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Endocrine disruptor screening program background

With the introduction of the endocrine disruptor screening program (EDSP), an ever increasing number of questions have arisen. Understanding that you do not have the luxury of a misstep at this stage of the regulatory process, Envigo is here to support you with answers to those questions, a suite of EDSP assays and guidance through the development process.  Envigo has been part of the EDSP since the beginning, and we follow developments each step of the way.

Because we worked with the EPA on some initial testing programs, Envigo is positioned to help you navigate your way through the EDSP. We are your trusted ally at all points in the EDSP process by answering your questions, helping you to arrive at a strategy, providing testing and giving you the regulatory support you may need.

 

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If you have a compound on the lists released by the EPA that are eligible for screening, you have 90 days in which to indicate your proposed response:

  • Withdraw
  • Cite existing data
  • Form consortia
  • Test

If you have decided to test, then you have two years in which to complete the testing and submit the new data.

The EPA will review existing data and newly submitted data before making a determination whether the compound will have to proceed to tier two testing.

In many cases, companies or consortia submitted waivers (OSRI: other scientifically relevant information) based on existing data. Apart from agreement in some cases to waive specific tests for which relevant data were already available, waivers were generally rejected as the existing studies did not address the required endpoints.

In 2009, the EPA published the first list of 67 chemicals that may affect the endocrine system along with test orders to determine their presence. In 2013, the agency published a second list of 109 additional chemicals, 41 of which are pesticide active ingredients (PAIs) and 68 are chemicals identified under the safe drinking water act (SDWA). The EPA has not yet issued the test orders for these chemicals.

If you are not sure how EDSP affects you, here is a list of FAQs to help you determine your needs:

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According to the definition adopted by the Environmental Protection Agency in 1997:

Kavlock et al. (1996) published the EPA definition of an endocrine disruptor as: "an exogenous agent that interferes with the synthesis, secretion, transport, binding, action, or elimination of natural hormones in the body which are responsible for the maintenance or homeostasis, reproduction, development and or behaviour."

Consistent with this definition, the Agency has also stated that it "...does not consider endocrine disruption to be an adverse effect per se, but rather to be a mode or mechanism of action potentially leading to other outcomes, for example carcinogenic, reproductive, or developmental effects, routinely considered in reaching regulatory decisions. Evidence of endocrine disruption alone can influence priority setting for further testing and the assessment of the results of this testing could lead to regulatory action if adverse effects are shown to occur."

The current Agency position is consistent with a broad definition of endocrine disruption that must entail research questions. However, the EPA also recognizes that regulatory decision-making is generally based on adverse effects using legislatively mandated risk-based criteria.

In the EU, the regulatory definition of an endocrine disruptor in relation to potential threat to human health described within the Final Joint DE-UK position paper dated 13 May 2011 is: “An endocrine disrupter is an exogenous substance or mixture that alters function(s) of the endocrine system and consequently causes adverse effects in an intact organism, or its progeny, or (sub)populations.”

The EU definition embodies two key elements on which one can build criteria for identifying an endocrine disruptor of regulatory importance: adversity and intact organism observations.

With regard to adversity, it is proposed that the global and widely accepted definition produced by WHO/IPCS in 2004 is used to determine whether effects caused by exposure to a chemical are adverse:

“A change in morphology, physiology, growth, reproduction, development or lifespan of an organism which results in impairment of functional capacity or impairment of capacity to compensate for additional stress or increased susceptibility to the harmful effects of other environmental influences (WHO/IPCS 2004).”

The endocrine system is responsible for controlling many functions of the body including immediate and life-long functions. Hormones stabilize or balance functions in the normal body; the levels of hormones are influenced by stimuli and are regulated by biological feedback systems. Any disruption to the balance and feedback systems can cause unwanted and undesirable changes particularly in reproduction, development and growth.

Endocrine disrupting chemicals can disrupt endocrine systems in different ways:

  • They can mimic a natural hormone and lock onto a receptor within the cell. The disruptor may give a signal stronger than the natural hormone, or a signal that occurs at the "wrong" time
  • They can bind to a receptor within a cell and thus prevent the correct hormone from binding. The normal signal then fails to occur and the body cannot respond properly
  • The disruptors can interfere or block the way natural hormones and receptors are made or  controlled. This interference or blockage may occur only if relatively large doses of the substance are present

If the endocrine disruptor stimulates or inhibits the endocrine system, then increased or decreased amounts of hormone may be produced. In some cases, even very small amounts of a disruptor may have a detectable effect. In addition, small amounts of different endocrine disruptor chemicals may have a cumulative effect. In some cases the by-products of the chemicals may have greater harmful effect than the parent chemical. (1)

(1)Canadian centre for occupational health & safety (http://www.ccohs.ca/oshanswers/chemicals/endocrine.html#_1_3).

The endocrine disruptor screening program is the result of a long regulatory process from concern to concept to legislation. The real legislative process kicked off in 1996, the first testing proposals issued in 2009 and the second set of proposals in 2014.

The screening program itself comprises two tiers of testing:

  • Tier one identifies the chemicals which have the potential to interact with the endocrine system.
  • Tier two determines the endocrine-related effects and establish the dose at which the effects occur.

Manufacturers of chemicals on the list may:

  • Submit a request for voluntary cancellation of the registration
  • Cite or submit existing data to EPA
  • Generate new data

Once a manufacturer has received a testing order, they have 90 days to submit their response to the EPA indicating what their plan of action will be. If the manufacturer decides to generate new data, they have two years to complete the testing and submit the resultant data. Several manufacturers of the same chemical may form a consortium with other parties to share the burden of cost. If a manufacturer has decided to go for either of the first two options, the EPA, upon completion of review, will decide whether to ask for additional Tier 2 testing.

It had been proposed that certain chemicals might be disrupting the endocrine systems of humans and wildlife. Some chemicals had been found to disrupt the endocrine systems of animals in laboratory studies, and evidence showed that endocrine systems of some fish and wildlife had been affected by chemical contaminants resulting in developmental and reproductive problems.

Due to these concerns, the US Congress passed the Food Quality Protection Act and the Safe Drinking Water Act (SDWA) Amendments in 1996 requiring that EPA screen pesticide chemicals for their potential to produce effects similar to those produced by the female hormones (estrogen) in humans and gave the EPA the authority to screen certain other chemicals and to include other endocrine effects. Since then, the EPA has expanded the EDSP to include male hormones (androgens) and the thyroid system, and to include effects on fish and wildlife. (1)

(1)http://www.epa.gov/endo/

In vitro

  • Estrogen and androgen receptor binding assays (OPPTS 890.1250)
  • Estrogen and androgen receptor transcriptional activation (human cell line – HeLa-9903)      (OPPTS 890.1300)
  • Androgen receptor binding (rat prostate) (OPPTS 890.1150)
  • Steroidogenesis (human cell line – H295R) (OPPTS 890.1550)
  • Aromatase (human recombinant) (OPPTS 890.1200)

In vivo

  • Uterotrophic assay (female rat) (OPPTS 890.1600)
  • Hershberger assay (male rat) (OPPTS 890.1400)
  • Pubertal male assay (OPPTS 890.1500)
  • Pubertal female assay (OPPTS 890.1450)
  • Amphibian metamorphosis (frog) (OPPTS 890.1100)
  • Fish short-term reproduction assay (OPPTS 890.1350)

 

If you have a compound on the lists released by the EPA that are eligible for screening, you have 90 days in which to indicate your proposed response:

  • Withdraw
  • Cite existing data
  • Form consortia
  • Test

If you have decided to test, then you have two years in which to complete the testing and submit the new data.

The EPA will review existing data and newly submitted data before making a determination whether the compound will have to proceed to tier 2 testing.

In many cases, companies or consortia submitted waivers (OSRI: other scientifically relevant information) based on existing data.  Apart from agreement in some cases to waive specific tests for which relevant data were already available, waivers were generally rejected as the existing studies did not address the required endpoints.

To learn more about the endocrine disruptor screening program, visit the US EPA website which offers an in-depth look at the history and development of the EDSP legislation.

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