possible explanation for vom Saal's non-monotonic dose-response
relationship in this example is that when acting as hormone mimics--ie.
within the range at which their impact is mediated by their interaction
with estrogen receptors--DES and bisphenol A stimulate prostate
growth. But at higher levels, levels sufficient to be toxic, they
cause damage to the prostate and this toxic effect overwhelms the
The problem for traditional toxicology is that an enlarged prostate
can cause health problems, too. Witness the impact of prostate enlargement
on millions of elder men.
examples of nonmonotonic dose response curves (NMDRC):
October 2006: Environmentally-relevant levels of the phthalate DEHP suppress aromatase activity in the brain of young male rats following perinatal exposure, while higher doses stimulate aromatase. This enzyme is crucial for masculinization of the male brain. The effects differed between males and females, and also differed depending upon when after birth aromatase was measured. Impacts on females were seen at the lowest dose tested, which was calculated to be similar to the median daily intake of German citizens. More...
August 2006: Takano et al. report that the phthalate DEHP alters allergic reactions in mice following low level exposures. Doses at 0.8, 4 and 20 μg increased the invasion of white blood cells compared to controls, with 20 μg having the largest effect. 100 μg had no effect compared to control. 0.8 was the lowest level tested. More...
July 2004: Lehmann et al. describe several non-monotonic dose-response curves in a study of the impact of a phthalate on gene expression. The phthalate, di(n-butyl) phthalate, suppresses activity of several genes involved in controlling testosterone synthesis in fetal rats. More...
February 2003: Welshons et al. examine in detail the strong non-monotonic dose-reponse curve displayed by estradiol over a wide range of exposure levels. The conclude that within the range of concentrations of estradiol normally found in serum--high parts per quadrillion to low parts per trillion--, responses to estradiol are mediated by the estrogen receptor. But that at much higher levels, those in the range normally used in toxicological experiments, estradiol's impact is not receptor mediated. More...
2003: Ralph et al. find that prostate cell response to
androgens at low levels of hexachlorobenzene (HCB) is the opposite
of the cellular response at high levels. A classic toxicological
test would have found that the decrease in response disappeared
somewhere below 100 nM (where it crosses the red line) and not bothered
to test at the very low levels beneath that. Those low level effects
may be far more relevant to the formation of prostate cancer than
the high levels.
red line is the level of response obtained by 2.5 nM androgen
dihydrotestosterone without any HCB present.
levels of HCB exposure around 1 nM (parts per billion), Ralph
et al. saw up to a doubling of the androgenic response
in the presence of DHT.
at very high levels, the androgenic response was repressed.
2002: Cavieres et al. find that a common, off-the-shelf
herbicide used to contol dandelions causes fetal loss in mice, with
the highest impact observed at the lowest level tested. More...
2002: Wetherill et al. report a striking NMDRC in studies
of the impact of low-level bisphenol A on prostate tumor proliferation.
1 nanomolar BPA produces a larger impact than 100 nM. More...
2001, Markowski et al. discovered a NMDRC in the effect of
low level dioxin exposure in utero on adult weight of offsprint.
The principal focus of their experiments was on the impact of dioxin
on rat behavior. More...
by Oehlmann et al. examining the effects of octylphenol on
the ramshorn snail Marisa cornuarietis reveal a strongly
non-monotonic dose-response curve for OP's impact on eggs per female
and spawning masses per female. Intermediate doses caused dramatic
increases in egg numbers and spawning mass numbers. More...