Should oral gavage be abandoned in toxicity testing of endocrine disruptors?

Abstract

For decades, hazard assessments for environmental chemicals have used intra-gastric gavage to assess the effects of ‘oral’ exposures. It is now widely used – and in some cases required – by US federal agencies to assess potential toxicity of endocrine disrupting chemicals (EDCs). In this review we enumerate several reasons why gavage is not appropriate for the assessment of EDCs using bisphenol A (BPA) as a main example. First, whereas human dietary exposures interact with the oral mucosa, gavage exposures avoid these interactions, leading to dramatic differences in absorption, bioavailability and metabolism with implications for toxicokinetic assumptions and models. Additionally, there are well acknowledged complications associated with gavage, such as perforation of the esophagus that diminish its value in toxicological experiments. Finally, the gavage protocol itself can induce stress responses by the endocrine system and confound the assessment of EDCs. These serious flaws have not been taken into account in interpreting results of EDC research. We propose the exploration of alternatives to mimic human exposures when there are multiple exposure routes/sources and when exposures are chronic. 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.

Evidence that bisphenol A (BPA) can be accurately measured without contamination in human serum and urine, and that BPA causes numerous hazards from multiple routes of exposure

“…Of importance is that the different estimates of exposure to BPA are based on the exposure models that are used (Gies et al, 2009), with one set of pharmacokinetic models being based entirely on single intra-gastric gavage exposure (LaKind et al, 2008; Volkel et al, 2002). In contrast, other exposure models assume that gavage exposure alone is inadequate to explain human serum levels of bioactive BPA (Vandenberg et al, 2010a, 2010b, 2013b, 2014b). …”

Perinatal exposure to endocrine disruptors: sex, timing and behavioral endpoints

“…This implies that an analysis of maternal behavior should be included, or at least considered as a possible variable, when assessing the effects of chemicals administered via maternal treatment [57]. An additional consideration regarding all the studies including maternal treatment, is that the chemical should be administered through the least invasive and stressful procedure available rather than the traditional intragastric gavage procedure used in toxicological studies conducted for regulatory purposes [58]. …”

Bisphenol-A Treatment During Pregnancy in Mice: A New Window of Susceptibility for the Development of Diabetes in Mothers Later in Life

“…With time it has been demonstrated that some of these oral manners of administration are not so suitable for the assessment of BPA. This is the case of oral gavage that does not appropriately model human dietary exposures (52). In addition, increasing evidence data have revealed that additional routes such as inhalation and contact can substantially contribute to human exposure.…”