Toxicity of Mixtures

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  

Building on this simple model, Marking and Dawson (1975) devised a more refined system to determine toxicity based on the formula  

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)  

More than additive toxicity A Less than additive toxicity 

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The advantages of combining toxicity testing with chemical analysis when dealing with complex mixtures of environmental chemicals are clearly evident. More useful information can be obtained than would be possible if one or the other were to be used alone. However, chemical analysis can be very expensive, which places a limitation on the extent to which it can be used. There has been a growing interest in the development of new, cost-effective biomarker assays for assessing the toxicity of mixtures. Of particular interest are bioassays that incorporate mechanistic... 

SHARED MECHANISM OF ACTION—AN INTEGRATED BIOMARKER APPROACH TO MEASURING THE TOXICITY OF MIXTURES... 

Particular attention is given to the development of new mechanistic biomarker assays and bioassays that can be used as indices of the toxicity of mixtures. These biomarker assays are typically based on toxic mechanisms such as brain acetylcholinesterase inhibition, vitamin K antagonism, thyroxin antagonism, Ah-receptor-mediated toxicity, and interaction with the estrogenic receptor. They can give integrative measures of the toxicity of mixtures of compounds where the components of the mixture share the same mode of action. They can also give evidence of potentiation as well as additive toxicity. 

The sheer complexity of environmental mixtnres of EDCs, possible interactive effects, and capacity of some EDCs to bioaccumulate (e.g., in fish, steroidal estrogens and alkylphenolic chemicals have been shown to be concentrated up to 40,000-fold in the bile [Larsson et al. 1999 Gibson et al. 2005]) raises questions about the adequacy of the risk assessment process and safety margins established for EDCs. There is little question that considerable further work is needed to generate a realistic pictnre of the mixture effects and exposure threats of EDCs to wildlife populations than has been derived from studies on individual EDCs. Further discussion of the toxicity of mixtures will be found in Chapter 2, Section 2.6. 

Alabaster, J.S., D.G. Shurben, and M.J. Mallett. 1983. The acute lethal toxicity of mixtures of cyanide and ammonia to smolts of salmon, Salmo salar L. at low concentrations of dissolved oxygen. Jour. Fish Biol. 22 215-222. 

Brown, V.M. The calculation of the acute toxicity of mixtures of poisons to rainbow trout. Water Res., 2(10) 723-733,1968. 

This approach was initially developed to estimate the potential toxicity of mixtures of polychlorinated dibenzo- -dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs), and polychlorinated dioxin-like biphenyls (PCBs). Over the years, a number of different TEF systems for PCDDs, PCDFs and PCBs have been used. A system was internationally agreed upon at a WHO Consultation in 1997 (WHO-TEF) as published by Van den Berg et al. (1998). A WHO update has been published recently (Van den Berg et al. 2006) (Table 10.3). 

The toxicity of mixtures of chemicals with the same target organ was examined in rats using nephrotoxicants with similar or dissimilar modes of action. 

Jonker, D., R.A. Woutersen, and V.J. Feron, 1996. Toxicity of mixtures of nephrotoxicants with similar or dissimilar mode of action. Food Chem. Toxicol. 34 1075-1082. 

Additive or more-than-additive toxicity of free cyanide to aquatic fauna has been reported in combination with ammonia (Smith et al. 1979 Leduc et al. 1982 Alabaster et al. 1983 Leduc 1984) or arsenic (Leduc 1984). However, conflicting reports on the toxicity of mixtures of HCN with zinc or chromium (Towill et al. 1978 Smith et al. 1979 Leduc et al. 1982 Leduc 1984) require clarification. Formation of the nickelocyanide complex markedly reduces the toxicity of both cyanide and nickel at high concentrations in alkaline pH. At lower concentrations and acidic pH, solutions increase in toxicity by more than 1000-fold, owing to dissociation of the metallo-cyanide complex to form hydrogen cyanide (Towill et al. 1978). Mixtures of cyanide and ammonia may interfere with seaward migration of Atlantic salmon smolts under conditions of low dissolved oxygen (Alabaster et al. 1983). The 96-h toxicity of mixtures of sodium cyanide and nickel sulfate to fathead minnows is influenced by water alkalinity and pH. Toxicity decreased with increasing alkalinity and pH from 0.42 mg CN/L at 5 mg CaCOj/L and pH 6.5, to 1.4 mg CN/L at 70 mg CaCOj/L and pH 7.5 to 730 mg CN/L at 192 mg CaCOj/L and pH 8.0 (Doudoroff 1956). 

Hermanutz, R.O. (1978) Endrin and malathion toxicity to flagfish (Jordanella floridae). Arch. Environ. Contam. Toxicol. 7, 159-168. Hermens, J., Leeuwangh, P. (1982) Joint toxicity of mixture of 8 and 24 chemicals to the guppy (Poecilia reticulata). Ecotoxicol. Environ. Saf. 6, 302-310. 

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. 

As summarized in Section 5.3.1, the vast majority of aquatic mixture toxicity studies report that the actual toxicity of mixtures is very close to the toxicity predicted by concentration addition. The application of Tier-3 approaches is mostly restricted... 

Belden et al. (2007) used a 3-step approach to evaluate the relative toxicity and the occurrence pattern of pesticide mixtures in streams draining agricultural watersheds. First, a landscape of interest was identified as the corn-soybean crop setting in the United States. Second, the relative toxicity of mixtures was compared... 

Calamari D, Marchetti R. 1973. The toxicity of mixtures of metals and surfactants to rainbow trout (Salmo gairdneri Rich). Water Res 7 1453-1464. 

Deneer JW. 2000. Toxicity of mixtures of pesticides in aquatic systems. Pest Manage Sci 56 516-520. 

European Centre for Ecotoxicology and Toxicology of Chemicals [ECETOC]. 2001. Aquatic toxicity of mixtures. Technical Report No. 80. Brussels (Belgium) ECETOC, 64 p. 

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