Yuki Sakuratani

Workgroup report: review of fish bioaccumulation databases used to identify persistent, bioaccumulative, toxic substances.

Chemical management programs strive to protect human health and the environment by accurately identifying persistent, bioaccumulative, toxic substances and restricting their use in commerce. The advance of these programs is challenged by the reality that few empirical data are available for the tens of thousands of commercial substances that require evaluation. Therefore, most preliminary assessments rely on model predictions and data extrapolation. In November 2005, a workshop was held for experts from governments, industry, and academia to examine the availability and quality of in vivo fish bioconcentration and bioaccumulation data, and to propose steps to improve its prediction. The workshop focused on fish data because regulatory assessments predominantly focus on the bioconcentration of substances from water into fish, as measured using in vivo tests or predicted using computer models. In this article we review of the quantity, features, and public availability of bioconcentration, bioaccumulation, and biota–sediment accumulation data. The workshop revealed that there is significant overlap in the data contained within the various fish bioaccumulation data sources reviewed, and further, that no database contained all of the available fish bioaccumulation data. We believe that a majority of the available bioaccumulation data have been used in the development and testing of quantitative structure–activity relationships and computer models currently in use. Workshop recommendations included the publication of guidance on bioconcentration study quality, the combination of data from various sources to permit better access for modelers and assessors, and the review of chemical domains of existing models to identify areas for expansion.

Hazard Evaluation Support System (HESS) for predicting repeated dose toxicity using toxicological categories.

Repeated dose toxicity (RDT) is one of the most important hazard endpoints in the risk assessment of chemicals. However, due to the complexity of the endpoints associated with whole body assessment, it is difficult to build up a mechanistically transparent structure–activity model. The category approach, based on mechanism information, is considered to be an effective approach for data gap filling for RDT by read-across. Therefore, a library of toxicological categories was developed using experimental RDT data for 500 chemicals and mechanistic knowledge of the effects of these chemicals on different organs. As a result, 33 categories were defined for 14 types of toxicity, such as hepatotoxicity, hemolytic anemia, etc. This category library was then incorporated in the Hazard Evaluation Support System (HESS) integrated computational platform to provide mechanistically reasonable predictions of RDT values for untested chemicals. This article describes the establishment of a category library and the associated HESS functions used to facilitate the mechanistically reasonable grouping of chemicals and their subsequent read-across.

External validation of the biodegradability prediction model CATABOL using data sets of existing and new chemicals under the Japanese Chemical Substances Control Law

External validation of the biodegradability prediction model CATABOL was conducted using test data of 338 existing chemicals and 1123 new chemicals under the Japanese Chemical Substances Control Law. CATABOL predicts that 1089 chemicals will have a BOD < 60% while 925 (85%) actually have an observed BOD<60%. The percentage of chemicals with an observed BOD value <60% tends to increase as the predicted BOD values decrease. In contrast, 340 chemicals were predicted to have a BOD ≥ 60% and 234 (69%) actually had an observed BOD ≥ 60%. The prediction of poor biodegradability was more accurate than the predictions of high biodegradability. The features of chemical structures affecting CATABOL predictability were also investigated.

Category analysis of the substituted anilines studied in a 28-day repeat-dose toxicity test conducted on rats: Correlation between toxicity and chemical structure†

In order to establish methods for estimating the repeat-dose toxicity of chemicals on the basis of their chemical structure, an analysis of a category formed for 14 substituted anilines was conducted. This analysis was based on the results of a 28-day repeat-dose toxicity test conducted on rats in which these 14 chemicals were studied. The intensities of the toxicological effects of the 14 substituted anilines on each target organ at specific dosages were described using the values and histopathological findings of the test. The results clarified the characteristics of the chemical structure that induced specific toxicological effects on specific targets at a particular dosage. Hemolysis was the most frequently observed finding in the test reports in the case of the 14 substituted anilines. Strong linear correlations between the dosage and proportion of decrease in the erythrocyte count were found in the case of chemicals that induced strong hemolytic effects. In particular, for dimethylanilines, strong linear correlations were found between the calculated hemoglobin-binding index and the proportion of decrease in the erythrocyte count at a particular dosage. Thus, the results of our analysis demonstrate that it is possible to correlate the values obtained for substituted anilines from 28-day repeat-dose toxicity tests with their quantitatively determined molecular properties. The intensity of hemolysis and the effects on the liver tended to be low in the case of chemicals with a high water solubility, such as aminophenols and benzene sulfonic acids. However, a similar trend was not observed in the case of the effects of these chemicals on the kidney. †Presented at the 13th International Workshop on QSARs in the Environmental Sciences (QSAR 2008), 8–12 June 2008, Syracuse, USA.

Chapter 3:Development of an Evaluation Support System for Estimating Repeated-Dose Toxicity of Chemicals Based on Chemical Structure

Repeated dose toxicity (RDT) testing is one of the important endpoints of Chemical Substances Control Law (CSCL). However, a reliable and satisfactory (Q)SAR or category approach method for evaluating the RDT of chemicals still remains undeveloped. In order to make an in silico evaluation of RDT for target chemicals from their chemical structure, a comprehensive collaboration of experts possessing a variety of knowledge on the analogue chemicals is necessary.The project, “Development of hazard assessment techniques using structure–activity relationship methods,” sponsored by New Energy and Industrial Technology Development Organization (NEDO) in Japan, aims to develop the “Hazard Evaluation Support System Integrated Platform (HESS)” for providing decision support information to experts to evaluate the RDT of chemicals by the category approach (project period: 2007–2011). This chapter contains an overview of HESS and describes the methodology for evaluating RDT by the category approach developed in this project.

A category approach to predicting the repeated-dose hepatotoxicity of allyl esters.

We tested a category approach to predict the hepatotoxic effects of repeated doses of allyl esters using a new database for repeated-dose toxicity. Based on information on hepatotoxic mechanism of allyl acetate, the category was defined as allyl esters that are hydrolyzed to allyl alcohol. Allyl alcohol is readily oxidized to acrolein in the liver, causing hepatotoxicity. Seventeen marketed allyl esters were obtained and grouped into category by identifying or predicting allyl alcohol formation. Allyl esters with a saturated straight alkyl carboxylic acid moiety (allyl acetate, hexanoate and heptanoate as tested species, and allyl butyrate, pentanoate, octanoate, nonanoate and decanoate as untested species) are likely similar in rate of ester hydrolysis, thereby defining subcategory 1. NOAEL and LOAEL for the hepatotoxic effects were estimated at 0.12 and 0.25 mmol/kg/d for the untested species, based on those of allyl acetate. The remaining nine allyl esters with other alkyl or aromatic carboxylic acid moieties were placed in subcategory 2: their hepatotoxicity levels were not predictable due to an unclear match between their degree of structural complexity and rate of hydrolysis. Our results demonstrate the usefulness of the category approach for predicting the hepatotoxicity of untested allyl esters with saturated straight alkyl chains.

Categorization of nitrobenzenes for repeated dose toxicity based on adverse outcome pathways

Adoption of the data-gap filling method for complex endpoints such as repeated dose toxicity (RDT) and reproductive/developmental toxicity is one of the most important issues affecting international chemical management at present. A categorization method based on adverse outcome pathways (AOPs) has recently been investigated for such complex endpoints. In this paper, we report results of the categorization of nitrobenzenes for RDT based on the AOPs obtained by analysing the detailed RDT test reports for 24 different nitrobenzenes already evaluated. In most RDT testing of nitrobenzenes without hydroxyl groups or acid groups, findings related to haemolytic anaemia and liver effects were observed at low dosages. It was, therefore, possible to assume common AOPs for haemolytic anaemia and liver effects induced by these nitrobenzenes. As a result, a group of nitrobenzenes was defined as a single category for both haemolytic anaemia and liver effects, respectively, based on these AOPs.

Development of a category approach to predict the testicular toxicity of chemical substances structurally related to ethylene glycol methyl ether

We propose a category approach to assessing the testicular toxicity of chemicals with a similar structure to ethylene glycol methyl ether (EGME). Based on toxicity information for EGME and related chemicals and accompanied by adverse outcome pathway information on the testicular toxicity of EGME, this category was defined as chemicals that are metabolized to methoxy- or ethoxyacetic acid, a substance responsible for testicular toxicity. A Japanese chemical inventory was screened using the Hazard Evaluation Support System, which we have developed to support a category approach for predicting the repeated-dose toxicity of chemical substances. Quantitative metabolic information on the related chemicals was then considered, and seventeen chemicals were finally obtained from the inventory as a shortlist for the category. Available data in the literature shows that chemicals for which information is available on the metabolic formation of EGME, ethylene glycol ethyl ether, methoxy- or ethoxyacetic acid do in fact possess testicular toxicity, suggesting that testicular toxicity is a concern, due to metabolic activation, for the remaining chemicals. Our results clearly demonstrate practical utility of AOP-based category approach for predicting repeated-dose toxicity of chemicals.