Medical researchers are increasingly finding that synthetic chemicals can damage health at low doses as well as high, making it hard to predict "safe" levels.

In the world of toxicology it has always been assumed that the harm that chemicals can do to human health is dependent entirely on the dose. As a result, toxicologists have sought to discover the dose at which a particular chemical causes acute illness. A line is then drawn with doses of the chemical below that level deemed safe and those above unsafe, or toxic.

This simple dose dependent model has made it easy for lawmakers to set limits on chemical use and approve or ban specific chemical products for the sake of human health.

This accepted wisdom is being increasingly challenged however, as the realization that many chemicals can have harmful effects even at very low doses previously deemed safe. What's more, these low dose effects are often entirely different to those observed at traditional "toxic" levels. To cloud the issue further, the same dose of a chemical can be toxic to one type of cell or enzyme but not another.

For years a growing number of doctors and health professionals practicing environmental medicine have maintained that chemicals in the environment, at levels lower than those considered toxic, contribute to the development of many serious illnesses such as cancers, diabetes, and hormonal problems. It is also suggested that environmental toxins are responsible for poorly understood chronic illnesses such as chronic fatigue syndrome (CFS), multiple chemical sensitivity (MCS), as well as developmental disorders such as ADHD and autism.

Dr. Sherry Rogers, author of a number of books on the subject including 'Detoxify or Die', and a well known spokesperson for environmental medicine, has done much to publicize the theory that chemicals in the environment are behind many of the diseases we are dealing with today. In Detoxify or Die she explains that chemicals are everywhere and cannot be avoided; our bodies cannot get rid of them all so they accumulate in our tissues; they are the root cause of many illnesses; and that measures taken to rid the body of these environmental toxins frequently results in significant improvements.

Dr. Rogers and her contemporaries have always been in the minority with these views but a growing number of researchers are identifying effects from chemicals at doses previously thought to be harmless.

Amongst the chemicals under the spotlight are plasticizers, mostly phthalates, which are used widely to soften plastics. These have received a lot of attention recently amid fears that their use in children's toys may pose a risk to the health of youngsters.

One example is the ubiquitous plastic-softening chemical, di-2-ethylhexyl phthalate (DEHP). A team of researchers in Germany recently found that in newborn male rats, DEHP suppressed the brain activity of an enzyme critical for male development, at the lowest doses tested (Oct. 29, 2006 Toxicology). This result was unexpected since higher doses of DEHP stimulated that enzyme's action. An example of a common chemical having health effects at low doses, different to those seen at higher doses.

The researchers from Charité University Medical School in Berlin headed by Anderson J.M. Andrade noted this enzyme suppressing action of DEHP would have been missed if they had simply followed common toxicology practices—extrapolating low-dose impacts from high-dose tests. As sperm counts in industrialized nations continue to decline it's worth pointing to the fact that the low dose that suppressed the enzyme aromatase in the rats was comparable to exposures the general human population is now routinely exposed to.

Kristina A. Thayer of the National Institute of Environmental Health Sciences in North Carolina in the US has conducted research into another plastic-softening agent called bisphenol-A. This chemical is known to mimic natural hormones such as estrogens, with worrying implications for involvement in the development of hormonally mediated cancers. In addition to this property of bisphenol-A, Thayer's research has now demonstrated low dose effects similar to those reported by the German team working with DEHP.

Sherry Rogers in Detoxify or Die describes research carried out at the Tufts Medical Center in Boston in which researchers found that bisphenol-A leaches out of the polycarbonates used in plastic food containers, drinks bottles, and baby bottles. The only reason they discovered this was because bisphenol-A was leaching out of plastic test tubes and interfering with experiment results. In fact the researchers were looking at the effects of estrogens on cancer cell growth. They found that estrogens encouraged cancer growth but that increased growth was also being seen without estrogens being added to the test tubes. They determined that bisphenol-A from the test tubes was contaminating the contents and acting like an estrogen, accelerating the growth of the cancer cells.

Taking heed of these recent research findings, Europe has adopted laws banning the use of phthalates and bisphenol-A in toys, baby bottles, and other products intended for use by children under 3 years of age. New laws also ban the use of some phthalates in cosmetics products. The state of California in the US has also pushed for a ban on these chemicals in children's toys but legal challenges from manufacturers have so far thwarted attempts.

Based on the traditional view of toxicology, regulatory agencies in most countries haven't required scientists to evaluate a chemical at exposures below that at which no obvious harm is apparent. This dose is referred to as the NOAEL, short for "No Observable Adverse-Effects Level".

A small number of scientists have campaigned for decades to draw attention to biological effects that occur below a NOAEL. These include what are known as "nonlinear effects", such as a toxicity that initially decreases as concentration goes down but then unexpectedly increases at lower doses.

The December 2006 issue of Toxicological Sciences describes work carried out by toxicologist Edward J. Calabrese of the University of Massachusetts and his research team to determine if these low dose effects are the norm or rare occurrences.

Calabrese's team analyzed databases of biological responses to potentially toxic chemicals, each throughout a broad range of doses. They looked at data showing how cell proliferation in 13 different yeast strains responded to various doses of 2,189 potential anticancer drugs. Almost 80 percent of the drugs had a NOAEL, they discovered. Among these, the group further looked for reports of biological effects triggered by doses below the NOAEL. Just by chance 25 percent of these drugs would be expected to exhibit activity above that seen with no exposure but the team found that in fact, 60 percent did.

The effects observed at those low doses were modest, up to 60 percent higher than those that occur in the absence of any exposure. Calabrese says that these and earlier findings by his team show that measurable biological effects at low doses appear to be more the norm than an anomaly.

Even environmental pollutants that don't have a NOAEL may have nonlinear effects at low doses, according to Bernard Weiss of the University of Rochester School of Medicine and Dentistry in New York. He has stated that toxicity estimates based on high-dose measurements greatly underestimate low-dose harm.

So based on a growing body of research with results like those discussed, it seems that of the tens of thousands of chemicals produced and used by industry that have not been tested for effects below the NOAEL, many may produce harmful effects on human health and that of wildlife at low doses.

What worries Dr. Sherry Rogers and others is not only that many chemicals may be harmful to health at low doses individually, but that the cumulative effects of exposure to low levels of many chemicals present in our environment are likely to be even more harmful. We've seen that there are no requirements to study biological effects of chemicals below the NOAEL and that the small amount of research that has been conducted shows harmful effects at doses lower than this level can indeed be harmful. The research on the combined effects of different chemicals acting together is virtually nonexistent. Worrying indeed.

It should be noted however that not all of the biological effects seen with low dose exposures can be considered harmful. In fact some effects actually seem to be positive in nature. X-rays and gamma radiation are well known for their cancer causing effects. Scientists know that someone who has had many X-rays throughout their life is at increased risk of developing cancer over someone who hasn't been X-rayed. The increased risk isn't huge but it is there. Now however, animal studies seem to show that exposure to low levels of radiation can defend against cancer-inducing biological changes. It's thought that these low dose exposures turn on some kind of biological protection mechanism in the body's cells that protect them against further higher strength radiation exposure. The low dose can be seen as a kind of vaccination against future radiation exposure, much like small doses of a virus in a regular vaccine protect against full-blown infection by that virus.

Given the research regarding low dose exposures to chemicals has yielded such important results it would seem vital that this kind of research is conducted routinely, especially with respect to chemicals used in food packaging, children's products, and cosmetics, for example. Only time will tell how this kind of research influences policy and regulations. In the meantime both humans and wildlife will continue to be the subjects of a giant experiment as a multitude of chemicals remain prevalent in the environment.



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