| |||||
|
|
|
|
|
|
| |||||
|
|
|
|||
| |||||
     |
 |
|
TECHNICAL ADVISOR'S REPORT TO THE FOOD, DRUG, AND COSMETIC PACKAGING MATERIALS COMMITTEE June 4, 1998 Lester Borodinsky, Ph.D.
It is a great pleasure for me to be with you once again in the role of the Committee's Technical Advisor. This report will describe one of the current technical issues we are dealing with in establishing satisfactory regulatory positions for plastic packaging materials. For the past several years, many of you have been acutely aware of the discussions and activities related to the endocrine issue. You are probably familiar with, or actually involved in, the scientific discussions surrounding the issue, which centers on the hypothesis that certain substances may be causing adverse health effects in humans or in wildlife due to the effects the substances have on normal endocrine hormonal action. The issue goes beyond the stage of scientific curiosity since regulatory authorities around the world have also been attending to the discussions and research relating to the matter. In fact, the United States Environmental Protection Agency (EPA) has not only been following the issue intently for several years, it has impaneled an advisory committee, the Endocrine Disruptor Screening and Testing Advisory Committee (EDSTAC), as a consequence of legislative action a year-and-a-half ago. Since it appears that EPA will be setting in motion testing requirements for many chemicals, the subject of this report is to provide an update on the status of the EDSTAC and related activities and provide some thoughts on the ultimate relevance of these activities.
Background In August 1996, Congress passed the Food Quality Protection Act (FQPA) and amended the Safe Drinking Water Act (SDWA), both of which included provisions for screening and testing of endocrine disrupting chemicals. The FQPA requires EPA to: "... develop a screening program, using appropriate validated test systems and other scientifically relevant information, to determine whether certain substances may have an effect in humans that is similar to an effect produced by naturally occurring estrogen, or other such endocrine effect as the Administrator may designate." The SDWA includes a provision that authorizes EPA to test any substance that may be found in sources of drinking water to which a substantial population may be exposed. The FQPA requires that EPA propose a screening program for pesticides (both active and inert ingredients) by August 1998, implement the program by August 1999, and report to Congress in August 2000. Recognizing the difficult and controversial scientific, emotional, and political components of the endocrine issue, EPA's Office of Prevention, Pesticides and Toxic Substances established EDSTAC to advise EPA on a strategy for screening and testing endocrine disrupting chemicals.1 EDSTAC is comprised of 45 individuals representing a number of "stakeholder" groups, including EPA, other federal and state government agencies, industry, water providers, national environmental and public health groups, labor, and academia. In addition to EDSTAC per se, four work groups - the Principles Work Group, the Communications and Outreach Work Group, the Priority Setting Work Group, and the Screening and Testing Work Group - were established to report to EDSTAC regarding specific tasks related to EDSTAC's mandate. Thus, well over 100 people have been directly involved in the EDSTAC process. After an organizational meeting on October 31-November 1, 1996, EDSTAC met eight times between December 1996 and April 1998 at various sites around the United States. At the initial meeting, EDSTAC concluded that the screening and testing program should focus on (1) the estrogen, androgen, and thyroid hormone systems, (2) wildlife as well as human effects, and (3) commercial chemicals and drinking water contaminants. On April 3, 1998, EDSTAC issued a draft report; a brief summary of the draft EDSTAC report follows.
April 1998 Draft EDSTAC Report In addition to introductory and background chapters, the draft EDSTAC report includes chapters about the "conceptual framework" for the screening and testing, priority setting, the screening and testing recommended, and communications and outreach.
Conceptual Framework and Principles EDSTAC provides a definition for an endocrine disruptor as "an exogenous chemical substance or mixture that alters the structure or functions(s) of the endocrine system and causes adverse effects - at the level of the organism, its progeny, populations, or subpopulations of organisms - based on scientific principles, data, weight-of-evidence, and the precautionary principle." Screening is defined as "the application of assays to determine whether a chemical substance or mixture may interact with the endocrine system" and testing is defined as "a customized combination of tests and endpoints designed to determine whether a chemical substance or mixture exhibits endocrine-mediated adverse effects and to identify, characterize, and quantify these effects." The conceptual framework sets forth an ordered sequence of elements, made up of (1) priority setting, (2) screening, and (3) testing. At each of the decision points in the conceptual framework, all available information is evaluated to determine whether and how to proceed to the next step(s), generally using a "weight-of-evidence" approach to make such determinations. A detailed depiction of the conceptual framework, included in the draft report as Figure 4.1, is attached below. In addition to the above definitions and ordered sequence, three important "issues" emerge in the conceptual framework: (1) the screening and testing should be relevant to both human health and ecological effects; (2) the screening and testing should address effects that relate to estrogenic-, androgenic-, and thyroid hormone-related processes, but the need for additional testing should be considered by EPA periodically; (3) the screening and testing should be capable of evaluating both chemical substances and "common mixtures." Priority Setting The EDSTAC report indicates that the universe of chemicals that should be considered for screening and testing is approximately 86,000. Because of the large number of substances, EDSTAC sets forth a priority setting element for use with the overall screening and testing framework. The elements of the initial sorting and priority are discussed below. Various items of information will be used to set priorities for screening and testing. This information falls into three categories: (1) exposure-related information; (2) effects-related information; (3) statutory criteria. The exposure-related information includes data from actual biological sampling (including data on humans), environmental, occupational, consumer product, and food-related data, environmental releases, production volumes, and fate and transport data and models. The effects-related information include toxicological laboratory studies and database information, epidemiological and field studies and database information, predictive biological activity or effects models, and the results of the so-called High Throughput Pre-Screening (HTPS; discussed below). The statutory criteria include specifically considering pesticides (as required by the FQPA), chemicals found in sources of drinking water affecting significant populations (as required by the SDWA), and chemicals that may have a cumulative effect with pesticides (as required by the FQPA). EDSTAC determined that approximately 25,000 of the 86,000 chemicals are polymers, which have received "special" treatment. All monomers and oligomer components of polymers would be prioritized and subjected to the screening and testing; the EDSTAC report does not provide a definition for the "oligomer components" referred to here. Polymers having a number average molecular weight less than 1000 Daltons will be treated like any other chemical, requiring them to be prioritized and subjected to the screening and testing. Polymers having a number average molecular weight greater than 1000 Daltons will be "held," pending the outcome of the screening and testing (where the latter is necessary) on the monomer and oligomer components; while the EDSTAC report indicates that a positive finding for a monomer or oligomer component requires that the component proceed to hazard assessment, the report does not provide any further reference as to how a polymer per se is to be treated if its monomers or oligomers are deemed to show positive results in the screening or testing. A small number of chemicals, mainly pesticides, for which a substantial amount of toxicological data (especially 2-generation reproduction studies; see section below on testing) and chemical use information are available, would be eligible to by-pass the Tier 1 Screening (discussed below), but still required to undergo the High Throughput Pre-Screening. In addition, another small set of chemicals is expected to have already been tested sufficiently so as to be eligible to by-pass both Tier 1 Screening and Tier 2 Testing to go on to hazard assessment; these, too, would appear to be subject to the HTPS battery. The EDSTAC estimates that the remaining chemicals (i.e., those other than polymers and chemicals with existing sufficient datasets) number approximately 60,000. Of these substances, EDSTAC believes that approximately 15,000 are produced in quantities in excess of 10,000 pounds per year. Accordingly, chemicals for which there are not sufficient testing data already in existence and that are produced at a rate exceeding 10,000 pounds/year will need to undergo HTPS for prioritization; those substances produced at rates less than 10,000 pounds/year will also need to be prioritized, but not by using HTPS. High Throughput Pre-Screening To help prioritize the more than 15,000 chemicals expected to be subject to the upper-most prioritization, EDSTAC envisions a High Throughput Pre-Screening (HTPS) battery of in vitro tests to be a part of the priority setting apparatus. In these tests, automated processes employing robotic technology and specialized equipment is anticipated to permit a rapid and inexpensive pre-screening battery. The following tests are proposed by EDSTAC as the HTPS battery:
Each of the above assays would involve multiple dose levels, probably five levels plus a control. It is interesting to note that EDSTAC recommends that the chemicals to be subject to HTPS include not only the substances for which little or no data exist so as to prioritize them for Tier 1 Screening, but also for those substances for which enough data exist to enable them to proceed directly to Tier 2 Testing or to Hazard Assessment. It appears that the recommendation to include the latter two categories is primarily for building a database of such information. EDSTAC does realize that several practical considerations regarding HTPS need to be considered, including demonstration of the feasibility of the HTPS system, collection and handling of the substances to be pre-screened, patent issues (some of the desired screens are currently under patent protection), cost, and validation. Mixtures Even though EDSTAC acknowledges that evaluating mixtures is complex and unclear for any toxic endpoint, since the evaluation for endocrine effects for single compounds is itself still emerging and fraught with scientific uncertainty, it is recommending that mixtures be included in the screening and testing program. For this purpose, EDSTAC is recommending that a set of six mixtures be included in the various demonstration and validation phases for the HTPS and Tier 1 Screening batteries. The recommended mixtures, which are intended to span a range of physical and chemical properties, are the following:
Screening and Testing Tier 1 Screening
in vivo As possible substitutes for some of the above assays, EDSTAC included the following:
in vivo The EDSTAC draft report includes reasonably detailed descriptions of all of the proposed and alternative assays as well as protocols for their conduct. EDSTAC recommends that all of the in vitro assays be conducted at multiple doses, while the in vivo assays should be conducted at one high dose of an unspecified level. The draft report also includes a summary of general principles for evaluating the results of these assays (as well as all of the other batteries involved in this process, including HTPS and Tier 2 Testing), referring to the need for a "weight of evidence" determination to make informed judgments. Examples of the principles set forth include: (a) results from in vivo assays have more weight than results from in vitro assays; (b) in vitro assays cannot be "gatekeepers," but are there only to contribute information; (c) results from in vitro assays with and without metabolic activation are worth more than results from in vitro assays without activation only. Tier 2 Testing
Tests for Other Animal Taxa It is worth noting at this point that the recommended 2-generation reproductive toxicity test is not the conventional test that has been used for many years, but is a significantly enhanced test that has numerous endpoints in addition to those that are considered in the conventional testing. The EDSTAC draft report includes reasonably detailed descriptions of the proposed and alternative tests as well as protocols for their conduct. The report notes that the cost for running the 2-generation reproductive toxicity test in accordance with the new harmonized Toxic Substances Control Act (TSCA)-FIFRA guidelines is $350,000 to $800,000 per chemical, depending on the route of administration. The draft report gave special attention to the so-called low dose issue. The low dose issue surrounds the hypothesis that a dose response curve may be non-monotonic such that conventional "high dose" testing may fail to detect a toxic response that occurs in the low dose region. The EDSTAC report notes that, while there is intense scientific debate surrounding this issue, the doses selected for T2T should include consideration of appropriately setting the low dose. However, despite this inclusion, EDSTAC also includes in their draft report a recommended research program to resolve the controversy. Validation and Standardization The EDSTAC acknowledges that very few (indeed, if any) of the tests or screening assays have been taken thorough a rigorous validation process. The Inter-Agency Coordinating Committee for the Validation of Alternative Methods (ICCVAM) has established a process for such validation, and the EDSTAC recognizes that the screens and tests need to be taken through this type of process. In this vein, the draft report sets forth a description of the validation and standardization process that will be needed, as well as EDSTAC's view of the current validation status of each of the screens and tests. Communication and Outreach The draft EDSTAC report addressed communications issues, such as descriptions of the process and results, their interpretation, the limitations and uncertainties of the data and results, the development of a publicly-accessible database of the information/data. May 5-6, 1998 SAB/SAP Meeting On May 5-6, 1998, two of the Environmental Protection Agency's (EPA) advisory groups, the Scientific Advisory Board and the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) Scientific Advisory Panel (SAB/SAP), held a joint informal meeting to begin their deliberations regarding a report by the Endocrine Disruptor Screening and Testing Advisory Committee (EDSTAC). The May 5-6 SAB/SAP meeting was an informal gathering held as a consultation prior to a formal review of the EDSTAC document. There was no intention of reaching a consensus at this meeting, but instead, the SAB/SAP will meet again on December 8-9, 1998 in Crystal City. Since this was an informal consultation, a transcript of the meeting will not be available, but minutes of the meeting will be available in about one month. The meeting was arranged primarily to follow the same chapter-by-chapter organization of the draft EDSTAC report. For each section (i.e., Introduction and Overview, Conceptual Framework, Priority Setting Process, and Proposed Screening Battery and Testing Scheme), a designated EPA official associated with the particular EDSTAC element first made a presentation to the SAB/SAP; the EPA official was always accompanied by one or more other EDSTAC members, some of whom were not government employees. In almost each of these sections of the meeting, a period of public comment was set aside after the official presentation; after each public comment, a short period of discussion or questioning of the public commenter was allotted. After the designated period for public comments, time was set aside for Panel discussion on the particular portion of the EDSTAC report. The last portion of the meeting was set aside so that the Agency could present its view of the near-term implementation of the endocrine disruptors program. As the foregoing summary of the EDSTAC report captures most of the issues presented by the EPA officials, I will summarize below my impressions of the comments and panel discussions. One important factor to keep in mind is that the SAB/SAP members span the range of general opinions on the endocrine issue, and that they are not EDSTAC members themselves, although most of them have understandably been following its activities over the last year-and-a-half. Conceptual Framework With regard to comments, some concern was placed on the designation that would be attached to those substances coming out of T1S; the response from EPA was to reiterate that EDSTAC could not reach a consensus on the matter of how to identify the substances that emerge from T1S and are recommended for the T2T tests. Another comment indicated that not enough hormonal systems were being included in the screening and testing; EPA's response was that the scope seems to satisfy that which can be reasonably and practically achieved. The panel discussion revisited the latter issue - one suggestion was that scope should be expanded from the proposal to examine only the estrogen, androgen, and thyroid hormone systems. On the other hand, other panel members noted that the proposed testing is sufficient in that the scope covers areas where the science is sufficiently advanced, especially within the timeframe required of the Agency. The Agency reiterated that latter thought, indicating that the constraints needed to be practical. Nobody seemed to like the reference to the "Hold Box," the EDSTAC's designation for the category of substances that did not need screening or testing initially or those that "passed" the screening; some on the panel seemed to think that this meant "hold forever," while others suggested that the wording be changed to indicate where the decisions have been made that the chemical is not a potential endocrine disruptor - there is no distinction between chemicals that had no evaluation and those that had an evaluation but showed negative screening or testing results. Another panelist commented that the general tone of the report is one that would leave a reader to believe that positive T1S results actually should be interpreted to indicate "endocrine disruptor," as the presumption seems to be that positive results from T1S will be confirmed by T2T. Priority Setting Several of the panel members thought that the pre-screening process (HTPS) seemed duplicative in light of the data needed in the subsequent screening assays. In fact, several of the panel members questioned the need for subjecting chemicals, for which there already exists a large toxicology database, to the HTPS assays. Another panel comment was that the HTPS per se may prove to be quick and relatively inexpensive, but that the analytical work needed on the 15,000 chemicals would be a bottleneck and may be far more expensive than the HTPS itself. Another issue discussed by the panel was the need for and utility of the mixture testing, which will focus initially only on six specific mixtures. Panel members questioned whether a "representative" mixture for most of these categories could be managed; the categories are vague and the possible combinations could be extremely large. In addition, some panel members questioned the need for including phytoestrogens in the program, adding that "we all know they are beneficial." Other panel members pointed out that this may not be any more of a correct presumption than that other chemicals are detrimental. There was a bit of discussion regarding the "patent" issue, as some of the screens or tests being proposed are covered by existing patents; EPA seemed to think that this is an easily overcome matter. Screening Battery and Testing Scheme The low dose issue received quite a bit of attention. Those that seem to be in favor of this approach were in a very small minority, the majority taking serious issue with the hypothesis. For example, questions were raised of the relevance of the hypothesis in the context of risk assessment, which was pointed out many times as the ultimate goal of the process. Other panel members criticized the draft as having focused on details of screening and testing but not including a clear explanation of the "problem" and how the program will improve the public health. A major area of discussion was that related to validation, the issues raised being those related to inter-laboratory validation, specificity of assay (i.e., how many false positives and false negatives), and how to actually approach the validation process. Numerous references were made to the Inter-Agency Coordinating Committee for the Validation of Alternative Methods (ICCVAM), convened by the National Institute for Environmental Health Sciences, which has established principles for scientific and regulatory validation of testing methods. Some of the panel members appeared skeptical that appropriate validation would be achieved. In addition, several of the panel members did not agree with EDSTAC's categorization of the current validation status of each of the screens and tests. Even though a few of the tests are validated, several panel members noted that the alterations and additions to these methods, as suggested by EDSTAC, have not been validated. EPA acknowledged that a significant effort to validate the screens and tests is needed. Discussion also turned to questions about precisely how positives and negatives would be defined; the draft report did not address this area and several panel members indicated that this was an important matter to settle before actual screening or testing is implemented. Similarly, panelists questioned the one-dose approach for some of the testing, noting that it might be impossible to distinguish a result from the background "noise" if the dose is not selected adequately. Much discussion centered around the matter of the definition of an "endocrine disruptor;" some of the panel members expressed concern that applying such a "label" might be a real disservice to science because real causes of disease might be overlooked in an effort to get at an "obvious" answer. Several of the panel members recognized that the data and information that will evolve out of the process will be used by individuals other than scientists and they expressed concern over this occurring. In addition, there was a good deal of discussion of the relationship (or lack thereof) between acquiring information on the mechanism of activity of a substance and begin able to use such information to predict the likelihood of adverse effects. Several panel members stressed the need for EPA to focus on human health as the primary factor in their deliberations. Implementation/Timeframes EPA noted that the process to implement the program will take 4-5 years. EPA has contracted for a "demonstration" of the HTPS system, which will encompass 50-100 substances that include known positives, known negatives, and unknowns. EPA is funding this effort and expects an approximate 6-month timeframe to complete the evaluation of the system, which is intended to validate all components of the HTPS. With regard to HTPS per se, EPA anticipates an additional year to collect and process the anticipated 15,000 substances. As to funding for HTPS, EPA anticipates paying for part of this, but expects to work out a "partnership" with industry on funding; the latter might be industry handling the costs for collection and analysis of the test materials. The validation and standardization of T1S and T2T, consistent with the principles set forth by ICCVAM, would occur concomitantly and would take approximately 2 years to complete. EPA is looking for a partnership with the private sector to accomplish this component of the process. The T1S validation would involve 11 screening assays, using 20-30 substances, while the T2T validation would involve 5 tests on 10-20 substances. It appears that EPA is targeting late 2000 for the initiation of actual Phase I portions of T1S and T2T. Regarding the more immediate regulatory timeframes, EPA indicated that the EDSTAC report will be put in final form and submitted to EPA in June 1998. EPA will publish its proposed screening and testing program in August 1998. A report of the full SAB/SAP review will be submitted to EPA in December 1998, and EPA is anticipating publishing its final screening and testing program in February/March 1998. As a side note, EPA indicated that the long awaited report from the National Academy of Sciences/National Research Council's (NAS/NRC) Committee on Hormone-Related Toxicants in the Environment, also sponsored by EPA, is now due out sometime in the Summer of 1998. Comments and Observations It is important to recognize that EPA has been playing an important role in the EDSTAC activities. Even though EDSTAC is an advisory committee to EPA, EPA staff played a significant role in EDSTAC. This might not be quite so apparent from a review of the membership of EDSTAC per se, but it seems to me that EPA staff played a significant role in the EDSTAC work groups; indeed, each of the presentations at the SAB/SAP meeting were made by EPA staff and the questions from the SAB/SAP panel were almost exclusively handled by EPA staff, including supporting staff accompanying the main EPA presenters. For this reason, it appears that the general direction that the EDSTAC has taken has been guided, at least in part, by EPA. Thus, while EPA's ultimate proposal in August 1998 regarding screening and testing may change in certain details from the recommendations of EDSTAC, it seems clear that EPA will establish a screening and testing paradigm philosophically along the lines outlined by EDSTAC. Thus, we can expect that EPA will initiate the screening and testing of existing substances, and such screening and testing will become a part of the EPA culture, at least for the near term. EPA appears to be making a clear effort to be the lead entity on this issue. An important question, of course, is: How will this screening and testing program affect the ways in which the Food and Drug Administration (FDA) views the issue? In part, it seems to me that this impact, if any, will have to await the outcome of the Tier 2 Testing that is performed on a variety of substances, as well as the ensuing hazard assessment and risk assessment phases. With these in hand, FDA will be able to determine if special attention needs to be paid to endocrine effects or if other, more conventional, toxic endpoints are the appropriate ones to continue to heed regarding toxicity testing. However, it seems to me that the adoption of a screening program by EPA will only reinforce the general attitude amongst some government toxicologists that the use of the results of screening batteries per se is a valid way to make regulatory safety assessments. We have, from time to time, seen FDA request the results of genotoxicity testing in instances where such data have not been deemed needed in the past; the "problem" with the requirement for such screening data is that it is not clear that it is actually possible to arrive at a determinative safety assessment using the results of screening studies, since they are really designed to screen substances for possible further study.
SAB/FIFRA SAP Co-Chairs: Co-Designated
Federal Officials: Members:
More About SPI: Vision and Mission . Membership . Business Units . Regional Offices . News and Publications . Calendar of Events . Terms and Conditions of Use |
|
||||||
|
|
 © Copyright 2005 The Society of the Plastics Industry.
|
|
|||||||
|
|
|
|
      | ||||||