Actions of Chemicals in Mixture

The following are the major subjects of the book the various institutions, agencies, and programs involved in chemicals regulation (Chapter 2). The data for hazard assessment (Chapter 3) and the hazard assessment process, i.e., identihcation and characterization of the various toxicological effects and the associated test methods (Chapter 4). Standard setting for threshold effects (Chapter 5) and non-threshold effects (Chapter 6). Exposure assessment (Chapter 7) and risk characterization (Chapter 8). Regulatory standards set by various bodies (Chapter 9) and combined actions of chemicals in mixture (Chapter 10). 

BASIC CONCEPTS AND TERMINOLOGY USED TO DESCRIBE THE COMBINED ACTION OF CHEMICALS IN MIXTURES... 

The main emphasis is paid to the identification of the basic principles for combined actions and interactions of chemicals (Section 10.2), and to the current knowledge on effects of exposures to mixtures of industrial chemicals, including pesticides and environmental contaminants. Test strategies to assess combined actions and interactions of chemicals in mixtures (Section 10.3) as well as toxicological test methods (Section 10.4) are addressed, approaches used in the assessment of chemical mixtures are presented (Section 10.5), and examples of experimental studies using simple, well-defined mixtures are given (Section 10.6). 

The in vitro and in vivo test methods available to study combined actions and toxicological and biochemical interactions of chemicals in mixtures are essentially the same as those used for the study of single chemicals in order to examine their potential general toxicity and special effects such as mutagenicity, carcinogenicity, and reproductive toxicity. 

In this chapter, we outline the issues and principles that are relevant to toxicity assessments of combined exposures. The scope of this overview is limited to combinations of chemicals, but excludes the topic of nonchemical stressors acting in concert with chemicals. Because the issues are of a generic nature, we draw on examples from human, environmental, and ecological toxicology. Section 3.2 briefly outlines approaches to mixture effects assessment (Chapter 4 elaborates these approaches in more detail), Section 3.3 discusses mixture effects in relation to modes and mechanisms of action, and Section 3.4 addresses the problems and possibilities of predicting mixture effects. In Sections 3.5 and 3.6, emphasis is on the predictability of synergism and on effects at low concentration or dose levels of chemicals in mixtures. Section 3.7 provides an overview of scarcely available data on mixture effects in real-world exposure scenarios. This chapter ends with an outlook to the future. 

Elaborating further on this, De Zwart and Posthuma (2005) emphasized the importance of assessing the modes of action of chemicals in a complex mixture. Only with good insight into the chemical composition and knowledge of the modes of action of the composing chemicals, it may be possible to predict toxicity of a complex mixture (see also Chapter 3). De Zwart and Posthuma propose a... 

A major issue in the assessment of the combined toxicological effect of chemicals in a mixture is the type of combined action to be expected. What kind of toxicity may be expected, given the toxicity profiles of the individual components Bliss (1939) was the first to provide a conceptual framework for the combined action of chemicals and later contributions were made by Finney (1942), Hewlett and Placket (1959, 1964), Placket and Hewlett (1952, 1963, 1967), Ashford and Cobby (1974), and Ashford (1981). 

As has already been outlined in the introduction, one of the main points to consider is whether there will be no interaction or interaction in the form of either synergism or antagonism. These three basic principles of combined actions of chemical mixtures are purely theoretical and one often has to deal with two or all three concepts at the same time, especially when mixtures consist of more than two compounds and when the toxicity targets are more complex. 

Chemicals in mixtures may interact with one another and modify the magnitude and sometimes also the nature of the toxic effect. As illustrated in Table 10.1, the combined action of chemicals that interacts can be divided into two categories complex similar action and complex dissimilar action (dependent action). 

When epidemiological studies form the basis for the risk assessment of a single chemical or even complex mixtures, such as various combustion emissions, it may be stated that in those cases the effects of combined action of chemicals have been incorporated. Examples can, for instance, be found in the updated WHO Air Quality guidelines (WHO 2000). Thus, the guideline value for, e.g., ozone was derived from epidemiological studies of persons exposed to ozone as part of the total mixture of chemicals in polluted ambient air. In addition, the risk estimate for exposure to polycyclic aromatic hydrocarbons was derived from studies on coke-oven workers heavily exposed to benzo[fl]pyrene as a component of a mixture of PAH and possibly many other chemicals at the workplace. Therefore, in some instances the derivation of a tolerable intake for a single compound can be based on studies where the compound was part of a complex chemical mixture. 

The method evaluates the data relevant to joint actions for each possible pair of chemicals in the mixture in order to make qualitative binary weight-of-evidence (BINWOE) determinations for the effect of each chemical on the toxicity of every other chemical. Two BINWOEs are needed for each pair one for the effect of chemical A on the toxicity of chemical B, and another for the effect of chemical B on the toxicity of chemical A. 

They considered it important to distinguish between simple and complex mixtures. According to Feron et al. (1998) a simple mixture consists of a relatively small number of chemicals (e.g., 10 or less) and the composition of the mixture is known, both qualitatively and quantitatively. An example would be a cocktail of pesticide residues in food. A complex mixture comprises tens, hundreds, or thousands of chemicals, and the qualitative and quantitative composition is not ftiUy known. They also emphasized to distinguish between whole-mixture analysis (top-down approach) and component-interaction analysis (bottom-up approach), the latter requiring an understanding of the basic concepts of combined action of chemicals. 

---