In 2017 the National Academies of Sciences, Engineering, and Medicine (NAS) published a report that it developed for the U.S. Environmental Protection Agency (EPA) to evaluate the evidence that chemicals are capable of causing health effects at low-doses. 

For this exercise, the NAS committee chose to define low dose as “…external or internal exposure that falls within the range estimated to occur in humans,” and only lightly touched on the separate, but related, topic of non-monotonic dose response curves (NMDRs).  

Low dose effects and NMDRs are often confused as they are frequently discussed together, e.g. in reference to the non-monotonic, low-dose hypothesis – the idea that the slope of the dose-response curve for some chemicals changes direction at low doses.

Before we can really dig into the NAS report on lose dose effects, first, it’s important to elaborate on this distinction. I will then explain how the NAS Low Dose committee report offers modest, but sound, guidance to the EPA regarding the use of systematic review and evidence integration to assist in the Agency’s hazard assessments and to evaluate the potential for chemicals to cause low dose effects.

Monotonic vs. non-monotonic dose response curves

A conventional assumption of toxicology is that the dose-response relationship between a chemical and an adverse health effect will have a monotonic shape: that is, the slope of the curve does not change sign. 

On the other hand, non-monotonic dose response curves change sign at one or more inflection points. In the case of chemicals that are purported to exhibit a U-shaped curve, effects are suspected to be more prominent at low and high doses than they are at intermediate doses.  

Some scientists have expressed a concern that evidence for such curves could be missed if the doses tested are not low enough, or if not enough doses are tested to reveal such a shape.

Although this non-monotonic, low-dose hypothesis is often discussed in relation to endocrine-related science, scientists at regulatory agencies across the globe, including the EPA and European Food Safety Authority (EFSA), have argued that the hypothesis could, in theory, apply to all chemicals, regardless of the mechanism by which they cause toxicity.

Some of those same regulatory agencies also have conducted rigorous reviews and have been unable to validate the non-monotonic, low-dose hypothesis using reproducible, relevant testing. 

For example, in 2013, EPA issued a draft report, State of the Science Evaluation: Nonmonotonic Dose Responses as They Apply to Estrogen, Androgen, and Thyroid Pathways and EPA Testing and Assessment Procedures, to evaluate the evidence on NMDR curves and to make judgments about EPA’s toxicity-testing practices and the implications for its risk-assessment procedures. The draft concluded that exposure to endocrine active chemicals (EACs) can result in NMDR curves for specific end points and that such curves were found more often in in vitro studies, at high doses, and for exposures of short duration. It also asserted that there was insufficient evidence that NMDR curves for adverse effects occur below thresholds derived from traditional toxicity testing.  

This lack of evidence is not surprising, however, since the non-monotonic, low-dose hypothesis runs contrary to the well-established principle of dose-response relationships. In other words, “the dose makes the poison; dose differentiates a poison from a remedy.” This principle is the cornerstone of drug development in modern pharmacology as well as safety assessment in modern toxicology.

Request to evaluate evidence of low-dose adverse effects via endocrine mediated pathway

At the request of the EPA, the NAS convened an ad hoc committee of experts to make recommendations for a strategy to evaluate evidence of low-dose adverse human effects that act through an endocrine mediated pathway

Unfortunately, the report mistakenly conflates endocrine activity with endocrine disruption and thus ignores the well-accepted WHO/IPCS definition of an endocrine disruptor, which requires making a distinction between mere activity and consequent causal effect.

Nevertheless, the committee was requested to perform systematic reviews of animal and human evidence for at least two chemicals and demonstrate how the results can be integrated and considered with other relevant data to draw conclusions about causal associations. 

The two systematic reviews address animal toxicology and human epidemiology evidence linking exposure to:

  • some phthalates to selected male reproductive disorders and diseases, and
  • some polybrominated diphenyl ethers (PBDEs) to selected neurobehavioral deficits and diseases.

Three key NAS low-dose report recommendations

The NAS Low Dose committee report makes some modest, but sound, recommendations to the EPA about an overall strategy for evaluating the potential for chemicals, including those that are endocrine active, to cause low dose effects. 

More specifically, the committee outlines how the EPA can use systematic review and evidence integration methods to assist in its hazard assessments. The strategy comprises three broad phases:

  1. Surveillance: described as detecting signals by searching, retrieving and re-evaluating existing data to look for evidence that a chemical may cause a health effect at low doses or that a health effect may have been missed by traditional toxicity testing methods;

  1. Investigation and analysis of the evidence: the agency should analyze existing data, generate new data to fill gaps, conduct a systematic review of evidence, and integrate evidence from human and animal studies. An additional recommendation was to conduct meta-analysis, combining data from individual studies, if appropriate. One or more of these options might be needed to answer questions about potential signals.

  1. Actions to take based on the evidence: possible actions include updating chemical assessments, regularly monitoring for new data, requiring new data or models to reduce uncertainties, or updating toxicity-testing designs and practice.Additional considerations, such as the public health significance and available resources, would also factor into the decision making.

The NAS report acknowledges that, while EPA is already conducting many activities consistent with this strategy, its efforts may not be aimed specifically at evaluating low-dose toxicity.

NAS committee makes three additional recommendations to EPA

Based on its experience conducting the two systematic reviews, the NAS committee made three further recommendations:

  1. Systematic reviews should include meta-analysis of the animal and human evidence, if appropriate. The results of meta-analyses should be used to examine quantitative relationships between EACs and end points of interest to inform the confidence ratings of the bodies of evidence, and, if possible, to estimate benchmark doses.

  1. EPA should develop policies and procedures to allow the agency to use and update existing systematic reviews. It is important that the existing systematic review’s study question directly addresses EPA’s topic of interest and that the methods are critically evaluated before the systematic review is used and updated.

  1. Do more to support animal-to-human extrapolations. Pharmacokinetic data should be generated and used to develop models that make it possible to infer human internal doses (not just intake) from biomonitoring data and animal internal doses from administered doses.

With respect to the two case studies referenced above, the report repeatedly makes the point that existing toxicology methods did identify the hazard, but that they might not accurately predict the level of exposures at which humans are affected. This is because the animal toxicology studies measured the administered (i.e., external) dose, whereas the human studies (exposure biomonitoring and/or epidemiology) measured the internal dose. 

The report is careful to note that the committee made no effort to conduct a risk assessment using the outcome of the case studies, and so their work was limited to assessing hazard potential only. 

Concluding thoughts

In conclusion, the NAS Low Dose committee report makes some modest, but sound, recommendations to the EPA about an overall strategy for evaluating the potential for chemicals, including those that are endocrine active (EACs), to cause low dose effects. More specifically, the committee outlines how the EPA can use systematic review and evidence integration methods to assist in its hazard assessments. 

As I have pointed out in this blog and in an earlier blog, systematic review has some obvious advantages in terms of improving transparency and objectivity in assessing the totality of relevant evidence applied to resolving environmental health questions.

However, it remains a highly subjective process, and further experience and discussion are needed to improve the methodology.