Non-Monotonic Chemicals: Why They Matter

MONOTONIC VERSUS NON-MONOTONIC

The lack of predictability is a serious flaw in the current government method which  assumes that the chemical being tested always expresses itself the same way at every concentration. It assumes a greater effect at high concentration, a lesser effect at lower doses. In scientific terms, this predictability is called a monotonic dose response.

But EDCs and many other compounds are not so predictable because they affect different biological structures when present in varying concentrations. This is especially true for natural hormones, endocrine disrupters, many pharmaceuticals and even the ethanol in wine, beer and spirits.

The Vandenberg/Myers study explained that, “For all monotonic responses, the observed effects may be linear or nonlinear, but the slope [of the plotted line or curve] does not change sign. This assumption justifies using high-dose testing as the standard for assessing chemical safety. When it is violated, high-dose testing regimes cannot be used to assess the safety of low doses.”

The study then pointed out that EDCs as a group violate the rule by being non-monotonic.

WHY DOES NON-MONOTONIC MATTER?

Many chemical compounds are simply toxic: they damage and kill cells. The higher the concentration, the more toxic and the more cells die – the dose makes the poison.
Regardless of the concentration, these chemicals kill cells the same way. And, at the level of no observed adverse effects, they stop killing, or are tolerated by cells. This is a monotonic dose response.

But non-monotonic chemicals can affect different mechanisms in the body depending on the concentration.

One well-known non-monotonic response is the “U” shaped curve of the “French Paradox” or the activity of pharmaceuticals including aspirin and many hormones.

With these compounds, there is no effect at low concentrations. As concentration levels increase, scientific studies show an increasing beneficial effect. Then, beyond that level, the beneficial effect diminishes and later, high levels can be toxic and damaging.

This odd behavior is non-monotonic because the substances act on different parts of the body at different concentrations. At high levels they are toxic. At lower levels, they act on a variety of microscopic cell receptors and structures that allow them to have a different and beneficial effect.
Indeed, research has shown that at very low levels, EDCs can magnify or suppress the effects of natural hormones in the body or cause their own unique syndromes.

But nothing in nature says non-monotonic behavior always goes from damaging to beneficial as the concentrations go from high to low. Significantly, the effects of EDCs and other low-concentration chemicals are generally unstudied and unknown. However, in those few cases where they are better understood, EDCs have been found to have damaging effects.

Clearly, EDCs are an example of non-monotonic behavior that can go from deadly toxic (poisoning cells) to invisibly deadly (tumors, genetic effects, metabolic disorders and other diseases).

Indeed, as a future article in this series will explore, an increasing number of studies indicate that EDCs may be responsible for part of the current obesity and diabetes epidemics. They may also contribute to the decline of endangered species including salmon, frogs and other “cold-blooded” animals which seem to be more susceptible than mammals to chemical compounds.