Toxic unit models

In summary, the different joint effect models of multicomponent pollutant mixtures (i.e., the toxic unit, additive and mixture toxicity indices) were presented. Using such models to analyze the joint effect of a group of toxic and carcinogenic organic compounds such as polycyclic aromatic hydrocarbons will be presented and evaluated in Sect. 3.2. 

The European Inland Fisheries Advisory Commission (EIFAC 1980) reviewed the toxicity of 76 binary mixtures of common effluent pollutants to fish. Mixture effects occurred at 0.4 to 26 times the exposure concentration expected under concentration-additive toxicity, with 87% of the data ranging between 0.5 and 1.5 times this concentration. Substances with concentrations lower than 0.2 toxic units (TU) appeared not to contribute to the toxicity of the mixtures. In contrast to the apparent lack of effects at low mixture concentrations, subsequent papers (Konemann 1981 Hermens et al. 1985 Deneer et al. 1988) showed that apparently equitoxic mixtures containing 8, 9, 11, 24, 33, and 50 organic chemicals at concentrations that were only small fractions of the individual EC50 values were indeed able to induce responses that agreed with the concentration-addition models. These formed the basis of an updated report (EIFAC 1987). 

BOX 5.1 Example of a spreadsheet calculation of the expected combined defined effect for a multiple mixture using different amounts of information. Note Tier-1 prediction relies on exposure and EC50 information (toxic unit summation), Tier-2 needs additional concentration response information for calculation of expected combined effects according to the reference models of response addition or concentration addition, and Tier-3 calculation (mixed models) requires information on the relevant mode of action. The sample is based on real analytical and effect data. Source Redrawn from data from Altenburger et al. (2004). 

A tiered system for mixture extrapolation is proposed. The lowest tier is based on extrapolation using toxicological point-estimate information such as EC50 values. This translates into the use of toxic units, toxic equivalencies, and similar techniques. The use of the entire concentration-response relationships of the separate compounds is recommended for Tier-2, in conjunction with the use of either concentration or response addition as a modeling approach. In Tier-3, a mixed-model approach can be considered, to more specifically address considerations on toxic modes of action. In the latter case, the approach may be extended to allow incorporation of the responses of different ecological receptors (Tier-4). Research needs have been clearly identified in community-level mixture assessments. 

In the study of Teuschler et al. (2000), the models for analyzing the data were selected beforehand, and it was also decided to only focus on environmentally relevant mixtures. The authors indicated that these 2 factors were decisive for choosing the concentration levels to test. The concentration levels were not selected in relation to a specific endpoint, using the toxic unit approach. This may have been avoided because several different hepatotoxic endpoints have been measured simultaneously. The concentrations tested enabled the use of 3 types of models a multiple regression CA model, the interaction-based HI, and the proportional-response addition method. A major problem with mixture toxicity research in general is the... 

Which effect assessment method should be applied in a particular situation depends on the nature of the mixture problem at hand. Because the diversity in assessment methods is large, it is important to clearly describe the problem. For example, derivation of a safe level for a proposed industrial mixture emission requires a different approach than the prioritization of a number of sites contaminated with mixtures. The former problem requires the assessment of realistic risks, for example, by the application of a suite of fate, exposure, and effect models, whereas the application of a simple consistent method suffices to address the latter problem, for example, a toxic unit approach. A successful and efficient assessment procedure thus starts with an unambiguous definition of the mixture problem at hand. The problem definition consists of the assessment motive, the regulatory context, the aim of the assessment, and a structured or stepwise approach to realize the aim. Elaboration of the problem definition is an iterative process (Figure 5.1) that strongly depends on factors such as resources, methods, data availability, desired level of accuracy, and results of previous studies. 

Tier 2 assumes either a uniform MOA for all compounds (i.e., concentration addition) or a complete nonuniform set of modes of action (i.e., response addition). Limited information on the MOA is typically available to use in the assessment, and the techniques are relatively simple. CA in tier 2 differs from that in tier 1 by using the full-dose-response curve. First, the concentration of the components is expressed in comparable units. Subsequently, these units are summed and a dose-response model is applied to predict the response. Examples include the application of RPFs, TEFs, and toxic units. These techniques are commonly used in human as well as in ecological risk assessment of mixtures, though the use of whole curve estimates is by far less common than the use of point estimates (tier 1). 

Playle RC. 2004. Using multiple metal-gill binding models and the toxic unit concept to help reconcile multiple-metal toxicity results. Aquat Toxicol 67 359-370. 

The CA concept uses the toxic unit (TU) or the toxicity equivalence factor (TEF), defined as the concentration of a chemical divided by a measure of its toxicity (e.g., EC50) to scale toxicities of different chemicals in a mixture. As a consequence, the CA concept assumes that each chemical in the mixture contributes to toxicity, even at concentrations below its no-effect concentrations. The IA or RA concept, on the other hand, follows a statistical concept of independent random events it sums the (probability of) effect caused by each chemical at its concentration in the mixture. In the case of IA, the only chemicals with concentrations above the no-effect concentration contribute to the toxicity of the mixture. The IA model requires an adequate model to describe the (full) dose-response curve, enabling a precise estimate of the effect expected at the concentration at which each individual chemical is present in the mixture. The concepts generally are used as the reference models when assessing mixture toxicity or investigating interactions of chemicals... 

The most basic model is the toxic unit model which involves determining the toxic strength of an individual compound, expressed as a "toxic unit." The toxicity of the mixture is determined by summing the strengths of the individual compounds (Herbert and Vandyke 1964) using the following model ... 

Initially, it would be desirable to use a simple model incorporating a linear relationship. Since the data are lacking for the determination of interactive effects, a simple additive toxic units model would make the fewest assumptions and require the minimal amount of data. Such a model would simply consist of... 

The IPAH model incorporated a number of factors that can modify the toxicity of the sediment-borne PAHs. Equilibrium partitioning was used to estimate the concentration of each PAH in the pore water of the sediment. The assumption was that the pore water material is the fraction that is bioavail-able. QSAR was also used to estimate the interstitial water concentration based on the octanol-water partition coefficient of several PAHs. Amphipods were used as the test organism to represent environmental toxicity. A toxic unit (TU) approach was used and the toxicity is assumed to be additive. The assumption of additivity is justified since each of the PAHs has a similar mode of action. Finally, a concentration-response model was formulated using existing toxicity data to estimate the probability of toxicity. 

A flowchart for estimating sediment toxicity is presented in Figure 6.2. First, a bulk sediment sample is taken and the PAH concentration and total organic carbon are measured. The equilibrium partitioning model is run to predict the concentration of each PAH in the interstitial water of the sediment. The predicted PAH concentrations are then converted to toxic units (TUs) using the 10-d amphipod LC50 as the toxicity benchmark. The TUs are then added up and processed through the concentration response model. The expected mortality is then converted to nontoxic, uncertain, and toxic predictions. 

Wiegers et al. (1997) have also applied the model to the concentrations of 10 PAHs (data for all 13 PAHs were not consistently available) for samples collected throughout Port Valdez, Alaska. Most of the samples were collected in the deep benthic areas, although samples from the Small Boat Harbor in the city and nearshore areas by Mineral Creek, the Valdez Marine Terminal, and the Solomon Gulch Hatchery have also been collected. All of the acute toxicity levels predicted in Port Valdez occur below the lowest levels set by the model. The sum of the toxic units (a measure of the total toxicity associated with the concentrations) is included in Table 6.2 as a comparison between samples collected from the identified subareas. 

What are the advantages of using a toxic units model for describing the toxicity of mixtures ... 

Lee JH, Landrum PF, Field LJ, Koh CH. Application of a sigmapolycyclic aromatic hydrocarbon model and a logistic regression model to sediment toxicity data based on a species-specific, water-only LC50 toxic unit for Hyalella azteca. Environ Toxicol Chem 2001 20 2102-13. 

As already mentioned, toxicity results obtained in the laboratory cannot always be interpreted directly. Often it is necessary to transform these values into units that are more meaningful in environmental management programs. One way to facilitate the use of toxicity data, whether for regulatory purposes or for modeling of toxicity, is to use toxic units. 

The TEC may be a test end-point, a test end-point corrected by a factor or other extrapolation model or a regulatory criterion or other benchmark value. A hazard quotient (HQ) greater than unity is treated as evidence that the chemical is worthy of concern. Suter (1996) also suggests that, if numerous chemicals occur at potentially toxic concentrations, an index of total toxicity could be calculated by the sum of toxic units (XTUs). This permits a comparison of COPECs and examines their distribution across areas within a site. The TUs are quotients of the concentration of a chemical in a medium divided by the standard test end-point concentration for that chemical. 

Accordingly, 1000 chemicals at 1/1000 LC50 concentration each will together kill 50% of the exposed organisms. The toxicity of a mixture can thus be expressed as the sum of the toxic units (TU dimensionless ratio of the exposure and the effective concentrations) contributed by each component (McCarty et ah, 1992). For QSAR modelling, these findings imply that the baseline toxicity equations can be extended for mixture assessments ... 

Schmidt, T.S., W.H. Clements, K.A. Mitchell, et al. 2010. Development of a new toxic-unit model for the bioassessmentof metals in streams. Environ. Toxicol. Ghent. 29 2432-2442. 

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