Ulrich et al. report on experiments that demonstrate endocrine-disrupting effects of DDT and HCH (hexachlorocyclohexane) in laboratory experiments with mice. The most important aspect of their work is that they found statistically significant responses to doses of these two compounds comparable to background levels measured in people living in the real world--that is, from people who had not been exposed occupationally. This paper is an important addition to the weight of evidence indicating that the old assumption of toxicology--that background levels are benign--is no longer a safe assumption.

It is also worth bearing in mind that Ulrich et al. worked with chronic exposures to adult mice on a reproductive tract outcome. Neither their target animals nor their endpoint are likely to be the most sensitive. In general, fetal development is a more sensitive stage in life and neural/behavioral endpoints are more sensitive than reproductive tract structural changes. This suggests that studies comparable to Ulrich et al. of the impacts on fetal exposure on behavior should be conducted. Fred vom Saal's neurobehavioral work with methoxychlor is consistent with this interpretation. Moreover, Ulrich et al. point out they may not have conducted their experiments on the most estrogen-sensitive strain of mice.These considerations suggests that careful study may reveal impacts at even lower doses.

What did they do?

Uhlrich et al. exposed adult female mice to chronic doses of DDT and HCH over a wide range of doses. Both compounds are well-established as endocrine disruptors. DDT binds competitively to the estrogen receptor. HCH does not, but instead achieves estrogenic activity through other mechanisms. Both are also both biaccumulative and virtually ubiquitous. Ulrich et al. observe that "virtually all humans have been exposed to these compounds."

The chemicals were delivered via "leaky" implants placed subcutaneously in the mice. The experimental protocol included both positive controls (receiving estrone) and controls. Dose was varied over a wide range of exposures, with the highest being 32x the lowest. Treatment continued only for one week.

They measured changes in the uterine (uterine epithelial height) and vaginal structure (vaginal epithelial thickness) of the mice following treatment and compared treated animals to the controls. They also measured contamination levels in the fat and the blood serum of the mice.

What did they find?

Mice treated with DDT and HCH showed altered uterine and vaginal characteristics in response to treatment. Because they measured contaminant levels in the blood, they were able to establish the blood levels at which effects were detected. "The lowest-observed-effect levels (LOELs) in the vaginal response were detected at blood concentrations of 42 ng/mL and 18 ng/mL for ß-HCH and o,p´-DDT, respectively." "Statistically significant increases in UEH <the uterine response> were detected at blood concentrations of 66 ng/mL and 18 ng/mL for ß-HCH and o,p´-DDT, respectively"

What does this mean?

Because Ulrich et al. actually measured the levels of DDT and HCH in the blood in at the LOEL level, they are in a position to compare this to typical human exposures. This is a highly unusual aspect of the study and a reason for its great importance. Most studies do not both vary the dose-delivered and measure the blood and fat concentrations.

Human occupational exposure to DDT and HCH leads to blood levels of these two compounds many times higher than the LOEL established by this work. For example, they cite data from studies in Argentine pesticide workers with HCH levels nearly 6 times the LOEL of this study.

Of greater interest is comparing these data to human exposures at background levels (i.e., not of pesticide workers). They report that "the concentrations of OC pesticides in different unexposed human populations were generally only 2.7-120 (DDT) or 2-140 (HCH) times lower than concentrations found to cause estrogenic responses in mice. However, in Israel, o,p´-DDT blood concentrations were found to be as high as 32 ng/mL (28), nearly double the minimal estrogenic blood level of 18 ng/mL observed in this study.

Ulrich et al. go on to comment: "Although it is difficult to determine if the response in humans is the same as in mice, it is alarming that the human blood concentrations are so similar to the estrogenic concentrations in mice. The mouse has proven to be a good model for approximating estrogenicity of a compound in humans."

"The extremely low levels required to cause statistically significant effects compared to control animals were unexpected. It is even more alarming that there is little difference between these levels and those that can be found in humans."

Rarely does one see the word "alarming" used in a scientific journal.

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