A bad mix: exposure may be “safe” only with one chemical at a time.

Sep 01, 2009

Christiansen S, M Scholze, M Dalgaard, AM Vinggaard, Marta Axelstad, Andreas Kortenkamp and Ulla Hass. Synergistic disruption of external male sex organ development by a mixture of four antiandrogens. Environmental Health Perspectives doi:10.1289/ehp.0900689.

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.

This type of response, called a synergistic response, makes it difficult to estimate the outcome of mixture exposures.

Because people are exposed to all sorts of chemical mixes – from environmental sources such as food, water, prescription drugs, air and dust – it is not possible to test for all possible chemical combinations. Therefore, regulators use information based on the toxicities of individual chemicals to determine safe exposures. For the chemical mixture used in this study, that logic would have resulted in an underestimate of the exposure risks.

Hypospadias, the condition in which the opening of the penis is at a location other than the tip, is a growing problem in human populations. Some scientists speculate that environmental chemicals could be contributing to this rise (Paulozzi et al. 1999).

There is a widely held view in chemical testing that exposure to chemical combinations at the NOAEL should not cause negative health effects. This study found that this is not always the case. When rats in this study were exposed to a mixture of the four anti-androgen chemicals at the NOAEL level, the rats had reduced anogenital distances. This indicates the rats were feminized by the exposures. Reduced anogenital distances are an increasing problem for humans as well (Swan et al. 2005).

Regulatory bodies have recently become interested in the risks associated with phthalate exposure. However, regulatory efforts have not tested for effects from mixtures people would routinely be exposed to (Marsee et al. 2006). This study highlights a compelling reason to take a closer look at the current risks associated with exposure to multiple chemicals at a time.

Context: Androgens

Androgens are steroid hormones that control many aspects of sexual development. Although androgens play roles in both males and females, they are best known for directing the development of the male reproductive system and the maintenance of masculine characteristics.

Certain chemicals in the environment are able to interfere with the function of androgens and are called “anti-androgens.” If the exposure to anti-androgen chemicals happens before birth, it can have significant consequences for the developing animal’s reproductive system. Animals affected by these chemicals can become demasculinized as well as have deformed sex organs. Some of the problems caused by these chemicals are irreversible, while other problems can be corrected with surgery.

Rats are often used in research studies to identify possible health concerns associated with chemical exposure. Common problems associated with anti-androgen exposure in male rats include retained nipples, reduction in sex organ weights and reduced anogenital distance – the distance from the anus to the base of the penis. Anogenital distance is used as a sensitive indicator of male feminization. The shorter the distance, the more female-like the animal is perceived to be. This measurement is also used in humans to predict reproductive disorders.

Hypospadias, a condition in which the opening of the penis is not located at the tip, but at some other location, is also a problem associated with anti-androgen exposure.

Chemicals known to be anti-androgens include certain phthalates, fungicides and prescription drugs. Phthalates are often added to plastics to change their flexibility, durability or transparency. Fungicides, such as vinclozolin and prochloraz, are used widely on food crops throughout the United States. Finasteride is an anti-androgen prescription drug used in the treatment of male pattern baldness and prostate cancer.

Although these chemicals all act as anti-androgens, they behave in different ways and have different mechanisms of actions within the cell.

When regulatory agencies are trying to determine what concentration of a chemical should be considered “safe” for human exposure, they often use the chemical's "NOAEL."  NOAEL stands for “no-observed-adverse-effect-levels." It is the highest tested dose of the chemical at which no negative effect could be seen. Doses above the NOAEL caused adverse effects. The NOAEL is often the point of departure for establishing safe exposures for people.

Very few health exposure standards for chemicals consider their potential interaction with other chemicals, even though people are regularly exposed to hundreds of chemicals, if not more. Instead, the NOAEL measured for the individual chemical, by itself, is normally used to estimate the safe exposure level. Health consequences of exposure to mixtures of chemicals are not well studied, especially when the chemicals have different mechanisms of action within the body.