Synopsis by Heather Hamlin and Wendy Hessler

Exposure to a mixture of environmental chemicals is far more harmful to male rats than exposure to the individual chemicals would predict, even when the level of each contaminant in the mixture causes no effect by itself. The results indicate that assessing the risk of chemicals one-compound-at-a-time will underestimate potential harm. People are exposed to hundreds of chemicals at a time, if not more.  People could be affected by mixtures of chemicals that are currently considered "safe" based on their individual toxicities.

What did they do?

Researchers fed groups of pregnant rats chemicals alone or a mixture throughout most of their pregnancy. The rats were given either a phthalate called DEHP, the fungicides vinclozolin or prochloraz, the drug finasteride or a mixture of the four chemicals.

Some groups were exposed to levels of the chemicals that previous research has suggested causes no harm (the "no observed adverse effect level," or NOAEL).  Others were exposed to the chemicals at the NOAEL level.

Once born, the baby rats were weighed, inspected for nipple retention and genital deformities, and measured for the distance between their anus and the base of their penis (anogenital distance). All males were scored for their degree of feminization. In some male animals, researchers also weighed reproductive organs and the kidney and liver. What did they find?

The mixture of DEHP, vinclozolin, prochloraz and finasteride, given at doses known to harm reproductive development, caused decreases in anogenital distance, increased prostate weights and retained nipples. The effects seen in relation to these conditions was additive and could be predicted given the responses observed when looking at the chemicals individually.

However, incidence of penis deformities were much stronger with the mixes than what would be predicted from the potency of the individual chemicals. For a significant number of rats, the penis opening was not at the tip, but was often located toward the base of the genitals.

In addition, some male rats had a groove resembling a vaginal opening that was often found at the base of the genitals. The extent of these deformities was described as synergistic, in which the outcome is more severe than what would be predicted from adding up the potencies of all the chemicals.

When individual chemicals were tested at their NOAEL, as expected, no negative effects were seen. However, when the chemicals were mixed together, the rats had reduced anogenital distances, indicating that the rats were becoming feminized.

What does it mean?

Prebirth exposure to a mix of chemicals - each with known hormonal effects - can cause more severe reproductive abnormalities than any one of the chemicals alone and more than the sum of the predicted effects of each one alone, according to this study with rats. The health effects varied and occurred even when the chemicals were mixed at levels where no effects are usually seen.

People are not exposed to just one chemical at a time, but to a host of chemicals, many of which have the potential to interfere with the function of androgen hormones.

This study raises concern that humans could also be affected by mixtures of chemicals that are currently considered "safe" based on their individual toxicities. Whether humans could have similar reproductive problems as the rats in this study depends on the numbers, concentrations and sensitivities to the chemicals.

Predictions regarding the effects chemical mixtures will have on human populations is based primarily on the effects of the toxicities of individual chemicals. When chemicals are mixed, it is expected that the effects will be additive. For example, if chemicals A and B cause the same effects, then adding them together should approximately double the problem.

This study found that for certain harmful effects, such as hypospadias, the mixture of anti-androgens used in this study caused a worse response than what was predicted from adding effects of single chemicals. The results add to a growing number of studies that find effects from mixtures can sometimes produce different and more severe effects than each chemical would by itself.

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