Document ID: chunk:federal_register_of_legislation:F2013C00288:reg:10:p1
Version: federal_register_of_legislation:F2013C00288
Segment Type: reg
Provision Reference: reg 10 (pt 1/2)
Character Range: 1224495–1227480

10             Appendix B: Mixtures of chemicals
A number of different types of joint action exist for mixtures of contaminants. Of these there are only predictive models for concentration addition (also called simple similar joint action) and response addition (also referred to as independent joint action). When all the chemicals in the mixture have the same mechanism of action, (that is, they exert their toxicity in the same manner at the same location), and they do not affect each other's biological activity in the organism, then the toxicity should conform to concentration addition (Plackett & Hewlett 1952).  If, however, the chemicals have different mechanisms of action and they affect each other's biological activity, then the toxicity of the mixture should conform to response addition (Plackett & Hewlett 1952). Other types of joint action include synergism, antagonism, supra-addition, complex similar and dependent joint action.

The available literature shows that for the vast majority of mixtures, the toxicity conforms to concentration addition with relatively small numbers of antagonistic and synergistic mixtures. For example, Deneer (2000), Faust et al. (1994), Warne and Hawker (1995) and Ross and Warne (1997) found that approximately 1030% of mixtures (regardless of the type of chemical, but focusing predominantly on organic chemicals) were antagonistic or synergistic, with each type of joint action being equally frequent and the remaining 7090% conformed to concentration addition, based on aqueous concentration toxicity data. Similar values but with higher percentages of antagonistic and synergistic mixtures, (that is, 43% antagonistic, 27% additive and 29% synergistic), were found in a recent review by Norwood et al. (2003) of the aquatic toxicity of mixtures of metals.

It has also been shown (Backhaus et al. 2000a, 2000b; Chevre et al. 2006; Dyer et al. 2000; Faust et al. 1994; Junghans et al. 2006) that concentration addition overestimated the toxicity of mixtures and yielded slightly higher estimates of the toxicity of mixtures than response addition when chemicals had different mechanisms of action.

A two-step mixed model independently proposed by Junghans (2004), Altenberger et al. (2004), and De Zwart & Posthuma (2005) is, however, theoretically superior to the concentration addition method to estimate the toxicity of mixtures. In this model, the first step is to estimate the combined toxicity of components that have the same mechanism of action using concentration addition and then, if necessary, to estimate the combined toxicity of components or groups of components that have different mechanisms of action using the response addition model. But as the concentration addition method results in higher estimates of toxicity than the response addition method, it is not necessary to use the more complicated two-step mixed model method.

Given the above, it is appropriate to use the concentration addition model to