Evaluating the effects of chemical exposures on adaptive functioning.

1. Although morphological and classical toxicological data have typically served as criteria for judging the effects of chemicals on the nervous system, there has been increasing interest in the use of behavioral end-points for examining the adverse effects of chemicals on nervous system function. 2. The present paper describes the current use of behavioral methods in neurotoxicity assessment and surveys some of the recent developments in the use of specialized methods for examining motor, sensory and cognitive changes following chemical exposures.     

Reduction,refinement and replacement: putting the immune system to work

Many chemicals are known to be, or have been implicated as, contact allergens, and allergic contact dermatitis is an important occupational and environmental health issue. It is the responsibility of toxicologists to identify those chemicals that have the potential to induce skin sensitisation, and to assess the conditions under which there will exist a risk to human health. This article describes progress that has been made in the development of new approaches to the toxicological evaluation of skin sensitisation, and the benefits to animal welfare that such developments have already produced, and are likely to produce in the future. In this context, the local lymph node assay is described with regard to hazard identification and risk assessment, and possible strategies for the development of in vitro approaches to safety assessment are discussed.     

Metabolomics in pesticide research and development: review and future perspectives

The emerge of metabolomics within functional genomics has provided a new dimension in the study of biological systems. In regards to the study of agroecosystems, metabolomics enables monitoring of metabolic changes in association with biotic or abiotic agents such as agrochemicals. Focusing on crop protection chemicals, a great effort has been given towards the development of crop protection agents safer for consumers and the environment and more efficient than the existing ones. Within this framework, metabolomics has so far been a valuable tool for high-throughput screening of bioactive substances in order to discover those with high selectivity, unique modes-of-action, and acceptable eco-toxicological/toxicological profiles. Here, applications of metabolomics in the investigation of the modes-of-action and ecotoxicological–toxicological risk assessment of bioactive compounds, mining of biological systems for the discovery of bioactive metabolites, and the risk assessment of genetic modified crops are discussed.     

Use of the Cultex® Radial Flow System as an in vitro exposure method to assess acute pulmonary toxicity of fine dusts and nanoparticles with special focus on the intra- and inter-laboratory reproducibility

Exposure of the respiratory tract to airborne particles (including metal-dusts and nano-particles) is considered as a serious health hazard. For a wide range of substances basic knowledge about the toxic properties and the underlying pathomechanisms is lacking or even completely missing. Legislation demands the toxicological characterization of all chemicals placed on the market until 2018 (REACH). As toxicological in vivo data are rare with regard to acute lung toxicity or exhibit distinct limitations (e.g. inter-species differences) and legislation claims the reduction of animal experiments in general (“3R” principle), profound in vitro models have to be established and characterized to meet these requirements. In this paper we characterize a recently introduced advanced in vitro exposure system (Cultex® RFS) showing a great similarity to the physiological in vivo exposure situation for the assessment of acute pulmonary toxicity of airborne materials.     

低剂量混合污染生态毒理与风险评价研究进展

环境中的化学品往往以低剂量混合形式存在.对单一化学品高剂量暴露下的生态毒性研究成果,难以适用于环境中低剂量混合物的生态毒理效应诊断及风险评价.文中概述了低剂量化学品混合污染生态毒理及风险评价方面的研究进展,主要包括低剂量化学品混合污染诊断的分子毒理研究方法、风险评价方法,并介绍了简单和复杂混合物的风险评价方案.对低剂量混合污染生态毒理与风险评价研究的发展动向提出了见解,指出低剂量化学混合物的研究需要寻找敏感终点,引入多学科手段,积累更多的数据,建立完善、统一的评价体系.     

Biokinetic and toxicodynamic modelling and its role in toxicological research and risk assessment

Toxicological risk assessment for chemicals is still mainly based on highly standardised protocols for animal experimentation and exposure assessment. However, developments in our knowledge of general physiology, in chemicobiological interactions and in (computer-supported) modelling, have resulted in a tremendous change in our understanding of the molecular mechanisms underlying the toxicity of chemicals. This permits the development of biologically based models, in which the biokinetics as well as the toxicodynamics of compounds can be described. In this paper, the possibilities are discussed of developing systems in which the systemic (acute and chronic) toxicities of chemicals can be quantified without the heavy reliance on animal experiments. By integrating data derived from different sources, predictions of toxicity can be made. Key elements in this integrated approach are the evaluation of chemical functionalities representing structural alerts for toxic actions, the construction of biokinetic models on the basis of non-animal data (for example, tissue-blood partition coefficients, in vitro biotransformation parameters), tests or batteries of tests for determining basal cytotoxicity, and more-specific tests for evaluating tissue or organ toxicity. It is concluded that this approach is a useful tool for various steps in toxicological hazard and risk assessment, especially for those forms of toxicity for which validated in vitro and other non-animal tests have already been developed.     

Evaluating the effects of chemical exposures on adaptive functioning

• 1.1. Although morphological and classical toxicological data have typically served as criteria for judging the effects of chemicals on the nervous system, there has been increasing interest in the use of behavioral end-points for examining the adverse effects of chemicals on nervous system function.
• 2.2. The present paper describes the current use of behavioral methods in neurotoxicity assessment and surveys some of the recent developments in the use of specialized methods for examining motor, sensory and cognitive changes following chemical exposures.

     

Metabolomics: a tool for early detection of toxicological effects and an opportunity for biology based grouping of chemicals-from QSAR to QBAR

BASF has developed a Metabolomics database (MetaMap(?) Tox) containing approximately 500 data rich chemicals, agrochemicals and drugs. This metabolome-database has been built based upon 28-day studies in rats (adapted to OECD 407 guideline) with blood sampling and metabolic profiling after 7, 14 and 28 days of test substance treatment. Numerous metabolome patterns have been established for different toxicological targets (liver, kidney, thyroid, testes, blood, nervous system and endocrine system) which are specific for different toxicological modes of action. With these patterns early detection of toxicological effects and the underlying mechanism can now be obtained from routine studies. Early recognition of toxicological mode of action will help to develop new compounds with a more favourable toxicological profile and will also help to reduce the number of animal studies necessary to do so. Thus this technology contributes to animal welfare by means of reduction through refinement (2R), but also has potential as a replacement method by analyzing samples from in vitro studies. With respect to the REACH legislation for which a large number of animal studies will need to be performed, one of the most promising methods to reduce the number of animal experiments is grouping of chemicals and read-across to those which are data rich. So far mostly chemical similarity or QSAR models are driving the selection process of chemical grouping. However, "omics" technologies such as metabolomics may help to optimize the chemical grouping process by providing biologically based criteria for toxicological equivalence. "From QSAR to QBAR" (quantitative biological activity relationship).     

International approach of the assessment of chemical risks

One of the primary objectives of the International Programme on Chemical Safety (IPCS) which is a cooperative venture of the International Labour Organization (ILO), the United Nations Environment Programme (UNEP) and the World Health Organization (WHO), is to carry out and disseminate evaluations of the risk to human health and the environment from exposure to chemicals. These evaluations are distributed to all Member States in order to provide a scientific and objective basis that national health or other relevant authorities may be able to use for planning, and for the development of regulatory and control measures. In view of frequent discrepancies in toxicological evaluations performed by different groups, it is recommended that a mechanism be established to assure a higher degree of uniformity and harmonization in the safety assessment of chemicals, and to develop globally acceptable standardized control measures.     

Prediction of toxicity from chemical structure

The basis for the prediction of toxicity from chemical structure is that the properties of a chemical are implicit in its molecular structure. Biological activity can be expressed as a function of partition and reactivity, that is, for a chemical to be able to express its toxicity, it must be transported from its site of administration to its site of action and then it must bind to or react with its receptor or target. This process may also involve metabolic transformation of the chemical. The application of these principles to the prediction of the toxicity of new or untested chemicals has been achieved in a number of different ways covering a wide range of complexity, from computer systems containing databases of hundreds of chemicals, to simple "reading across" between chemicals with similar chemical/toxicological functionality. The common feature of the approaches described in this article is that their starting point is a mechanistic hypothesis linking chemical structure and/or functionality with the toxicological endpoint of interest. The prediction of toxicity from chemical structure can make a valuable contribution to the reduction of animal usage in the screening out of potentially toxic chemicals at an early stage and in providing data for making positive classifications of toxicity. This revised version was published online in July 2006 with corrections to the Cover Date.     

Data-Driven Method to Estimate Nonlinear Chemical Equivalence

There is great need to express the impacts of chemicals found in the environment in terms of effects from alternative chemicals of interest. Methods currently employed in fields such as life-cycle assessment, risk assessment, mixtures toxicology, and pharmacology rely mostly on heuristic arguments to justify the use of linear relationships in the construction of “equivalency factors,” which aim to model these concentration-concentration correlations. However, the use of linear models, even at low concentrations, oversimplifies the nonlinear nature of the concentration-response curve, therefore introducing error into calculations involving these factors. We address this problem by reporting a method to determine a concentration-concentration relationship between two chemicals based on the full extent of experimentally derived concentration-response curves. Although this method can be easily generalized, we develop and illustrate it from the perspective of toxicology, in which we provide equations relating the sigmoid and non-monotone, or “biphasic,” responses typical of the field. The resulting concentration-concentration relationships are manifestly nonlinear for nearly any chemical level, even at the very low concentrations common to environmental measurements. We demonstrate the method using real-world examples of toxicological data which may exhibit sigmoid and biphasic mortality curves. Finally, we use our models to calculate equivalency factors, and show that traditional results are recovered only when the concentration-response curves are “parallel,” which has been noted before, but we make formal here by providing mathematical conditions on the validity of this approach.     

MicroRNA在环境毒理学中的研究进展

MicroRNA（miRNA）是一类长为20～24nt的非编码单链小分子RNA,主要存在于真核生物中,具有组织特异性、无开放阅读框等特点,在转录或翻译水平调控基因表达,参与细胞增殖、分化、凋亡,并与炎症、肿瘤等疾病发生、发展密切相关。环境毒理学研究表明,当生物暴露于环境化学物质时,会引起相关miRNA表达发生变化,进而导致其靶基因表达发生改变。因此,有必要明确环境化学物质、miRNA和相关靶基因三者问的作用关系。在环境毒理学研究和环境监测中,miRNA可作为识别环境中化学物质基因毒性和致癌性的生物标记物,并可用于预测环境化学物质对生物体的毒性。     

An Assessment of Toxic Substances Pollution in the Hong Kong Marine Environment

The Environmental Protection Department (EPD) of the Hong Kong Special Administrative Region Government (HKSARG) commissioned a consultancy study in 1999 to better understand the potential sources, fates, and existing pollution state of toxic substances in Hong Kong's marine environment. A desk-top survey and assessment was first performed on a comprehensive initial list of 556 toxic substances. A Preliminary Priority Toxic Substances List (PPTSL) of 135 chemicals was established, consisting of heavy metals, inorganic compounds, organo-metallic compounds, and trace organics. A territory-wide baseline field sampling and laboratory analysis exercise was then undertaken during 2001–2002 to determine the level of these PPTSL chemicals in the potential pollution sources (effluent discharges, stormwater discharges, air deposition) and the receiving marine environment (water, sediment, biota). A draft Priority Toxic Substances List (PTSL) was developed, taking into account chemicals detected in the local marine environment and those listed under the Stockholm Convention, the Rotterdam Convention, and the International Maritime Organization's Harmful Antifouling System Convention. The draft PTSL chemicals were subject to ecological and incremental human health risk assessments. Based on the risk assessment results, 17 Chemicals of Potential Concern (COPC) for Hong Kong's marine environment were identified, most of which were heavy metals in the sediment. The study findings suggest that Hong Kong's marine environment is not widely polluted with chemicals present at concentrations of toxicological concern. Although a number of potentially problematic pollutants (COPC) were identified, they are confined to a few “hot spots” and are unlikely to pose a territory-wide risk. Based on the study recommendations, the EPD initiated in 2004 a toxic substances monitoring program to keep the COPC in the marine environment under close surveillance.     

Derivation of Risk Management Criteria for Chemicals of Unknown Toxic Potency at Contaminated Sites

Environmental investigations of former industrial sites often detect the presence of chemicals for which no soil criteria exist and for which regulatory agencies have not derived estimates of toxic potency. This poses a considerable problem for making informed risk management decisions involving sites where such chemicals are present. As a result, a methodology has been developed for making risk-based decisions for chemicals of unknown toxic potency in soil at contaminated sites. The method is based on principles and procedures used by the US Food and Drug Administration (USFDA), the US Environmental Protection Agency (USEPA) and the Canadian Council of Ministers of the Environment (CCME). After analyzing the data on hundreds of carcinogenic and non-carcinogenic substances, the USFDA and other leading researchers have concluded that, if no toxicological data is available on a chemical, exposures less than 1.5?µg/person/day (i.e., 0.02?µg/kg body weight/day) are unlikely to result in appreciable health risks even if the substance was later found to be a carcinogen. To develop maximum soil concentrations that will be protective of human health (i.e., Risk Management Criteria or RMC), the above exposure limit of 0.02?µg/kg body weight/day has been assumed to be protective of risks from exposure to chemicals lacking toxicological data. Using a stochastic risk assessment model for estimating exposures to chemicals from contaminated sites, our analyses indicate that a soil concentration of 2?µg/g would be protective of human health for land uses that include residential, commercial, and industrial development provided no major indirect pathways exist at the site. If indirect pathways exists (e.g., vapor infiltration of soil gases, uptake of chemicals into garden produce, etc.), alternate RMC could be developed, that include such indirect pathways, using the methodology provided in this paper. Used by experienced risk assessors, the approach is a scientifically defensible screening method that will preclude many chemicals from unnecessary evaluation, while allowing risk assessors to focus efforts on chemicals of greater concern and make informed risk management decisions.     

Alternatives to animal testing in the safety evaluation of products

The conventional method for assessing the safety of products, ranging from pharmaceuticals to agrochemicals, biocides and industrial and household chemicals - including cosmetics - involves determining their toxicological properties by using experimental animals. The aim is to identify any possible adverse effects in humans by using these animal models. Providing safe products is undoubtedly of the utmost importance but, over the last decade or so, this aim has come into conflict with strong public opinion, especially in Europe, against animal testing. Industry, academia and the regulators have worked in partnership to find other ways of evaluating the safety of products, by non-animal testing, or at least by reducing the numbers of animals required and the severity of the tests in which they are used. There is a long way to go before products can be evaluated without any animal studies, and it may be that this laudable aim is an impossible dream. Nevertheless, considerable progress has been made by using a combination of in vitro tests and the prediction of properties based on chemical structure. The aim of this review is to describe these important and worthwhile developments in various areas of toxicological testing, with a focus on the European regulatory framework for general industrial and household chemicals.     

Concentration Addition,Independent Action and Generalized Concentration Addition Models for Mixture Effect Prediction of Sex Hormone Synthesis In Vitro

Humans are concomitantly exposed to numerous chemicals. An infinite number of combinations and doses thereof can be imagined. For toxicological risk assessment the mathematical prediction of mixture effects, using knowledge on single chemicals, is therefore desirable. We investigated pros and cons of the concentration addition (CA), independent action (IA) and generalized concentration addition (GCA) models. First we measured effects of single chemicals and mixtures thereof on steroid synthesis in H295R cells. Then single chemical data were applied to the models; predictions of mixture effects were calculated and compared to the experimental mixture data. Mixture 1 contained environmental chemicals adjusted in ratio according to human exposure levels. Mixture 2 was a potency adjusted mixture containing five pesticides. Prediction of testosterone effects coincided with the experimental Mixture 1 data. In contrast, antagonism was observed for effects of Mixture 2 on this hormone. The mixtures contained chemicals exerting only limited maximal effects. This hampered prediction by the CA and IA models, whereas the GCA model could be used to predict a full dose response curve. Regarding effects on progesterone and estradiol, some chemicals were having stimulatory effects whereas others had inhibitory effects. The three models were not applicable in this situation and no predictions could be performed. Finally, the expected contributions of single chemicals to the mixture effects were calculated. Prochloraz was the predominant but not sole driver of the mixtures, suggesting that one chemical alone was not responsible for the mixture effects. In conclusion, the GCA model seemed to be superior to the CA and IA models for the prediction of testosterone effects. A situation with chemicals exerting opposing effects, for which the models could not be applied, was identified. In addition, the data indicate that in non-potency adjusted mixtures the effects cannot always be accounted for by single chemicals.     

Role of modern chemistry in sustainable arable crop protection

Organic chemistry has been, and for the foreseeable future will remain, vitally important for crop protection. Control of fungal pathogens, insect pests and weeds is crucial to enhanced food provision. As world population continues to grow, it is timely to assess the current situation, anticipate future challenges and consider how new chemistry may help meet those challenges. In future, agriculture will increasingly be expected to provide not only food and feed, but also crops for conversion into renewable fuels and chemical feedstocks. This will further increase the demand for higher crop yields per unit area, requiring chemicals used in crop production to be even more sophisticated. In order to contribute to programmes of integrated crop management, there is a requirement for chemicals to display high specificity, demonstrate benign environmental and toxicological profiles, and be biodegradable. It will also be necessary to improve production of those chemicals, because waste generated by the production process mitigates the overall benefit. Three aspects are considered in this review: advances in the discovery process for new molecules for sustainable crop protection, including tests for environmental and toxicological properties as well as biological activity; advances in synthetic chemistry that may offer efficient and environmentally benign manufacturing processes for modern crop protection chemicals; and issues related to energy use and production through agriculture.