Registration, Evaluation And Authorisation Of Chemicals Research Articles

Alternative Methods for Skin-Sensitization Assessment.

Skin sensitization is a term used to refer to the regulatory hazard known as allergic contact dermatitis (ACD) in humans or contact hypersensitivity in rodents, an important health endpoint considered in chemical hazard and risk assessments. Information on skin sensitization potential is required in various regulatory frameworks, such as the Directive of the European Parliament and the Council on Registration, Evaluation and Authorization of Chemicals (REACH). The identification of skin-sensitizing chemicals previously required the use of animal testing, which is now being replaced by alternative methods. Alternative methods in the field of skin sensitization are based on the measurement or prediction of key events (KE), i.e., (i) the molecular triggering event, i.e., the covalent binding of electrophilic substances to nucleophilic centers in skin proteins; (ii) the activation of keratinocytes; (iii) the activation of dendritic cells; (iv) the proliferation of T cells. This review article focuses on the current state of knowledge regarding the methods corresponding to each of the key events in skin sensitization and considers the latest trends in the development and modification of these methods.

BREXIT’S EFFECTS ON GERMAN-UK COOPERATION IN CHEMICAL INDUSTRY

Europe is the second largest chemicals producer in the world, yield only to the Asian region, where China is the undisputed leading country. The chemical industry is of great importance for both countries and it determines the structure of their economies. In turn, Brexit significantly affected the current dynamics and state of bilateral relations. Fairly long, stable trade and economic relations with Great Britain were of great importance for German business that did not hide its interest in adopting the agreement, which exclude rigorous trade tariffs and barriers. Being the largest EU economy with a clear export orientation, Germany was not ready to lose a huge export market. That is why Germany has made a significant contribution to negotiation process regulating the UK’s exit from the EU and put an effort to reach the consensus among parties concerned. Managing the UK’s departure from the European Union was not an exception from such ambitious program of six-month Germany’s Presidency of the Council of the EU (July–December 2020). Despite the fact that the Agreement on the UK’s withdrawal from the Eropean Union, which formally ended the state’s membership in the EU, had been adopted, a qualitatively new document was required. The Trade and Cooperation Agreement (TCA) was adopted, which determines a new framework for relations between the EU and the UK. The TCA significantly determines the entire spectrum of cooperation areas and includes the new interplay in the chemical industry, including the implementation of REACH (Registration, Evaluation and Authorisation of Chemicals) regulation. This article focuses on current state of German-UK economic ties and illustrates the role of chemical industry in the economies of both countries as well as points out the countries’ performance in the global industry.

Distributions for time, interspecies and intraspecies extrapolation for deriving occupational exposure limits.

This work aimed at improving the empirical database of time (i.e., exposure duration), interspecies and intraspecies extrapolation when deriving occupational exposure limits (OELs). For each extrapolation step, a distribution was derived, which can be used to model the associated uncertainties. For time and interspecies extrapolation, distributions of ratios of dose descriptors were derived from studies of different length or species. National Toxicology Program (NTP) study data were manually assessed, and data from REACH (Registration, Evaluation and Authorisation of Chemicals) registration dossiers were evaluated semi‐automatically. Intraspecies extrapolation was investigated by compiling published studies on human toxicokinetic and toxicodynamic variability. A new database was established for toxicokinetic differences in interindividual susceptibility, including many inhalation studies. Using NTP data produced more reliable results than using REACH data. The geometric mean (GM) for time extrapolation subacute/chronic agreed with previous evaluations (GM = 4.11), whereas the GM for subchronic/chronic extrapolation was slightly higher (GM = 2.93) than the GMs found by others. No significant differences were observed between systemically and locally acting substances. Observed interspecies differences confirmed the suitability of allometric scaling, with the derived distribution describing remaining uncertainty. Distributions of intraspecies variability at the 1% and 5% incidence level had medians of 7.25 and 3.56, respectively. When compared with assessment factors (AFs) currently used in the EU, probabilities that these AFs are protective enough span a wide range from 10% to 95%, depending on the extrapolation step. These results help to select AFs in a transparent and informed way and, by allowing to compare protection levels achieved, to harmonise methods for deriving OELs.

Quantitative Structure-Activity Relationship (QSAR) Studies on the Toxic Effects of Nitroaromatic Compounds (NACs): A Systematic Review.

Nitroaromatic compounds (NACs) are ubiquitous in the environment due to their extensive industrial applications. The recalcitrance of NACs causes their arduous degradation, subsequently bringing about potential threats to human health and environmental safety. The problem of how to effectively predict the toxicity of NACs has drawn public concern over time. Quantitative structure–activity relationship (QSAR) is introduced as a cost-effective tool to quantitatively predict the toxicity of toxicants. Both OECD (Organization for Economic Co-operation and Development) and REACH (Registration, Evaluation and Authorization of Chemicals) legislation have promoted the use of QSAR as it can significantly reduce living animal testing. Although numerous QSAR studies have been conducted to evaluate the toxicity of NACs, systematic reviews related to the QSAR modeling of NACs toxicity are less reported. The purpose of this review is to provide a thorough summary of recent QSAR studies on the toxic effects of NACs according to the corresponding classes of toxic response endpoints.

Respiratory health and silicosis in artisanal mine workers in southern Brazil.

Artisanal and small-scale mining (ASM) are an important source of employment in southern Brazil. Mining workers are frequently exposed to unhealthy work conditions which increase the risk of occupational diseases. In this study, we assessed the association of sociodemographic factors and the occupational history of artisanal mining workers with the risk of adverse respiratory outcomes. The study was conducted with 258 artisanal mining workers in southern Brazil, who were exposed to dust (mainly crystalline silica) in their work. Information on sociodemographic variables and occupational histories was collected between 2017 and 2018. To estimate the worker's exposure to inhalable dust we use the Advanced REACH (Registration, Evaluation, and Authorization of Chemicals) Tool (ART). Study participants were all men, with an average age of 40 years. Median crude dust exposure estimated by ART was 13.2 mg/m³ and median crude crystalline silica exposure was 1.6 mg/m3 . The prevalence ratio (PR) for self-reported silicosis was 3.08 (95% confidence interval, 1.39-7.17) in workers with 20 years or more of mining work. Factors associated with silicosis were age, pack-years of tobacco use, and body mass index. Smokers were over twice as likely to report respiratory symptoms. Our findings indicate that a high prevalence of silicosis and other associated diseases in mining workers is associated with both unhealthy work environment conditions and the health profile of workers. This study is an important step for understanding health outcomes from work in ASM.

Electron configuration-based neural network model to predict physicochemical properties of inorganic compounds.

Registration, evaluation, and authorization of chemicals (REACH), the regulation of chemicals in use, imposes the characterization and report of the physicochemical properties of compounds. To cope with the financial burden of the experiments, the use of computational models is permitted for prediction of properties. Although a number of physicochemical property prediction models have been developed, their applicability domain is limited to organic molecules since most available data are concerned with organic molecules, and most of the molecular descriptors are restricted to organic molecule calculations. Prediction models developed for inorganic compounds were intended to predict endpoints relevant to novel material design. Therefore, no models were available for predicting endpoints of inorganic compounds that are significant to regulatory perspectives. In this study, boiling point, water solubility, melting point, and pyrolysis point prediction models were developed for inorganic compounds based on their composition. The electron configuration of each element in the molecule was used as a descriptor in this study. The dataset covered a wide range of endpoints and diverse elements in their structure. The performance of the models was measured using R2, mean absolute error, and Spearman's correlation coefficient, and indicated good prediction accuracy of continuous endpoints and prioritization of inorganic compounds.

The European Chemical Industry Guidance on REACH Exposure Assessment Strategies for Substances in Articles

Under the European Regulation on Registration, Evaluation and Authorization of Chemicals (REACH) safety assessments of hazardous substances should cover all identified end-uses, including those that lead to the inclusion into articles. Characterization of risks to human health and/or the environment from the subsequent service life cycle stage requires a substantial level of detail on article composition, design, manufacturing process, use patterns under normal reasonably foreseeable conditions, i.e., the information that is not typically available or provided to chemical manufacturers by their downstream users.To overcome this lack of supply chain communication and to ensure consistency in understanding and addressing the problem across all REACH stakeholders, the European Chemical Industry Council (CEFIC) has developed a practical guidance/framework for REACH registrants to help them screen for the necessity of developing exposure scenarios for the service life stage of their substances based on the (limited) information available in the downstream sector use maps. The decision-making framework in the guidance utilizes REACH use description elements such as contributing scenario names, sector of use, and technical function of the substance, as well as the article characteristics known to drive release/exposure potential (e.g. article matrix, shape, intended use pattern).The presentation will outline the decision tree and include introduction to the Release from Articles Potential (RAP) Excel-based tool designed to assist on the determination of a substance’s release/emissions based on its technical function in the article. Application of the workflow will be demonstrated with examples for two substances used in the road construction applications and polymer production.

Aquatic toxicity structure-activity relationships for the zwitterionic surfactant alkyl dimethyl amine oxide to several aquatic species and a resulting species sensitivity distribution

Amine oxide (AO) is a cationically charged surfactant at environmental pH and has previously been assessed in the OECD (Organization for Economic Cooperation and Development) High Production Volume (HPV) chemicals program. Typical of cationic chemicals, AO is highly aquatically toxic. In this study we vastly improve the knowledge of AO toxicity by developing acute Quantitative Structure Activity Relationships (QSARs) for an alga (Desmodesmus subspicatus), an invertebrate (Daphnia magna) and a fish (Danio rerio) using the appropriate array of OECD Test Guidelines. A chronic toxicity QSAR was also determined for the most sensitive taxon, Desmodesmus. Pure AO spanning the chain lengths of C8 to C16 were tested individually with trace analytical confirmation of exposures in all tests. The QSARs were all of high quality (R2 0.92–0.98) with slopes ranging from −0.338 to −0.484. QSARs were then used to normalize toxicity outcomes for a larger, previously published data set used in HPV, European REACH (Registration, Evaluation, and Authorization of Chemicals), and peer reviewed publications. Two additional species, Lemna gibba (macrophyte) and Ankistrodesmus falcatus (alga) were studied in exposures to dodecyl (C12) AO to provide sufficient taxonomic diversity to conduct a Species Sensitivity Distribution (SSD) analysis. The SSD 5th percentile hazardous concentration (HC5) to C12 AO was found to be 0.052mg/L which is similar to an existing AO 28-d, 3-community periphyton community bioassay normalized to C12 AO (No-observed-effect-concentration or NOEC=0.152mg/L). The statistical properties of the SSD was probed suggesting that new studies of additional taxa would be required that were at least 10-fold more sensitive than the most sensitive taxon to move the HC5 lower by a factor of 3. The overall AO hazard assessment suggests a large margin of safety relative to published environmental exposure data.

A Comparative Review on Chemical Registration Management Regulations

Inappropriate production, storage and use of chemical could cause chemical incident. Chemical registration will contribute to the safe management of chemical. Represented by U.S. TSCA (Toxic Substances Control Act) regulations and the European REACH (Registration, Evaluation and Authorization of Chemicals), the awareness of building chemical registrations or chemical database is raising. By carrying out extensive research and comparing the chemical registration regulation status of eight selected countries/regions, the study is to compare the current management status of chemical registration in different developed and developing countries, which may provide information and overview for preventing, controlling and reducing chemical incident, improving safe management of chemical, and supporting the development of chemical registration database.

How synergistic or antagonistic effects may influence the mutual hazard ranking of chemicals

The presence of various agents, including humic materials, nanomaterials, microplastics, or simply specific chemical compounds, may cause changes in the apparent persistence, bioaccumulation, and/or toxicity (PBT) of a chemical compound leading to an either increased or decreased PBT characteristics and thus an increased or decreased hazard evaluation. In the present paper, a series chloro-containing obsolete pesticides is studied as an illustrative example. Partial order methodology is used to quantify how changed P, B, or T characteristics of methoxychlor (MEC) influences the measure of the hazard of MEC, relative to the other 11 compounds in the series investigated. Not surprisingly, an increase in one of the three indicators (P, B, or T) lead to an increased average order and thus an increased relative hazard as a result of a synergistic effect. A decrease in one of the indicator values analogously causes a decreased average order/relative hazard through an antagonistic effect; the effect, however, being less pronounced. It is further seen that the effect of changing the apparent value of the three indicators is different. Thus, persistence apparently is more important that bioaccumulation which again appears more important than toxicity, which is in agreement with previous work. The results are discussed with reference to the European chemicals framework on registration, evaluation and authorization of chemicals (REACH) framework.

Do we really want to REACH out to in vitro?

To comply with international regulations on chemicals, such as REACH (registration, evaluation, and authorization of chemicals), an enormous amount of toxicity testing is required. Traditional tests will fall short, since these strongly rely on in vivo studies, in particular for neurotoxicity. Therefore, a shift to alternative/in vitro toxicity testing is essential, in particular for neurotoxicity testing. However, the use of in vitro models and in vitro endpoints appears far from well accepted. This brief personal view highlights some of the concerns regarding in vitro research, e.g. using clonal cell lines such as PC12 cells and SH-SY5Y cells, to illustrate that many of these concerns may not be justified. A better characterization of specific in vitro models as well as a better understanding of the motive for using these in vitro models for neurotoxicity testing in the scientific community is necessary. The future of neurotoxicity testing will involve an increased use of in vitro experiments that are carefully designed with respect to compatibility of the exposure paradigm, the in vitro model and the chosen endpoint(s).

European solvent industry group generic exposure scenario risk and exposure tool

The European Solvents Industry Group (ESIG) Generic Exposure Scenario (GES) Risk and Exposure Tool (EGRET) was developed to facilitate the safety evaluation of consumer uses of solvents, as required by the European Union Registration, Evaluation and Authorization of Chemicals (REACH) Regulation. This exposure-based risk assessment tool provides estimates of both exposure and risk characterization ratios for consumer uses. It builds upon the consumer portion of the European Center for Ecotoxicology and Toxicology of Chemicals (ECETOC) Targeted Risk Assessment (TRA) tool by implementing refinements described in ECETOC TR107. Technical enhancements included the use of additional data to refine scenario defaults and the ability to include additional parameters in exposure calculations. Scenarios were also added to cover all frequently encountered consumer uses of solvents. The TRA tool structure was modified to automatically determine conditions necessary for safe use. EGRET reports results using specific standard phrases in a format consistent with REACH exposure scenario guidance, in order that the outputs can be readily assimilated within safety data sheets and similar information technology systems. Evaluation of tool predictions for a range of commonly encountered consumer uses of solvents found it provides reasonable yet still conservative exposure estimates.

Regulatory issues in management of chemicals in OECD member countries

The chemical risk assessment is determinant for the approval of any kind of chemical. Each aspect of chemical is taken into consideration for the new chemical legislation registration, evaluation, and authorization of chemicals (REACH). However, some improvements can be made in order to select and authorize a chemical. QSAR techniques have been used for the study of several kind of toxicological properties in order to realize a deeper study concerning to risk assessment. For this reason, this work is focused into present a review of chemical legislation policies in the European Union (EU) and in Russia, and changes in chemicals regulations to meet the requirement of REACH. Also, we reported the used of several approaches and chemo- bioinformatics tools applied to QSAR methodologies for the several parameters relative to toxicity and how they can be used for regulatory purposes in risk assessment.

Guidelines for Transportation, Handling, and Use of Fast Pyrolysis Bio-Oil. 1. Flammability and Toxicity

An alternative sustainable fuel, biomass-derived fast pyrolysis oil or “bio-oil”, is coming into the market in Europe. Fast pyrolysis pilot and demonstration plants for fuel applications producing tonnes of bio-oil are in operation, and commercial plants are under design. There will be increasingly larger amounts of bio-oil transportation on water and by land, leading to a need for further specifications and supporting documentation. The properties of bio-oil are different from conventional liquid fuels and, therefore, may need to overcome both technical and marketing hurdles for its acceptability in the fuels market. Multiple material safety data sheets (MSDSs) are currently being used by different producers, but there is a desire to update these as more information becomes available. In order to standardize bio-oil, quality specifications are being adopted. The first bio-oil burner fuel standard in ASTM D7544 was approved in 2010. CEN standardization has been initiated in Europe. In the EU, a new chemical regulation system REACH (Registration, Evaluation and Authorisation of Chemicals) exists. Registration under REACH has to be perfomed if bio-oil is produced or imported into the EU. In the USA and Canada, bio-oil has to be filed under the TSCA (US Toxic Substances Control Act) and DSL (Domestic Substance List), respectively. In this paper, the state of the art on standardization is discussed, and new data for the transportation guidelines is presented. The focus is on flammability and toxicity.

European Union regulatory politics in the shadow of the WTO: WTO rules as frame of reference and rhetorical device

This contribution asks how the World Trade Organization (WTO) affects European Union (EU) regulatory politics. While WTO rules have no direct effect, authors who take a rational choice institutionalist perspective argue that these rules are enforced domestically through the mobilization of exporters triggered by the WTO dispute settlement system. This contribution challenges the plausibility of this argument and offers an alternative perspective rooted in historical and discursive institutionalism. It contends that WTO rules act as both a frame of reference influencing actors' perceptions of the scope of legitimate policy outcomes and as a rhetorical device that may be used by actors in domestic political battles over regulatory policy decisions. Two recent decisions on EU regulation with international trade effects are process-traced to demonstrate the value of the alternative perspective against the rational choice institutionalism model: Registration, Evaluation and Authorization of Chemicals (REACH) and the proposed ‘carbon border tax’ in the framework of the EU emissions trading scheme post-2013.

국제환경규제 유해물질의 최근 동향 및 국내 수출기업에 미치는 영향

2000년 중반기 이후, 산업 경쟁력에서 환경 규제, 특히 제품 함유 유해물질 규제가 EU를 중심으로 점차 강화되어 큰 영향을 미쳐왔고, 이는 1990년 초 섬유산업에서 시작하여 전기전자산업을 거쳐 전 산업으로 확장되고 있다. 본 총설에서는 EU의 제품 함유 유해물질 규제 흐름을 알아보고, EU에서 규제하고 있는 유해물질의 종류, 규제 사유, 관련 근거 및 법령을 주요 섬유제품 에코라벨인 Oeko-Tex Standard, 전기전자 제품의 RoHS (Restriction of the use of certain hazardous substances in electrical and electronic equipment) 및 REACH (Registration, Evaluation and Authorization of CHemicals)의 SVHC (Substances of Very High Concern, 고위험성 물질)를 중심으로 고찰해 보면서 NGO (Non-Governmental Organization) 단체들의 활동으로 도출되고 있는 ChemSec (the International Chemical Secretariat)의 SIN (Substitute It Now) list와 그 의미를 조사해보았다. 또한, 국내 수출기업이 국제시장에서 받고 있는 클레임 사례를 통해 규제 유해물질이 시장에 주는 영향을 살펴보고, 유해물질로 인한 국제환경규제의 단기 및 중장기 대응 방안을 고찰해 보기로 한다. Starting with textile products in the middle of 1990, environmental requirements on prohibition of hazardous substances in products have been led by EU member countries and expanded to electrical and electronic equipment with implementaion of RoHS (Restriction of the use of certain hazardous substances in electrical and electronic equipment) in 2006. Under EU REACH (Registration, Evaluation and Authorization of CHemicals), the concept of SVHC (Substances of Very High Concern) and resulting regulatory duties regarding it have been introduced to the supply chain of almost all industry sectors. In this technical review, kinds of hazardous substances, reasons for restrictions and related directives and regulations are reviewed with its influence on the international market. Suggestions are made how to cope with environmental regulations as well as mid-to-long term market strategy to secure global market competitiveness.

Finding maximal transcriptome differences between reprotoxic and non‐reprotoxic phthalate responses in rat testis

The chemical legislation of the EU, Registration, Evaluation, and Authorization of Chemicals (REACH), stipulates that about 30 000 chemical substances are to be assessed on their possible risks. Toxicological evaluation of these compounds will at least partly be based on animal testing. In particular, the assessment of reproductive toxicity is a very complicated, time-consuming and animal-demanding process. Introducing microarray-based technologies can potentially refine in vivo toxicity testing. If compounds of a distinct chemical class induce reproducible gene-expression responses with a recognizable overlap, these gene-expression signatures may indicate intrinsic features of certain compounds, including specific toxicity. In the present study, we have set out the first steps towards this approach for the reproductive toxicity of phthalates. Male rats were treated with a single dose of either reprotoxic or non-reprotoxic phthalates, and were analyzed 24 h afterwards. Subsequently, histopathological and gene-expression profiling analyses were performed. Despite ambiguous histopathological observations, we were able to identify genes with differential expression profiles between the reprotoxic phthalates and the non-reprotoxic counterparts. This shows that differences in gene-expression profiles, indicative of the type of exposure, may be detected earlier, or at lower doses, than classical pathological endpoints. These findings are promising for 'early warning' biomarker analyses and for using toxicogenomics in a category approach. Ultimately, this could lead to a more cost-effective approach for prioritizing the toxicity testing of large numbers of chemicals in a short period of time in hazard assessment of chemicals, which is one of the objectives of the REACH chemical legislation.

Refining ConsExpo Evaporation and Human Exposure Calculations for REACH

ABSTRACT REACH (Registration, Evaluation, and Authorization of CHemicals) and other regulations require assessing potential exposure to substances in consumer products in order to determine if the potential risk from the product use is acceptable. In order to assess inhalation exposure due to evaporation of the volatile substance in a consumer product the vapor concentration must be determined. The vapor concentration may be measured or estimated using mathematical modeling. Both options have many advantages and disadvantages but because of the large number of substances and products to be evaluated, modeling is usually the first choice. The primary objective was to present an approach based on sound science to refine an exposure analysis by refining the mass transfer coefficient in the ConsExpo evaporation calculations for use in the subsequent inhalation exposure calculations. This study recommends use of the Sparks et al. (1996) method for estimating the mass transfer coefficient for indoor evaporation. Three case studies demonstrated the Sparks method provided a better agreement of the predicted vapor concentrations to experimental results than the default mass transfer methods. A second objective was to critically evaluate the two ConsExpo default methods used to estimate the mass transfer coefficient and several limitations were identified.

New public QSAR model for carcinogenicity.

BackgroundOne of the main goals of the new chemical regulation REACH (Registration, Evaluation and Authorization of Chemicals) is to fulfill the gaps in data concerned with properties of chemicals affecting the human health. (Q)SAR models are accepted as a suitable source of information. The EU funded CAESAR project aimed to develop models for prediction of 5 endpoints for regulatory purposes. Carcinogenicity is one of the endpoints under consideration.ResultsModels for prediction of carcinogenic potency according to specific requirements of Chemical regulation were developed. The dataset of 805 non-congeneric chemicals extracted from Carcinogenic Potency Database (CPDBAS) was used. Counter Propagation Artificial Neural Network (CP ANN) algorithm was implemented. In the article two alternative models for prediction carcinogenicity are described. The first model employed eight MDL descriptors (model A) and the second one twelve Dragon descriptors (model B). CAESAR's models have been assessed according to the OECD principles for the validation of QSAR. For the model validity we used a wide series of statistical checks. Models A and B yielded accuracy of training set (644 compounds) equal to 91% and 89% correspondingly; the accuracy of the test set (161 compounds) was 73% and 69%, while the specificity was 69% and 61%, respectively. Sensitivity in both cases was equal to 75%. The accuracy of the leave 20% out cross validation for the training set of models A and B was equal to 66% and 62% respectively. To verify if the models perform correctly on new compounds the external validation was carried out. The external test set was composed of 738 compounds. We obtained accuracy of external validation equal to 61.4% and 60.0%, sensitivity 64.0% and 61.8% and specificity equal to 58.9% and 58.4% respectively for models A and B.ConclusionCarcinogenicity is a particularly important endpoint and it is expected that QSAR models will not replace the human experts opinions and conventional methods. However, we believe that combination of several methods will provide useful support to the overall evaluation of carcinogenicity. In present paper models for classification of carcinogenic compounds using MDL and Dragon descriptors were developed. Models could be used to set priorities among chemicals for further testing. The models at the CAESAR site were implemented in java and are publicly accessible.

A Cautiously Pessimistic Appraisal of Trends in Toxic Regulation

Many of the most dramatic and politically salient environmental disasters have involved toxic substances of one form or another. Yet despite the iconic status of these events, regulation of toxic substances in the United States (and elsewhere) is criticized by a broad cross section of stakeholders and experts. Among those on the left, the primary statute, the Toxic Substances Control Act (TSCA), is considered moribund and structurally unsound because of the high barriers it creates to regulatory action. Critics on the right challenge the tenuous scientific bases for regulation and question, often on the basis of cost-benefit analyses, the rationality of the regulations that exist. Other countries are establishing innovative regulatory programs, most notably in the European Union (EU) and Canada. The brightest light in the firmament is surely the Registration, Evaluation, and Authorization of Chemicals (REACH) program recently enacted in the EU. REACH, at least on the surface, corrects many of the perceived defects in TSCA. This Article adopts a guarded view of recent regulatory and scientific developments. While the regulatory advances in the EU will undoubtedly alter the landscape of toxics regulation in the United States and elsewhere, they incorporate many compromises that qualify their procedural and regulatory mandates. The past thirty years have demonstrated that toxics regulation is inextricably tied to scientific understanding. Science informs the architecture of regulatory regimes and supplies the factual grounding for agency decisions. The likelihood is low, if not negligible, that advances in toxicogenomics will significantly improve toxics regulation over the next decade or so. Policymakers and stakeholders should be leery of claims, whether regulatory or scientific, that the tensions in toxics regulation can be resolved. For the foreseeable future, the problems are too complex and our understanding too modest for difficult choices to be avoided. This recognition does not imply that toxics regulation in the United States cannot be improved, such as by adopting certain elements of REACH, or that investments in toxicological science are futile. Rather, it suggests that toxics regulation, particularly in the near term, must take into account the prevailing constraints – it should not be premised on transcending knowledge gaps, but instead on empowering agencies, in conjunction with stakeholders, to manage the unavoidable uncertainties effectively