2014/02/05

Science 2.0

Close Enough For NIEHS Work
http://www.science20.com/steve_hentges/close_enough_niehs_work-129098.
The subject of endocrine disruption is not particularly new, with extensive scientificand regulatory attention to endocrine disrupting chemicals (EDCs) over the last 20years or so. A common definition, from the World Health Organization/International
Programme on Chemical Safety (*see attached pages) , is:An endocrine disruptor is an exogenous substance [i.e. a substance not originating inan organism] or mixture that alters function(s) of the endocrine system andconsequently causes adverse health effects in an intact organism, or its progeny,or(sub)populations.”
Quite a few natural and synthetic chemicals exhibit endocrine activity but, in spite of
20 years of research, the field of endocrine disruption continues to be ill-defined andhighly controversial. Two of the current controversies revolve around the related
concepts of low-dose effects and non-monotonic dose response curves (NMDRC).
In the field of toxicology, a bedrock principle is that “the dose makes the poison,”meaning that a toxicological response is generally expected to increase (or decrease)monotonically with increasing dose. In contrast, the NMDRC concept suggests that theslope of the dose-response curve for endocrine active compounds may change frompositive to negative, or vice versa, with increasing dose, for example resulting in Ushaped or inverted U-shaped dose-response curves.

Although NMDRCs will not be further discussed in this article, interested readers canlearn more in a recent draft report on the topic from the US Environmental Protection
Agency, which highlights the lack of reproducible evidence regarding NMRDCs andillustrates some of the key shortcomings of the research purportedly showing
NMDRCs.

One of the challenges in discussing low-dose effects is the lack of a clear definition. Low-dose
effects are generally considered to mean effects that occur at levels below the no-effect levels
established in traditional toxicology studies. More pertinently for this article, the term is sometimes
more specifically defined as effects that occur in the range of typical human exposures.

Accordingly,for studies focused on evaluating potential low dose effects and NMDRCs, dose
selection is a critical and controversial study design parameter. In this regard, a recent study
claiming that the common chemical bisphenol A (BPA), considered by some to be an endocrine
disruptor, caused adverse effects at a human-relevant dose was of particular interest. The authors
signaled the significance of the low dose by referring to its human relevance at least six times inthe body of the relatively short paper. If it’s worth repeating six times, it must be important, right?

Important or not, the new study,funded by a grant from the National Institute of Environmental
Health Sciences (NIEHS), is not unique in touting the human relevance of the dosetested. Inspection of a list of NIEHS-funded studies addressing BPA reveals another 24 that also
highlight the human relevance of the dose(s) tested, although none so obsessively as the mostrecent example.

At first blush, we should congratulate NIEHS for consistently funding studies of such direct
relevance to human health. But before congratulations are offered, maybe we should take a closerlook.

Does the science match the warning level? Credit: National Institute of Environmental HealthSciences.

In the new study, mice were provided a diet that contained 5 mg BPA/kg of diet (5parts permillion). Based on food consumed, the authors estimated BPA intake to be 20 µg/mouse perday. Although the authors didn’t report the bodyweight of their mice, we can estimate, based onstandard weights for the mouse strain tested, that the daily intake was on the order of 1,000 µg
BPA/kg bodyweight per day.

For this dose to be human-relevant as claimed, people should be consuming approximately thesame amount of BPA on a bodyweight adjusted basis, and therein lies the rub. Althoughcharacterized as a human-relevant dose, extensive data have shown that typical human exposures
to BPA are orders of magnitude lower.

It is well established that BPA has a half-life in the body of only a few hours and is quantitatively
excreted in urine in the form of a biologically inactive metabolite. As stated by the European Food
Safety Authority in its comprehensive BPA exposure assessment, “[u]rine is therefore the matrix ofchoice for biomonitoring, and the urinary concentration of total (unconjugated plus conjugated) BPA
is the biomarker of choice to estimate BPA exposure.”

Recognizing this, numerous biomonitoring studies that measure total BPA in urine have been
conducted around the world, most notably population-scale studies conducted by the US Centers
for Disease Control (CDC) and Health Canada. These studies consistently show that human
exposure to BPA is typically less than 0.1 µg BPA/kg bodyweight per day, which is approximately
10,000-fold lower than the so-called human-relevant dose given to mice in the recent study.

The same large discrepancy between typical human exposure and the dose(s) tested ispresent inall of the other NIEHS-funded studies that claim human-relevant doses were used. Surprisingly,
neither the recent study, in spite of the repeated references to a human-relevant dose, nor any of
the other NIEHS-funded studies, make any mention whatsoever of these wellestablished,scientifically robust and widely accepted human exposure measurements.

Insteadof relying on these population-scale studies to provide a scientifically solid baseline ofactual human exposures, all of the NIEHS-funded studies tested doses (or in vitro concentrations)comparable only to levels reported to be present in human blood in various small-scalestudies. But by doing this, the NIEHS-funded studies also ignore the consensus of biomonitoringand bioanalytical experts that measurement of BPA in human blood is not a reliable method for
estimating exposures, most prominently including CDC and the US Food and Drug Administration.

Experts from these authorities have made no secret of their critical views of the validity of BPA
blood measurements:“Taken together, these results suggest that blood or its products (serum/plasma) is an unfavorable
matrix for the biomonitoring of BPA exposure in the general population.” (CDC, Ye et al. 2012)“However, for the reasons that follow, it is seldom possible to verify that serum concentrations ofthese compounds are valid measures of exposure.”(CDC, Calafat et al. 2013)“The lack of concordance with intake estimates … based on fullyvalidated urinary measurements of
BPA conjugates … makes it likely thatmeasurements of ng/ml levels of aglycone BPA in humanplasma were compromised by the ubiquitous BPA contamination in the environment.” Doerge et al.
2010“The simplest explanation for this discordance is sample contamination leading to false positive
determinations of aglycone BPA in human blood, which otherwise would contain levels
undetectable by any current analytical methodology.”(FDA, Twaddle et al. 2010)“[B]lood biomarkers of BPA likely represent only contamination.” (Wolff 2011
So what’s going on here? All of the 25 NIEHS-funded studies make similar claims of humanrelevant doses, all rely on data considered by the world’s experts to be questionable at best,and all ignore the most reliable measures of human exposure. The result is that thestudies are of very limited relevance to human health since the reported effects occur
at doses far above typical human exposures, not at human-relevant doses as claimed.
Can all of this be the result of coincidence? No, NIEHS has stated that studies it
supports will focus on “low environmentally relevant doses of BPA.” We can only
conclude that being off by a factor of 10,000 is close enough for NIEHS-supported
research. But rather than congratulating NIEHS, two important questions remain: Howdid NIEHS and its grantees get it so wrong – 25 times and counting – and how many
millions of dollars of precious grant money has been spent on research that can be of
only very limited relevance to address important public health issues related to BPA?
Note in proof: After writing this article, another NIEHS-funded study was published with the same
claim of human-relevant doses. It’s now 26 times and counting.

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