Simple Definition

The low-dose hypothesis is a theory advanced by some researchers who have speculated that extremely low-dose exposures to certain substances actually cause a more significant biological reaction than has been observed at higher doses. According to the low-dose hypothesis, biological response resulting in negative health effects occurs at doses well-below those levels previously tested and determined to be safe by regulatory authorities.

Although this low-dose hypothesis is often discussed in relationship to endocrine-related science, scientists at regulatory agencies have conducted rigorous reviews and have been unable to validate this hypothesis using reproducible, relevant testing.

Advanced Definition

A fundamental principle of pharmacology and toxicology is that the larger the dose of a particular substance, the greater the response in the human body. This applies to therapeutic treatment using pharmaceuticals as well as for toxicity. When evaluating toxicity of chemicals, scientists test a wide range of doses, from low microgram levels to a higher milligram range (thousands of times higher than micrograms). In doing so, they seek to identify a threshold level at which no harmful biological responses are observed.

Contrary to this well-established principle, some researchers have published studies that indicate in certain circumstances, a different dose response interaction can possibly occur. These researchers have speculated that a more significant response could occur at a low dose as compared to those observed at higher doses. These “low-dose effects” are postulated to occur at doses well below those levels previously tested and determined to be safe by regulatory authorities. The idea that some chemicals can cause a biological response and negative health effects at these very low-dose levels, is called the “low-dose hypothesis.”

Regulatory agencies in the U.S. and the European Union have conducted thorough reviews of the scientific literature of the low-dose hypothesis and continue to express skepticism that it is valid. EPA reports: “An EPA led work group of scientific experts reviewed various studies and the results were detailed in a draft paper, State of the Science Evaluation: Nonmonotonic Dose Responses as they Apply to Estrogen, Androgen, and Thyroid Pathways and EPA Testing and Assessment Procedures, submitted to the National Academy of Sciences on June 18, 2013. The purpose of the state of the science paper is to help EPA policy makers determine if NMDRs (non-monotonic dose responses) capture adverse effects that are not detected using current chemical testing strategies and if there are adverse effects that current EPA testing misses.”

The National Academy of Sciences’ (NAS) Board on Environmental Studies and Toxicology reviewed the paper to provide an expert peer review and requested public comment. NAS provided their findings and recommendations to EPA on May 2, 2014.

EPA is currently reviewing the NAS findings and recommendations to determine the next steps for incorporating their feedback noting: “EPA appreciates the rigorous scientific review of this paper and believes the NAS review will greatly improve the scientific soundness of the paper. The final paper will help EPA determine if current chemical testing strategies are protective of public health for exposures to endocrine disrupting chemicals.”

The European Food Safety Authority (EFSA) has similarly concluded:

“In its scientific opinion, EFSA’s Scientific Committee notes the lack of international consensus on the existence/relevance of low-dose effects. On a case-by-case basis, if triggered by unusual findings, an extended dose-response analysis of doses administered at wider ranges could be performed. Generally, EFSA considers that adverse effects occurring at the lowest observable effect level should continue to be used to guide safety assessments, whether due to endocrine activity or another toxic effect. This will protect against other possible endocrine-related effects at higher doses.”

Expanded Definition

The low-dose hypothesis suffers from numerous scientific shortcomings:

    1. There is no broad consensus on the definition of “low dose” – a low dose could refer to a level of exposure below that to which humans are ordinarily exposed, or a level that is below what regulatory agencies have established for safety testing, or an exposure below a “safe” health guidance value established by an authoritative body. Without a clear definition structured in a manner that is scientifically testable, the low-dose hypothesis cannot be validated.
    2. Some scientists claiming to have found evidence in support of the low-dose hypothesis have declined requests to make their underlying data available for independent, scientific verification in a public forum. Data from more than half of the published studies alleging low-dose effects (6 of 11 investigations) were conducted by one group of investigators. Thus, independent scientists were not able to fully examine and independently verify their conclusions.
    3. Independent and scientifically peer-reviewed research conducted by EPA’s leading endocrine research laboratory in the Office of Research and Development, published in 2010, was unable to reproduce purported low-dose effects.
    4. A comprehensive review by an independent panel of experts in 2008 concluded, “There are several large, robust, well designed studies with multiple dose groups using several strains of rats and mice, and none of these detected any adverse reproductive effects at low to moderate dosage levels of BPA administered via the relevant route of human exposures.”
    5. An advisory committee of the German Society of Toxicology, evaluating claims of low-dose effects and their reproducibility, concluded that “positive results from some explorative studies have not been confirmed in subsequent studies with higher numbers of animals or a priori defined hypotheses.”
    6. Both the U.S. Food and Drug Administration (FDA) and the European Food Safety Agency (EFSA) have concluded that even in cases where biological responses are detected, not all observations at low doses are necessarily adverse, or precursors to adverse effects, in living organisms.
    7. A peer-reviewed commentary analyzing a recent paper from proponents of the low dose hypothesis concluded that the authors had clearly overstated the scientific evidence.The scientific weaknesses of this paper included:
      • Inappropriate, selective citation of studies “without examining whether their putative examples are consistent and coherent with other relevant information.”
      • Assuming that “any statistically significant association indicates causation of an adverse effect.”
      • Failure to evaluate all studies equally and the lack of uniformity in the evaluation of specific studies (i.e., studies with positive results are evaluated differently than those with null results).
      • Lack of documentation as to whether “exposures in studies are truly ‘‘low-dose’’ and relevant to humans.”
      • A large number of examples presented “would be – and indeed have been – questioned by many scientists.”

An issue that is often confused with the low-dose hypothesis, but which should be considered separately, is “non-monotonic dose-response relationships.” In most toxicity testing of chemicals it is understood that the higher the dose of a chemical, the greater the effect and the likelihood of an adverse effect. Non-monotonic dose-response curves are produced when the response is increasing with the dose at some points and decreasing as the dose increases at others. This can result in U-shaped curves or other irregular patterns. In its opinion, EFSA recommends that these relationships should be the subject of future scientific activities. However, EFSA notes that these effects are not unique to endocrine active substances and should be considered across the spectrum of chemical substances.

A more recent (2017) NAS report – without endorsing either the “low-dose hypothesis” or NMDRs but acknowledging disagreements among scientists – recommends a three-pronged strategy to the EPA for evaluating the possibility of low dose effects. The strategy recommends that EPA adopt a process for monitoring, investigating, and taking appropriate action. The report acknowledges that EPA is already practicing elements of this strategy, but that they should bring more focus to it for evaluating chemicals that might cause adverse effects at low doses.