In March 2012, the top-ranked scientific peer-reviewed journal Endocrine Reviews published a scientific review article “Hormones and Endocrine-Disrupting Chemicals: Low-Dose Effects and Nonmonotonic Dose Responses”. Twelve scientists from different disciplines reviewed the body of scientific literature concerning two issues. Firstly, they were interested in how so called non-monotonic dose responses (NMDR) were observed. NMDRs are a mathematical phenomenon in toxicology, when the biological response of a cell, tissue or whole organism does not increase with an increasing dose, but when the slope of the response curve changes its sign (e.g. from positive to negative, or vice versa). This observation is considered highly unusual because in toxicology, until now, it has been assumed that “the dose makes the poison”—and in mathematical terms that implies for the dose response relationship to have either a negative OR a positive slope (but never both). In conclusion, NMDRs were found to be common, however often considered to be statistical flukes, and possibly discounted for this reason. The authors therefore urge researchers to include more (low) doses in studies when a possible NMDR is observed.
The second question under investigation was whether low doses of selected chemicals could be linked to adverse effects in various scientific studies. For this purpose the authors defined “low dose” and then performed a weight of evidence analysis for each of the 5 different substances, asking a set of questions that studies needed to adhere to for highest ranking. In particular, the relevant questions were:
- Does the test system respond to hormones? For example, this could mean that a positive control was included in the study design.
- Does the test system respond to low doses (of hormone, test chemical)? Low doses were defined as either doses below the currently established no observed adverse effect level (NOAEL) or levels of known human exposure (from biomonitoring studies).
- Is the test system free from contamination? For example, contamination may occur due to feed containing natural EDCs (soya).
- Have findings been reproduced in different labs? Reproduction of a finding can be considered verification, if the exact same study design was chosen.
In conclusion, the authors found sufficient scientific evidence for low dose effects in four of the five case studies:
- for bisphenol A and effects on the prostate,
- bisphenol A and effects on the mammary gland
- atrazine and amphibian sexual development and
- dioxin and spermatogenesis.
In one case, perchlorate and the thyroid system, there was not sufficient evidence to conclude low dose effects in humans, with the perfomed weight of evidence analysis.
From their extensive analysis the authors conclude that “Whether low doses of EDCs influence certain human disorders is no longer conjecture, because epidemiological studies show that environmental exposures to EDCs are associated with human diseases and disabilities. We conclude that when nonmonotonic dose-response curves occur, the effects of low doses cannot be predicted by the effects observed at high doses. Thus, fundamental changes in chemical testing and safety determination are needed to protect human health.”
An opposing view was recently published by Lorenz Rhomberg and Julie Goodman “Low-dose effects and nonmonotonic dose–responses of endocrine disrupting chemicals: Has the case been made?”. The authors of this commentary reject the conclusions from the Vandenberg Review as anecdotal because of selectively cited studies. According to Rhomberg and Goodman, Vandenberg et al.’s one-sided view lacks sufficient evidence to be accepted as general phenomenon.
The director of NIEHS (National Institutes of Environmental Health Sciences), Linda Birnbaum, wrote in a recent commentary that research needed to move forward by including low doses of suspected EDCs and examining a wide range of biological endpoints. She stated that “It is time to start the conversation between environmental health scientists, toxicologists, and risk assessors to determine how our understanding of low-dose effects and nonmonotonic dose responses influence the way risk assessments are performed for chemicals with endocrine-disrupting activities. Together, we can take appropriate actions to protect human and wildlife populations from these harmful chemicals and facilitate better regulatory decision making.”
A first step in this direction was taken mid-September 2012, when academic scientists, regulatory experts and industry decision makers met for a workshop on the low dose issue in Berlin. A report of the workshop is expected soon.
Fagin, D. (2012). Toxicology: The learning curve. Nature 490, 462–465 (25 October 2012)