Volume 18, Number 3 .... September 1996

Health and Safety

My 20 cents worth

More on the book Our Stolen Future which I mentioned in the May column. As is so often the case, the most insightful and thought provoking portion of the book is towards the end in the chapter entitled "Beyond Cancer".

The authors suggest that we need a new paradigm for toxicology. And in classic form for a paradigm shift, as outlined by the late Thomas S. Kuhn in The Structure of Scientific Revolutions the evidence is overwhelming but unconvincing to those within the mainstream of toxicology.

So let me ante up my 20 cents (pair o' dimes) and give a one-sided perspective on the history of toxicology.

Since we developed the ability to reason, and perhaps well before that, the human animal has understood things that were poisonous, i.e., acutely toxic. You eat it, you drop dead. Your friends don't make the same mistake and survive to spawn the next generation. For a good amount of time we have also understood cumulative poisons like lead (eventually a topic to be discussed in this column) and arsenic poisoning.

In the sixteenth century, a Swiss physician by the name of Paracelsus observed that materials can be lethal in large doses but not poisonous in small amounts. Hence his axiom "the dose makes the poison". For this observation he is considered by some to be the father of toxicology.

Extending the idea of a lethal dose we can easily see the utility of measurements like the LD50, the dosage where half a test population is killed. And with careful work and study, we can determine the safe level of exposure to toxins.

However, in 1775, humankind was forced to accept that exposure to chemicals could cause cancer. That was the year Percivall Pott, a British physician, correlated sores on the scrotums of many chimney sweeps with exposure to coal tar. It turned out the sores were a form of skin cancer. And lo there was carcinogenicity.

While safe levels of exposure to many toxins can be established, the same is not true of carcinogens. In general, lower exposure to carcinogens means you are only less likely to get cancer. It has been difficult to define a point where a dosage is low enough that you are no more likely to get cancer from the exposure than you would have otherwise. You often hear of levels of pollutants discussed in terms of causing less than, say, one additional case of cancer per 100,000 people.

But things have progressed since 1775. We now are beginning to understand mechanisms for toxicity and even carcinogenicity. Nearly twenty years ago I heard a lecture on toxicology. The lecturer was discussing the problems with animal studies and the example cited was that of PCB's. Different animals, it seems, metabolize polychlorinated biphenyls differently. People don't do a very good job and it remains in the body (and causes cancer). Other mammals, rats as I recall, excrete the stuff within a couple of days after exposure. The difference was explained by the different mechanisms used by ours and the rats' livers to solubilize the oily substance and render it water soluble and therefore excretable.

Today we can understand interactions on levels that were inconceivable even only twenty years ago. But we have restricted our investigations of toxic materials; we are locked within an out-of-date paradigm. We haven't considered other forms of interaction between chemicals and animals. A chemical can interact with a cell and kill it or alter or attack its DNA (mutagenicity). If the chemical is present in a high enough quantity, the first can lead to death in the animal. Altering the DNA in even one cell can, but doesn't necessarily, cause cancer (carcinogenicity) or genetic defects in the next generation (teratogenicity).

But we haven't considered what else chemicals can do in the body. Our Stolen Future persuasively posits that they can also interact with the biochemistry of the body. Some chemicals can mimic or interfere with hormones, chemical messengers, in the body. They can disrupt the endocrine system. This is the paradigm shift that toxicology has not yet accepted.

One of the many amazing things about the efficiency of the body is how very little of these endocrine messengers are necessary. Biologically active amounts are measured in the parts per billions. Differences in the parts per trillion range have been observed in animal studies. Perhaps the most compelling example described in Our Stolen Future is a study of mouse behavior.

Frederick vom Saal began his research while a postdoctoral student at the University of Texas at Austin in 1976. Among other tasks, he bred mice for research. He noticed odd behavioral patterns emerging in the mouse population. Odder still, they were genetically identical mice so the behavior patterns were not inherited. He first began to study the relatively rare aggressive female. He found there was about one aggressive female out of six in the population. As they were all raised in similar environments and all were genetically identical, he began to consider the mouse's prenatal environment as the cause of the behavioral differences.

When considering how mice are positioned in utero, he realized that the odds were about one in six that a female pup would be wedged between two males. He began to suspect that hormones, specifically testosterone, from the males on each side could have led to the observed higher aggression in the females.

By performing Caesarean sections on mice and noting the relative positions of the pups he was able to correlate their position in the womb with their observed behavior - the "wombmate" effect. Upon further research, vom Saal found that males exposed to higher levels of estrogen, the female sex hormone, by being adjacent to two sisters, displayed higher rates of sexual activity and larger prostates than their brothers.

How much more estrogen or testosterone is a female mouse exposed to by having two male "wombmates"? It is surprisingly small. 35 parts per trillion difference in their exposure to estradiol and one part per billion in testosterone. In the book, one part per trillion is illustrated as one drop of gin into 660 tank train cars full of tonic. That's a six mile long train!

Another problem with the old toxicology paradigm. Hormone systems do not have a linear dose-response behavior. Increasing the dose of a hormone can decrease its effect. This means that testing for effects of endocrine disrupting chemicals cannot be done at artificially high doses. It seems the body becomes a bit suspicious of hormone signals at thousands of times what is normal and sort of ignores the message.

And why am I wasting your time and precious space in the WAAC Newsletter going on about endocrine disrupters? Xenoestrogens or estrogen mimics (see previous health and safety columns for much more on that subject) are endocrine disrupters that we are exposed to in our work. Other endocrine disrupters interfere with thyroid hormones which direct the formation and differentiation of the brain during its (or our) development.

What is frightening is that it seems the wages of exposure are visited on our children. Or, from a what about me perspective, our parents' exposure might have serious repercussions for us. Perhaps most frightening of all, society's exposure might have a bearing on our continued survival as a species and the survival of many other species.

By acknowledging the problem and sensibly attacking it, we can begin to make a change. We can, with effort, make things no worse and possibly even make them better.

The book: Our Stolen Future: Are We Threatening Our Fertility, Intelligence, and Survival? ­ A Scientific Detective Story. Theo Colborn, Diane Dumanoski, and John Peterson Myers. Dutton, Penguin Books USA, New York. 1996, $24.95 hardback.