How America became obsessed with BPA
Why was the route of exposure to BPA ignored?(cont'd)
In a 1999 paper for the journal Regulatory Toxicology and Pharmacology Ashby increased the statistical power of the original studies with a greater number of randomly selected animals but he failed to confirm what vom Saal and others had found.
“The failure of the present experiment to confirm the reported increase in prostate weight caused by BPA (Nagel et al., 1997) and DES (vom Saal et al., 1997), or the decrease in sperm efficiency caused by BPA (vom Saal et al., 1998), agrees with the results of similar repeat studies on BPA and DES reported by Cagen et al. (1999). In addition, we found no significant effects for either of the test agents on the sexual maturation (vaginal opening) or reproductive tissue weights in the female offspring of mice exposed to either BPA or DES.”
There were criticisms of the Ashby and Cagen studies, including that one or the other had failed to play music quietly in the background and the mice became stressed, and that his study was conducted in an industrial toxicology lab. Given that replication is a key factor in science when it comes to deciding whether to adopt new evidence that seems to overturn consensus, Ashby and Cagen’s research raised significant doubt about vom Saal’s claims within the field of toxiclogy, particularly as these attempts at replication had greater, albeit still limited, statistical power.
Ashby’s work has been denounced by environmental activists on the “Our Stolen Future” website as “incompetent” – citing an exchange of letters by vom Saal and others with Ashby over the study protocols and endorsing vom Saal’s perspective on the matter. Our Stolen Future charged that the use of an estrogen DES as a positive control which then failed rendered Ashby and Cagen’s critique of vom Saal invalid. Ashby has retired, and could not be found; Cagen did not respond to questions about his work; however, vom Saal told STATS that:
“Ashby and Cagen both sought my advise [sic] about their studies, but of course I had no control over what they did; in fact I made suggestions that were rejected. They obviously chose the DES dose based on our published data about BPA in our 1997 PNAS article, which has been replicated - in fact Ashby's DES data were identical to ours. Not one person on either of those publications had every published a paper on the reproductive system in male mice, and they asked me to train them how to do the research (this is acknowledged in their publications) - they thought that this was possible to accomplish in a few hours. That is an indictment of the level of training that people think is appropriate to conduct a GLP [Good Laboratory Practice – international protocols that have the force of Federal law in the U.S.] study.
But the National Toxicology Program’s subpanel on BPA in 2001 concluded that the DES control was insufficient to render the findings unusable. Instead, the subpanel found that the strength and statistical power of those studies finding no association between low dose exposure to BPA and adverse effects, a group of studies which included John Ashby’s work, was “noteworthy.”
“As a group these studies are very consistent, the conclusions are supported by appropriate statistical analyses, and the Statistics Subpanel confirmed the lack of BPA effects.”
The BPA subpanel also noted that the food fed to the mice by vom Saal had double the amount of dietary estrogens as the food fed to the studies which found no association, and that this could have had an impact on the results. The NTP panel noted the possible effect of vom Saal using a closed colony of mice and that:
“the studies that reported a positive low dose effect did not specifically analyze their dosing solutions or starting material, and one has to recognize this is always a potential confounder. Thus, without analyses done at the time of the actual study, one cannot unequivocally rule out potential effects of contaminants or errors in the preparation of dosing solutions.”
Unfortunately – and somewhat controversially – vom Saal terminated the entire colony of mice he did his research on, which meant that other researchers were unable to exactly replicate this crucial element of his original research. The statistics subpanel also reanalyzed vom Saal’s data on a study that found a statistically significant reduction in sperm efficiency in mice given BPA and found that the computation was in error, and there was no statistically significant relationship. This raised the question about the statistical validity of other studies by vom Saal, but as he did not provide the raw data to the biostatistics subpanel for reanalysis, the panel simply noted that it couldn’t confirm the validity of vom Saal’s findings.
Reviews by the Japanese Government’s Office of Chemicals Safety, Pharmaceutical and Food Safety Bureau, Ministry of Health, Labor and Welfare in 2001, The European Commission’s Scientific Committee on Toxicity, Ecotoxicity and the Environment’s (CSTEE) in 2002, Harvard’s Center for Risk Analysis in 2004 Gradient in 2006 (Goodman et al), the European Food Safety Authority in 2006, the Center for the Evaluation of Risks to Human Reproduction in 2007 and Gradient in 2009 (Goodman et al) all reaffirmed the unreliability of the studies claiming low dose effects of BPA as means for determining human risk exposures. And EFSA noted:
“The effects of BPA reported in some studies at low doses in sensitive animal systems were small changes in organ weight or changes in tissue architecture, increased or decreased receptor expression, changes in hormone concentrations in plasma or tissues, small changes in the time required to attain puberty landmarks, and behavioural effects. The Panel noted that the changes observed were often not sustained through adulthood. The biological consequences of many of the changes in the affected animals are unknown and some, such as small increases in prostate weight, are not considered as precursors of pathological change. While some of the changes may be indicative of biomarkers of effect in very sensitive species and strains, in the light of present knowledge, they cannot be readily interpreted as adverse effects.
The Panel also noted that in some studies reporting low-dose effects, only a single dose level was investigated, or there was absence of a dose-response relationship where several dose levels had been used. Many studies also used only small numbers of animals per dose group. There are also a number of other potential confounding factors in these types of study that may contribute to the lack of consistency in the database.”
EFSA reiterated the point to STATS: “the scientists considered that many of the studies indicating low dose effects of BPA were contradictory and not well conducted.”