The Dose Is The Poison (Not Always!): Non-Monotonic Behavior

The phrase “The dose is the poison,” carries with it the implication that if something is toxic, then less will be less toxic. And a lot less is safe.

This just seems so terribly logical: half as much is half as toxic. One-hundredth as much is one-hundredth as toxic. A millionth as much is a millionth as toxic. Lesser and lesser until it’s hard – or impossible — to easily detect with instruments.

And if you can’t detect it, then you can pretend it’s not really there, so how could it be toxic?

My goodness! The proponents of “The dose is always the poison,” would argue that common sense tells us that nothing that small could possibly be of harm.

Except that our noses can detect things fainter than many instruments. And thousands of well-done scientific studies prove that hormones in our bodies function in impossibly small parts per billion and parts per trillion.

And so do the hormone-disrupting chemicals behind the Stealth Syndromes.

Updating A Last-Century Paradigm

The concept of  “the dose is the poison,”  underpins federal regulatory decisions that insist that, “The solution to pollution is dilution.”

The “dose is the poison,” paradigm works well for toxic substances whose effects can be easily seen in the outright injuries and deaths of lab animals or gross anatomical changes that the naked eye of a standard optical microscope could reveal.

Science, however, has progressed into the Twenty-First Century where scientific instruments can accurately, quickly and consistently measure concentrations of parts per trillion and smaller. Along with those modern instruments have come advances in knowledge of the molecular operations of the cell and the effects of low hormone disruptor levels.

Science and its instruments have progressed, but those at corporations and bureaucrats in charge of the regulatory machinery – including the FDA – often have not. They ignore the smaller concentrations that act over time to promote metabolic, endocrinological, and carcinoenic harms.

In many ways, this reluctance to accept science at the molecular level reflects the stubborn resistance of old-time physicists who refused to accept the validity of quantum theory because it was too odd for them to comprehend.

For more on the regulatory problems and public health problems this causes, please see:

Observed Effects

In any study, it’s no surprise that what you’re looking for often determines what you discover.

Old-line corporate and government scientists tend to stick with the old science they are comfortable with.

This results in today’s over-reliance on observing test animal behavior, testing blood and serum levels, dissecting them to weigh organs and examine cells under a standard optical microscope to see if cells are normal or not.

The valid science of hormone-disrupting EDCs, on the other hand, takes place at the molecular level. Some of those include:

  1. Disrupting signaling pathways inside the cell,
  2. Interactions with DNA that can imitate mutations by stopping or overproducing various proteins and other molecules, (a process called epigenetics),
  3. Altering cell mechanisms like protein production, or metabolic pathways that power the cell.

These processes are invisible to the naked eye.

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For that reason, old-line investigators distrust more modern methods because they  are more comfortable handling test animals, dissecting bits of their flesh and looking through a microscope with their own two eyes at thin sections of tissue through an optical microscope.

Those techniques are still enormously valuable in many cases and are well-established in much of laboratory work.

But they fail when science must look into the basic workings of a cell to determine the effects of improbably small concentrations of chemicals on impossibly tiny molecules.

Non-Linear behavior Invalidates the absolutes of “Dose Is The Poison”

“Dose is the poison” assumes that test effects and doses will go in a predictable straight line. However, but hormones, EDCs, many pharmaceuticals and a vast number other substances do not behave in a linear fashion.

Take estrogen, which, in high concentrations, is cytotoxic: It kills cells.

The cytotoxic effects act in a fairly linear fashion until the dose falls to a level where there are no observed adverse effects (in a traditional dose=poison sense).

Those used to observing test effects in a cytotoxic manner could declare an end to effects at the  first signs of the No Observed Adverse Effects Level (NOAEL). Then, perhaps, they might guess that an acceptable daily exposure would be 1/500 of that.

But they would be wrong. At that level, estrogen would not function properly and would seriously disrupt the hormone system in both men and women.

Lowest Levels Often Equal Biggest Impacts

And, in fact, when the estrogen level drops much, much farther to the pico level (parts per trillion) the results are totally different: at that level, estrogen functions like a hormone — as it is supposed to.

Significantly, “Dose is the poison” researchers would have stopped at the NOAEL level, pulled a guesstimate from their jockey shorts and called it a day.

Breast Cancer Drug Tamoxifen Another Example

Another example is literally life or death for women with breast cancer. While many women with estrogen-dependent breast cancer have had their lives saved with the drug, Tamoxifen, that life-saving therapy  is only possible because researchers were intelligent enough to recognize that it acted in a non-linear manner.

In very high doses, Tamoxifen is toxic.

At its lowest levels, it actually encourages breast cancer cells to grow.

An old-line  “dose is the poison” scientist would simply think this suggest that Tamoxifen was toxic and dismiss it as useless in cancer chemotherapy.

But researchers who have learned to look for all outcomes – not just the ones they have been taught to expect — found that there is an intermediate level that is therapeutic.

In Tamoxifen therapy there is a “flare” of cancer growth as treatment begins. But as the level of Tamoxifen increases in the blood, the flare passes and therapy begins.

A similar flare is experienced in some treatments for prostate cancer with other drugs.

New science — rarely practiced in government and corporate labs — accepts that many factors result in some chemicals being more active at low doses than at high doses.

More reading on Non-Monotonic behavior

Where We Stand on EDCs

Endocrine-Disrupting Chemicals May 01, 2018 An Endocrine Society Position Statement

+non-monotonic “endocrine society” vandenberg

endocrine society statement on edcs

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