Does "the dose make the poison?"

A core assumption of traditional toxicology is "the dose makes the poison." Generations of toxicologists have begun their studies by learning this, countless experiments have provided support, and the laws protecting people from undue exposure all assume that it is true.

"The dose makes the poison" is taken to mean that the higher the dose, the greater the effect. And this implies that low exposures are less important. Indeed, based on "the dose makes the poison" it is commonly argued that "background" levels of contamination aren't worth worrying about.

Yet new evidence emerging from modern scientific research that combines toxicology, developmental biology, endocrinology and biochemistry is demonstrating that this assumption is wrong, at least in its simplest and most-widely used form. And the implications for this new realization are profound, because it means that the safety standards used to protect public health are built upon false assumptions and likely to be inadequate.

Two core patterns in this emerging research violate simplistic uses of "the dose makes the poison."

• One arises because sensitivity to contamination is not the same at all stages of the life of an individual. The same low dose that may pose no risk to an adult can cause drastic effects in a developing fetus.
• The second involve dose-response curves in which low levels of a contaminant actually cause greater effects than higher levels, at the same stage of development. These dose-response curves, shaped like inverted-U's, are called "non-monotonic dose-response curves."

Both of these patterns require a more sophisticated view of what it means for "the dose makes the poison."

In the case of sensitivity varying from one stage of development to the next, "the dose makes the poison" is valid as long as one doesn't wrongly assume that measurements at one stage can be extrapolated to another. The assumption holds true (as long as there is no non-monotonic dose response curve, see below) within a stage of development, but not among them.

A recent dramatic example of this differential sensitivity was found in work comparing the impact of an herbicide on tadpoles vs. frogs. In frogs, the change from tadpole to frogs is exquisitely sensitive to chemical disruption of development. A dose of atrazine (a commonly used herbicide) 30,000 times lower than the lowest level known to affect adult frogs caused 20% of tadpoles to become hermaphroditic (containing both male and female sexual organs) in adulthood.

This pattern seen in frogs is not an exception. The scientific literature is full of examples demonstrating that in its early stages of development and organism can be more vulnerable than during adulthood. Thus it is important to realize that "the adult dose does not make the fetal poison."

Inverted-U or non-monotonic dose-response curves (NMDRCs) provide a more difficult challenge to the traditional interpretation of "the dose makes the poison," i.e., that higher doses have greater impacts to lower doses. In NMDRCs, lower doses can have larger impacts than higher doses. One recent example arose in work on proliferation of prostate tumors:

A very low dose (1 nanomolar) of bisphenol A induces a stronger response than a much higher dose (100 nanomolar). The response to 1 nM is significantly greater than the control. More on this experiment...

Many examples of NMDRCs are now being published in the scientific literature (more...). This raises three questions:

Why were they not found commonly before? Several factors may have contributed to the infrequency with which NMDRCs were reported previously in the scientific literature.

• One may be simply that few scientists looked. Driven by "the dose makes the poison," toxicologists would perform experiments at higher doses and work down the dose-response curve until they found a level at which no response was detectable. Experiments at doses 1/10th to 1/100th of that no-response level made no sense. But without experiments at much lower doses, the low-dose effects of NMDRCs could not be detected.
• A second impediment arose from the statistical design used to analyze results in toxicology. Designs built on the assumption that 'the dose makes the poison' are unlikely to find NMDRCs.

Why do they occur? This is an active area of research. Several ideas have been offered.

• One is that within the range of very low doses showing NMDRC patterns, enzymatic defenses against chemical contaminants are not activated. The supposition here is that at these very low levels, the contaminants are at levels that are within the range where their biological activity resembles the normal hormonal mechanisms controlling development. As contaminant levels rise, defense mechanisms are activated, shutting down the original response.
• Another is that as the low dose rises into a higher range, the contaminant stimulates new responses, perhaps activating different hormonal pathways, that then operate in a negative feedback loop to shut down the system involved in the original response.
• A third explanation has been proposed for signaling systems based on receptors, for example, the estrogen receptor. As dose increases, the proportion of receptors that are occupied rises. If there are a finite number of receptors, and if the response is receptor mediated, then at some point in the dose-response curve all receptors will be occupied, i.e., saturated. Further increases in dose cause no further increase in response, because there are no more receptors available to occupy. As the dose increases beyond this saturation point, at even higher levels other effects will start to occur, including outright toxicity/poisoning. At these high levels, the response disappears because the system is no longer capable of responding. More...

What do they mean for public health? NMDRCs are extremely troubling for regulatory toxicology because their presence undermines the validity of generations of toxicity testing that have been based on the assumption that "the dose makes the poison." Prevailing federal safety standards are built upon research methods that are unlikely to find low-dose effects, and very few chemicals have been tested in ways that would reveal them.

For that reason NMDRCs were the subject of intense debate among scientists as it became clear they were not uncommon. The U.S. National Toxicology Program went so far as to convene a special "low-dose panel" of scientists to conduct a full scale review. The panel's findings, published in 2001, confirmed the reality of NMDRCs.

So what do NMDRCs mean for "the dose makes the poison?" In a literal sense, the dose still does, as for example, in the graph of prostate tumor proliferation above: A dose of 1 nanomolar bisphenol A produces a different response than does 100 nanomolar. Dose does matter. But with BPA and prostate proliferation, "a very low dose makes a higher poison." It is no longer safe to assume that lower doses have lower impacts than higher doses. The science used to establish public exposure standards needs to incorporate this new concept.