"the dose make the poison?"
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.
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.
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.
core patterns in this emerging research violate simplistic uses
of "the dose makes the poison."
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
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."
of these patterns require a more sophisticated view of what it means
for "the dose makes the poison."
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.
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.
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."
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:
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...
examples of NMDRCs are now being published in the scientific literature
(more...). This raises three questions:
were they not found commonly before? Several factors may
have contributed to the infrequency with which NMDRCs were reported
previously in the scientific literature.
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.
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.
do they occur? This is an active area of research. Several
ideas have been offered.
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.
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...
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.
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.
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.