2013/08/21

Science 2.0

Does Chemical X Cause Disease Y, And How Do We Know?
http://www.science20.com/steve_hentges/does_chemical_x_cause_disease_y_and_how_do_we_know-118888

That question is particularly relevant this week in light of numerous media articles reporting that
exposure to a common chemical is linked to obesity in children and adolescents. Underlying thearticles is a new study on bisphenol A (BPA) published this week in Pediatrics. The key question isthat of causation versus statistical association.

The new study is a cross-sectional epidemiology study in which the data analyzed is all collected at
the same time. The data are from the NHANES (National Health and Nutrition Examination Survey)
database, which collects extensive health and nutrition information on a nationally representative
sample of about 5,000 people each and every year. Also collected is biomonitoring data from analysisof blood or urine samples for more than 300 chemicals, including BPA. To be more precise, theanalysis measures metabolites of BPA, the significance of which is discussed below.

The availability of the NHANES database has led to a proliferation of cross-sectional studies “linking”
exposure to various chemicals with a wide range of disease conditions or other healthparameters. While cross-sectional studies do have some legitimate uses, they also have significant
limitations.

Image credit: BevNet
An important limitation is that because all of the data is collected at the same time, there is no way toknow if the exposure preceded the disease, which is critical to establishing causation, or whether thedisease preceded the exposure. Related to this lack of temporal information is the possibility ofreverse causation. In the new study, did BPA cause obesity or is it possible, even likely, that obesepeople are exposed to more BPA by consumption of more food? Extensive testing has shown that
diet is the source of most BPA exposure. There is simply no way to know in a cross-sectional study
and, thus, no possibility to establish causation.

The lack of temporal information is particularly important for chemicals that have short physiologicalhalf-lives. Numerous studies on laboratory animals and humans show that BPA is eliminated in urine

with a half-life of only a few hours. For this reason, BPA levels in urine show high variability not only
day-to-day, but even within a day. Although the authors of the new study state that it is “unclear if asingle measure of BPA would be indicative of long-term exposure,” it is actually quite clear that single
measures are not predictive of past or future exposures. Consistent with other studies, one from agroup of researchers in Denmark, published a couple weeks ago, concluded: “A consequence of theconsiderable variability in urinary excretion of BPA may be misclassification of individual BPA exposurelevel in epidemiological studies.”

Other signals that something is amiss are the lack of a clear dose-response and inconsistencies within
the study. For example, a statistical association was reported between BPA exposure and body massindex (BMI) greater than the 95th percentile, which was defined as obesity, but not for body mass index
greater than the 85th percentile, which was defined as being overweight. Is it really plausible that BPA
could cause obesity, but have no effect on being overweight? Other parameters that might be
expected to be related to obesity also showed no association with BPA exposure.

The limited results reported in the study might easily be due to confounders that were not considered,or simply chance statistical associations. As discussed by others, “using cross-sectional datasets like
NHANES to draw such conclusions about short-lived environmental chemicals and chronic complex
diseases is inappropriate.”

Finally, although not discussed by the authors, the biological plausibility of the reported statisticalassociations must be considered. Studies on humans and non-human primates show that BPA isefficiently converted to biologically inactive metabolites during absorption from the gastrointestinal tract
and by the liver before entering circulation. Systemic exposure to BPA itself is less than 1% of theamount absorbed. Although BPA is well known to be weakly estrogenic, could this low level besufficient to activate estrogen receptors in the body and lead to health effects? In a word, the answer
is no, according to new research from scientists at the Pacific Northwest National Laboratory andFDA. Using reported urine levels, including values from the NHANES database, the researchers
estimated blood levels and compared these with the levels that would be required to activate fivedifferent receptors. Even for the highest affinity receptor, the authors conclude “Our results show
limited or no potential for estrogenicity in humans.”

Based on all we know, it seems extremely unlikely that BPA causes obesity.