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



Hormesis is a flawed theory
John Peterson Myers
Environmental Health Sciences
609 East High St
Charlottesville VA 22902

A researcher from the University of Massachusetts, Edward Calabrese, has been promoting the theory of hormesis: that chemicals with harmful effects at high doses can have beneficial effects at low doses. He then argues that this means health standards can be relaxed because if low doses are beneficial, then there is no need to achieve stringent cleanup standards.

Calabrese has it half-right. Low doses can have impacts that can't be predicted from high dose experiments. But this has exactly the opposite policy implications than those reached by Calabrese. Traditional high dose testing will miss many low dose adverse effects.

Hence Calabrese's recommendations that clean-up standards be relaxed are dangerous. Acknowledging that high dose experiments can't predict low dose results should lead to a strengthening of standards, not a relaxation.

How can exposure to something that isn't overtly toxic be a problem? Altered gene expression in development changes the path taken by the developing organism. A good example is work by Ho et al. on how exposure to bisphenol A during development causes prostate cancer in adult rats. At birth there is nothing obviously wrong with the rat, but by adulthood it is at high risk to prostate cancer. According to Ho et al., the low dose of bisphenol A prevents a gene from shutting down, something Calabrese would regard as stimulatory because this gene is involved in promoting cell division.

Think of it this way. If you were a pilot steering a boat from New York to London, it would be toxic if someone blew up your engine. But if they altered the compass so that it led you 3 degrees off course from the very start of the trip, by the time you reached Europe you'd be on the shores of France. Small shifts in the course of development can have profoundly adverse impacts even though they may not be overtly toxic at the time of exposure.

Welshon's et al. have presented a detailed analyses at the molecular level on how low dose impacts can't be predicted from high dose experiments.

Reponse of estrogen responsive gene to estradiol, from Welshons et al. 2003.

Nonmonotonic dose response curve

Their key observation is that estrogenic compounds like estradiol and bisphenol A can increase gene expression at extremely low levels of exposure, while having overtly toxic impacts at much higher levels.

The low dose increases in gene expression can take place at exposure levels millions of times lower than those required to cause over toxicity. In the graph above, adapted from Welshons et al. 2003, estradiol at high levels shuts down an estrogenic response in a yeast-assay. At those high levels, it is overtly toxic. At doses more than a million-fold beneath that, estradiol causes expression of this estrogen-responsive gene. That lower level is the normal physiological level of action of estradiol. As the dose increases above that level, estrogen receptors become fully occupied, so the system reaches an asymptote at about 1 ppt. No additional response is seen until 1 ppm, a level at which estradiol is overtly toxic.

According to vom Saal, at high, toxicological doses estrogenic compounds like estradiol and bisphenol A that act through estrogen receptors can actually turn off genes that they had turned on at low doses. They also start to interact with other hormone receptors, starting other physiological processes that can involve negative feedback loops, shutting down the low dose response.

"These facts are taught to students in an introductory endocrinology course," comments vom Saal." "For hormone-mimicking chemicals, non-monotonic dose-response relationships are thus expected for at least some responses."

Calabrese would look at a pattern like this and see low dose stimulation and high dose toxicity: hormesis. The problem with his interpretation is the hundred-plus studies demonstrating adverse effects of BPA at low levels of exposure. Turning on estrogen-responsive genes at times during development when they are not supposed to turn on affects many tissues adversely, and in animal experiments causes prostate cancer (in adulthood after exposure in the womb), increases the risk of breast cancer, defeminizes female brain structures, masculinizes female behavior, induces insulin resistance, etc.

Calabrese bases his arguments on widespread occurrence of 'hormetic' responses in the literature. A 'hormetic' response is a special case of a larger set of dose-response curves called 'non-monotonic dose response curves' (NMDRCs), named thus because the slope of the curve changes sign somewhere along the curve (a term out of mathematics). Hence a J-shaped or U-shaped or inverted-U shaped curve are all non-monotonic. These contrast with monotonic curves, in which the slope never changes sign (in other words, if the curve or line is upward it always remains upward (although it can flatten out).

In general, Calabrese ignores the mechanism by which NMDRCs might occur. This makes it easier for him to argue that low dose stimulation is beneficial. If he were to acknowledge that the mechanism involves low dose stimulation of gene expression, he would have to admit that turning genes on at inappropriate times will lead to adverse effects.

One conspicuous example of this comes from research by Retha Newbold on the estrogenic drug diethylstilbestrol. Newbold has shown that high doses of DES cause weight loss in adults following exposure in the womb. Lower doses within the range that lead to a wide array of adult disorders of the reproductive tract have no effect on adult weight. But doses far beneath those (1 ppb) cause grotesque obesity.

Calabrese's argument that low dose stimulation is beneficial ignores the larger biological point that stimulation that is not part of the normal program in development is likely to lead to problems. Stimulate cell proliferation and you risk cancer. Stimulate the immune system and you risk a hyperallergenic response. This is especially relevant in a world in which hyper-reactive immune systems are tied to asthma, auto-immune diseases, eczema, etc.

Bottom line: the notion that widespread observations of hormetic responses justifies weakening health standards is naive and wrong. Calabrese is right that current regulations should recognize the ubiquity of non-monotonic dose response system. But the appropriate response to this observation is not to weaken standards but to strengthen them, because the adverse impacts of low dose stimulation of gene expression can't be predicted by today's regulatory testing.







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