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    Gavage Testing In Animals Is Not An Accurate Way To Measure Toxicology
    By News Staff | June 25th 2014 09:06 AM | 1 comment | Print | E-mail | Track Comments

    If you have read about feminized frogs due to pesticides, or other scary claims by environmentalists, you may wonder why the EPA does not use those studies when registering chemicals.

    The reason is because they often have no parallel to the real world. Chemical companies, despite claims by their cultural detractors, want to be overly cautious, while anti-science activists want to use enough exposure to create the effect they want to write about. In both cases, they use gavage dosing.

    Oral gavage refers putting a tube down their throats to deliver substances directly to the stomach. It has been used for decades and is at present the dosing scheme preferred for assessing potential toxicity of endocrine disrupting chemicals (EDC) by regulatory agencies. Researchers who are trying to show negative effects even take that a step farther and use surfactants to increase the uptake of the chemical.

    So if you see a horror story about Product X, what you may not know unless you read the Methods part of the study, is that the animal may have had more chemicals than you could consume if you mixed it with 5,000 glasses of water per day.



    Laura Vandenberg and colleagues reviewed more than 60 papers and reports and conclude that oral gavage in animal studies does not mimic how humans are exposed to chemicals. Credit: UMass AMherst

    Environmental health scientist Laura Vandenberg at the University of Massachusetts Amherst suggests that gavage dosing needs to be modernized. Vandenberg, with colleagues at the University of Missouri-Columbia and Université de Toulouse, France, writes, "We conclude that gavage may be preferred over other routes for some environmental chemicals in some circumstances, but it does not appropriately model human dietary exposures for many chemicals. Because it avoids exposure pathways, is stressful and thus interferes with endocrine responses, gavage should be abandoned as the default route of administration for hazard assessments of EDCs."

    Though gavage does offer precise dose and timing control, the authors say it is not appropriate for assessing EDCs, using Bisphenol A (BPA) as a primary example. Its drawbacks include the fact that gavage bypasses the mouth, which means animals experience "dramatic differences in absorption, bioavailability and metabolism" than humans experience when eating food, which is thought to be way most people are exposed to BPA. Further, gavage carries well-known risks including perforation of the esophagus that diminish its value.

    Finally, the authors point out that the gavage protocol itself can induce stress responses in the endocrine system, which may confound EDC assessment. "We propose the exploration of alternatives to mimic human exposures when there are multiple exposure routes/sources and when exposures are chronic," they urge. Their work appears in the current issue of Environmental Health.

    Vandenberg and colleagues say they chose BPA because exposure is widespread in humans, low doses have been linked to adverse effects in laboratory animals, exposure is linked to a wide range of human diseases, and unanswered questions remain about how best to model exposure routes and sources. The lack of detailed understanding of all potential routes of exposure applies to many chemicals used in a wide range of products, they add.

    The researchers reviewed more than 60 papers and reports, pointing out that "for hypothesis testing, route of exposure may not be of central importance, but for hazard assessment, risk assessors typically require that studies use a route of exposure that is deemed 'relevant' to humans."

    They point to recent studies in dogs and monkeys where scientists could study different BPA absorption when it was administered both by mouth and by traditional gavage. Given to dogs under the tongue, BPA entered into circulation largely in an unconjugated form, that is, without having been converted to an inactive form by the liver in so-called first-pass metabolism. By comparison, over 99 percent of the BPA was metabolized rapidly in the dogs with gavage.

    Similarly, less than 1 percent of administered BPA was bioavailable in blood in a gavage experiment with monkeys, while BPA fed in a piece of fruit resulted in over 7 percent of administered BPA being bioavailable in blood.

    The authors point out that while "all dosing methods have pros and cons that must be considered in the design of a study," recent studies suggest that gavage may interfere with the study of EDCs and viable alternatives do exist.

    EDCs and drugs can be administered by milling a compound into feed, dissolving it in drinking water, feeding animals from a pipette or adding a compound to a wafer or other food.

    Also, implanted devices and osmotic pumps "are of particular interest in BPA studies because they can provide constant exposures to low doses that produce serum concentrations that approximate those found in humans. These routes of exposure may be relevant also because there are important and significant non-oral sources of BPA exposure," Vandenberg and colleagues state.


    Citation: Laura N Vandenberg, Wade V Welshons, Frederick S vom Saal, Pierre-Louis Toutain, John Myers , 'Should oral gavage be abandoned in toxicity testing of endocrine disruptors?', Environmental Health 2014, 13:46 25 June 2014. doi:10.1186/1476-069X-13-46. Source: University of Massachusetts at Amherst

    Comments

    This blog completely mischaracterizes the findings of the article on which it purportedly reports. I was senior author of the article, so I should know. Here is the full citation: Vandenberg, LN, WV Welshons, FS vom Saal, P-L Toutain and JP Myers. 2104 Should oral gavage be abandoned in toxicity testing of endocrine disruptors? Environmental Health 13:46. http://bit.ly/1wrhOl5 doi:10.1186/1476-069X-13-46

    Our main point was that the use of gavage as a means of delivering toxicants to animals or people in toxicology experiments is likely to lead to underestimates of toxicity. Put simply, gavage experiments will indicate a toxicant is less hazardous to people than it actually is.

    There are two main reasons for this:

    (1) gavage bypasses an important route of delivery, the soft tissues of the mouth, which can absorb toxicants with very high efficiency, acting almost like an IV delivery system. This means that more of the chemical gets into the blood stream than gavage experiments indicate. Gavage delivers the chemical straight to the stomach where it often can be quickly absorbed and metabolized by the liver. So gavage reduces the actual amount of chemical that can reach sensitive tissues.

    (2) gavage stresses both experimental and control groups. This narrows the gap between experimental and control groups and makes it harder to find important adverse effects even if they are occurring.

    Our article provides many appropriate references documenting these points.

    Here is one of the peer-reviewer's take:

    The authors ruined a perfectly good flight to Phoenix, Arizona where I am traveling to attend the annual Society of Toxicology meeting and am presenting a paper that uses oral gavage. Rats (pun intended)!
    In all seriousness, while I have thought about many of the issues the authors raised as it relates to stress, I have not considered the range of limitations of gavage that were presented in this review, particularly as it relates to absorption through mucosal membranes in the mouth and upper esophagus.
    Thus, I believe this is a critical comprehensive report that should be advanced for publication as soon as possible. It is well written and lays out a very balanced view of the appropriate arguments. Given the recent findings from the FDA, this analysis of the flaws in gavage should be disseminated in order that other scientists such as myself can start the process of rethinking their study design, and regulatory agencies can be informed that the goal post of truth has been moved yet again. This has far reaching consequences and costs for regulators, labs, and scientists, but, not heeding the advice of the authors could have larger costs on the public's health.

    The full text of this review and those of the other peer-reviewer are available here: http://bit.ly/1mexYs4

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