Endocrine Disruptors

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Fate and Transport in the Environment

Methods for Monitoring in the Environment

Methods for Measuring Human Exposure

Exposure Pathway

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PCBs - Harmful Effects

PCBs - Dose Response

Sites of Toxicity

Mechanisms of Toxicity

Toxicokinetics

Biomarkers

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PCBs – Dose Response

The issue of dose-response relationships is perhaps the most controversial issue regarding EDCs. One of the reasons is that EDCs often act by mimicking or antagonizing the actions of naturally occurring hormones. These hormones (often more potent than exogenous EDCs) are present at physiologically functional concentrations, so the dose-response considerations for EDCs are often different than for other environmental chemicals, which are not acting directly on the endocrine system. Evaluation of dose response data should not be considered complete until after examining several sources of data (ex. toxicity studies, epidemiologic studies, and field studies.) The following list outlines major points to considered prior to beginning a study or evaluating results, in both animal or human populations.

  • Selection of dose categories must include both toxic and mechanistic endpoints.
  • A very concise and clear understanding of the mechanism of toxicity is essential. Many EDCs show biphasic dose response curves, which make results more open to criticism if the method of disruption is not established.
  • Low dose effects of EDCs are terribly scrutinized because of the debate over whether there are adequate testing methods to accurately measure and record them.
  • Timing of exposure is critical for understanding dose response relationships in EDCs. Numerous studies exist where age of exposure is known risk factor. Some examples of things to consider are differences between developing brain and fully differentiated brain, and differences between breeding seasons.
  • Individual differences throughout the population can affect how the body reacts to different exposures (ex. age, sex, diet, disease state).
  • A common dose response relationship for all effects and for all endocrine disruption mechanisms should not be expected. This conclusion is based on the knowledge that there are many different kinds of hormonal actions of chemicals categorized as endocrine disruptors. These activities include estrogenic, antiestrogenic, antiandrogenic, growth factor modulation, cytokine and thyroid modulation, modulation of hormone metabolism, and many others.



Definitions

  • MRL – minimum risk level is an estimate of daily human exposure that is likely to be without an appreciable risk of adverse effects (noncarcinogenic) over a specified duration of exposure.
  • CEL - cancer effect levels are of exposure associated with carcinogenic effects (shown in Table 3-2 and Figure 3-2 in the ATSDR web site above)
  • NOAEL – level of exposure indicating no-observed-adverse-effect
  • LOAEL – level of exposure indicating lowest-observed-adverse-effect
    • "Less serious" effect - not expected to cause significant dysfunction or death, or significance to the organism is not entirely clear
    • "Serious" effect - evokes failure in a biological system and can lead to morbidity or mortality
    • The distinction between serious and less serious is important because it can help identify at what dose major health effects occur, although the classification is subjective.

The following graphs are just a very small example of existing studies done supporting positive associations between PCBs and adverse health effects.


This graph shows a positive relationship between estimated individual amounts of the rice oil intake and case severity of Yusho.


Among other things, this graph shows a significant dose-dependent reduction in the cleavage percentage with increasing doses of PCB. This graph was presented in a study looking at the reproductive toxicologic effects of PCBs on the maturation and fertilization of oocytes and on the preimplantation phase of embryo development. Source: Krogenæs AK, Nafstad I, Skåre JU, Farstad W, Hafne AL. 1998. In vitro reproductive toxicity of polychlorinated biphenyl congeners 153 and 126. Reproductive Toxicology 12(6): 575-580.

The following graph shows dose-response data from rats on carcinogenicity with oral exposures. The human equivalent dose is also provided as a reference point.


Tumor Type -- Liver hepatocellular adenomas, carcinomas, cholangiomas, or cholangiocarcinomas
Test animals -- Female Sprague-Dawley rats
Route -- Diet
Reference -- Brunner et al., 1996; Norback and Weltman, 1985
Administered
Dose (ppm) Human Equivalent Dose (mg/kg)/day Tumor
Incidence

Table to be added here:

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