The potential of computer-based quantitative structure activity approaches for predicting acute toxicity of chemicals

Within the EU, the management of the risks of chemicals currently falls under a new legislation called Registration, Evaluation, and Authorization of Chemicals (REACH). Within the next 10 years, existing (eco)toxicological data gaps for the more than 100 000 chemicals on the European Inventory of Existing Commercial Substances (EINECS) should be filled. The challenge is to provide this toxicity information in a fast, cost effective manner, avoiding the use of experimental animals as much as possible. In this regard, REACH has provisions to allow for the use of in vitro and/or in silico methods, e.g. those based on (Quantitative) Structure Activity Relationships [(Q)SARs], to provide toxicity information or identify hazards of chemicals. This information can subsequently be used to identify priority chemicals for further risk evaluation. A QSAR is based on the assumption that the biological activity of a new or untested chemical can be inferred from the molecular structure, or properties of similar compounds whose activities have already been assessed. Therefore, using the chemical structure of chemical compounds as the sole input, one can build a toxicity prediction model based on parameters that define the physico-chemical properties and relative reactivity of the compounds. The objective of this thesis was to apply OECD guidelines in the development of validated QSAR models that describe acute toxicity of selected groups of EINECS chemicals to various organisms. In addition, an estimate was made of the total number of EINECS chemicals that could be possibly evaluated using (Q)SAR approaches. Based on experimental toxicity data from literature and in silico calculated log Kow (a measure of hydrophobicity) values, a QSAR advisory tool was developed that directs users to the appropriate QSAR model to apply for predicting toxicity of substituted mononitrobenzenes to five types of organisms within specified log Kow ranges. In a next study, QSAR models were developed to predict in vivo acute toxicity of chlorinated alkanes to fish based on data from in vitro experiments, and even based on in silico log Kow data only. Furthermore, using toxicity data from acute immobilization experiments with daphnids, an interspecies QSAR model was developed to predict toxicity of organothiophosphate pesticides to fish based on these data for daphnids and in silico log Kow values. The QSAR models for the mononitrobenzenes, chlorinated alkanes, and organothiophosphates covered in total 0.7 % of the 100 196 EINECS chemicals. In a final step, using chemical classification software, 54 % of the EINECS chemicals were grouped into specific classes that can in theory be subject to QSAR modeling. The safety assessment of one group of compounds that could not be classified e.g. botanical extracts might be done by further development of a method recently reported for the safety assessment of natural flavour complexes used as ingredients in food. This would result in an additional 3 % of the EINECS chemicals that could potentially be covered by SAR approaches, bringing the total percentage of EINECS compounds that can be covered by (Q)SAR approaches to 57. In conclusion, the results of this thesis reveal that, (i) in vitro experiments and even in silico calculations can help to reduce or replace animals used for experimental toxicity testing and (ii) despite the fact that individual QSARs may often each cover only limited, i.e. less than 1%, of the EINECS compounds, (Q)SAR approaches have the potential to cover about 57 % of the EINECS compounds. <br/

Promises and pitfalls of Quantitative Structure-Activity Relationship approaches for predicting metabolism and toxicity

The description of quantitative structure¿activity relationship (QSAR) models has been a topic for scientific research for more than 40 years and a topic within the regulatory framework for more than 20 years. At present, efforts on QSAR development are increasing because of their promise for supporting reduction, refinement, and/or replacement of animal toxicity experiments. However, their acceptance in risk assessment seems to require a more standardized and scientific underpinning of QSAR technology to avoid possible pitfalls. For this reason, guidelines for QSAR model development recently proposed by the Organization for Economic Cooperation and Development (OECD) [ Organization for Economic Cooperation and Development (OECD) (2007) Guidance document on the validation of (quantitative) structure¿activity relationships [(Q)SAR] models. OECD Environment Health and Safety Publications: Series on Testing and Assessment No. 69, Paris] are expected to help increase the acceptability of QSAR models for regulatory purposes. The guidelines recommend that QSAR models should be associated with (i) a defined end point, (ii) an unambiguous algorithm, (iii) a defined domain of applicability, (iv) appropriate measures of goodness-of-fit, robustness, and predictivity, and (v) a mechanistic interpretation, if possible [ Organization for Economic Cooperation and Development (OECD) (2007) Guidance document on the validation of (quantitative) structure¿activity relationships [(Q)SAR] models. The present perspective provides an overview of these guidelines for QSAR model development and their rationale, as well as the promises and pitfalls of using QSAR approaches and these guidelines for predicting metabolism and toxicity of new and existing chemicals

Economic valuation of potential products from Jatropha seed in five selected countries: Zimbabwe, Tanzania, Mali, Indonesia, and The Netherlands

Currently, Jatropha seeds are mainly used to produce biodiesel, and a resultant press cakeis obtained as a by-product. Jatropha press cake fractionation and conversion into variouspotential products using biorefinery, could improve the economic value of Jatropha seed.The objectives of this study were to calculate the potential generated income and economicvalue of products from Jatropha. These were classified into two product groups: 1) Ruralproducts, and 2) Industrial products. The potential generated income is the summation ofthe net profit and the labour costs. Using the national gross domestic product (GDP) percapita as a reference, we calculated and compared the potential economic value, whichexpresses the number of people that could obtain a certain income for every hectare ofJatropha plantation, in five selected countries. These countries consisted of four developingcountries: Tanzania, Mali, Zimbabwe, and Indonesia, and a developed country, theNetherlands. This study shows that the potential generated income from rural productsper hectare of (imported) Jatropha was much lower than the income of one person inIndonesia and the Netherlands. In Zimbabwe, Tanzania, and Mali, the potential economicvalue per hectare Jatropha suggests that manufacturing rural products can generate potentialincome for one person. Manufacturing industrial products can generate potentialincome for one person in the Netherlands and approx. 7e39 people in Indonesia,Zimbabwe, Tanzania, and Mali. In conclusion, the potential generated income is highlydependent on the GDP per capita and the price of the selected products in each country

On the number of EINECS compounds that can be covered by (Q)SAR models for acute toxicity

The new EU legislation for managing chemicals called REACH aims to fill in gaps in toxicity information that exist for the chemicals listed on the European Inventory of Existing Chemical Substances (EINECS). REACH advocates the use of alternatives to animal experimentation including, amongst others, (quantitative) structure¿activity relationship models [(Q)SARs] to help fill in the toxicity data gaps. The aim of the present study was to provide a science-based estimate of the number of EINECS compounds that can be covered by (Q)SAR models for acute toxicity. Using the ECOSAR software, 54% of the 100 196 EINECS chemicals were classified into 49 classes that can be potentially covered by (Q)SAR models. The largest proportion of the classified compounds (40% of the EINECS list) falls into the classes of non-polar and polar narcotics. Compounds that were not classified include, for example, fish oils, botanical and animal extracts, and crude oil distillates. With rapid improvements in analytical tools, the number of EINECS compounds for which toxicity evaluations may be based on (Q)SAR approaches may be extended by further developing the method recently developed for the safety assessment of natural flavor complexes used as ingredients in food. This method is based on identification of the individual components in a mixture, and judgment of the safety of these identified individual compounds using toxicity information on structurally similar congeners in the respective classes. Such (Q)SAR approaches may be applied to an additional 2938 EINECS compounds, representing botanical and animal extracts, leading to a total estimate of 57% of the EINECS compounds for which (Q)SAR-based approaches may assist in their safety assessment. It is concluded that, despite the fact that individual (Q)SARs may often each cover only a limited number, i.e. less than 1%, of the EINECS compounds, the potential for applying (Q)SAR approaches for safety assessment of EINECS compounds may prove to be significant

Disruption of thyroid hormone-mediated Xenopus laevis tadpole tail tip regression by hexabromocyclododecane (HBCD) and 2,2',3,3',4,4',5,5',6-nona brominated diphenyl ether (BDE206)

Thyroid hormone regulates amphibian metamorphosis, including the transformation of a tadpole into a froglet and regression of the tail. Xenopus laevis tadpole tail tips in organ culture (ex vivo) undergo regression when exposed to 3,3',5-triiodo-l-thyronine (T(3)) and interference by chemicals with this process was utilized as a bioassay to detect thyroid hormone disruption. In the present study the bioassay was further validated by investigating its response to compound induced T(3)-antagonism and - potentiation. Tadpole tail tips were exposed to two brominated flame retardants (BFRs) in presence or absence of T(3) at its EC(50) (20nM). T(3)-induced tail tip regression was antagonized by 2,2',3,3',4,4',5,5',6-nona brominated diphenyl ether (BDE206) and potentiated by hexabromocyclododecane (HBCD) in a concentration dependent manner, which was consistent with results obtained with a in vitro T(3)-dependent proliferation bioassay termed the T-screen. Neither compound induced any effect in the absence of T(3). The results indicate that studying possible hormone disrupting effects of agonistic, antagonistic or potentiating compounds should include combined exposure with the natural hormone at around its EC(50) concentration. The results obtained with the tail tip exposures were in accordance with the T-screen predictions, and occurred at BFR-concentrations that were only 5-50 times those of T(3). The bioassay proved to be suitable not only for detecting T(3)-agonism, but also for antagonism and potentiation

Cassava for food and energy: exploring potential benefits of processing of cassava into cassava flour and bioenergy at farmstead and community levels in rural Mozambique

As in most of sub-Sahara Africa, rural people in Mozambique use firewood as their main source of energy. The use of firewood is associated with several health problems, and the time spent collecting it reduces time for other activities. Cassava is grown as a reserve crop in Mozambique where it is considered a ‘woman's crop’. Because the crop is drought-tolerant and resistant to diseases, it needs little attention and hence little labor input. This paper examines how the rural people in the case of Mozambique can use their current reserve crop, cassava, to meet their energy needs and food requirements and to increase their annual income. Cassava processing chains were modeled to assess (i) the effect of introducing an anaerobic digester for the digestion of cassava peels and other material (dung, kitchen waste and maize residues) at family level (BAU (business as usual) + family digester) and (ii) the effect of introducing an ethanol plant with treatment of stillage and production of electricity (BAU + community ethanol). The results show that it is economically viable to have BAU + family digester system and BAU + community ethanol. Sensitivity analysis showed that an increase in crop yield and the local price of cassava are the most important factors to increase the economic viability of the BAU + family digester system. Sensitivity analysis of the BAU + community ethanol system showed that this system is mainly affected by the price of ethanol. Besides the economic benefits, the proposed systems have other benefits, such as efficient recycling of nutrients and pollution reductio

Cassava for food and energy: exploring potential benefits of processing of cassava into cassava flour and bioenergy at farmstead and community levels in rural Mozambique

As in most of sub-Sahara Africa, rural people in Mozambique use firewood as their main source of energy. The use of firewood is associated with several health problems, and the time spent collecting it reduces time for other activities. Cassava is grown as a reserve crop in Mozambique where it is considered a ‘woman's crop’. Because the crop is drought-tolerant and resistant to diseases, it needs little attention and hence little labor input. This paper examines how the rural people in the case of Mozambique can use their current reserve crop, cassava, to meet their energy needs and food requirements and to increase their annual income. Cassava processing chains were modeled to assess (i) the effect of introducing an anaerobic digester for the digestion of cassava peels and other material (dung, kitchen waste and maize residues) at family level (BAU (business as usual) + family digester) and (ii) the effect of introducing an ethanol plant with treatment of stillage and production of electricity (BAU + community ethanol). The results show that it is economically viable to have BAU + family digester system and BAU + community ethanol. Sensitivity analysis showed that an increase in crop yield and the local price of cassava are the most important factors to increase the economic viability of the BAU + family digester system. Sensitivity analysis of the BAU + community ethanol system showed that this system is mainly affected by the price of ethanol. Besides the economic benefits, the proposed systems have other benefits, such as efficient recycling of nutrients and pollution reductio

Quantum chemistry based QSAR prediction and priority setting for toxicity of nitrobenzenes on EINECS list

Fifteen experimental literature data sets on the acute toxicity of substituted nitrobenzenes to algae (Scenedesmus obliquus, Chlorella pyrenoidosa, C. vulgaris), daphnids (Daphnia magna, D. carinata), fish (Cyprinus carpio, Poecilia reticulata), protozoa (Tetrahymena pyriformis), bacteria (Phosphobacterium phosphoreum), and yeast (Saccharomyces cerevisiae) were used to establish quantum chemistry based quantitative structure¿activity relationships (QSARs). The logarithm of the octanol/water partition coefficient, log Kow, and the energy of the lowest unoccupied molecular orbital, Elumo, were used as descriptors. Suitable QSAR models (0.65 <r2 <0.98) to predict acute toxicity of substituted mononitrobenzenes to protozoa, fish, daphnids, yeast, and algae have been derived. The log Kow was a sufficient descriptor for all cases, with the additional Elumo descriptor being required only for algae. The QSARs were found to be valid for neutral substituted mononitrobenzenes with no -OH, -COOH, or -CN substituents attached directly to the ring. From the 100,196 European Inventory of Existing Commercial Substances (EINECS), 497 chemicals were identified that fit the selection criteria for the established QSARs. Based on these results, an advisory tool has been developed that directs users to the appropriate QSAR model to apply for various types of organisms within specified log Kow ranges. Using this tool, it is possible to obtain a good indication of the toxicity of a large set of EINECS chemicals and newly developed substituted mononitrobenzenes to five different organisms without the need for additional experimental testin