This paper, at first, outlined the photochemical oxidant pollution of the atmosphere caused by various volatile organic compounds (VOCs), defined as "organic compounds that are gaseous when emitted or dispersed into atmosphere", the major causative substances and mechanisms of the pollution, and the oxidant generation capacity, which is used to comprehensively understand the combined effects of various VOCs. The history of VOC emission regulations in Japan, the concept of setting emission standards, and the monitoring by using the total volatile organic compounds (TVOC) were also outlined. In addition, the status of self-motivating action by industries were outlined. Since FY2005, when the VOC emission control regulation was introduced, VOC emissions in Japan have been steadily decreasing, far exceeding the initial target (30% reduction from FY2000 levels by FY2010).

Humans and organisms in the environment are simultaneously exposed to multiple chemical substances, while risk assessment is usually conducted separately for every single substance. In order to assess the risk due to exposure to multiple chemicals, it is essential to conduct a risk assessment of mixture effects. Since the risk assessment of single chemicals is the basis of that of mixture effect, various modeling techniques used for the assessment of single chemicals are generally applied to the assessment of mixture effect. The modeling techniques for exposure assessment include those for estimating concentration in the environmental media, estimating internal concentration in the human body, and estimating model parameters along with the flow of chemical substances in the environment. The modeling techniques for hazard assessment include modeling the toxicity mechanism, modeling the dose-response relationship, and estimating the no-observed adverse effect level. Modeling techniques also play an essential role in the risk assessment of mixture effects for determining how to combine the effects of multiple chemicals and in what range of chemicals.

Combined exposure to multiple chemicals is one of the primary concerns related to risk assessment. In this study, the feasibility of using environmental fate models in exposure assessment of combined exposure was discussed. Specifically, spatio-temporal changes in the concentrations of three paddy herbicides (halosulfuron methyl, pyrazosulfuron ethyl, and cyclosulfamuron) were predicted for whole Japanese rivers, and the ecological risk assessment of combined exposure was estimated based on the predicted concentrations. The hazard index (HI), which is the sum of hazard quotients of the three herbicides, was calculated for the rivers. Temporal trends of the HI were demonstrated for six river mouths. The contribution of each herbicide when HI reached its maximum was also shown for the six rivers. Pyrazosulfuron ethyl made the largest contribution in the range of 0.62 to 0.95. The environmental fate model has potential to use for prioritizing target chemicals in exposure assessment and setting conditions for ecotoxicity tests.

Laws and regulations regarding chemical safety require that chemicals be evaluated for long-term persistence in the environment. Methods and criteria for evaluating environmental persistence differ among the laws and regulations. Since biodegradation is one of the main degradations that chemicals undergo in the environment, persistence is usually evaluated by biodegradability tests. In general, in standardized biodegradability tests, microorganisms are exposed to only one chemical substance, whereas in the real environment, microorganisms are combined-exposed to a variety of chemicals. Under combined exposures, biodegradation of coexisting substances may be enhanced or, conversely, inhibited. This manuscript introduces definitions of biodegradability/persistence in the laws and regulations and issues in evaluation, biodegradability test methods, and the effects of combined exposure on biodegradation.

Current risk assessment practices are largely based on evaluating the toxicity of single chemicals. However, humans and environmental organisms are simultaneously exposed to a large number of chemicals. In the case of mixtures, it has long been pointed out that a single chemical substance may cause unanticipated health effects and that the hazards of mixtures cannot be properly assessed. Although there is currently no globally unified method for handling and evaluating mixtures, various evaluation methods have been proposed, mainly by the World Health Organization (WHO), Europe, and the United States. The present report outlines the actual evaluation of mixtures, focusing on their hazardous properties, based on the handling and evaluation methods of mixtures being worked on by overseas organizations and others.

Environmental specimen bank (ESB) is a facility to support sound chemical management by archiving environmental/human samples for long term without changing their chemical/physical properties and providing the opportunity to conduct retrospective analysis in future in order to reveal exposure status to a variety of chemicals and their mixtures. Basic principle, precautions and operation of ESB are summarized with particular attention on the study of mixture effects of chemicals, and examples of further research topics are presented.

The ecological hazard and risk assessment of individual chemicals in Japan have been far behind the other developed countries such as the US and European countries and have long been limited to fish acute toxicity assessment for pesticides. After the recommendation by Organization for Economic Cooperation and Development (OECD) in 2002, ecological hazard and risk assessment for industrial chemicals was implemented in Chemical Substances Control Law (CSCL) and that for pesticides was expanded to crustaceans and algae in 2003 by Ministry of the Environment. Environmental standard for water quality to protect aquatic organisms was also first implemented in 2003 for zinc while the guidance for the ecological risk assessment for human pharmaceuticals was implemented at last in 2016 by Ministry of Health, Labor, and Welfare. Due to the increasing number of chemicals manufactured, used, and wasted, the ecological hazard and risk assessment for complex mixtures have become concern and investigated but the component-based approach in the ecological risk assessment has not yet well established and is far behind that in human health risk assessment. Alternatively, whole mixture approach such as the direct bioassay of effluent and ambient water has been implemented in some developed countries but the attempt to implement the Japanese version of Whole Effluent Toxicity system was ended up with the voluntary-based measure. Therefore, component-based approach for the grouping of chemicals based on chemical structure, use and mode of action should be started by the development of guidance documents possibly used in CSCL and other regulations with utilizing new approach methods (NAMs) in addition to conventional ecological testing combined with proper whole mixture approach for monitoring effluent and ambient water to cover such growing numbers of diverse small production volume chemicals.

To assess the combined exposure of chemicals, it is necessary to comprehensively measure various chemicals in environmental media. The main instruments used to measure organic compounds are gas chromatography or liquid chromatography coupled with mass spectrometry. Selected reaction monitoring (SRM) measurements with triple quadrupole mass spectrometers are often used for simultaneous multi-target analysis. Nevertheless, because of the possibility of retrospective analysis, AIQS-GC, an automated identification and quantification system using GCMS scan mode, and AIQS-LC, using data-independent analysis (DIA) with LC-QTofMS, have been developed and are becoming popular. On the other hand, strategies to evaluate multiple exposures include filtering only substances with a common structure from measurements of non-targeted analyses or purifying only compounds with a similar structure from within a mixture.