By Lynn L. Bergeson and Margaret R. Graham
On January 19, 2017, the U.S. Environmental Protection Agency (EPA), together with a host of other federal agencies, announced revisions via a final rule to modernize, strengthen, and make more effective the Federal Policy for the Protection of Human Subjects that was originally promulgated as a Common Rule in 1991. 82 Fed. Reg. 7151. The Federal Register publication states that this final rule is intended to “better protect human subjects involved in research, while facilitating valuable research and reducing burden, delay, and ambiguity for investigators, and “these revisions are an effort to modernize, simplify, and enhance the current system of oversight.” The rule will become effective on January 19, 2018. The compliance date is also January 19, 2018, with some exceptions.
The final rule differs in important ways from the proposed rule issued on September 8, 2015; most significantly, several proposals are not being adopted. Other minor changes have been to improve the rule and for purposes of clarity and accuracy. Some of the changes include:
- It does not adopt the proposal to require that research involving nonidentified biospecimens be subject to the Common Rule, and that consent would need to be obtained in order to conduct such research.
- To the extent some of the proposals relied on standards that had not yet been proposed, the final rule either does not adopt those proposals or includes revisions to eliminate such reliance.
- It does not expand the policy to cover clinical trials that are not federally funded.
- It does not adopt the proposed new concept of ‘‘excluded’’ activities. Generally, activities proposed to be excluded are now either described as not satisfying the definition of what constitutes research under the regulations or are classified as exempt.
- The proposed revisions to the exemption categories have been modified to better align with the longstanding ordering in the final rule. It does not include the proposed requirement that exemption determinations need to be made in specified ways.
- It does not include the proposed standardized privacy safeguards for identifiable private information and identifiable biospecimens.
- It does not adopt the most restrictive proposed criteria for obtaining a waiver of the consent requirements relating to research with identifiable biospecimens.
The final rule makes the following significant changes to the Common Rule:
- Establishes new requirements regarding the information that must be given to prospective research subjects as part of the informed consent process.
- Allows the use of broad consent (i.e., seeking prospective consent to unspecified future research) from a subject for storage, maintenance, and secondary research use of identifiable private information and identifiable biospecimens. Broad consent will be an optional alternative that an investigator may choose instead of, for example, conducting the research on nonidentified information and nonidentified biospecimens, having an institutional review board (IRB) waive the requirement for informed consent, or obtaining consent for a specific study.
- Establishes new exempt categories of research based on their risk profile. Under some of the new categories, exempt research would be required to undergo limited IRB review to ensure that there are adequate privacy safeguards for identifiable private information and identifiable biospecimens.
- Creates a requirement for U.S.-based institutions engaged in cooperative research to use a single IRB for that portion of the research that takes place within the United States, with certain exceptions. This requirement becomes effective three years after publication of the final rule.
- Removes the requirement to conduct continuing review of ongoing research for studies that undergo expedited review and for studies that have completed study interventions and are merely analyzing study data or involve only observational follow up in conjunction with standard clinical care.
More information on the Federal Policy for the Protection of Human Subjects is available on the U.S. Department of Health & Human Services’ website.
By Lynn L. Bergeson, Oscar Hernandez, Ph.D., Lara A. Hall, MS, RQAP-GLP, and Margaret R. Graham
On December 29, 2016, the U.S. Environmental Protection Agency (EPA) issued a notice regarding the availability of final test guidelines, OCSPP Series 850 Group A -- Ecological Effects, part of a series of test guidelines established by the Office of Chemical Safety and Pollution Prevention (OCSPP) for use in testing pesticides and chemical substances to develop data for submission to EPA under the Federal Food, Drug and Cosmetic Act (FFDCA), the Federal Insecticide, Fungicide and Rodenticide Act (FIFRA), and the Toxic Substances Control Act (TSCA). The notice states that these test guidelines “serve as a compendium of accepted scientific methodologies and protocols that are intended to provide data to inform regulatory decisions,” and they “provide guidance for conducting the test, and are also used by EPA, the public, and companies that submit data to EPA.” The test guidelines will be accessible through EPA Docket ID Numbers EPA-HQ-OPPT-2009-0150 through EPAHQ-OPPT-2009-0159, and EPA-HQ-OPPT-2009-0576 on www.regulations.gov.
The changes to test guidelines are varied. Some of the changes include:
- Simple cosmetic changes, e.g., presentation of test conditions, test validity criteria, and equations for calculating response measurements;
- Housekeeping changes, e.g., the addition of final versions of draft guidelines that had not been prepared in final yet;
- The addition of a limit test option to several acute invertebrate toxicity tests;
- Changes from “cut off” dosages in existing guidelines to limit concentrations and a change in the limit concentration for industrial chemicals from “1,000 milligrams/liter (mg/L)” to “100 mg/L” for acute toxicity tests and “10 mg/L” for chronic tests; and
- Changes to terminology, e.g., to clarify 10-day versus acute exposures for sediment-dwelling invertebrate toxicity tests and saltwater versus marine conditions.
The addition of a limit test option aligns well with the new TSCA mandate to reduce vertebrate testing as a matter of federal policy. EPA notes that certain guidelines were not issued in final, but remain available for reference as draft guidelines. In that certain ecological effects guidelines relate to guidelines already developed for the Endocrine Disruptor Screening Program (EDSP), EPA notes that it will consider test design elements from the relevant EDSP guidelines in the development of OSCPP 850 series guidelines.
By Lynn L. Bergeson, Karin F. Baron, and Margaret R. Graham
On December 20, 2016, the U.S. Environmental Protection Agency (EPA) announced the start of a pilot program to evaluate the usefulness and acceptability of a mathematical tool (the GHS Mixtures Equation), which is used in the Globally Harmonized System of Classification and Labeling of Chemicals (GHS). EPA states that the goal of the pilot program is to “evaluate the utility and acceptability of the GHS Mixtures Equation as an alternative to animal oral and inhalation toxicity studies for pesticide formulations.”
For this pilot program, EPA is requesting submission of acute oral and acute inhalation toxicity study data paired with mathematical calculations (GHS Mixtures Equation data) to support the evaluation of pesticide product formulations; instruction for doing so are available on the GHS Equation Pilot Program webpage, and Guidance on the GHS Mixtures Equation is available in the Guidance on the Application of the CLP (Classification, Labeling and Packaging) Criteria.
The program is an interesting approach considering the conceptual differences of risk assessment and hazard determination that exist at the core of EPA risk approaches and GHS fundamentals. Also, the definition of the EPA Categories compared to GHS has been problematic for hazard communication applications.
Mixture calculation tools rely on the availability of data for all components and would only be applicable if the data for each were generated using the same species under similar exposure conditions.
This pilot program is being developed under EPA’s initiative to develop non-animal alternatives for acute toxicity testing, as well as EPA’s Office of Pesticide Programs’ Strategic Vision for Adopting 21st Century Science Methodologies. More information on these initiatives can be found on our Pesticide Law and Policy blog under key phrase “toxicity testing.”
By Lisa M. Campbell, Lisa R. Burchi, and Timothy D. Backstrom
On September 19, 2016, the U.S. Environmental Protection Agency’s (EPA) Office of Inspector General (OIG) issued a report, EPA Needs a Risk-Based Strategy to Assure Continued Effectiveness of Hospital-Level Disinfectants, the result of OIG’s review of EPA’s Antimicrobial Testing Program (ATP) to “determine whether the program ensures the efficacy of EPA-registered hospital sterilants, disinfectants, and tuberculocides (“hospital-level disinfectants”); and to evaluate options for improving the ATP.” OIG found that the ATP “does not assure that hospital-level disinfectant products continue to be effective after they are registered,” specifically that:
- Once the EPA tests a product and it passes, it is listed as Agency Confirmed Efficacy on the agency’s website and is typically not tested again; the long-term efficacy of the product cannot be assured.
- EPA relies on manufacturers to voluntarily submit product samples for testing. In the last three years, out of the approximately 300 registered hospital disinfectant products that have not been tested, manufacturers submitted only 12 samples to EPA for ATP efficacy testing.
Importantly, however, OIG concludes: “Although the program as currently designed and conducted does not assure that most hospital disinfectant products continue to be effective, at this point it is redundant and unnecessary to make adjustments, since the EPA is concurrently having the products re-registered.”
OIG makes two major recommendations:
- EPA should suspend administering the current Antimicrobial Testing Program until completion of the one-time re-registration process.
- EPA should develop a risk-based antimicrobial testing strategy to assure the effectiveness of public health pesticides used in hospital settings once products are in the marketplace. At a minimum, OIG states, the strategy should:
- Include a framework for periodic testing to assure products continue to be effective after registration.
- Define a program scope that is flexible and responsive to current and relevant public health risks.
- Identify risk factors for selecting products to test.
- Identify the method to be used for obtaining samples for testing.
- Designate a date to commence risk-based post-registration testing.
In its response, EPA agreed with OIG’s recommendations, and stated it will develop a plan to coordinate and implement the discontinuation of the present-day program, with the closure of the ATP program to take place by November 2017. EPA also stated that by December 2018 it plans to develop a risk-based strategy to assure the effectiveness of public health pesticides used in hospital settings once products are in the marketplace.
Registrants of the affected products should monitor closely the development of EPA’s plans both to discontinue the program and to establish this new risk-based strategy for assuring product efficacy.
by James V. Aidala
The threat of the Zika Virus grows every day, and the need for clear information is especially pressing if you are pregnant. How do you prevent getting infected with the Zika Virus, and what insect repellents are best? The first question is easy to answer: public health experts agree that women who are pregnant or who might be pregnant should use insect repellents. The answer to the second question is not so simple.
I am a former senior official at the U.S. Environmental Protection Agency (EPA), and familiar with how the U.S. evaluates and approves pesticides, which include insect repellents. It is not easy for the average consumer to know what works and what does not work. Unfortunately, EPA policies have made this question much more complicated, having made important distinctions between some “natural”-type repellents and other products available in the marketplace.
Years ago, EPA de-regulated a number of natural, non-toxic materials from being subject to the registration requirements of the federal pesticide law (the Federal Insecticide, Fungicide, and Rodenticide Act). This made sense at the time since garlic, pepper, rotten eggs, vinegar, and other common chemicals are sometimes used as pesticides. Before de-regulation, these products were also subject to the same requirements as synthetic chemical pesticides with long unpronounceable names (e.g., diethyltoluamide, better known as DEET) which EPA requires to have volumes of efficacy and safety test data. Being natural does not mean a substance is non-toxic; some natural ingredients are fully evaluated and widely used. But in the interest of efficient use of resources EPA issued a list of products that could be sold as pesticides, but would not be subject to EPA data requirements and review (EPA calls them “minimum risk pesticides”).
This list of pesticides which are not subject to EPA evaluation, and which are not required to have data which proves they are effective, includes a number of botanical ingredients, such as oil of citronella, geranium, rosemary, peppermint, and many others. Many of these products can be used as pesticides -- some may work better than others -- and many work for the intended use (example: rotten eggs, or as EPA refers to them -- “putrescent whole egg solids” -- are used as a deer repellent).
Many of these ingredients have been marketed as “natural” insect repellents, and labeled as “safe” or “non-toxic” using words that will not appear on products where EPA reviews and approves the instructions on the product label.
Here is the bureaucratic distinction which matters greatly to EPA, but will not be understood by consumers:
- If the repellant label includes “public health claims” -- that it repels mosquitoes that may cause a disease (like Zika Virus or West Nile Virus) -- then the product has to have data showing that it works;
- If the product just says “repels mosquitoes,” it is not required to have data that shows it is effective, and may very well be ineffective.
Few, if any, humans outside of EPA label experts realize this important distinction: if there is no health claim on the label, then it is, in effect, a situation of “buyer beware.”
What remains: EPA’s deregulation of these products means it is legal to sell products which do not work, as long as the ingredients appear on the EPA minimum risk pesticides list.
Consumer Reports (CR) recently reported in May of this year on studies conducted on repellents. Their results:
- Using a “natural” mosquito repellent, with active ingredients such as citronella or clove, lemongrass, or rosemary oils, might seem like a good idea, especially if you’re pregnant or planning to be.
- But five of the six plant-based repellents we tested…lasted one hour or less against Aedes mosquitoes, the kind that can spread Zika.
Not all repellents with the same ingredient are equally effective, and they found that some formulations of the chemical repellents also do not work for very long in their tests. Some botanical pesticides are effective and have the public health claims on the label (example: lemon eucalyptus, a botanical ingredient not on the exempt product list, and CR testing did find it to be effective).
To reduce confusion about what works, EPA for years has struggled to correct the situation by trying to impose changes to the requirements for insect repellents.
Unfortunately, to end the confusion about the difference between “repels mosquitoes” and “repels mosquitoes that can cause the Zika Virus,” EPA has to conduct a rulemaking which requires a long and bureaucratic process to complete. The good news is that EPA is working on such a solution. The bad news is that they have been working on it for almost ten years and they still have more work to do. There are details and petitions and proposals and reasons why it has taken so long, but it is the kind of story that gives bureaucracy a bad name.
With the onset and fears about the Zika Virus, however, EPA should make the needed changes immediately to ensure that consumers are not misled into using products which are not proven effective in repelling mosquitoes.
From a consumer’s point of view, it really is that simple. Legally, it is more complicated. In the meantime, EPA should be loud and clear in its communication about the distinction, even if they cannot take immediate action to reduce the confusion.
By Lisa M. Campbell and Timothy D. Backstrom
On March 8, 2016, the U.S. Environmental Protection Agency (EPA) published a notice in the Federal Register stating that the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) Scientific Advisory Panel (SAP) will hold a three-day meeting scheduled for April 19-21, 2016, from 9:00 a.m. to 5:00 p.m. (EDT) to consider and review Chlorpyrifos: Analysis of Biomonitoring Data. The meeting will be held at EPA’s Conference Center, Lobby Level, One Potomac Yard (South Bldg.), 2777 S. Crystal Drive, Arlington, Virginia 22202. The meeting will be webcast. More information will be posted online.
The notice states that written comments are encouraged through April 5, 2016, and that requests for oral comments are encouraged to be submitted by April 12, 2016, but that both may be submitted until the date of the meeting. Nominations of candidates to serve as ad hoc members of FIFRA SAP for the meeting are requested on or before March 23, 2016.
In this meeting, EPA states that it will solicit comment from FIFRA SAP on the evaluation of biomonitoring data using the physiologically-based pharmacokinetic (PBPK) model, proposed points of departure and extrapolation/uncertainty factors, and examples of a proposed approach to use the PBPK model to simulate internal doses of chlorpyrifos from current exposure patterns from drinking water, food, and worker exposure. The FIFRA SAP has been reviewing the human health effects of chlorpyrifos since 2008. The notice states that “at this point in time, the Agency’s analysis of biomonitoring data from the cord blood collected as part of the Columbia University epidemiology studies has progressed to a point where peer review would be useful” and that “[s]pecifically, the Agency has done additional characterization of the pharmacokinetic profile of simulated exposures from oral and dermal exposures using the PBPK model.”
The notice states that in 2008 and 2012, the FIFRA SAP “cautioned EPA against using the biomonitoring data from epidemiology studies … to directly derive points of departure due to uncertainties associated with a lack of knowledge about timing of indoor chlorpyrifos applications and a single measure of exposure (cord blood).” The 2012 FIFRA SAP recommended that EPA use the PBPK model to further characterize the dose estimates in the epidemiology studies.
The notice states that EPA would have preferred to complete its analysis of the available biomonitoring prior to commencing rulemaking, but that the timing for the proposal was directed by the U.S. Court of Appeals for the Ninth Circuit, which ordered EPA to respond to an administrative petition to revoke all chlorpyrifos tolerances by October 31, 2015.
More information on the Ninth Circuit case is available in our blog item Circuit Court Grants Writ of Mandamus Requiring EPA to Act on Petition to Ban Chlorpyrifos.
EPA’s decision to utilize biomonitoring data that was collected as part of the Columbia University epidemiology studies for chlorpyrifos to derive proposed points of departure for risk assessment purposes will be highly controversial. If EPA proceeds to use biomonitoring data from epidemiological studies to derive points of departure for risk assessment purposes, the implications for all pesticide product risk assessments could be significant. Whether EPA can defensibly do so from both a scientific and legal standpoint is a subject that will likely be debated strongly. All pesticide registrants should monitor these developments closely.
By Timothy D. Backstrom, Lisa M. Campbell, and James V. Aidala
In an opinion issued on September 10, 2015, the U.S. Court of Appeals for the Ninth Circuit vacated the U.S. Environmental Protection Agency’s (EPA) unconditional registration for the pesticide sulfoxaflor and remanded the matter to EPA to obtain further studies and data regarding the effects of sulfoxaflor on bees and bee colonies. Sulfoxaflor is a new insecticide in the class of insecticides referred to as neonicotinoids, but its mechanism of action is distinct from other neonicotinoids. The Petitioners in this case were various trade organizations representing commercial beekeepers, as well as some individual beekeepers. The registrant Dow AgroSciences LLC (Dow) intervened in the action.
EPA granted an unconditional registration for sulfoxaflor on May 6, 2013, subject to a variety of risk mitigation measures, including a lower application rate, longer intervals between applications, and certain crop-specific label restrictions. EPA had previously proposed to issue a conditional registration for sulfoxaflor in January 2013, citing pollinator data gaps that could be addressed by requiring Dow to conduct and submit further studies. Under that proposal, use of sulfoxaflor would have been allowed at a reduced application rate during the time needed to complete data development. The court found that the subsequent decision by EPA to register unconditionally sulfoxaflor was not supported by substantial evidence, as required by Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) Section 16(b), both because EPA failed to adhere to its own scientific methodology and because the rationale that EPA provided for granting an unconditional registration could not be reconciled with the analysis upon which EPA based its prior proposal to register conditionally sulfoxaflor.
EPA evaluated the potential risk to bees and bee colonies from sulfoxaflor use utilizing the Pollinator Risk Assessment Framework, a scientific risk assessment methodology developed after consultations between EPA, Canada’s Pest Management Regulatory Agency, and the State of California, and presented by EPA to the FIFRA Scientific Advisory Panel in 2012. The court found that the rationale provided for EPA’s unconditional registration decision could not be reconciled with findings that EPA itself made using this methodology or with the rationale EPA provided for its prior proposal to issue a conditional registration. EPA had decided it was necessary to proceed to Tier 2 of the pollinator risk assessment after reviewing risk quotients and residue data in Tier 1 of the assessment. EPA found the available data for Tier 2 to be insufficient to allow indefinite use of sulfoxaflor, even at a reduced application rate. The court could not reconcile this finding with the subsequent decision to grant an unconditional registration, even with the specified mitigation measures. The court found that “given the precariousness of bee populations, leaving the EPA’s registration of sulfoxaflor in place risks more potential environmental harm than vacating it.” The court stated that “EPA has no real idea whether sulfoxaflor will cause unreasonable adverse effects on bees, as prohibited by FIFRA.”
EPA argued that with a reduced application rate, the risk quotients and residue analysis in Tier 1 was “close enough” to sufficient to avoid the specified quantitative trigger for a Tier 2 analysis, thereby rendering any deficiencies in the available Tier 2 data irrelevant. The court effectively stated in response that close enough is not good enough, citing another recent Ninth Circuit decision in which a risk concern that is triggered by a margin of exposure less than or equal to 1000 was held to be triggered when the margin was exactly 1000. Thus, this court once again placed EPA on notice that it must follow its own methodology with precision, and that EPA cannot justify deviations from its own methodology by simply stating that it is exercising expert judgment.
This is an unusual case because the registration of a new pesticidal active ingredient has been vacated on substantive as opposed to procedural grounds. The court’s rationale reflects a lack of judicial deference to what EPA typically refers to as the scientific “weight of the evidence.” While the term itself does not appear in the opinion, the court is insisting that EPA must follow its standard methodology without allowing for any deviations based on professional judgment. Although in this instance the court has supported the position of opponents of pesticide use, judicial reluctance to accept scientific “weight of the evidence” conclusions could also make it harder for EPA to impose additional restrictions when new but inconclusive evidence appears.
This case could cause EPA to be more explicit in adding procedures to its standard analytic methodologies that allow deviations from the methodology based on professional judgment. The case could also cause EPA to reconsider its recent reluctance to avoid issuing conditional registrations and its preference for unconditional registrations for new active ingredients. In any case, decisions that afford EPA less discretion to use “weight of the evidence” reasoning when basing scientific conclusions on less than conclusive data or studies could have an impact on a number of EPA practices and policies involving interpretation of scientific data.
By Lara A. Hall, MS, RQAP-GLP, Jane S. Vergnes, Ph.D., DABT®, and Lisa M. Campbell
On Tuesday, August 25, 2015, in a Federal Register notice, the U.S. Environmental Protection Agency (EPA) announced the addition of three Office of Chemical Safety and Pollution Prevention (OCSPP) final test guidelines to its 890 Series, entitled “Endocrine Disruptor Screening Program Test Guidelines,” as follows:
These test guidelines are part of a series of test guidelines established by OCSPP for use in developing data on potentially adverse effects of pesticides and chemical substances on the endocrine system for submission to EPA under the Federal Food, Drug, and Cosmetic Act (FFDCA) section 408 (21 U.S.C. 346a), the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) (7 U.S.C. 136, et seq.), and the Toxic Substances Control Act (TSCA) (15 U.S.C. 2601, et seq.). These final guidelines have been revised based on public comments received following the release of draft test guidelines in January 2015, existing EPA test guidelines, and concurrent Organisation for Economic Co-operation and Development (OECD) test guidelines.
EPA worked with OECD to harmonize test guidelines for MEOGRT and LAGDA. The specific OECD Guidelines for the Testing of Chemicals, Section 2, that apply to MEOGRT and LAGDA, are available here. Substantive changes reflected in the final OCSPP MEOGRT and LAGDA test guidelines include:
1. The test will end following hatching of the second generation (F2) offspring. The option for extending the MEOGRT through reproduction by the F2 generation has been removed from the final test guideline pending additional data. This is consistent with the decision made in the draft OECD test guideline for MEOGRT. This test guideline may be updated as new information and data are considered. For example, guidance on extending the F2 generation through reproduction may be potentially useful under certain circumstances (e.g., chemicals with high bioconcentration potential or indications of trans-generational effects in other taxa).
2. The mean water temperature over the duration of the MEOGRT has been changed to 25 ± 2 °C to be consistent with the analogous OECD test guideline.
3. The LAGDA developmental stage terminology has been clarified to avoid confusion with what is meant by complete metamorphosis.
4. An effort was made to clarify and provide more explicit guidance as to what specific histopathology is appropriate based on the results of the study, e.g., the conduct of liver and kidney histopathology in the MEOGRT and LAGDA test guidelines with respect to overt toxicity.
5. The rationale for use of solvent control only, dilution water control only, or pooled controls in the statistical analyses for the MEOGRT and LAGDA was clarified.
6. The guidelines have been modified to address commenters' concerns that they be more flexible and less prescriptive. Examples have been provided as appropriate to add clarity.
The JQTT draft test guideline (OCSPP 890.2100) was revised to address comments provided by the public, the draft OECD test guideline for the avian two-generation toxicity test in the Japanese quail, as well as the existing EPA test guidelines and OECD test guidelines for avian one-generation toxicity tests.
EPA revised the terminology, procedures, endpoints measured, figures, tables, and appendices in the JQTT test guideline to clarify specific points raised by public commenters, and to address commenters' concerns that they be more flexible and less prescriptive, as follows:
1. The revised test guideline includes fewer endpoints. For example, the revisions eliminated behavioral endpoints to reduce the overall numbers of birds required for the study; eliminated endpoints that are difficult to obtain (i.e., hormone levels measured in embryo blood samples); and eliminated redundant endpoints and statistical analyses.
2. For clarity, the test terminates with measurement of the 14-day survival of the F2 generation chicks. This is the minimum length of the study necessary to evaluate and measure a chemical's effect on the first generation’s (F1) reproductive performance. If delayed reproduction is observed in F1 birds, a decision to extend the F2 generation may be made. If extended, the test should be terminated when F2 birds are approximately 6 weeks old, when 90 percent of control animals have reached sexual maturity. The decision to limit the length of the JQTT is consistent with EPA's efforts to move to extended one-generation reproduction test protocols for Tier 2 testing rather than require multigenerational studies. Extended one-generation reproduction tests are scientifically justified in many cases, reduce the use of animals in testing, and reduce costs.
Electronic access to OCSPP test methods and guidelines is available here.
The release of these final testing guidelines marks another significant step in the overall Endocrine Disruptor Screening Program (EDSP), making way for the anticipated Tier 2 testing phase with the List 1 chemicals. EPA recently released Tier 1 weight-of-evidence assessments for List 1 substances in the EDSP and registrants are now receiving the associated data evaluation records (DER) for the Tier 1 screening studies. The purpose of the Tier 1 screening was to identify potential interactions with three hormonal pathways (estrogen, androgen and thyroid) in the endocrine system. As a result of the potential interactions with one or more of these pathways observed, EPA has recommended Tier 2, multigenerational studies across various species for 18 of the 52 List 1 chemicals, including the MEOGRTS (13 chemicals) and LAGDA (5 chemicals). Test Orders for Tier 2 studies will be issued following completion of the Information Collection Request (ICR) process within the Office of Management and Budget (OMB). The public review and comment period for this ICR concludes on September 2, 2015, with a response from OMB to follow in early October 2015. In the interim, registrants are closely reviewing their respective assessments and DERs, and industry groups are assessing the approach employed by EPA in these Tier 1 assessments, including but not limited to, the statistical reanalysis of study data and conclusions drawn by EPA.
By Lara A. Hall, Lisa M. Campbell, and Jane S. Vergnes, Ph.D.
The release of the first Tier 1 assessments in the Endocrine Disruptor Screening Program (EDSP) by the U.S. Environmental Protection Agency (EPA) on June 30, 2015, is a significant bench-mark in the program since the original List 1 test orders were initially issued in October 2009. Fifteen of the original 67 List 1 chemicals were subsequently cancelled or discontinued by the respective pesticide registrants. The intended purpose of the Tier 1 screening was to identify potential interactions of the remaining 52 chemicals with three hormonal pathways (estrogen, androgen and thyroid) in the endocrine system. EPA evaluated the data from 11 screening assays (five in vitro and six in vivo), along with other scientifically relevant information (OSRI) comprised of existing toxicology studies and peer reviewed published literature, and drew preliminary conclusions about the potential of these 52 chemicals to disrupt endocrine functions. Importantly, EPA noted on the EDSP webpage that “a result indicating potential should not be construed as meaning that EPA has concluded that the chemical is an endocrine disruptor.”
The individually published weight-of-evidence (WoE) assessments and anticipated data evaluation records (DER) can be accessed online for the 52 chemicals involved in the Tier 1 screening assessment. EPA summarized its conclusions from EPA’s Tier 1 WoE assessments as follows:
- No evidence of potential interaction with any of the endocrine pathways was identified for 20 chemicals.
- Fourteen chemicals showed potential interaction with one or more pathways, but based on the available information, do not pose a risk for endocrine disruption.
- Eighteen chemicals showed potential interaction with the thyroid pathway, 17 of which also showed potential interaction with the androgen pathway, and 14 of which showed potential interaction with the estrogen pathway.
To explore further any potential adverse effects on the endocrine system that may be caused by the 18 chemicals that EPA categorized in the third group noted above, EPA has recommended the following Tier 2, multigenerational studies across various species for them:
- A comparative thyroid assay for four chemicals that EPA found to have potential interaction with the thyroid pathway in mammals;
- The Medaka Extended One Generation Reproduction Test, MEOGRT (Draft Test Guideline OCSPP 890.2200), for 13 chemicals that EPA found to have potential interaction with the estrogen or androgen pathways in wildlife; and
- The Larval Amphibian Growth and Development Assay, LAGDA (Draft Test Guideline OCSPP 890.2300), for five chemicals that EPA found to have potential interaction with the thyroid pathway in wildlife.
EPA has not yet issued its final Tier 2 non-mammalian Office of Chemical Safety and Pollution Prevention (OCSPP) test guidelines (890 Series). Public comment on the proposed guidelines closed on March 31, 2015. It is expected that the release of these remaining guidelines will signal the approach of the Tier 2 test orders, which EPA is likely to issue in 2016. Although a formal public comment period is not expected to be opened for the Tier 1 assessments, affected registrants should have the opportunity to respond directly to EPA regarding WoE assessments and forthcoming DERs.
This release of the Tier 1 WoE assessments, the anticipated release of Tier 2 test guidelines, along with EPA’s commitment to further the development of high-throughput (HTP) assays and computational tools will significantly influence the prioritization of List 2 chemicals in the EDSP and the timing of the List 2 test orders. The revised List 2 includes 109 chemicals for Tier 1 screening. As with List 1, List 2 candidates reportedly were selected based on EPA’s review concerning their possible presence in public drinking water and/or registration review status within EPA, and not because of their potential to interfere with the endocrine systems of humans or other species.
By Lisa M. Campbell and Jane S. Vergnes, Ph.D.
On June 19, 2015, the U.S. Environmental Protection Agency (EPA) announced a plan for incorporating validated high throughput assays and a computational model into the Endocrine Disruptor Screening Program (EDSP) to screen chemicals for their ability to interact with the endocrine system. These proposed new methods would serve as an alternative for three of the eleven current assays in the EDSP Tier 1 screening battery, specifically the estrogen receptor binding (ER), estrogen receptor transactivation (ERTA), and uterotrophic assays.
These computational high-throughput (HTP) tools will have the potential to impact significantly the prioritization for testing and will have a significant impact on List 2 test orders. EPA states that use of these alternative methods will accelerate the pace of screening, decrease costs, and reduce animal testing. In addition, this approach advances the goal of providing sensitive, specific, quantitative, and efficient screening using alternative test methods to some assays in the Tier 1 battery to protect human health and the environment. EPA has stated its commitment to the development of HTP and computational tools to improve regulatory science, as recommended in the 2007 National Research Council report, “Toxicity Testing in the 21st Century: A Vision and a Strategy,” and to meet its statutory obligations in the face of challenging budget constraints.
Comments are due by August 18, 2015. EPA specifically seeks comment on the following issues, which are related to its stated intention to use the scientific tools discussed as alternatives to some of the current EDSP Tier 1 screening assays:
- The use of the ToxCastTM “ER Model” for bioactivity as an alternative method for the current ER binding and ERTA Tier 1 screening assays.
- The use of the ToxCastTM “ER Model” for bioactivity as an alternative method for the current uterotrophic Tier 1 screening assay.
- The use of results from the ToxCastTM “ER Model” for bioactivity on over 1800 chemicals as partial screening for the estrogen receptor pathway.
EPA concludes that the ToxCastTM “ER Model” meets the criteria for use as “other scientifically relevant information” to satisfy Tier 1 for the ER, ERTA, and uterotrophic assays. EPA’s conclusion is based upon the findings of the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) Scientific Advisory Panel (SAP) peer review held in December, 2014 that endorsed the ToxCastTM “ER Model” as a replacement for the ER and ERTA assays, and additional data developed by EPA to address the SAP’s concerns regarding the uterotrophic assay. Recipients of EDSP Tier 1 test orders would have three options for addressing the Tier 1 requirements with respect to the three EDSP Tier 1 endpoints that EPA considers validated:
- Cite existing ToxCastTM “ER Model” data, if it is applicable.
- Generate new data using the 18 ER HTP assays and the ToxCastTM “ER Model.”
- Generate Tier 1 data using the validated methods for the ER, ERTA, and uterotrophic endpoints in the traditional EDSP Tier 1.
EPA is careful to note that activity in the ToxCastTM “ER Model” is not a determination that a chemical causes endocrine disruption, only that is has the potential to do so, and that further testing (Tier 2) would be needed to make a determination regarding the ability to cause “adverse effects in an intact organism or its progeny, or subpopulations,” as stated in the World Health Organization International Programme on Chemical Safety definition.
More detailed information on the Endocrine Disruptor Screening Program and its use of computational tools is available at: http://www.epa.gov/endo/ or http://www.epa.gov/endo/pubs/pivot.htm.