Concentration-response versus biology-based methods

S.A.L.M. Kooijman 2006/10/03

The present EU-project Nomiracle succeeds a previous EU-project Mixtox, which resulted a.o. in an Excel spreadsheet for the analysis of toxicity data for mixtures of compounds. We naturally applied this spreadsheet to our data on the effects of mixtures of metals on the survival of Folsomia candida. Jan Baas found that the outcome of the spreadsheet is sensitive to the type of baseline model that is selected (concentration addition versus independent action), and for each of the two possible choices the type of interaction changed several times during the 21 d exposure. With our biology-based methods we found no interaction between the metals, which strongly suggests that these inconsistent outcomes are just artifacts.

On invitation by Hans Løkke and David Spurgeon, I discussed in the Nomiracle meeting at Antwerp why the spreadsheet produces problematic results. This is because it is based on concentration-response curves of the log-logistic family (including e.g. log-probit, gamma and Weibull models), and this whole family is problematic for modelling effects on survival. The reasons are in the assumptions behind these models:

Three compelling reasons why these assumptions cannot be true are Notice that goodness-of-fit arguments are not among these reasons! But just selecting another descriptive curve, goodness-of-fit could easily be improved, but the above-mentioned problems will remain.

Concentration-response curves for lethal effects are, therefore, not realistic. They are also problematic in eco-toxicity applications. This is because

The arguments for sublethal effects are only slightly different. These are all strong reasons to cease the application of the concentration-response methods, especially because the much more powerful biology-based methods are available.

Contrary to biology-based methods, concentration-addition and independent-action are different concepts for concentration-response methods for mixtures of compounds. Since the slopes of any pair of compounds are typically different (and change in time), concentration addition is really weird for this method, and leads to complex implicit survival probabilities as functions of the (external) concentration of the compounds. No justification is known. For biology-based methods, however, concentration-addition comes naturally as a consequence of independent action. If changes in the internal concentration can be neglected, the effect on the survival probability is via the product of concentration and exposure time; this is well known in pharmacology, and in some practical application of toxicants (for instance in disinfection of buildings). This further underpins the need for the retirement of concentration-response methods.

In Antwerp, I briefly discussed the alternatives that the biology-based methods offer and how they can be used for extrapolation pruposes. JRC-ECB will organise a workshop in 2007 on biology-based methods for environmental risk assessment, for which Tjalling Jager and I will provide the content. We will organise a DEB tele-course in 2007. The free registration for this course is already open.

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