03-9300. Announcement of Final Priority Data Needs for 10 Priority Hazardous Substances

AGENCY:

Agency for Toxic Substances and Disease Registry (ATSDR), U.S. Department of Health and Human Services (HHS).

ACTION:

Notice.

SUMMARY:

This Notice announces the final priority data needs for 10 priority hazardous substances (see attached Table 1) as part of the continuing development and implementation of the ATSDR Substance-Specific Applied Research Program (SSARP). The Notice also serves as a continuous call for voluntary research proposals. The SSARP is authorized by the Comprehensive Environmental Response, Compensation, and Liability Act of 1980 (Superfund) or CERCLA, and amended by the Superfund Amendments and Reauthorization Act of 1986 (SARA) [42 U.S.C. 9604(i)].

At the time the SSARP was initiated on October 17, 1991, a list of priority data needs for 38 priority hazardous substances was announced in the Federal Register (56 FR 52178). The list was subsequently revised based on public comments and published in final form on November 16, 1992 (57 FR 54150). In 1997, ATSDR finalized the priority data needs for a second list of 12 substances that was subsequently announced in the Federal Register (62 FR 40820).

Ten substances constitute the third list of hazardous substances for which priority data needs have been identified by ATSDR. The 10 substances, which are included in the ATSDR Priority List of Hazardous Substances established by ATSDR and the U.S. Environmental Protection Agency (EPA) (66 FR 54014, October 25, 2001), are:

• asbestos
• benzidine
• chlorinated dibenzo-p-dioxins
• 1,2-dibromoethane
• 1,2-dichloroethane
• 1,1-dichloroethene
• ethylbenzene
• pentachlorophenol
• 1,1,2,2-tetrachloroethane
• total xylenes

In developing this list, ATSDR solicited input from EPA and the National Institute of Environmental Health Sciences (NIEHS), both of which also reviewed the draft priority data needs before they were made available for public comment. The priority data needs were initially announced by ATSDR in the Federal Register on August 14, 2001 (66 FR 42660). The public was invited to comment on them during a 90-day period. ATSDR received comments from four industry groups and a nonprofit private organization concerning programmatic and substance-specific issues pertaining to the implementation of the research program. ATSDR has identified several generic issues resulting from the public comments. These issues and ATSDR's responses are presented below. ATSDR has finalized the priority data needs for these 10 substances. Both the priority data needs documents (that provide ATSDR's rationale for assigning priority to a data need) and the response to public comments documents are available by requesting them in writing from ATSDR (see ADDRESSES section of this Notice).

This Notice also serves as a continuous call for voluntary research proposals. Private-sector organizations may volunteer to conduct research to address specific priority data needs in this Notice by indicating their interest through submission of a letter of intent to ATSDR (see ADDRESSES section of this Notice). The letter should include a brief statement that addresses the priority data need(s) to be filled and the methods to be used. A Tri-Agency Superfund Applied Research Committee (TASARC) comprised of scientists from ATSDR, the National Toxicology Program (NTP), and EPA will review all submissions.

DATES:

The ATSDR voluntary research program is a continuous program, and private-sector organizations can volunteer to fill identified data needs from now until that time when ATSDR announces that other research has been initiated for a specific data need.

ADDRESSES:

Private-sector organizations interested in volunteering to conduct research to fill identified priority data needs should write to Dr. William Cibulas, Chief, Research Implementation Branch, Division of Toxicology, ATSDR, 1600 Clifton Road, NE., Mailstop E-29, Atlanta, Georgia 30333, or e-mail Dr. Cibulas at [e-mail]. Requests for the priority data needs documents and response to public comments documents should be addressed similarly.

FOR FURTHER INFORMATION CONTACT:

Dr. William Cibulas, Chief, Research Implementation Branch, Division of Toxicology, ATSDR, 1600 Clifton Road, NE., Mailstop E-29, Atlanta, Georgia 30333, telephone [phone].

SUPPLEMENTARY INFORMATION:

 

Background

The Comprehensive Environmental Response, Compensation, and Liability Act of 1980 (Superfund) or CERCLA, as amended by the Superfund Amendments and Reauthorization Act of 1986 (SARA) [42 U.S.C. 9604(i)], requires that ATSDR (1) develop jointly with EPA a list of hazardous substances found at National Priorities List (NPL) sites (in order of priority), (2) prepare toxicological profiles of these substances, and (3) assure the initiation of a research program to address identified priority data needs associated with the substances.

The primary purpose of this research program is to provide the public and scientific communities with answers to some of the key questions regarding health effects and exposure to these substances. For ATSDR, this research program supplies necessary information to improve the database to conduct public health assessments. This link between research and public health assessments, and the process for distilling priority data needs for ranked hazardous substances from data needs identified in associated ATSDR toxicological profiles, are described in the ATSDR “Decision Guide for Identifying Substance-Specific Data Needs Related to Toxicological Profiles” (54 FR 37618, September 11, 1989).

At the time the Substance-Specific Applied Research Program (SSARP) was initiated on October 17, 1991, a list of priority data needs for 38 priority hazardous substances was announced in the Federal Register (56 FR 52178). The list was subsequently revised based on public comments and published in final form on November 16, 1992 (57 FR 54150). In 1997, ATSDR finalized the priority data needs for a second list of 12 substances (62 FR 40820). Currently, a total of 190 priority data needs have been identified for these 50 substances as described in “Update on the Status of the Superfund Substance-Specific Applied Research Program” (67 FR 4836, January 31, 2002).

In 2001, ATSDR identified the priority data needs for 10 additional hazardous substances and announced them in draft form on August 14, 2001 (66 FR 42660). The public was invited to comment on the draft priority data needs during a 90-day period. The agency responded to all the comments and revised the priority data needs, as needed.

ATSDR's Response to Public Comments

As mentioned in the SUMMARY section of this Notice, ATSDR has identified several generic public comments on the priority data needs for the 10 hazardous substances. These comments and ATSDR's responses are presented below.

Comment: Request for ATSDR to clarify if and how any further testing requests or regulatory requirements for testing will be subject to public scrutiny.

Response: ATSDR published the draft priority data needs (PDNs) in the August 14, 2001, Federal Register Notice with a public comment period of 90 days. A final list of PDNs will be published following completion of deliberations on the comments received. In the event that a study is to be conducted via the mechanisms described in the Federal Register Notice—e.g., industry-sponsored voluntary research, or university-based research supported by the Comprehensive Environmental Response, Compensation, and Liability Act (CERCLA) funds—the study protocol and final report will be reviewed by ATSDR's external peer reviewers, and all documents related to the project will be made available for public inspection at ATSDR. Also, any testing that results from coordination with the U.S. Environmental Protection Agency (EPA) and development of a Toxic Substances Control Act (TSCA) test rule will be subjected to a public comment period consistent with EPA guidelines. ATSDR publishes an update of its Substance-Specific Applied Research Program in the Federal Register every three years.

Comment: Concern that the Federal Register Notice makes no mention of the use of in vitro methodologies.

Response: ATSDR agrees with the commenter and will more explicitly state its support of innovative methodologies, including non-animal testing, in future notices about the agency's Substance-Specific Applied Research Program. In a recently published Federal Register Notice updating the status of this research program (67 FR 4836, January 31, 2002), the agency stated that “ATSDR encourages the use of in vitro assessment methods and other innovative tools for filling priority data needs. For example, the agency believes that physiologically based pharmacokinetic (PBPK) modeling could serve as a valuable tool in predicting across route similarities (or differences) in toxicological responses to hazardous substances. Therefore, on a case-by-case basis, a priority data need can be filled using existing data and modeling.” In fact, in the ATSDR voluntary research program (a component of ATSDR's Substance-Specific Applied Research Program), the Halogenated Solvents Industry Alliance, Inc. (HSIA) has conducted studies to fill ATSDR's priority data needs for volatile organic compounds using PBPK modeling.

Also, ATSDR is a member of the National Toxicology Program's (NTP) Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM) and supports development, validation, and acceptance of alternative toxicological test methods that reduce, refine, and replace the use of animals, as appropriate. Through its participation on ICCVAM, ATSDR keeps informed of reliable and valid alternative test methods.

Comment: Request for ATSDR to withdraw the endocrine disruption and developmental neurotoxicity priority data needs because there are no validated animal tests for these end points.

Response: ATSDR has identified a priority data need to assess the potential for pentachlorophenol to affect endocrine functions and for reproductive studies with ethylbenzene. As a result of the agency's evaluation of the comments received from the Pentachlorophenol Task Force, the priority data need for in vivo endocrine disruptor studies via oral exposure to pentachlorophenol has been changed. This change resulted because the Pentachlorophenol Task Force submitted a recently completed two-generation reproduction study that was subsequently published in a peer-reviewed journal. ATSDR accepted the data and no longer assigned priority to this research need. With regard to ethylbenzene, no new information has been available to ATSDR, and the priority data need for ethylbenzene remains unchanged. For the same reason, ATSDR will not withdraw the priority data need for developmental neurotoxicity testing for xylenes.

ATSDR is a nonregulatory, science-based agency. The agency is mandated (in consultation with EPA and agencies and programs of the Public Health Service) to assess whether adequate information on the health effects of hazardous substances is available. Where adequate information is not available, ATSDR, in cooperation with NTP, is required to assure the initiation of a research program to determine these health effects. Toward this end, ATSDR established the Tri-Agency Superfund Applied Research Committee (TASARC) consisting of scientists from ATSDR, EPA, and NTP to collaborate on mutual research needs and to discuss issues relevant to the proposed studies, such as the validation status and regulatory acceptance of proposed test methods. It should be noted that ATSDR does not develop testing guidelines or methodologies for toxicological research.

Consistent with the CERCLA mandate, on August 14, 2001, ATSDR published a Federal Register Notice announcing the identification of key research needs for 10 additional hazardous substances, and provided a rationale for these determinations in support documents (i.e., priority data needs documents are available for all 10 substances). However, the agency did not identify, propose, or discuss specific test methods to be used to fill the data needs (66 FR 42660). There are no universally agreed upon and validated animal tests to fill the priority data needs for endocrine disruption and developmental neurotoxicity, similar to a lack of such tests to fill the priority data needs for biomarker and mechanistic studies. Consequently, these studies require basic research or other mechanisms to satisfy the information need. Therefore, in filling these research needs, ATSDR does not specify or require that certain (animal) tests be performed. Instead, ATSDR remains open to receiving scientific information to fill these research needs from a variety of sources, including organizations that may propose innovative methodologies involving non-animal tests. In such cases, the agency generally consults with programmatic experts at the National Institute of Environmental Health Sciences (NIEHS) and EPA, and outside scientists to advise the agency on the appropriateness and validation status of the proposed methods for filling its research needs. Also, ATSDR is working closely with organizations such as NTP's Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM) to stay abreast of testing validation issues. In fact, ATSDR is participating fully in this committee's effort to validate a battery of in vivo and in vitro tests to assess endocrine disruption.

Comment: Concern about ATSDR calling for more lethal poisoning tests on animals and request that ATSDR withdraw its proposal to conduct more acute toxicity tests on animals for these 10 substances.

Response: The ATSDR Substance-Specific Applied Research Program is designed to address the most important public health research needs for citizens exposed to hazardous environmental substances. ATSDR has not required, and will not require, LD₅₀ or other lethality data as an adjunct to the process. However, ATSDR often requests short-term (acute) toxicity data on non-lethal end points in order to determine the agency's health guidance values (minimal risk levels [MRLs]) for citizens who are possibly exposed to chemicals for durations of 14 days or less.

If the agency considers the existing acute duration (14 days or less) database to be inadequate for fully characterizing the short-term toxicity of a particular hazardous substance, it will identify the need to conduct additional [inhalation and/or oral] studies for determining critical targets and establishing dose-response relationships.

Comment: Concern that ATSDR's requests for more information ignore sophisticated analyses that can be conducted using, for example, structure-activity relationships (SAR).

Response: In evaluating the need for additional data on a particular end point and assigning priority to data needs for the 10 substances, ATSDR first reviewed the available chemical-specific data for a given end point. In addition, ATSDR conducted SAR analyses on these substances and used the information in a strength-of-evidence approach to determine the need to assign priority for the missing information.

Comment: Request that ATSDR defer final assessment of its priority data needs until the industry groups have completed their work under EPA's voluntary children's chemical evaluation program (VCCEP), the hazardous air pollutants (HAPs) test rule, and an enforceable consent agreement (for 1,2-dichloroethane) among others.

Response: ATSDR has developed a process for assigning priority to data needs identified in the agency's toxicological profiles for hazardous substances. Specifically, the process for prioritizing the data needs is based on a logical scientific approach as described in ATSDR's Decision Guide (54 FR 37618, September 11, 1989). The identified priority data needs (PDNs) are then subjected to public and peer review. Currently, ATSDR considers these PDNs to be the most critical research needs for these hazardous substances. However, the agency will continue to evaluate new data for these substances obtained through additional testings, e.g., industry groups' participation in other federal agencies' programs. Specifically, ATSDR is working closely with EPA on these activities where we have identified overlapping research priorities. Therefore, the status of these PDNs may change in the future. In this current Federal Register Notice announcing the final list of PDNs, ATSDR states that these PDNs remain on the agency's list but that they may potentially be filled by individual industry groups working under specific EPA programs (see Table 1).

In summary, as a result of the agency's evaluation of all the public comments received for the 10 hazardous substances, two priority data needs were changed. Specifically, in vivo endocrine disruptor studies via oral exposure and multigeneration reproduction study involving multiple matings and examining male and female fertility via oral exposure were initially identified as priority data needs for pentachlorophenol. During the public comment period, ATSDR received from the Pentachlorophenol Task Force a recently completed two-generation reproduction study that was subsequently published in a peer-reviewed journal. ATSDR accepted the data and no longer assigned priority to these research needs. No changes were made to the priority data needs for the other nine substances as a result of the public comments.

Implementation of Substance-Specific Applied Research Program

Regarding the implementation of the SSARP, in section 104(i)(5)(D), CERCLA states that it is the sense of Congress that the costs for conducting this research program be borne by the manufacturers and processors of the hazardous substances under the Toxic Substances Control Act of 1976 (TSCA) and by registrants under the Federal Insecticide, Fungicide, and Rodenticide Act of 1972 (FIFRA), or by cost recovery from responsible parties under CERCLA. To execute this statutory intent, ATSDR developed a plan whereby parts of the SSARP are being conducted via regulatory mechanisms (TSCA/FIFRA), private-sector voluntarism, and through the direct use of CERCLA funds. CERCLA also requires that ATSDR consider recommendations of the Interagency Testing Committee (ITC), established under Section 4(e) of TSCA, on the types of research to be done. ATSDR actively participates on this committee; however, none of the proposed 10 substances are now on the ITC priority testing list.

The priority data needs identified in this Notice reflect the opinion of the agency, in consultation with other federal programs, of the research needed pursuant to ATSDR's authority under CERCLA. They do not represent the priority data needs for any other program. Consistent with section 104(i)(12) of CERCLA as amended (42 U.S.C. 9604(i)(12)), nothing in this research program shall be construed to delay or otherwise affect or impair the authority of the President, the Administrator of ATSDR, or the Administrator of EPA to exercise any authority regarding any other provision of law, including the Toxic Substances Control Act of 1976 (TSCA) and the Federal Insecticide, Fungicide, and Rodenticide Act of 1972 (FIFRA), or the response and abatement authorities of CERCLA. In developing this research program, ATSDR has worked with other federal programs to determine common substance-specific data needs, as well as mechanisms to implement research that may include authorities under TSCA and FIFRA, private-sector voluntarism, or the direct use of CERCLA funds.

When deciding the type of research that should be done, ATSDR considers the recommendations of the Interagency Testing Committee established under section 4(e) of TSCA. Federally funded projects that collect information from 10 or more respondents and that are funded by cooperative agreements are subject to review by the Office of Management and Budget (OMB) under the Paperwork Reduction Act. If the proposed project involves research on human subjects, the applicants must comply with Department of Health and Human Services regulations (45 CFR part 46) regarding the protection of human subjects. Assurance must be provided that the project will be subject to initial and continuing review by the appropriate institutional review committees. Overall, data generated from this research program will lend support to others conducting human health assessments involving these 10 substances by providing additional scientific information for the risk assessment process.

Substance-Specific Priority Data Needs

The final priority data needs are identified in Table 1. Unique identification numbers (37A through 46G) are assigned to the priority data needs for this list of 10 priority hazardous substances; the priority data needs for the first 50 substances were assigned identification numbers 1A through 36E (67 FR 4836). Parts of the proposed research are unique to CERCLA and may be most appropriately addressed by ATSDR programs as follows.

ATSDR's responsibility as a public health agency addressing environmental health issues is, when appropriate, to collect human data to validate substance-specific exposure and toxicity assumptions. ATSDR will obtain this information by conducting exposure and health effects studies, and by establishing and using substance-specific subregistries of people enrolled in the agency's National Exposure Registry who are potentially exposed to these substances. When a subregistry or a human exposure study is identified as a priority data need, the responsible ATSDR program will determine its feasibility, which depends on identifying appropriate populations and funding.

In addition, the need to collect, evaluate, and interpret environmental data from contaminated media around hazardous waste sites remains a priority data need for all 10 priority hazardous substances ATSDR has identified for this third set.

However, some of this information has already been collected through individual state programs and the EPA's CERCLA activities; therefore, ATSDR will evaluate the extant information from these programs to better characterize the need for additional site-specific information.

ATSDR acknowledges that the conduct of human studies to determine possible links between exposure to hazardous substances and human health effects may be accomplished through mechanisms other than agency programs. We encourage private-sector organizations and other governmental programs to use ATSDR's priority data needs to plan their research activities, including identifying appropriate populations and conducting studies to answer specific human health questions.

Dated: April 10, 2003.

Georgi Jones,

Director, Office of Policy and External Affairs, Agency for Toxic Substances and Disease Registry.

Table 1.—Final Substance—Specific Priority Data Needs (PDNs) for Third Set of 10 Priority Hazardous Substances

Substance	PDN ID	Priority data needs
Asbestos	37A	Epidemiologic studies of individuals occupationally exposed to asbestos levels lower than those experienced before the institution of current occupational standards governing the use of asbestos, but higher than current levels in the general population. These studies should be performed in conjunction with the immunotoxicity studies.
	37B	Immunotoxicity studies of individuals occupationally exposed to asbestos.
	37C	Development of human and rat lung retention models to aid in extrapolating between rat and human data.
	37D	Improved analytical methods for screening samples and determining the chemical structure of asbestos fibers. Also, techniques are needed to normalize studies in which different analytical methods were employed.
	37E	Exposure levels, fiber size distribution, and asbestos fiber type in areas with natural geologic deposits of friable asbestos and at hazardous waste sites. Also, techniques for estimating air levels of asbestos from soil concentrations and activity scenarios.
	37F	Exposure levels in humans living near hazardous waste sites and in other populations, such as humans living in areas with naturally high levels of friable asbestos.
	37G	Potential candidate for subregistry of exposed persons.
Benzidine	38A	Dose-response data for acute- and intermediate-duration exposure via the oral route (the study of intermediate-duration exposure should include evaluation of reproductive and endocrine organ histopathology, lymphoid tissues histopathology as well as examination of relevant blood components, and nervous system histopathology).
	38B	Exposure levels in humans living near hazardous waste sites.
	38C	Exposure levels in children.
	38D	Potential candidate for subregistry of exposed persons.
Chlorinated dibenzo-p-dioxins (CDDs)	39A	Studies via oral exposure designed to assess childhood susceptibility.
	39B	Comparative toxicokinetic studies examining the relative absorption of CDDs across exposure routes and the relative contribution of each exposure route to total body burdens.
	39C	Exposure levels in humans living near hazardous waste sites.
	39D	Exposure levels in children.
1,2-Dibromoethane	40A	Dose-response data in animals for acute- and intermediate-duration exposure by the oral route (the study of intermediate-duration exposure should include evaluation of neuropathology and observation for overt signs of neurotoxicity).
	40B	Multigeneration reproductive toxicity studies via oral exposure.
	40C	Developmental toxicity studies via oral exposure.
	40D	Immunotoxicity battery studies via oral exposure.
	40E	Exposure levels in humans living near hazardous waste sites and in other populations, such as workers exposed to 1,2-dibromoethane.
	40F	Exposure levels in children.
	40G	Potential candidate for subregistry of exposed persons.
1,2-Dichloroethane *	41A	Dose-response data in animals for acute-duration (14-day) exposure by the inhalation route, including a comparison of young and adult animals.
	41B	Dose-response data in animals for acute-duration (14-day) exposure by the oral route, including a comparison of young and adult animals.
	41C	Dose-response data in animals for intermediate-duration exposure by the inhalation route (the study should be performed in conjunction with the neurotoxicology battery of tests).
	41D	Neurotoxicology battery of tests following inhalation exposure.
	41E	Neurotoxicology battery of tests following oral exposure.
	41F	Dose-response data in animals for chronic-duration exposure by the oral route.
	41G	Developmental toxicity data for inhalation exposure (assessment of developmental cardiotoxicity and neurotoxicity).
	41H	Developmental toxicity data for oral exposure (assessment of developmental cardiotoxicity and neurotoxicity).
	41I	Additional analyses and studies for comparative toxicokinetics across species, ages, routes, and durations.
	41J	Children's susceptibility.
	41K	Exposure levels in humans living near hazardous waste sites.
	41L	Exposure levels in children.
	41M	Potential candidate for subregistry of exposed persons.
1,1-Dichloroethene *	42A	Dose-response data in animals for acute-duration exposure by the inhalation route.
	42B	Dose-response data in animals for chronic-duration exposure by the inhalation route.
	42C	Dose-response data in animals for acute- and intermediate-duration exposure by the oral route.
	42D	Carcinogenicity studies in two species following inhalation exposure.
	42E	Reproductive toxicity studies assessing male and female end points following inhalation exposure.
	42F	Developmental toxicity studies following oral exposure.
	42G	Immunotoxicology battery of tests following oral exposure.
	42H	Battery of neurobehavioral tests following inhalation exposure.
	42I	Children's susceptibility.
	42J	Exposure levels in humans living near hazardous waste sites.
	42K	Exposure levels in children.
	42L	Potential candidate for subregistry of exposed persons.
Ethylbenzene *	43A	Dose-response data for acute-duration exposure by the inhalation route.
	43B	Dose-response data for chronic-duration exposure by the inhalation route.
	43C	Dose-response data for acute- and intermediate-duration exposure by the oral route; the study of intermediate-duration exposure should include an evaluation of clinical signs of neurotoxicity and histopathology of reproductive organs, endocrine glands, and nervous system.
	43D	Multigeneration toxicity study examining reproductive end points and indicators of endocrine disruption following inhalation exposure.
	43E	Two-species developmental study with continued assessment of offspring during postnatal development following oral exposure.
	43F	Studies for comparative toxicokinetics.
	43G	Exposure levels in humans living near hazardous waste sites.
	43H	Exposure levels in children.
	43I	Potential candidate for subregistry of exposed persons.
Pentachlorophenol	44A	Comparative toxicokinetic studies.
	44B	Exposure levels in humans living near hazardous waste sites.
	44C	Exposure levels in children through play activities near contaminated environmental media.
	44D	Potential candidate for subregistry of exposed persons.
1,1,2,2-Tetrachloroethane	45A	Two-species developmental toxicity study by the oral route.
	45B	Immunotoxicity battery following oral exposure.
	45C	Mammalian in vivo genotoxicity assays.
	45D	Exposure levels in humans living near hazardous waste sites.
	45E	Exposure levels in children.
	45F	Potential candidate for subregistry of exposed persons.
Total xylenes	46A	Dose-response data for chronic-duration exposure by the oral route. This study should be done in conjunction with the neurotoxicology battery of tests.
	46B	Neurotoxicology battery of tests following oral exposure.
	46C	Two-generation reproductive study following oral exposure.
	46D	Developmental toxicity study that includes neurodevelopmental end points following oral exposure.
	46E	Exposure levels in humans living near hazardous waste sites.
	46F	Exposure levels in children.
	46G	Potential candidate for subregistry of exposed persons.
* Some of the toxicity priority data needs may potentially be filled by individual industry groups working under specific EPA programs.