A condensed version of this post was originally published on The Conversation with the title “Can low doses of chemicals affect your health? A new report weighs the evidence.“
Toxicology’s founding father, Paracelsus (1493-1541), is famous for his paraphrased proclamation: “the dose makes the poison.” This phrase represents a pillar of traditional toxicology: Essentially, chemicals are harmful only at high enough doses.
Standard toxicity tests don’t always detect the effects that chemicals can have at lower levels. There are many reasons for this shortcoming, including a focus on high dose animal testing as well as failure to include endpoints relevant to low dose disruption. And, even when the data do suggest such effects, scientists and policymakers may not act upon this information in a timely manner.
Recognizing these challenges, the U.S. Environmental Protection Agency (EPA) asked the National Academy of Sciences convene a committee to study the issue in detail. How can we better identify whether chemicals have effects at low doses? And how can we act on this information to protect public health?
After several years of work, the committee’s report was released in July. This landmark report provides the EPA with a strategy to identify and systematically analyze data about low-dose health effects, as well as two case study examples. It is an evidence-based call to action, and scientists and policymakers should take notice.
Delving into definitions
Before discussing the report, let’s review some definitions…
We know that animal experiments usually use high doses, but in comparison, what is a “low dose?”
This issue was a matter of considerable debate, but ultimately, the committee decided to proceed with a fairly general definition of low dose as “external or internal exposure that falls with the range estimated to occur in humans.” Therefore, any dose that we would encounter in our daily lives could be included, as well as doses that would be experienced in the workplace.
The committee also clarified the meaning of “adverse effects.” When a chemical produces a visible malformation, it is easy to conclude that it is adverse. But, when a chemical causes a small change in hormone levels, it is more difficult to conclusively state that the change is adverse. Are all hormone changes adverse? If not, what is the threshold of change that should be considered adverse?
In this context, an adverse effect was defined as “a biological change in an organism that results in an impairment of functional capacity, a decrease in the capacity to compensate for stress, or an increase in susceptibility to other influences.”
A strategy to identify low dose toxicity
With these semantics settled, the committee developed a 3-part strategy to help with timely identification, analysis, and action on low-dose toxicity information:
(1) Surveillance: Active monitoring of varied data sources and solicitation of stakeholder input can provide information on low dose effects of specific chemicals, especially since EPA’s standard regulatory testing framework may not always identify such effects. Human exposure and biomonitoring data should also be collected to help define relevant exposure levels of concern across the population.
(2) Investigation & Analysis: Systematic review and related evidence integration methods can be used to conduct targeted analysis of the human, animal, and in vitro studies identified in the surveillance step. Each of these approaches has different strengths and weaknesses, so examining the evidence together offers insight that a single approach could not provide.
(3) Actions: New evidence can be incorporated into risk assessments or utilized to improve toxicity testing. For example, protocols could be updated to include newly identified outcomes relevant to endocrine disruption.
Leading by example: systematic review case studies
To put their strategy into practice, the committee conducted two systematic reviews of low dose EDC effects.
The first case study looked at phthalates, chemicals that increase the flexibility of plastic products such as shower curtains and food wrapping.
The committee found that diethylhexyl phthalate and other selected phthalates are associated with changes in male reproductive and hormonal health. Overall, the data were strong enough to classify diethylhexyl phthalate as a “presumed reproductive hazard” in humans.
The second case study focused on polybrominated diphenyl ethers (PBDEs), flame retardants used for over 30 years. Though they are now being phased out, these chemicals remain a concern for humans. They are still present in older products and can persist in the environment for many years.
Based on data showing the impact of these chemicals on learning and IQ, the panel concluded that developmental exposure is “presumed to pose a hazard to intelligence in humans.”
Questions and challenges for the future
During its review, the committee encountered a variety of barriers that could impede similar investigations into specific chemicals.
First, when reviewing evidence, it’s important to assess any systematic errors – also known as biases – that might have led to incorrect results. These errors can arise from study design flaws, such as failure to properly blind the researchers during analysis.
Some journals have strict guidelines for reporting details related to bias, but many do not. Better adherence to reporting guidelines would improve scientists’ ability to assess the quality of evidence.
Second, the committee noted a discrepancy between the concept of doses used in human and animal studies, which made it difficult to compare data from different sources.
For example, most toxicologists simply report the dose that they delivered to animals. But some of that administered dose might not actually be absorbed. The actual internal dose of chemical circulating in the body and causing harm may differ from the amount that was administered. By contrast, epidemiologists usually think about dose as the level of chemical they detect in the body, but they may not know how much of the chemical an individual was actually exposed to.
Biological modeling techniques can help scientists draw the connection between administered and internal doses and more closely compare results from animal and human studies.
Finally, many toxicology studies focus on only a single chemical. This is a valuable way to identify how one chemical affects the body. However, given that we are all exposed to chemical mixtures, these procedures may be of limited use in the real world.
The committee suggested that toxicologists incorporate real-world mixtures into their studies, to provide more relevant information about the risk to human health.
Leveraging toxicity testing for answers about low dose effects
This report demonstrates one of the challenges facing the field of toxicology and environmental health: How well can existing and emerging laboratory techniques predict adverse outcomes in humans? (If you’ve read some of my previous posts, you know that this issue is of particular interest to me.)
Traditional animal experiments usually use high doses, which don’t necessarily reflect the real world. These studies can be an important first step in identifying health hazards, but they cannot accurately predict how or at what levels the chemicals affect humans. The committee noted that more relevant doses and better modeling could help mitigate this problem.
Emerging high-throughput testing techniques use cell-based methods to detect how a chemical changes specific molecular or cellular activities. These newer methods are increasingly used in toxicology testing. They have the potential to quickly identify harmful chemicals, but have yet to be fully accepted or validated by the scientific community.
For these two case studies, the committee noted that high-throughput tests were not particularly helpful in drawing conclusions about health effects. Many of these studies are narrowly focused – looking at, for example, just a single signaling pathway, without indicating a chemical’s overall influence on an organism. Nevertheless, these methods could be used to prioritize chemicals for further in-depth testing, since activity in one pathway may predict a chemical’s capacity to cause harm.
Putting the report into action
Despite the imperfections of our testing methods, there’s already ample evidence about low-dose effects from many chemicals (including the two cases studies from the committee). The EPA should implement this new strategy to efficiently identify and act on problematic endocrine-disrupting chemicals. Only through such strong, science-based efforts can we prevent adverse effects from chemical exposures – and allow everyone to live the healthy lives that they deserve.