The impacts of chemical mixtures.

No one experiences just one chemical at a time. Hundreds of synthetic chemicals contaminate every living person. Yet almost all applied and basic science underpinning modern regulation has tested one chemical at a time.

		The graphs to the left are gas chromatographs of baby urine obtained from the diapers of two infants at 1 yr of age. The upper trace is from an infant that was breast fed. The lower was bottle fed. Even at this young age, these babies were carrying many different contaminants.
	from Bush et al. 1990.

Recent studies relevant to the effects of mixtures: More on mixtures

This raises important questions about how chemicals interact with one another. Is there any interaction? If so, is it such that two (or more) chemicals produce more of an effect than one by itself, and if so, are the interactions predictable on the basis of the effects of single chemicals, one at a time? Mixtures are one of the huge unknowns in toxicology. The numbers of chemical combinations experienced by people living in the real world is staggeringly large. With any one person carrying detectable levels of several hundred chemicals at one time, and with the mixtures varying from person to person, it is beyond the capacity of modern science to test all mixtures, or even all common mixtures. At the pace of modern regulatory science, it literally would take thousands of years to resolve issues of safety using experimental methodology. What is known, however, raises disquieting questions. While studies are few, they clearly demonstrate that chemicals can interact with one another in causing effects.

Some of these interactions are inhibitory. Some are additive. Some are synergistic, with the magnitude of synergy unpredictable, at least to date, based on known scientific findings.

Additive interactions among a small number of compounds provide a difficult but manageable challenge to estimate impacts of mixtures. They require extensive series of experiments that begin with measuring potency of compounds separately and then examine their combined impacts. One of the most elegant series of experiments of this sort to date has been carried out by Rajapakse et al. (2001, 2002) using mixtures of 17ß-estradiol with various weakly estrogenic compounds . They ascertained that interactions among the chemicals they studied, including bisphenol A, are additive.

Rajapakse et al.'s 2002 study is especially interesting because it involved 11 weakly estrogenic compounds in addition to 17ß-estradiol. The combination of these 11, even though each of the xenoestrogens was at a level individually where no effect was observable, together with 17ß-estradiol they doubled the effect of 17ß-estradiol. Without Rajapakse et al.'s elegant experimental analysis, the likely conclusion would have been that their impact was synergistic because the doubling effect was so dramatic.

While experimentation may be manageable with small numbers of compounds in mixtures, as noted above, humans are contaminated by many contaminants simultaneously, most of which are virtually unstudied with respect to specific endocrine impacts. The elegant models developed by Rajapakse et al. may prove difficult to extrapolate to complex mixtures. Work published in September, 2002 finding low-level non-monotonic effects of a common commercial mixture of lawn herbicides on fetal loss in mice indicates that current regulatory toxicology fails to encompass real-world situations, substituting the precision of reductionist one-chemical-at-a-time experiments for more accurate and appropriate methods.

Synergistic interactions are the most problematic, because they indicate that the effects of multiple chemicals together can be significantly more powerful than might be predicted simply by adding up their effects one at a time. Regulatory science rarely incorporates any interactions; it is incapable, at present, of coping with synergies. That is why industry responds so aggressively to hints of synergy in the scientific literature. Synergy profoundly challenges traditional risk analysis calculations.

The Food Quality Protection Act of 1996 acknowledged that mixtures are the rule rather than the exception, and began to lay the groundwork for a new approach by requiring that compounds with similar mechanisms of action be considered jointly when calculating whether exposures have exceeded tolerance levels. This is a good step, but the specific implementation employed by FQPA is very simplistic: it doesn't begin to address the possibility that chemicals might interact synergistically within mixtures. EPA is moving slowly to implement the FQPA's new requirements, with a major test case focused on the organophosphate pesticides.

In the meantime, new scientific studies of mixtures and synergies are emerging with increasing frequency. They have reinforced the conclusion, above, that synergy is a real part of real world toxicology, and must be acknowledged in the structure of regulations.

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