| 33. |
- Nilsson, Robert
(författare)
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The molecular basis for induction of human cancers by tobacco specific nitrosamines
- 2011
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Ingår i: Regulatory toxicology and pharmacology. - : Elsevier BV. - 0273-2300 .- 1096-0295. ; 60:2, s. 268-280
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Tidskriftsartikel (refereegranskat)abstract
- Cellular DNA damage that is misrepaired or not repaired, constitutes a necessary, although not sufficient prerequisite for induction of cancer. For carcinogenic oral snuffs with extremely high concentrations of tobacco specific nitrosamines (TSNA) the DNA adduct levels predicted from animal experiments exceed those found in unexposed individuals. On the other hand, and supported by extensive Swedish epidemiological data, no significant increase of TSNA-induced DNA damages can be anticipated in humans from the use of low-nitrosamine oral snuffs. The extrapolated adduct concentrations are orders of magnitude lower than those found in the corresponding human tissues, a discrepancy that is difficult to account for by species differences. Furthermore, in exposed subjects the observed increment in the background levels of pyridyloxobutyl(POB)-hemoglobin adducts - a relevant indicator for TSNA activation - lie in a range predicted by rodent data. When based on the same type of tissues this provides justification for extrapolating rates of TSNA induced adduct formation from animals to humans. A TSNA exposure that does not affect the background level of pro-mutagenic DNA lesions should be considered as virtually safe. The high background concentrations of methylated and POB-DNA adducts in unexposed humans must be ascribed to other sources than tobacco.
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| 34. |
- Nordberg, Anna, et al.
(författare)
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Towards more efficient testing strategies - analyzing the efficiency of toxicity data requirements in relation to the criteria for classification and labelling
- 2008
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Ingår i: Regulatory toxicology and pharmacology. - : Elsevier BV. - 0273-2300 .- 1096-0295. ; 50:3, s. 412-419
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Tidskriftsartikel (refereegranskat)abstract
- This contribution is based on the assumption that the aim of toxicity testing as required by chemicals legislation is to identify as many chemicals of concern to human health and the environment as possible, given a limited amount of resources allocated to testing. Based on this assumption we propose a method for the optimization of test systems for industrial chemicals, based on the calculation of efficiency ratios for tests and test systems. The efficiency ratio of a toxicity test depends on the monetary cost of performing the test and the probability that the test will identify a chemical of concern, as estimated by the rules for classification and warning labelling. Efficiency ratios are estimated based on the results of basic standardized toxicity testing for acute toxicity, subacute toxicity, irritation and sensitization of 1409 industrial chemicals notified in the European Union between 1994 and 2004. This careful evaluation of the regulatory consequences of testing indicated that many of these substances are classified based on short-term testing of acute toxicity, irritation and sensitization and that most of the substances classified due to a 28-day study were also classified based on short-term testing. These results indicate that, within the classification and labelling system, it is currently more efficient to perform short-term testing of a larger number of substances rather than to perform subacute toxicity studies on substances already tested for acute toxicity.
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| 35. |
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| 36. |
- Norrgren, Leif
(författare)
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Optimizing the design of a reproduction toxicity test with the pond snail Lymnaea stagnalis
- 2016
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Ingår i: Regulatory Toxicology and Pharmacology. - : Elsevier BV. - 0273-2300 .- 1096-0295. ; 81, s. 47-56
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Tidskriftsartikel (refereegranskat)abstract
- This paper presents the results from two ring-tests addressing the feasibility, robustness and reproducibility of a reproduction toxicity test with the freshwater gastropod Lymnaea stagnalis (RENILYS strain). Sixteen laboratories (from inexperienced to expert laboratories in mollusc testing) from nine countries participated in these ring-tests. Survival and reproduction were evaluated in L. stagnalis exposed to cadmium, tributyltin, prochloraz and trenbolone according to an OECD draft Test Guideline. In total, 49 datasets were analysed to assess the practicability of the proposed experimental protocol, and to estimate the between-laboratory reproducibility of toxicity endpoint values. The statistical analysis of count data (number of clutches or eggs per individual-day) leading to ECx estimation was specifically developed and automated through a free web-interface. Based on a complementary statistical analysis, the optimal test duration was established and the most sensitive and cost-effective reproduction toxicity endpoint was identified, to be used as the core endpoint. This validation process and the resulting optimized protocol were used to consolidate the OECD Test Guideline for the evaluation of reproductive effects of chemicals in L stagnalis. (C) 2016 Elsevier Inc. All rights reserved.
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| 37. |
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| 38. |
- Oskarsson, Agneta
(författare)
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Meeting report: International workshop on endocrine disruptors: Exposure and potential impact on consumers health
- 2013
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Ingår i: Regulatory Toxicology and Pharmacology. - : Elsevier BV. - 0273-2300 .- 1096-0295. ; 65, s. 7-11
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Tidskriftsartikel (refereegranskat)abstract
- The French Agency for Food, Environmental and Occupational Health and Safety (Anses) hosted a twoday workshop on Endocrine Disruptors: Exposure and Potential Impact on Consumers Health, bringing together participants from international organizations, academia, research institutes and from German, Swedish, Danish and French governmental agencies. The main objective of the workshop was to share knowledge and experiences on endocrine disruptors (ED) exposure and potential impact on consumers' health, to identify current risk assessment practices and knowledge gaps and issue recommendations on research needs and future collaboration. The following topics were reviewed: (1) Definition of ED, (2) endpoints to be considered for Risk assessment (RA) of ED, (3) non-monotonic dose response curves, (4) studies to be considered for RA (regulatory versus academic studies), (5) point of departure and uncertainty factors, (6) exposure assessment, (7) regulatory issues related to ED. The opinions expressed during this workshop reflect day-to-day experiences from scientists, regulators, researchers, and others from many different countries in the fields of risk assessment, and were regarded by the attendees as an important basis for further discussions. Accordingly, the participants underlined the need for more exchange in the future to share experiences and improve the methodology related to risk assessment for endocrine disrupters.
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| 39. |
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| 40. |
- Rudén, Christina, et al.
(författare)
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Improving REACH
- 2006
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Ingår i: Regulatory toxicology and pharmacology. - : Elsevier BV. - 0273-2300 .- 1096-0295. ; 44:1, s. 33-42
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Tidskriftsartikel (refereegranskat)abstract
- The European Commission has proposed a new system for chemicals control, the REACH system. The objectives of REACH with respect to risk assessment call be summarized in the form of two overarching goals. First, REACH aims at improved knowledge about the properties and the uses of individual chemical substances. Secondly, REACH is intended to increase the speed and efficiency of the risk assessment process and to make producers and importers of chemicals responsible for this process. The implementation of the REACH proposal will lead to increased availability of toxicological information but not to the extent that would be needed to achieve a Sound scientific basis for risk assessment of individual substances. In this paper, we propose certain amendments of the Current REACH proposal. The Purpose of these proposals is to improve priority-setting and testing strategies and to simplify the risk assessment procedures.
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| 41. |
- Rudén, Christina
(författare)
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Principles and practices of health risk assessment under current EU regulations
- 2006
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Ingår i: Regulatory toxicology and pharmacology. - : Elsevier BV. - 0273-2300 .- 1096-0295. ; 44:1, s. 14-23
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Tidskriftsartikel (refereegranskat)abstract
- Risk assessments serve as the foundation of regulatory decision-making on whether to take actions to reduce (or otherwise manage) a toxicological or ecotoxicological risk or not. To understand the complex process that leads from the generation of scientific data, via risk assessment to risk management decision-making, close studies of the scientific basis and risk assessment methods must be undertaken. This paper consists of two main parts. In the first part the principles of the European Union process for risk assessments, as defined by legislations and official guidelines, are briefly outlined. In the second part the actual workings of this system are exemplified by the results from case studies of the risk assessment processes for trichloroethylene and for acrylamide. The analysis and comparison of these two cases illustrates: (1) that generation of a large amount of data does not ensure consensus among risk assessors, (2) that controversy can regard different levels of detail, (3) that controversy can arise at different organizational and theoretical levels, (4) that risk assessments may be subject to (public) criticism even if the experts agree, and (5) that scientific controversies have a significant policy component.
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| 42. |
- Rudén, Christina
(författare)
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The use and evaluation of primary data in 29 trichloroethylene carcinogen risk assessments
- 2001
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Ingår i: Regulatory toxicology and pharmacology. - : Elsevier BV. - 0273-2300 .- 1096-0295. ; 34:1, s. 3-16
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 43. |
- Rudén, Christina
(författare)
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The use of mechanistic data and the handling of scientific uncertainty in carcinogen risk assessments - The trichloroethylene example
- 2002
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Ingår i: Regulatory toxicology and pharmacology. - : Elsevier BV. - 0273-2300 .- 1096-0295. ; 35:1, s. 80-94
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Tidskriftsartikel (refereegranskat)abstract
- The purpose of this paper is to explore how risk assessors actually use mechanistic data in carcinogen risk assessment and to discuss how the handling of scientific uncertainty may affect the outcome of the risk assessment. The analysis is performed by comparing 29 trichloroethylene risk assessment documents in general and 2 of these, namely the ECETOC (1994, Trichloroethylene: Assessment of Human Carcinogenic Hazard, Technical Report No. 60) and the OECD/EU (1996, Initial Assessment Report for the 4th SIAM (Screening Information Data Set Initial Assessment Meeting), May 1996: Trichloroethylene, sponsor country, United Kingdom [Draft]), in more detail. It is concluded that in this example the ECETOC required less evidence for considering a carcinogenic mechanism irrelevant to humans than did the OECD/EU risk assessors. There are examples of when two risk assessors have selected different primary data for their argumentation and also examples of how one and the same primary publication was interpreted differently. Biased data selection and evaluation of primary data that correlate to the risk assessor's overall conclusions have also been identified. The general comparison of all 29 TCE risk assessment documents indicates that the assessment of scientific uncertainty in the mechanistic data affects the overall conclusions.
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| 44. |
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| 45. |
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| 46. |
- Schenk, Linda
(författare)
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Awareness and understanding of occupational exposure limits in Sweden
- 2013
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Ingår i: Regulatory toxicology and pharmacology. - : Elsevier BV. - 0273-2300 .- 1096-0295. ; 65:3, s. 304-310
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Tidskriftsartikel (refereegranskat)abstract
- The efficiency of a risk management tool, such as occupational exposure limits (OELs), partly depends on the responsible parties' awareness and understanding of it. The aim of this study was to measure the awareness and understanding of OELs at Swedish workplaces and to collect opinions on their use and function. Through a web-based questionnaire targeting workers that are exposed to air pollutants or chemicals, and persons working with occupational health and safety or in management at workplaces where workers are exposed to air pollutants or chemicals 1017 responses were collected. The results show that awareness and understanding of Swedish OELs is low among workers, as well as managers and occupational health and safety employees. Statistically significant, but small, differences were found depending on the size of the company and the position in the company. Based on the results, it is recommended that authorities and the social partners target this lack of awareness and understanding regarding OELs. Also, other tools to ascertain a safe working environment with regards to chemicals exposure might be useful for Swedish workplaces.
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| 47. |
- Schenk, Linda, 1980-, et al.
(författare)
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Management of bias and conflict of interest among occupational exposure limit expert groups
- 2021
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Ingår i: Regulatory toxicology and pharmacology. - : Elsevier BV. - 0273-2300 .- 1096-0295. ; 123
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Tidskriftsartikel (refereegranskat)abstract
- Our aim was to evaluate policies and procedures for management of conflict of interest (CoI) and other sources of bias, implemented in Occupational Exposure Limit (OEL) expert groups. First, we compiled procedural criteria applicable to OEL-setting, based on literature on CoI and systematic reviews. Second, we identified 58 global OEL-sources and sought the underlying expert groups and operating procedures. We identified eleven active groups, of which five have documented CoI policies. In all five, CoI management is based on declarations of interests (DoIs) and removal of experts from decisions in which they have an interest. Notable differences include publication of DoIs (three of five groups), limitation of DoI to current interests (two groups), quantitative limits for financial interests (none specified to ≥€10,000 per interest), control procedures for undisclosed CoI (one group), and procedures in case of discovery of undisclosed CoI (three groups). Methods to evaluate study quality are described by three groups, while reproducible and comprehensive strategies to identify and select data receive less attention. We conclude that procedures to manage CoI and bias are not broadly implemented, or at least not openly and transparently communicated. This lack of visible procedures is remarkable, considering OEL's impact on health and economy.
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| 48. |
- Schenk, Linda, et al.
(författare)
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Occupational Exposure Limits : A Comparative Study
- 2008
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Ingår i: Regulatory toxicology and pharmacology. - : Elsevier. - 0273-2300 .- 1096-0295. ; 50:2, s. 261-270
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Tidskriftsartikel (refereegranskat)abstract
- Occupational exposure limits (OELs) are used as an important regulatory instrument to protect workers' health from adverse effects of chemical exposures. The OELs mirror the outcome of the risk assessment and risk management performed by the standard setting actor. In this study we compared the OELs established by 18 different organisations or national regulatory agencies. The OELs were compared with respect to: (1) what chemicals have been selected and (2) the average level of exposure limits for all chemicals. Our database contains OELs for a total of 1341 substances; of these 25 substances have OELs from all 18 organisations while more than one-third of the substances are only regulated by one organisation. The average level of the exposure limits has declined during the past 10 years for 6 of the 8 organisations in our study for which historical data were available; it has increased for Poland and remained nearly unchanged for Sweden. The average level of OELs differs substantially between organisations; the US OSHA exposure limits are (on average) nearly 40 % higher than those of Poland. The scientific or policy-related motivations for these differences remain to be analysed.
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| 49. |
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| 50. |
- Wang, Xuying, et al.
(författare)
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Bioaccessibility of nickel and cobalt in powders and massive forms of stainless steel, nickel- or cobalt-based alloys, and nickel and cobalt metals in artificial sweat
- 2019
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Ingår i: Regulatory toxicology and pharmacology. - : Academic Press Inc.. - 0273-2300 .- 1096-0295. ; 106, s. 15-26
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Tidskriftsartikel (refereegranskat)abstract
- Nickel (Ni)and cobalt (Co)are the most common metal allergens upon skin contact at occupational settings and during consumer handling of metals and alloys. A standardized test (EN, 1811)exists to assess Ni release from articles of metals and alloys in massive forms intended for direct and prolonged skin contact, but no corresponding test exists for other materials such as powders or massive forms of alloys placed on the market or to determine the release of Co, for which only limited data is available. Differences in Ni and Co release from massive forms of a range of common stainless steels and some high-alloyed grades compared to Ni and Co metals were therefore assessed in artificial sweat for 1 week at 30 °C according to EN 1811. A comparable modified test procedure was elaborated and used for powders and some selected massive alloys. All alloys investigated released significantly less amount of Ni (100–5000-fold)and Co (200–400,000-fold)compared with Ni and Co metal, respectively. Almost all alloys showed a lower bioaccessible concentration (0.007–6.8 wt% Ni and 0.00003–0.6 wt% Co)when compared to corresponding bulk alloy contents (0.1–53 wt% Ni, 0.02–65 wt% Co). Observed differences are, among other factors, related to differences in bulk composition and to surface oxide characteristics. For the powders, less Ni and Co were released per surface area, but more per mass, compared to the corresponding massive forms.
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