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

 

 
Scientific findings of the impacts of endocrine disrupters at low doses
 
 

Research on endocrine disrupting compounds is revealing that endocrine-disrupting compounds have impacts at levels dramatically lower than thought relevant to traditional toxicology. Recent examples:

In mice, adult exposure to levels of bisphenol A experienced by almost all Americans causes insulin resistance. When adult humans develop insulin resistance, 25% go on to develop Type 2 diabetes. More...

In mice, exposure to bisphenol A in the womb at extremely low levels alters mammary gland development around puberty. The changes, which involved increased numbers of terminal buds and an increased sensitivity to estrogen, are consistent with an increased risk to breast cancer. The levels of exposure are within the range that many people experience More...


Two estrogenic contaminants cause adverse effects in prostate development in mice at levels to which millions of Americans are exposed each year. The results raises questions about the possible contributions of these compounds, the birth control agent ethinylestradiol and the plastic monomer bisphenol A, in human prostate diseases, including prostate cancer. The study also shows the futility of predicting the developmental consequences of low-dose exposures based on high-dose experiments. More...


Mice exposed to bisphenol A at one-fifth the level currently considered safe by the US EPA show altered maternal behavior toward pups. The changes involve less attentiveness, more time away and less nursing. These results suggest that current BPA standards may need to be strengthened by a factor of 5,000. This would make it difficult to employ BPA in many of its current, widespread uses. More...


Exposure in the womb to extremely low levels of bisphenol A alters sexual differentiation of the brain and behavior in rats. One area of the brain that typically is larger in females than males showed a reversal in size dimorphism. And sexual differences were eliminated in a measurement of behavior in which males typically differ from females. More...


Several 'weakly' estrogenic compounds including bisphenol A and endosulfan are as powerful as estrogen at increasing calcium influx into cells and stimulating prolactin secretion. The effects are mediated by a cell membrane surface receptor instead of nuclear hormone receptors, the focus of most studies to date. Changes in calcium and prolactin occur at extremely low doses, well within the range of human exposures. More...


Cadmium provokes estrogenic responses at extremely low levels of exposure. Research published in Nature Medicine reveals that cadmium provokes estrogenic responses in rats at levels much less than 1% of those traditionally used in toxicological studies. The effects include alterations in the uterus and mammary gland, increases in estrogen-controlled gene expression, and, following exposure in the womb, increases in adult weight and the speed of reaching sexual maturity. The authors call for more research on links between breast cancer and cadmium exposure. 15 July 2003. More...

Scientists from the University of Missouri have published an analysis indicating that regulatory testing for endocrine-active substances must be changed radically if there is any hope to detect developmental disruption at low contamination levels. They conclude that current methods are physically incapable of revealing low level impacts mediated by hormone receptors, because at the high levels used, the receptor systems will be saturated (swamped) and incapable of showing any response to changes in contaminant dose. Under these circumstances, it is literally impossible to extrapolate from commonly-used high level experiments to the risks created by low level exposures.

The researchers also suggest that background contamination of experiments by hormonally-active substances is likely to be widespread and to have further undermined regulatory testing, by making it highly likely that this background contamination prevented toxicologists from detecting low level impacts. Instead of finding a real effect, the experiment would have been interpreted erroneously as having demonstrated no effect.

The net result is that the standards currently used may need strengthening by a factor of 10,000 or greater. 11 March 2003. More...

 

Research on the impact of atrazine on frog sexual development reveals that levels of atrazine as low as 0.1 parts per billion induce hermaphroditism in Xenopus laevus, the "laboratory rat" of the frog world. Atrazine contamination at ten-fold higher can be found in rainwater in the United States, in regions where atrazine is not in agricultural use. Up to 40 parts per billion can be measured in rainwater in areas of atrazine use. EPA's current water quality standard for atrazine allows 3 ppb in drinking water, 30 times higher than required to affect over 15% of males exposed. Previous work on atrazine and frog development had indicated that levels 30,000 times higher were necessary to produce effects. This new research highlights the need to carry out toxicological studies at environmentally relevant exposure levels. More...


Three recently published (Fall 2001) studies using laboratory animals of the low dose effects of bisphenol A (BPA) reinforce public health concerns about the possible impacts of this ubiquitous plastic compound. In one, Dr. Caroline Markey and colleagues describe effects on mammary gland tissue in adult mice after exposure in the womb that raises plausible questions about BPA involvement in stimulation of breast cancer. In a second, Jorge Ramos et al. report on impacts that low level BPA exposure has on adult prostate, the details of which resemble processes involved in human prostate cancer. And the third, by a scientific team from Japan led by Dr. Motoharu Sakaue, demonstrates that BPA suppresses sperm count in adult mice. Added to already disturbing information about BPA impacts, these new studies highlight the need for an urgent reconsideration by FDA and EPA of the need for better protections for people from BPA exposure.


Markowski, VP, G Zareba, S Stern, C Cox and B Weiss. 2001. Altered Operant Responding for Motor Reinforcement and the Determination of Benchmark Doses Following Perinatal Exposure to Low-Level 2,3,7,8-Tetrachlorodibenzo-p-dioxin. Environmental Health Perspectives 109:621-627.


Markowski et al. demonstrate that even at extraordinarily low levels-- parts per trillion--dioxin can reduce motivation in rats to perform in standard psychological testing. The levels at which these impacts are detected are comparable to background levels in people around the world. More...


Park, D, SC Hempleman, and CR Propper. 2001. Endosulfan Exposure Disrupts Pheromonal Systems in the Red-Spotted Newt: A Mechanism for Subtle Effects of Environmental Chemicals. Environmental Health Perspectives 109:669-673.


Park et al. discover that exposure to extremely low levels of a commonly-used pesticide, endosulfan, interferes with reproduction in the red-spotted newt, a salamander. Their experiments reveal an impact at 5 parts per billion (ppb), which was the lowest concentration they used. This concentration is well within the range of endosulfan contamination regularly encountered in the real world. More...


Rubin, BS, MK Murray, DA Damassa, JC King and AM Soto. 2001. Perinatal Exposure to Low Doses of Bisphenol A Affects Body Weight, Patterns of Estrous Cyclicity, and Plasma LH Levels. Environmental Health Perspectives 109: 675-680.


In experiments with rats, Rubin et al. confirm results obtained by Howdeshell et al. (1999) on the effects of early exposure to bisphenol A on adult female weight, and extend the understanding of bisphenol A impacts to include effects on other aspects of reproduction. More...


A review panel convened by the National Toxicology Program and the US National Institute of Environmental Health Sciences confirms the existence of low-dose effects well beneath levels revealed by traditional toxicological testing. More...

 


Kaltreider, RC, AM. Davis, JP Lariviere, and JW Hamilton 2001. Arsenic Alters the Function of the Glucocorticoid Receptor as a Transcription Factor. Environmental Health Perspectives 109:245-251.


At extremely low levels (10 ppb), arsenic inteferes with glucocorticoid-receptor control of DNA transcription. This may be important in understanding the links between low level chronic exposure to arsenic, cancer and diabetes. More...


 

 

US National Toxicology Program's scientific peer review of low-dose effects of endocrine disrupting compounds. October 2000.


 

Ulrich, EM, A Caperell-Grant, S-H Jung, RA Hites, and RM Bigsby. 2000. Environmentally Relevant Xenoestrogen Tissue Concentrations Correlated to Biological Responses in Mice. Environmental Health Perspectives 108:973-977.

This paper demonstrates that DDT and HCH both induce estrogenic changes in mice when exposed chronically to very low doses of these compounds. Most alarming according to the authors, is the fact that they observed statistically significant results within the range of background exposures experienced by people in the real world. More...


 

  Gupta, C. 2000. Reproductive malformation of the male offspring following maternal exposure to estrogenic chemicals. Proceedings of the Society for Experimental Biology and Medicine 224:61-68.

Gupta shows that bisphenol A, arochlor 1016 (a PCB mixture) and DES enlarge the adult prostates of mice exposed in utero to very low levels, confirming effects first found by Fred vom Saal. More...


 
 

 

Gray, LE, J Ostby, E Monosson and WR Kelce. 1999. Environmental antiandrogens: low doses of the fungicide vinclozolin alter sexual differentiation of the male rat. Toxicology and Industrial Health 15: 48-64.


Previous studies of the impact of vinclozilin, a widely-used fungicide, had reported that the lowest level of contamination at which an impact could be produced in developing offspring was 50 to 100+ milligrams/kilogram (parts per million, delivered per day to a pregnant female). Gray et al. report here that when they examine developmental endpoints known to be sensitive to anti-androgenic drugs, they find vinclozilin produces detectable effects at the lowest levels used in their experiment, 3.125 parts per million. The impacts detected included hypospadias (down to 50 ppm), ectopic testes (100 ppm), the number of nipples (3.125 ppm) and sperm count declines. Male pups exposed to 100 ppm vinclozolin were about 70% female-like in their phenotype. More...

 



 
 

Howdeshell, K, AK Hotchkiss, KA Thayer, JG Vandenbergh and FS vom Saal. 1999. Plastic bisphenol A speeds growth and puberty. Nature 401: 762-764.


Howdeshell et al. found that female mice, exposed in the womb by delivering low doses of bisphenol A (2.4 parts per billion) to the mother in food, pass a milestone in sexual development significantly earlier than unexposed mice. They also show that position in the womb interacts with contamination: those females positioned between female litter mates were most effected by bisphenol a, while those between males were least effected. More...

 


 
Christian M and G Gillies. 1999. Developing hypothalamic dopaminergic neurones as potential targets for environmental estrogens. Journal of Endocrinology 160:R1-R6.

Christian and Gillies demonstrate impacts of octylphenol at parts per trillion levels in a cell culture preparation using hypothalamic cells taken and cultured from fetal rat brains. More...

 


 
 

 

Welshons, WV, SC Nagel, KA Thayer, BM Judy, and FS vom Saal. 1999. Low-dose bioactivity of xenoestrogens in animals: fetal exposure to low doses of methoxychlor and other xenoestrogens increases adult prosate size in mice. Toxicology and Industrial Health 15:12-25.


Experimental manipulation of serum concentrations of several synthetic estrogenic compounds causes an increase in the prostate size of the exposed male mice once they reach adulthood. The concentration of the contaminants necessary to produce this change is extremely low: as little as 2 parts per billion of bisphenol A, .02 parts per billion DES, and 20 parts per billion methoxychlor caused significant increases. The research on DES and bisphenol A had been published earlier. This paper presents new data on methoxychlor.


 
 

 

Porter, WP, JW Jaeger and IH Carlson. 1999. Endocrine, immune and behavioral effects of aldicarb (carbamate), atrazine (triazine) and nitrate (fertilizer) mixtures at groundwater concentrations. Toxicology and Industrial Health 15: 133-150.


Porter et al. experiment with combinations of two common pesticides and a fertilizer, exposing adult male mice to mixtures and concentrations within the range of exposures regularly encountered in human drinking water in agricultural regions in mid-West of the United States. Exposure was through voluntary consumption of drinking water. Measuring endocrine, immune and behavioral variables, they observed significant changes in endocrine, immune and behavior in response to mixtures of the contaminants, but rarely in response to single compounds at the same concentration. More...

Porter et al. also comment on the inadequacies of current testing protocols used to establish regulatory standards. More...


 

 

Rice, DC and S Hayward 1999. Effects of postnatal exposure of monkeys to a PCB mixture on concurrent random interval-random interaval and progressive ratio performance. Neurotoxicology and Teratology 21:47-58.


Rice and Hayward report that male monkeys that had been dosed with a low level PCB mixture (7.5 parts per billion, representative of the doses typically found in human breast milk) differed significantly from controls in one of the measures used to assess their behavior. "The PCB-treated monkeys emitted more responses than controls over the first few sessions of the PR (progressive ratio schedule), which may be indicative of retarded acquisition of their steady state PR performance."

Rice has commented in scientific lectures that the treatment level (7.5 ppb) was misreported to her before the onset of the experiments, and that had it been reported properly (the value given was much higher than 7.5 ppb) she would not have done the experiments because it seemed unlikely there would be any impact.


 

MacLusky, NJ, TJ Brown, S Schantz, BW Seo and RE Peterson. 1998. Hormonal interactions in the effects of halogenated aromatic hydrocarbons of the developing brain. Toxicology and Industrial Health 14:185-208.

As discussed in Our Stolen Future (Chapter 7), RE Peterson's lab has shown that extremely low doses of dioxin experienced in utero can disturb reproductive function and behavior in adulthood (Mably et al. 1992a,b,c). Here, MacLusky et al. show that fetal exposure to a low level of dioxin (0.7 µg/kg or 0.7 ppb) "disturbed sexual differentiation of reproductive behavior, potentiating the expression of feminine sexual behavior and reducing masculine behavior."

They also studied cognitive function in rats exposed in utero. Here their experiments revealed an enhancement in rat performance in maze tests, comparing treated animals to controls. Treated animals committed significantly fewer errors.

More...


 

 

Rice, DC. 1998. Effects of postnatal exposure of monkeys to a PCB mixture on spatial discrimination reversal and DRL performance. Neurotoxicology and Teratology 20(4):391-400.


This is one paper in a series by Deborah Rice and by Rice and Stephen Hayward that explore the consequences of low level neonatal PCB exposure in monkeys for their subsequent performance in a variety of behavioral tests.

The experiments involved monkeys that had been exposed at birth to different levels of PCBs. The exposures were within the range of levels measured in Canadian women (Rice did this work on the scientific staff of Health Canada, in Ottowa, Ontario, Canada). Specifically, blood PCB levels were 0.30-0.37 ppb for controls and 1.84-2.84 ppb for treated levels). This exposure was achieved by dosing the infant chimps with7.5 ppb/day of a PCB mixture representative of that found in human milk.

Rice has commented in scientific lectures that the treatment level (7.5 ppb) was misreported to her before the onset of the experiments, and that had it been reported properly (the value given was much higher than 7.5 ppb) she would not have done the experiments because it seemed unlikely there would be any impact.


 

  Nagel, SC, FS vom Saal, KA Thayer, MG Dhar, M Boechler and WV Welshons. 1997. Relative binding affinity-serum modified access (RBA-SMA) assay predicts in vivo bioactivity of the xenoestrogens Bisphenol A and Octylphenol. Environmental Health Perspectives 105:70-76.
 

Nagel et al. present data demonstrating that bisphenol A can alter fetal mouse development at extraordinarily low levels of exposure. Pregnant female mice were fed bisphenol A mixed in corn oil at two concentrations: 2 and 20 micrograms per kg of body weight (parts per billion). Prostate weight was then determined at the age of 6 months. Males exposed to both levels of bisphenol A experienced an increase in prostate size.

 

These results are profoundly important for two reasons.

  • They demonstrate the remarkable sensitivity of fetal development to low level hormone disruption.
  • They reveal bisphenol A effects on mice at levels, when corrected for body size differences, are within the range of bisphenol A regularly ingested by people as a result of the use of polycarbonate plastics in common products.
In this paper Nagel et al. also combine several different types of information to predict the potency of bisphenol A and octylphenol. Bisphenol A is more powerful than predicted simply on the basis of binding affinity alone, while octylphenol is less powerful. Studies like this are important in understanding why simplistic arguments about the quantity of phytoestrogens in the diet are misleading. More...
 

vom Saal, F, BG Timms, MM Montano, P Palanza, KA Thayer, SC Nagel, MD Dhar, VK Ganjam, S Parmigiani and WV Welshons. 1997. Prostate enlargement in mice due to fetal exposure to low doses of estradiol or diethylstilbestrol and opposite effects at high doses. Proceedings of the National Academy of Sciences USA 94:2056-61.


 
This paper establishes that low level variation in estradiol and DES can both effect significant changes in adult prostate characteristics, when exposure occurs during fetal development.

  • Relative to controls, males treated with as little as 0.02 nanograms/gram (0.02 parts per billion) DES had heavier prostate glands.
  • Relative to controls, males that experienced a change in free serum estradiol less of than one part per trillion had heavier prostate glands (by 27%), a 6-fold increase in the number of androgen receptors in the prostate, a 2-fold increase in the number of androgen receptors per prostate cell, and a 40% increase in the number of cells per prostate.
  • For both DES and estradiol, the dose response curve relating exposure to impact were non-monotonic, i.e., intermediate exposures produced larger prostates than low or high exposures. While dose-reponse relationships like this are common in physiological processes, they are not expected by traditional toxicology. More...

 

 

Gaylor, DW. 1992. Incidence of developmental defects at the No Observed Adverse Effect Level (NOAEL). Regulatory Toxicology and Pharmacology 15:151-160.



"The NOAEL is the dose at which it is judged there is no significant increase in the incidence of any important adverse biological effect." The NOAEL level is used to establish the reference dose, or RfD. Setting the RfD usually involves looking at animal data, determining a NOEAL, and then using a safety factor (for example, 10) to allow for greater sensitivity of some people compared to others. It is assumed that exposures at or below the RfD generally result in negligible effects.

Gaylor asked about the incidence of adverse developmental for expsoures at the NOAEL level. He found that in 24% of cases, the observed risk of abnormal fetuses exceeded 1% at the NOAEL.


 
 

 

 
 

 

 

 

 

 

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