An excerpt from Chapter 7, A Single Hit

The EPA's reassessment of the risks of dioxin was already under way when Richard Peterson's Wisconsin study hit with the shock of an unanticipated asteroid. Here was evidence that dioxin could have dramatic effects at very low doses-at levels close to those routinely found in humans. In a matter of months, the tide turned and the dioxin debate shifted from dioxin's cancer-causing potential to its developmental and reproductive toxicity. In short order, EPA scientists repeated the studies giving dioxin to pregnant rats and found similar effects in female offspring.

This turnaround in scientific thinking was stunning. The studies suggested that the worst fears about dioxin might, in fact, be justified. Dioxin might after all be more dangerous than anyone had suspected, but contrary to what many had thought, its greatest threat was not cancer. The newly emerging hazard was its power to disrupt natural hormones.

Dioxin's bad reputation helped insure a steady flow of
funding to a host of researchers who were probing what this chemical did to the body and how it did it, but the University of Wisconsin lab headed by Peterson was one of the few places exploring its effects on the endocrine system. Robert Moore, one of Peterson's colleagues at the School of Pharmacy and the Environmental Toxicology Center, had set off on this line of research because he believed it held the greatest potential for explaining the toxic effects of the notorious 2,3,7,8-TCDD.

Dioxin posed a fascinating challenge for toxicologists like Moore and Peterson because it is not your ordinary poison. Animals given lethal doses of dioxin don't keel over quickly; they lose their appetite and undergo a mysterious wasting before they actually die weeks later. Dioxin also produces a variety of other nonlethal responses that occasionally seem contradictory. It somehow disrupts estrogen responses, acting sometimes as if it were an estrogen impostor and sometimes as if it were blocking estrogen, yet studies have shown that dioxin is not a simple estrogen mimic like DES. It produces apparently estrogenic or antiestrogenic effects without consorting with the estrogen receptor. For all the years of research, exactly how dioxin does its harm has remained elusive. Peterson and Moore thought the endocrine system might hold the key to this mystery.

As they had suspected, their experiments with adult male rats confirmed that dioxin could interfere with hormone levels. When adult rats were given dioxin, it caused their testosterone levels to drop and their testicles and accessory sex organs to lose weight. But it took a lot of dioxin to produce such responses-almost enough to start killing some of the rats used in the experiments.

Although Moore and Peterson felt it was easier to explore the mechanism of toxicity if one used high doses, this approach began to fall into disfavor by the mid-1980s. Critics were attacking high dose experiments saying that they did not have direct relevance to the real world where humans and animals are exposed to much smaller amounts of dioxin.

In the end, Moore and Peterson had little choice. The National Institute of Health, which was funding their work, pushed them toward working with lower doses that the federal agency regarded as more immediately relevant to human health risks. "We got the message that we had to get out of high dose research if we wanted to stay funded," Moore said.

Well before their high-dose TCDD experiments had ended, Moore read a 1983 paper by Dorothea Sager, a researcher at the University of Wisconsin's Green Bay campus, which found a variety of changes, including reduced fertility, in male rats exposed to PCBs through their mother's milk. Sager's work demonstrated the critical importance of timing, not just in the severity of the impact but also in its very nature. Her findings inspired Moore and Peterson to look for similar patterns as a result of TCDD exposure. They brought in a graduate student, Tom Mably, to conduct the actual experiments.

This team looked beyond the simple question of whether or not rats exposed to dioxin could later produce offspring. This all-or-nothing approach was grossly inadequate. They wanted instead to look at more sensitive aspects of reproductive health, such as sperm counts and mating behaviors, that are not often measured in toxicity research. As Moore puts it, "we were looking for answers in different ways. We were turning over different rocks." In fact, Moore reflects, if they had done no more than the usual fertility tests, the work would have sunk into obscurity without a ripple.

Mably's results far exceeded their expectations.

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