Isn't synergy obvious? Here's the definition from Klaassen, Casarett & Doull's Toxicology (5th ed.):
Sounds easy.An additive effect occurs when the combined effect of two chemicals is equal to the sum of the effects of each agent given alone (example: 2+3=5).
A synergistic effect occurs when the combined effects of two chemicals are much greater than the sum of the effects of each agent given alone (example: 2+2=20).
Ok, so here's a simple example. I have two chemicals, A and B.
A 4.0 µM dose of A yields an effect of 1.2 units.
A 6.0 µM dose of B yields an effect of 2.2 units.
Question: What is the effect of a combined dose of 4.0 µM of A and 6.0 µM of B, if they act additively; that is, they are not synergistic?
Seems straightforward, right? 1.2 + 2.2 = 3.4, so we expect a total effect of 3.4 units. That's certainly what the definition of Klaassen gives.
Not so! Here's a trick: What if A and B are the same chemical? They obviously can't be "synergistic"; a definition of synergy that allows the same chemical to synergize with itself defies logic. I can keep the chemical in two separate containers, labelled "A" and "B", but the chemical itself is the same. Then I must get a combined effect of 3.4 units, right? Still, no. Consider the case where A and B are the same chemical, and the dose-response curve looks like this:
Klaassen's definition—which is a very common one in toxicology—only works if the dose-response curves of each chemical is linear (furthermore, it must go through the origin). But many, many chemicals have nonlinear dose-response curves, so this is a pretty poor definition of synergy, and leads us to the wrong answer frequently. This can have big impacts on how we understand combination exposures, including low-level multiple exposures like xenoestrogens.
As described in this brief description of my dissertation, Tom Webster and I have developed an extension of the method of concentration addition to allow for combinations of full agonists, partial agonists, and competitive antagonists. I was greatly aided in this work by the award of an EPA STAR Fellowship from 2004-2007.
For more information:
Berenbaum MC. 1989. What is synergy? Pharmacol Rev. 41(2): 93-141.
Greco WR, Bravo G, Parsons JC. 1995. The search for synergy: a critical review from a response surface perspective. Pharmacol Rev. 47(2): 331-85.
Kortenkamp A, Altenburger R. 1998. Synergisms with mixtures of xenoestrogens: a reevaluation using the method of isoboles. Sci Total Environ. 221(1): 59-73.
Silva E, Rajapakse N, Kortenkamp A. 2002. Something from "nothing"—eight weak estrogenic chemicals combined at concentrations below NOECs produce significant mixture effects. Environ Sci Technol. 36(8): 1751-6.