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.
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
Recent studies relevant to the effects of mixtures:
More on mixtures
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
the pace of modern regulatory science, it literally would take thousands
of years to resolve issues of safety using experimental methodology.
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.
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.
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.
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.
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
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.
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
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