Background: Terms and Concepts
Explanation and exploration of few key concepts and terms relevant to the discussion of endocrine disruptors and their effects. Written by Ben Lemmond.
Additive and Synergistic Interaction
In almost every environment outside of the laboratory, people and animals are exposed to a mixture of several chemicals at once. How do we describe the overall effects of the mixture, since each substance may possess different effects and different potency?
Interactions between chemicals can be categorized as: synergistic, where the total effect of a mixture of chemicals is more than the sum of the individual effects; additive, where the effects of the mixture is the sum of the individual effects. Also, interaction can occur where the total potency of a mixture is less than the sum of individual potencies.
These interactions can occur in many ways. Sometimes, one chemical affects certain enzymes that detoxify (or in some cases, activate) another chemical. Some endocrine disruptors reduce the levels of certain hormones, so that an increase in another hormone that is normally maintained in balance with the reduced hormone causes the overall effect (hormone imbalace) to be more potent than the effect of individual changes in hormone levels caused by one single chemical.
Many endocrine disrupting chemicals appear to have additive and sometimes synergistic interactions with each other. This further highlights the importance of evaluating chemicals as environmentally-relevant mixtures, instead of studying chemicals in isolation.
Bioaccumulation
Small levels of chemicals found in environmental media – soil, air, and water – are absorbed by plants and animals at the bottom of the food chain. When predators eat these animals, they ingest all the toxins that have accumulated in their food, and as these chemicals move up the food chain they become more and more concentrated. Since humans are at the top of the food chain, all of the toxic chemicals that accumulate in our food end up in our bodies at much higher concentrations than those found in the environment. This is how we are exposed to chemicals that are found in minute quantities in the environment, even chemicals that are no longer used or heavily regulated – such as dioxins, DDT, PCBs, pesticides, mercury, and others.
What is a 'metabolite'?
A metabolite is a chemical that is produced as another chemical is broken down, or 'metabolized', by the body. In some cases, these breakdown byproducts are more toxic or toxic in a different way than the parent compound. For example, DDE is the principle product of the body's attempt to break down DDT, the infamous pesticide banned in 1972. DDE is a known endocrine disruptor with anti-androgenic properties, while DDT is a weakly estrogenic chemical (mimics the natural estrogen hormone in organisms).
How are ‘safe’ levels determined?
The standard practice for determining ‘safe’ levels of certain chemicals involves finding the most relevant animal and/or human studies of that chemical, determining the level of exposure at which no effect was observed, and dividing the amount of that exposure by one or several ‘uncertainty factors’ to account for the shortcomings of the study used (for example, lack of adequate studies in humans or lack of studies of long-term effects). The result: a level considered (but not guaranteed) to be adequately protective of humans.
While this process is logical and justifiable in many ways, there are many important shortcomings of the process itself that deserve mention. Obviously, the studies chosen influence the results - and studies do not always measure every possible effect of a chemical, and sometimes they miss the dose range of these effects completely. This flaw is becoming increasingly apparent as knowledge of endocrine disruption improves, since many of the effects of endocrine disruptors are in fact more pronounced at extremely low doses.
Dose-Response
In toxicology, a key step in determining a causal link between an exposure to a certain chemical and an adverse health effect is being able to mathematically describe the relationship between the independent (dose) and dependent (response) variables - in other words, being able to describe this relationship as a function, or by using a graph to plot the values of the independent and dependent variables as coordinates (x amount of dose produces y amount of effect). This graph is called a "dose-response curve". Traditional dose-response curves have a sigmoidal (or "S-shaped") curve - which translates, practically, into a dose-response relationship where at the low and high ends of exposure, incremental changes in exposure produce less and less of a change in effect. Graphically, this appears as a curve flattening out at the low and high ends of dosage, with a steep curve in between. However, many endocrine disruptors do not follow this type of dose-response pattern. Many, in fact, defy some of the most basic generalities of dose-response relationships - namely, that higher doses produce more effects. Many endocrine disruptors are more active at low doses; some even produce opposite effects at lower and higher doses (relative to a central, baseline effect dose).
So far, there is much information available about specific cellular mechanisms, but major gaps remain in understanding the implications of the cellular responses to EDCs for the whole organism, implying that we need a better understanding also of the pharmacokinetics of EDCs (see Kavlock et a. 1996, for a more detailed review).
Additionally, political pressure to ignore data of low-dose effects for chemicals such as BPA, which have major economic significance, has led to exclusion of many of these studies from the regulatory assessments of these chemicals. Our current regulation for BPA is largely based off of 3 studies published before 1988 that do not test low doses of BPA (therefore ignoring the evidence, which amounts to hundreds of studies, showing low-dose effects and non-monotonic dose-response curves for BPA).
