Center for Interdisciplinary Research
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The intuitive answer, for most people, is synergy, since the combination of A and B produces a larger effect than the individual effects summed. The definition of synergistic as greater than additive is fine; the issue lies in what we mean by additive. The intuitive answer uses the definition of additivity known as effect summation. Surprisingly (perhaps) this turns out not to be a very useful way to think about it.

To see why, suppose I tell you that A and B are actually the same compound. The sham combination of A and B is, in fact, just 20 uM of A. The effect of the sham combination is larger than each 10 uM increment separately because the dose-response curve is here concave up. Most toxicologists and pharmacologists would not call this synergism.

OK, maybe that seems like cheating. Suppose instead that A and B are different compound with B exactly half as potent as A at every dose, i.e., B acts as if it is a two-fold dilution of A. 5 uM of A and 10 uM of B thus yield the same results. A combination of 5 uM of A and 10 uM of B is equivalent to 10 uM of A (applying TEFs as is done for dioxins). The results, shown below, look the same as before.

The combination again yields a larger effect than each component by itself. But rather than synergism, we have a special case of what is called additivity of doses, i.e., dose additivity or, as it is more frequently called, concentration additivity.

Let's examine these ideas mathematically. We'll define

Three definitions of additivity are typically used:
effect summation: f_ab[A,B] = f_a[A] + f_b[B]

independent action: f_ab[A,B] = f_a[A] + f_b[B] + f_a[A] f_b[B]

concentration addition: A/E_i,a + B/E_i,b = 1

where E_i,a and E_i,b are, respectively, the concentrations of A and B that individually lead to effect level i.

Reference: Berenbaum MC: What is synergy? Pharmacol Rev 1989; 41(2):93-141.

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