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Endocrine Disrupting Compounds

Posted By Kevin Connor (ARCADIS-US) and Dan Petersen (USEPA), Tuesday, April 03, 2012

Background

The attention given to endocrine disrupting compounds (EDCs) is not new, dating back at least to the early 1990s and the release of Theo Colborn’s Our Stolen Future, which highlighted the concerns over environmental chemicals with the estrogenic activity. Initiatives to screen chemicals for endocrine or endocrine-like activity soon followed, but were prolonged for several years because of concerns over the reliability, specificity, and significance of the available tests and screening assays. Currently, the U.S.EPA Endocrine Disruptor Screening Program (EDSP) is underway, designed to screen numerous industrial chemicals for estrogenic, androgenic or thyroid hormone-like activities. Yet, according to EPA, the science related to measuring and demonstrating endocrine disruption is [still] relatively new and validated test methods are still being developed (www.epa.gov/endo).

With the ongoing addition of chemicals to the list of potential EDCs, and with results from the first phase of testing forthcoming, new questions are arising over the significance of the Tier 1 screening assays (e.g., binding to estrogen receptor) and how to interpret and communicate the data.

Bringing additional recent attention to EDCs, as a subdiscipline of toxicology and risk assessment, are the following developments:

  • The USEPA Endocrine Disruptor Screening Program (EDSP) is expanding its reach beyond pesticides, to include new chemicals, and as part of this effort, the Agency is seeking public comment on a variety of issues.
  • Recent studies in China have reported lowered sperm counts in Chinese workers with exposures to bisphenol-A (BPA), one of the originally named environmental estrogens.
  • U.S.EPA selected modulation of neonatal thyroid hormone levels (T4 and TSH) and lowered sperm quality as critical effects in the 2009 Dioxin Reanalysis; and used the data on these effects to derive the draft Reference Dose (RfD).

Objective for a Work Group

The objective of this Work Group would be to consider new topics and ideas under the EDC subheading which are relevant to human health risk assessment, and to promote ideas through SETAC, possibly even sponsoring or implementing research and analyses that could advance the human health risk assessment of potential EDCs.

This Work Group would endeavor to bring new light to the current state of the science, and would avoid repeating the work of previous groups, such as that by the former EDSTAC (Endocrine Disruptor Testing and Advisory Committee) under USEPA. The means for achieving this objective would include proposing technical sessions and symposia on current topics, proposing research, sponsoring sessions to attract research and analyses, and perhaps by conducting some research and reviews/analyses ourselves.

Prospective Technical Topics

  • How to define the scope of the issue: It is clear that the focus on EDCs has expanded greatly beyond environmental estrogens, to androgens, progestins, and thyroid hormones. However, there are also clear limits (a substance that raises insulin (a hormone) levels (e.g., table sugar) should not warrant attention as an EDC. Also, are only direct effects to be considered (e.g., binding to a steroiiod hormone receptor, or can the induction of P450s that act on estrodiol be as relevant?
  • Selection of candidate compounds. Should there be some prerequisite to becoming a compound of interest? Are the exemptions from testing valid? How has the case been made to exclude a chemical from Tier 1 testing? How are new chemicals selected as candidates for screening? QSARS, or more fundamental structural considerations?
  • Screening tests. Can we draw any conclusions from initial tests? Are the tests producing surprises, and likely false positive?. False negatives? Do tests really need to be high-volume, high-throughput? (Are there that many EDCs out there?)
  • Tier 2 testing and beyond. How is endocrine disruption to be judged, since hormones are in constant state of flux? Can it be argued that any health hazards identified by the EDSP are already addressed by other routine tests in reproductive and development toxicology?
  • An estrogen equivalency (EEQ) approach to risk assessment: There would be a host of technical issues to confront, e.g., pharmacokinetic differences between exogenous vs. endogenous estrogens. If numerous vegetable-derived compounds have significant EEQs, how do we reconcile these background exposures and the supposed hazards of weakly estrogenic industrial chemicals? Could a database of relative potency (REP) data be developed?
  • More traditional approaches to risk assessment, e.g., margin of safety approach. Such approaches have their own set of challenges. What level of endocrine modulation represents an adverse effect?
  • How are the potential hazards to be communicated to the public? Are they "real-world" hazards? Do we need human correlates to verify effects observed in vitro, and biological correlates to believe effects reported in human populations? Many have raised the question, is endocrine disruption a mechanism, and not an endpoint? Is there merit to this question? Do EDCs warrant a separate classification in toxicology?

Tags:  EDCs  endocrine disrupting compounds  Human Health 

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Risk Assessments of Dissimilar Mixtures

Posted By Mark Richardson (SNC. LAVALIN), Tuesday, April 03, 2012

Background

The toxicity of constituents is not always independent when they are present in mixtures. The scientific literature has an increasing assortment of research articles concerning the interactive toxicological effects of chemicals. Increasingly, agencies such as the EPA and ATSDR are formulating guidance on how to assess mixtures. In human health risk assessment, we routinely consider mixtures of polycyclic aromatic hydrocarbons (PAHs), polychlorinated biphenyls (PCBs), and dioxins and dioxin-like compounds – all families of compounds with similar chemical structure and toxicity and for which international concensus has been reached on a means of mixture risk assessment. . However, it is becoming increasingly apparent that mixtures of substances with dissimilar chemical structure may have similar modes of action, similar target organs, and similar toxic effects. As such, these mixtures warrant an effective evaluation of interactions.

Recently, it was shown that elemental mercury, methyl mercury, and lead should be evaluated as a mixture with toxicological interactions, when co-exposure is confirmed or assumed (SNC-Lavalin Inc 2010). That report can be downloaded from the US FDA at: http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMateria...

Objective for a Work Group

The objectives of this Work Group will be established once the working group initiates its activities. However, likely issues of focus will include new topics and ideas related to evaluating dissimilar mixtures when conducting human health risk assessments, and to promote SETAC sponsorship of research and analyses that will advance the human health risk assessment of dissimilar mixtures.

Technical Approach

Initially, the working group will work to identify methods for grouping dissimilar metals into relevant categories for evaluation of toxicological interactions (perhaps based on target organ, mechanism of action, frequency of co-occurrence in the environment, etc), and then begin the process of identifying and compiling data and published studies relevant to preparing interaction profiles.

Tags:  Human Health Toxicity Mixtures PHAs PCBs 

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