Elsa Nielsen

Toxicological risk assessment of chemicals : a practical guide

Introduction. Data for Hazard Identification and Characterisation. Hazard Assessment. Exposure Assessment. Risk Characterisation. Combination Effects.

Toxicological risk assessment of elemental gold following oral exposure to sheets and nanoparticles - A review.

Elemental gold is used as a food coloring agent and in dental fillings. In addition, gold nanoparticles are gaining increasing attention due to their potential use as inert carriers for medical purposes. Although elemental gold is considered to be inert, there is evidence to suggest the release of gold ions from its surface. Elemental gold, or the released ions, is, to some extent, absorbed in the gastrointestinal tract. Gold is distributed to organs such as the liver, heart, kidneys and lungs. The main excretion route of absorbed gold is through urine. Data on the oral toxicity of elemental gold is limited. The acute toxicity of elemental gold seems to be low, as rats were unaffected by a single dose of 2000mg nanoparticles/kg of body weight. Information on repeated dose toxicity is very limited. Skin rashes have been reported in humans following the ingestion of liquors containing gold. In addition, gold released from dental restorations has been reported to increase the risk of developing gold hypersensitivity. Regarding genotoxicity, in vitro studies indicate that gold nanoparticles induce DNA damage in mammalian cells. In vivo, gold nanoparticles induce genotoxic effects in Drosophila melanogaster; however, genotoxicity studies in mammals are lacking. Overall, based on the literature and taking low human exposure into account, elemental gold via the oral route is not considered to pose a health concern to humans in general.

Cumulative dietary exposure of the population of Denmark to pesticides.

We used the Hazard Index (HI) method to carry out a cumulative risk assessment after chronic dietary exposure to all monitored pesticides in fruit, vegetables and cereals for various consumer groups in Denmark. Residue data for all the pesticides were obtained from the Danish monitoring programme during the period 2004-2011. Food consumption data were obtained from DANSDA (the DAnish National Survey of Diet and physical Activity) for the period 2005-2008. The calculations were made using three different models to cope with residues below the limit of reporting (LOR). We concluded that a model that included processing factors and set non-detects to ½ LOR, but limited the correction (Model 3), gave the most realistic exposure estimate. With Model 3 the HI was calculated to be 0.44 for children and 0.18 for adults, indicating that there is no risk of adverse health effects following chronic cumulative exposure to the pesticides found in fruit, vegetables and cereals on the Danish market. The HI was below 1 even for consumers who eat more than 550 g of fruit and vegetables per day, corresponding to 1/3 of the population. Choosing Danish-produced commodities whenever possible could reduce the HI by a factor of 2.

A semi-quantitative model for risk appreciation and risk weighing.

Risk managers need detailed information on (1) the type of effect, (2) the size (severity) of the expected effect(s) and (3) the fraction of the population at risk to decide on well-balanced risk reduction measures. A previously developed integrated probabilistic risk assessment (IPRA) model provides quantitative information on these three parameters. A semi-quantitative tool is presented that combines information on these parameters into easy-readable charts that will facilitate risk evaluations of exposure situations and decisions on risk reduction measures. This tool is based on a concept of health impact categorization that has been successfully in force for several years within several emergency planning programs. Four health impact categories are distinguished: No-Health Impact, Low-Health Impact, Moderate-Health Impact and Severe-Health Impact. Two different charts are presented to graphically present the information on the three parameters of interest. A bar plot provides an overview of all health effects involved, including information on the fraction of the exposed population in each of the four health impact categories. Secondly, a Health Impact Chart is presented to provide more detailed information on the estimated health impact in a given exposure situation. These graphs will facilitate the discussions on appropriate risk reduction measures to be taken.

Survey on methodologies in the risk assessment of chemical exposures in emergency response situations in Europe

A scientifically sound assessment of the risk to human health resulting from acute chemical releases is the cornerstone for chemical incident prevention, preparedness and response. Although the general methodology to identify acute toxicity of chemicals has not substantially changed in the last decades, there is ongoing debate on the current approaches for human health risk assessment in scenarios involving acute chemical releases. A survey was conducted to identify: (1) the most important present and potential future chemical incident scenarios and anticipated changes in chemical incidents or their management; (2) information, tools and guidance used in different countries to assess health risks from acute chemical releases; and (3) needs for new information, tools, guidance and expertise to enable the valid and rapid health risk assessment of acute chemical exposures. According to the results, there is an obvious variability in risk assessment practices within Europe. The multiplicity of acute exposure reference values appears to result in variable practices. There is a need for training especially on the practical application of acute exposure reference values. Although acutely toxic and irritating/corrosive chemicals will remain serious risks also in future the development of plausible scenarios for potential emerging risks is also needed. This includes risks from new mixtures and chemicals (e.g. nanoparticles).

Opinion of the Scientific Committee on Consumer Safety (SCCS)--The safety of the use of formaldehyde in nail hardeners.

2015 Elsevier Inc. All rights reserved. The substance formaldehyde (CAS Number 50-00-0) is anticipated to be classified as a carcinogen category 1B under the CLP Regulation (EC) No. 1272/2008. However, such substances may be used in cosmetic products by way of exception where, subsequent to their classification as CMR substances of category 1A or 1B under Part 3 of Annex VI to Regulation (EC) No. 1272/2008, all of the conditions of Article 15.2 of the Cosmetics Regulation are fulfilled: (a) They comply with the food safety requirements as defined in Regulation (EC) No. 178/2002 of the European Parliament and of the Council of 28 January 2002 laying down the general principles and requirements of food law, establishing the European Food Safety Authority and laying down procedures in matter of food safety; (b) there are no suitable alternative substances available, as documented in an analysis of alternatives; (c) the application is made for a particular use of the product category with a known exposure; and (d) they have been evaluated and found safe by the SCCS for use in cosmetic products, in particular in view of exposure to these products and taking into consideration the overall exposure from other sources, taking particular account of vulnerable population subgroups. Formaldehyde is used in nail hardeners for its specific crosslinking functionality with keratin. The use of formaldehyde in nail hardeners is currently restricted as specified in the Entry 13 of Annex III of Regulation (EC) No. 1223/2009 – i.e., a maximum concentration in the finished products of 5% (as formaldehyde); labelled as ‘contains formaldehyde’ when the finished cosmetic product contains formaldehyde in a concentration above 0.05% and with the warning ‘protect cuticles with grease or oil’. On 23 May 2013, the European Commission published a call for data on formaldehyde use in cosmetics and/or formaldehyde released by others substances used in cosmetics, seeking also information of the suitable alternatives. The Commission only received a full application from Cosmetics Europe which supports the use of formaldehyde in nail hardeners at the maximum level of 2.2% (as free formaldehyde). In view of the data that became available, the independent Scientific Committee on Consumer Safety (SCCS) was asked (i) to assess if condition d) of Article 15.2 is fulfilled, in order to confirm or not the safe use of formaldehyde in nail hardeners at the maximum level of 2.2% (as free formaldehyde) and (ii) to indicate if there are any further scientific concerns with regard to the use of formaldehyde in nail hardeners.

A call for action: Improve reporting of research studies to increase the scientific basis for regulatory decision-making

This is a call for action to scientific journals to introduce reporting requirements for toxicity and ecotoxicity studies. Such reporting requirements will support the use of peer‐reviewed research studies in regulatory decision‐making. Moreover, this could improve the reliability and reproducibility of published studies in general and make better use of the resources spent in research.

Clarification of some aspects related to genotoxicity assessment

Abstract The European Commission requested EFSA to provide advice on the following: (1) the suitability of the unscheduled DNA synthesis (UDS) in vivo assay to follow‐up positive results in in vitro gene mutation tests; (2) the adequacy to demonstrate target tissue exposure in in vivo studies, particularly in the mammalian erythrocyte micronucleus test; (3) the use of data in a weight‐of‐evidence approach to conclude on the genotoxic potential of substances and the consequent setting of health‐based guidance values. The Scientific Committee concluded that the first question should be addressed in both a retrospective and a prospective way: for future assessments, it is recommended no longer performing the UDS test. For re‐assessments, if the outcome of the UDS is negative, the reliability and significance of results should be carefully evaluated in a weight‐of‐evidence approach, before deciding whether more sensitive tests such as transgenic assay or in vivo comet assay would be needed to complete the assessment. Regarding the second question, the Scientific Committee concluded that it should be addressed in lines of evidence of bone marrow exposure: toxicity to the bone marrow in itself provides sufficient evidence to allow concluding on the validity of a negative outcome of a study. All other lines of evidence of target tissue exposure should be assessed within a weight‐of‐evidence approach. Regarding the third question, the Scientific Committee concluded that any available data that may assist in reducing the uncertainty in the assessment of the genotoxic potential of a substance should be taken into consideration. If the overall evaluation leaves no concerns for genotoxicity, health‐based guidance values may be established. However, if concerns for genotoxicity remain, establishing health‐based guidance values is not considered appropriate.

Physicologically Based Toxicokinetic Models of Tebuconazole and Application in Human Risk Assessment

A series of physiologically based toxicokinetic (PBTK) models for tebuconazole were developed in four species, rat, rabbit, rhesus monkey, and human. The developed models were analyzed with respect to the application of the models in higher tier human risk assessment, and the prospect of using such models in risk assessment of cumulative and aggregate exposure is discussed. Relatively simple and biologically sound models were developed using available experimental data as parameters for describing the physiology of the species, as well as the absorption, distribution, metabolism, and elimination (ADME) of tebuconazole. The developed models were validated on in vivo half-life data for rabbit with good results, and on plasma and tissue concentration-time course data of tebuconazole after i.v. administration in rabbit. In most cases, the predicted concentration levels were seen to be within a factor of 2 compared to the experimental data, which is the threshold set for the use of PBTK simulation results in risk assessment. An exception to this was seen for one of the target organs, namely, the liver, for which tebuconazole concentration was significantly underestimated, a trend also seen in model simulations for the liver after other nonoral exposure scenarios. Possible reasons for this are discussed in the article. Realistic dietary and dermal exposure scenarios were derived based on available exposure estimates, and the human version of the PBTK model was used to simulate the internal levels of tebuconazole and metabolites in the human body for these scenarios. By a variant of the models where the R(-)- and S(+)-enantiomers were treated as two components in a binary mixture, it was illustrated that the inhibition between the two tebuconazole enantiomers did not affect the simulation results for these realistic exposure scenarios. The developed models have potential as an important tool in risk assessment.

Assessment of genetically modified cotton GHB614 × T304‐40 × GHB119 for food and feed uses, import and processing under Regulation (EC) No 1829/2003 (application EFSA‐GMO‐NL‐2014‐122)

The three-event stack cotton GHB614 9 T304-40 9 GHB119 was produced by conventional crossing to combine three single events, GHB614, T304-40 and GHB119. The genetically modified organisms (GMO) Panel previously assessed the three single cotton events and did not identify safety concerns. No new data on the single cotton events that could lead to modification of the original conclusions on their safety were identified. Based on the molecular, agronomic, phenotypic and compositional characteristics, the combination of the single cotton events and of the newly expressed proteins in the three-event stack cotton did not give rise to food and feed safety concern. The GMO Panel considers that the three-event stack cotton GHB614 9 T304-40 9 GHB119 has the same nutritional impact as its comparator and the non-GM reference varieties tested. The GMO Panel concludes that the three-event stack cotton GHB614 9 T304-40 9 GHB119, as described in this application, is nutritionally equivalent to and as safe as its comparator and the non-GM reference varieties tested, and no post-market monitoring of food/feed is considered necessary. In the case of accidental release of viable GHB614 9 T304-40 9 GHB119 cottonseeds into the environment, this three-event stack would not raise environmental safety concerns. The post-market environmental monitoring plan and reporting intervals are in line with the intended uses of cotton GHB614 9 T304-40 9 GHB119 seeds. The GMO Panel concludes that cotton GHB614 9 T304-40 9 GHB119, as described in this application, is as safe as its comparator and the tested non-GM reference varieties with respect to potential effects on human and animal health and the environment.