Mixture toxicity index

The third scheme proposed by Konemann [348] uses a mixture toxicity index (MTI) defined as... 

Various techniques, such as graphic illustrations (e.g., isobolograms), mixture toxicity indices (e.g., an additivity index), formulas, or fully parameterized models, exist for predicting an expected combined effect based on concentration addition or response addition (for review, see Bodeker et al. 1990). The quantitative relationship between the expected combined effect calculated according to concentration addition or response addition depends (in addition to other factors) primarily on the steepness of the concentration response relationship of the individual components (Drescher and Bodeker 1995). Concentration addition predicts a higher combined effect as compared to response addition when the mixture components have steep concentration response relationships, whereas the opposite is true for flat concentration response relationships of the mixture components. 

Figure 2. Relationship between the number of moles of ethylene oxide in octyl- or nonyl-phenol polyoxyethylene glycol ether surfactant molecules and the toxicity index of these surfactants in mixtures with (a) paraquat and (b) dalapon on corn plants.

Figure 3. Relationship between the number of moles of ethylene oxide in octylphenol (%), nonylphenol ( ), or laurylphenol ( J) polyoxyethylene glycol ether surfactant molecules and the toxicity index of these surfactants in mixtures with (a) paraquat, (b) dalapon, and (c) amitrole on corn plants. Herbicides applied at 1/64, 10, and 5 lb./ acre, respectively surfactant concentration was 0.005M in all cases. Toxicity index calculated by expressing fresh weight for each treatment as percentage of untreated control and subtracting this value from 100 (58)...

Although the toxic units and additive index are useful in determining toxicity in some cases, they have disadvantages. Their values depend on the relative proportion of chemicals in the mixture. Also, because of the logarithmic form of the concentration in log-linear transformations such as Probit and Logit, it is desirable to have a toxicity index which is logarithmic in the toxicant concentration. For these reasons, Konemann (1981) introduced a multiple toxicity index (MTI) ... 

The toxicity index is the volume of air or water with which the mixture of radionuclides must be diluted so that breathing the air or drinking the water will result in accumulation of radiation dose at a rate no greater than 0.5 rem/year. However, the toxicity index still does not measure ultimate hazards and risk, because it does not take into account the mechanisms by which the radionuclides could be released to air or water and transported to humans. 

The battery of test approach for toxicity testing is now a universally-accepted concept. It has recently been applied in Latin American countries and is presently recognized as a critical tool for the assessment of complex mixtures. Interpretation of hazard by reducing complex ecotoxicological data into a single numerical value (e.g., PEEP index) is generally favoured by decision-makers involved in various facets of environmental regulation. 

Recently, some models have been derived to analyze the occurrence of interactive joint action in binary single-species toxicity experiments (Jonker 2003). Such detailed analysis models are well equipped to serve as null models for a precision analysis of experimental data, next to the generalized use of concentration addition and response addition as alternative null models. However, in our opinion these models are not applicable to quantitatively predict the combined toxicity of mixtures with a complexity that is prevalent in a contaminated environment, because the parameters of such models are typically not known. Recently a hazard index (Hertzberg and Teus-chler 2002) was developed for human risk assessment for exposure to multiple chemicals. Based on a weight-of-evidence approach, this index can be equipped with an option to adjust the index value for possible interactions between toxicants. It seems plausible that a comparable kind of technique could be applied in ecotoxicological risk assessments of mixtures for single species. However, at present, the widespread application of this approach is prevented by lack of available information. 

The term toxic unit (TU) plays an important role in mixture concentration-response analysis. It is defined as the actual concentration of a chemical in the mixture divided by its effect concentration (e.g., c/EC50 Sprague 1970). The toxic unit is equivalent to the hazard quotient (HQ), which is used for calculating the hazard index (HI Hertzberg and Teuschler 2002). The term hazard quotient is generally used more in the context of risk assessment (see Chapter 5 on risk assessment), and the term toxic unit is used more in the context of concentration-response analysis, and therefore the latter term is used here. Toxic units are important for 2 reasons. First, toxic units are the core of the concept of concentration addition concentration addition occurs if the toxic units of the chemicals in a mixture that causes 50% effect sum up to 1. Second, toxic units can help to determine which concentrations of the chemicals to test when a mixture experiment needs to be designed. 

Additivity and no interactions. Additivity concepts that explain a shared adverse effect across chemicals include dose or concentration addition, which assumes chemicals share a common toxic MOA, and RA, which assumes chemicals act by toxicologically (and thus also statistically) independent MOA. There is also a body of research on the use of statistical dose-response modeling of empirical data to examine the joint toxic action of defined mixtures where the claim is that MOA assumptions are not necessary (Gennings et al. 2005). Dose addition methods scale the component doses for relative toxicity and estimate risk using the total summed dose, for example, using relative potency factors (RPFs), toxicity equivalency factors (TEFs), or a hazard index (HI). In contrast, RA (also named independent action ) is... 

RPF Relative potency factor. A factor that expresses the toxic potency of a mixture component relative to an index compound. In the RPF approach, RPF values of mixture components are summed and the risk of the whole mixture is estimated using dose-response data of the index compound. 

TEF Toxicity equivalency factor. Ratio of the toxicity of a chemical to that of another structurally related chemical (or index compound) chosen as a reference. TEFs are toxicity potency factors used to evaluate the toxicities of highly variable mixtures of dioxin-like compounds. The most toxic members, 2,3,7,8-TCDD and 1,2,3,7,8-pentachlorodibenzo-p-dioxin, are... 

As described in Chapter 1, the Navy has developed an approach for the management of mixtures of toxic gases in disabled submarines. That approach uses a cumulative exposure index (CEI), which assumes that the effects of exposure to mixtures of the irritant gases are additive but not synergistic. The subcommittee concludes that the use of the CEI approach is appropriate in protecting the health of the crew. That conclusion is consistent with the conclusions regarding the effects of exposure to mixtures of chemicals in other NRC... 

Dose additivity It is assnmed that each chemical behaves as a concentration or dilntion of every other chemical in the Cumnlative Assessment Group (or chemical mixture). The response of the combination is the response expected from the eqnivalent dose of an index chemical. The equivalent dose is the sum of the component doses, scaled by each chemical s toxic potency relative to the index chemical (USEPA, 2002). 

In search of less expensive, less toxic, and lower viscosity eluants, a few authors have proposed diluting the active ingredient with a common SEC eluant such as toluene, dichloromethane, or chloroform. To lower the operating temperature and minimize polymer degradation, mixtures of m-cresol with chlorobenzene (50 50, v/v, 43°C), dichloromethane (50 50, room temperature), and chloroform have been used, with 0.25 wt% benzoic acid added to prevent adsorption. In the same vein, o-chlorophenol has been diluted with chloroform (25 75) and used at 20°C. The main disadvantage in this latter solvent was a small dnidc for the polymer, which rendered refractive index measurements difficult. In addition, careful purification of the phenol is required to obtain a detection signal. Dichloroacetic acid diluted to 20 vol% with dichloromethane has been proposed as the mobile phase. However, even at this concentration, PA tends to degrade at room temperature. 

EPA recommends three approaches (1) if the toxicity data on mixture of concern are available, the quantitative risk assessment is done directly form these preferred data (2) when toxicity data are not available for the mixture of concern, data of a sufficiently similar mixture can be used to derive quantitative risk assessment for mixture of concern and (3) if the data are not available for both mixture of concern and the similar mixture, mixture effects can be evaluated from the toxicity data of components. According to EPA, the dose-additive models reasonably predict the systemic toxicity of mixtures composed of similar (dose addition) and dissimilar (response addition) compounds. Therefore, the potential health risk of a mixture can be estimated using a hazard index (HI) derived by summation of the ratios of the actual human exposure level to estimated maximum acceptable level of each toxicant. A HI near to unity is suggestive of concern for public health. This approach will hold true for the mixtures that do not deviate from additivity and do not consider the mode of action of chemicals. Modifications of the standard HI approach are being developed to take account of the data on interactions. 

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