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Low Dose effects

One area of endocrine disruption which is a subject of huge debate is the issue of low dose effects. What a 'low dose' is is not always clear, but it's generally treated as a dose much lower than would normally be expected to have an effect.

This page provides a very brief introduction to the debate. For more information, look at the papers themselves and look in Journals such as Environmental Health Perspectives and Environmental Science and Technology (e.g. Renner, 1998).

Scientific basis

There are two particularly important aspects to low dose effects:

1) The inherent sensitivity of the endocrine system and development

As described on the complexity page, the interacting endocrine and developmental systems are extremely complex and sensitive. Science does not yet properly understand the operation and interaction of these systems, so it is not possible to properly evaluate the impact of chemicals on them. It is quite possible that very low doses of a chemicals could have very significant effects.

2) Additivity and synergism

The addition of a small quantity of a chemical to the body may have effects because it acts in addition to another chemical which is already there. For example, an oestrogen such as nonylphenol could act in addition to a natural oestrogen already present.

In synergism the combination of two chemicals results in a more than additive response - for example one chemical might lead to an increase in the number of receptors in a cell, whilst the second chemical binds and activates them.

Additivity and synergism can lead to no threshold effects, were even the tiniest amount of chemical added could have an effect, because its activity adds to a chemical which is already there. A parallel is:

You are trying to look over a wall which is higher than you. You have a small brick to stand on - it's still not high enough by a long way. Then you try a block of concrete - you can almost see over, but you're not quite there. You put the brick on top of the concrete block - now you can just see over the wall.

If the threshhold for activity is equivalent to seeing over the wall, you can see how if the block of concrete - the natural oestrogen - is just too small, you cannot see over, there is no activity. If the brick, an environmental oestrogen, is very small but just big enough, it can add to the block and allow you to see over the wall or activate the system. The turtle experiments below are an example of such a system.

Some of the research evidence

1) Turtles

In the red-eared slider turtle gonadal sex is determined by the temperatue eggs are incubated at, with higher temperatures leading to the production of endogenous estrogen and the development of females. Sheehan et al. (1999) incubated eggs at a temperature which normally generates a minority of females, then added a single dose of 17beta-oestradiol to the shells. The lowest oestradiol dose tested, 400 pg/egg (40 ng/kg) sex reversed 14.4% of the animals. A dose response curve suggested no threshold dose for oestradiol addition. This is a perfect illustration of additivity leading to no threshold.

2) Bisphenol a in mice

In contrast to the clear and undisputed findings of the turtle research, the situation with low dose effects of bisphenol a is a subject of huge and continuing scientific debate. Research by a group led by Fred vom Saal has found that bisphenol a and methoxychlor exposure of pregnant mice resulted in increases in prostate weight in their offspring (vom Saal et al., 1998; Welshons et al., 1999). However, industry-funded studies have failed to repeat these results (Ashby, 1999; Cagen et al, 1999). In the latest twist, vom Saal's team has shown low dose effects on female offspring, a delay in oestrus (see bisphenol a page).

3) Vinclozolin in rats

The fungicide vinclozolin is a well know antiandrogen, listed on the pesticides page. Research by L. Earl Gray's team (Gray et al., 1999) has established that alterations in sexual differentiation of developing male rat occur with low doses of vinclozolin given to their dams during preganancy and just after birth. Alterations including retention of nipples occurred at the lowest dose tested, 3.125 mg/kg/day. The authors conclude:

"In summary, studies of vinclozolin that did not include endpoints sensitive to antiandrogenic effects and were not designed to detect transgenerational efffects have reported LOEL [lowest observed effect levels] for vinclozolin of 100 mg/kg/day or higher. In contrast, in the current study we found that vinclozolin treatment induced reproductive malformations below 100 mg/kg/day, and ano-genital distance was shortened, areolas were induced, and other endpoints were affected by treatment with vincolzolin at 3.125 mg/kg/day, our lowest dosage level"

Some problems with Low Dose research


As low dose research is often looking for subtle, but potentially significant, changes, there have been major problems with reproducibility. The dispute over bisphenol a is one example, another is the research that was done by Richard Sharpe's team at Edinburgh University, which initially showed that exposure of rats in the womb to octylphenol (OP) or butylbenzyl phthalate (BBP) led to reductions in testicular weight (Sharpe et al., 1995). The BBP experiments were repeated by others, and the OP experiments by Sharpe et al. - none of the repeated experiments showed effects. The authors explained the situation in a letter to Environmental Health Perspectives (Sharpe and Turner, 1998). The reason for the lack of reproducibility of the original results is unknown.

One suggested problem obtaining reproducible results is influences of the conditions in which lab animals are kept. For example, John Ashby of AstraZeneca's central toxicology lab has said that the number of animals in each cage and whether sexes are mixed in the cages may make a major difference (C&I, 1999).

Oestrogen resistant animals

Spearow et al. (1999) examined how responsive different strains of juvenile mice were to 17beta-estradiol (E2), the main female hormone. They found a more than 16-fold variability in response between different strains, with low doses of E2 eliminating spermatid maturation in some strains, whilst 16 times as much E2 had no effect on the widely used CD-1 strain. This strain is widely used in research, and has been bred for large litter sizes. This research suggests that CD-1 mice may give a very misleading view of hormone disrupting effects.

This page was last updated in October 1999
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Ashby, J. 1999. Dose levels of 0.01-0.2µg/kg/day diethylstilbestrol are not suitable for use as a positive control in endocrine toxicity studies. Regulatory Toxicology and Pharmacology 29, p235-237.

Cagen, S. Z., Waechter, J. M., Dimond, S. S., Breslin, W. J., Butala, J. H., Jekat, F. W., Joiner, R. L., Shiotsuka, R. N., Veenstra, G. E. and Harris, L. R. 1999. Normal reproductive organ development in CF-1 mice following prenatal exposure to bisphenol a. Toxicological Sciences 50, p36-44.

C&I. 1999. Hormone studies flawed, researcher warns. Chemistry and Industry, 18th October, p784.

Gray, L. E., Ostby, J., Monosson, E. and Kelce, W. R. 1999. Environmental antiandrogens: low doses of the fungicide vinclozolin alter sexual differentiation of the male rat. Toxicology and Industrial Health 15, p48-64.

Nagel, S. C., vom Saal, F. S., Thayer, C. A., Dhar, M. G., Boechler, M. and Welshons, W. V. 1997. Relative binding affinity-serum modified access (RBA-SMA) assay predicts the relative in vivo bioactivity of the xenoestrogens bisphenol a and octylphenol. Environmental Health Perspectives 105, p70-76.

Renner, R. 1998. Results of low-dose exposure may challenge the theoretical basis of toxicology. Environmental Science and Technology Nov 1, p485A-486A.

Sharpe, R. M., Fisher, J. S., Millar, M. M., Jobling, S. and Sumpter, J. P. 1995. Gestational and lactational exposure of rats to xenoestrogens results in reduced testicular size and sperm production. Environmental Health Perspectives 103, p1136-1143.

Sharpe, R. M. and Turner, K. J. 1998. Endocrine disrupters and testis development. Environmental Health Perspectives 106 (5).

Sheehan, D. M., Willingham, E., Gaylor, D., Bergeron, J. M. and Crews, D. 1999. No threshold dose for estradiol-induced sex reversal of turtle embryos: How little is too much? Environmental Health Perspectives 107, p155-159.

Spearow, J.L., Doemeny, P., Sera, R., Leffler, R. and Barkley, M. 1999. Genetic variability to endocrine disruption by estrogen in mice. Science 285:5431, p1259-1261.

vom Saal, F. S., Cooke, P. S., Buchanan, D. L., Palanza, P., Thayer, K. A., Nagel, S. C., Parmigiani, S. and Welshons, W. V. 1998. A physiologically based approach to the study of bisphenol a and other estrogenic chemicals on the size of reproductive organs, daily sperm production, and behavior. Toxicology and Industrial Health 14, p239-260.

Welshons, W. V., Nagel, S. C., Thayer, K. A., Judy, B. M. and vom Saal, F. S. 1999. Low-dose bioactivity of xenoestrogens in animals: fetal exposure to low doses of methoxychlor and other xenoestrogens increases adult prostate size in mice. Toxicology and Industrial Health 15, p12-25.

URL: http://website.lineone.net/~mwarhurst/lowdose.html