Our Stolen Futurea book by Theo Colborn, Dianne Dumanoski, and John Peterson Myers


Non-monotonic Dose Response Curves

For a 2007 update

At the heart of today's approach to chemical regulation is an assumption about the relationship between dose and response. Higher doses are supposed to cause greater harm. This assumption--that "the dose makes the poison"--is used to plan tests of chemicals to identify which ones are dangerous and to determine the level of exposure beneath which contamination should pose no risk.

  This old assumption may be true for many chemicals and for many classic health effects, but it is demonstrably misleading for endocrine disrupting chemicals. What this means is that countless experiments that have been done to test the safety of chemicals in use may have lulled us falsely into a sense of security, because they will miss effects that follow what is called a "non-monotonic" dose-response curve.


In a non-monotonic dose response curve (NMDRC) , the shape of the dose response curve reverses as the level of contamination goes up. Some NMDRC are shaped like U's, with high responses at low and at high levels of contamination. Others are shaped like inverted U's with the greatest response in intermediate ranges. The puzzling but observable fact is that low doses may actually cause greater impact than high doses for a specific response.

Welshons et al. interprete this in the following way: At high doses, the contaminant is overtly toxic, poisioning the system and hence (in the example below), causing shrinkage of the prostate. At an intermediate dose (but very low dose... in the example below 0.2 parts per billion), DES turns on genes that stimulate prostate growth.


Fred vom Saal, Wade Welshons and their colleagues at the University of Missouri, Columbia have reported a series of non-monotonic dose-reponse curves in studying the impact of fetal exposure in mice to subsequent impacts postnatally. For example, the graph above shows that low doses of both bisphenol-A and diethylstilbestrol (DES) cause significant enlargement of the adult prostate weight of mice exposed in the womb (in other words, if a male mouse fetus is exposed to either of these chemicals in the womb, then after it grows up its prostate is enlarged significantly). If exposed, however, to higher doses of bisphenol-A or DES, there is no enlargement. In fact, at higher doses, the prostate is smaller than those of mice not exposed in the womb. This same effect has been found by Dr. Chhanda Gupta.

vom Saal's results in this publication are also important in revealing the extraordinary sensitivity of urogenital tract development to tiny variations in 17ß-estradiol concentration. The experiments involved implanting tiny Silastic capsules containing estradiol in the pregnant mouse and using that procedure to alter the amount of free estradiol experienced by the male fetus from 0.2 picograms per milliliter (parts per trillion) to 0.3 pg/ml. This 0.1 pg/ml produced a significant change in prostate size in adulthood.

Welshons, vom Saal and colleagues explore some of the molecular mechanisms underlying these low-level responses in a subsequent publication.



One 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 stimulatory effect.

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.

Some 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...

January 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.

The red line is the level of response obtained by 2.5 nM androgen dihydrotestosterone without any HCB present.

At 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.

But at very high levels, the androgenic response was repressed.



September 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...

June 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...

In 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...

Experiments 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...



In 1999, M Christian and G Gillies from the Imperial College School of Medicine in London reported striking non-monotonic dose response curves for the impact of octylphenol and 17ß-estradiol on dopaminergic behavior of fetal rat brain cells. Impacts seen at parts per trillion levels disappeared as the dose was increased byeond parts per million. More...


Another 1999 result, from Go et al., examined endocrine disruption by synthetic pyrethroids. Their work revealed complex variations in the impact of d-trans allethrin over a range of doses tested. This synthetic pyrethroid inhibited an estrogen response at some levels, enhanced at others and proved toxic at higher levels. More...

A classic example of non-monotonic dose-response curves comes from a study by vom Saal et al. examining the effect of DES on territorial behavior in mice:
  vom Saal, F, S Nagel, P Palanza, M Boechler, S Parmigiani and W Welshons. 1995. Estrogenic Pesticides: Binding Relative to Estradiol in MCF-7 Cells and Effects of Exposure During Fetal Life on Subsequent Territorial Behavior in Male Mice. Toxicology Letters 77:343-350, 1995.
Fetal mice were exposed in utero to low doses of DES, o,p'-DDT and methoxychlor and then examined during adulthood for the rate of territorial marking in a novel territory. Each chemical had a strong, dose dependent effect upon this element of behavior, with increases above controls evident at all levels tested. The response to DES, however, did not follow a classic monotonic dose-response pattern, however. The rate of territory marking increased at very low doses as dose increased, but then decreased at the highest level.

According to vom Saal et al, "The results ... reveal that the lowest prenatal dose of DES examined (0.001 µg) significantly increased urine-marking behaviour (P < 0.05) relative to control males. However, males whose mothers were fed the 10 µg dose of DES showed significantly lower rates of urine marking than did the males in the 0.10 µg group. This type of inverted U function is typical of studies of the effects of estrogen on development."

They also observe that "significant behavioural effects of pre-natal exposure to this low dose of DES were not predictable on the basis of published studies, in which much higher doses have been used."





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