[Federal Register: January 31, 2002 (Volume 67, Number 21)][Notices] [Page 4835-4854]From the Federal Register Online via GPO Access [wais.access.gpo.gov][DOCID:fr31ja02-158] [[Page 4835]]-----------------------------------------------------------------------Part IVDepartment of Health and Human Services-----------------------------------------------------------------------Agency for Toxic Substances and Disease Registry-----------------------------------------------------------------------Update on the Status of the Superfund Substance-Specific Applied Research Program; Notice[[Page 4836]]-----------------------------------------------------------------------DEPARTMENT OF HEALTH AND HUMAN SERVICESAgency for Toxic Substances and Disease Registry[ATSDR-178] Update on the Status of the Superfund Substance-Specific Applied Research ProgramAGENCY: Agency for Toxic Substances and Disease Registry (ATSDR), Department of Health and Human Services (HHS).ACTION: Notice.-----------------------------------------------------------------------SUMMARY: This Notice provides the status of ATSDR's Superfund-mandated Substance-Specific Applied Research Program (SSARP) which was last updated in a Federal Register notice in 1999 (64 FR 2760). Authorized by the Comprehensive Environmental Response, Compensation, and Liability Act of 1980 (CERCLA, also known as the Superfund statute), as amended by the Superfund Amendments and Reauthorization Act of 1986 (SARA) 42 U.S.C. 9604 (i), this research program was initiated on October 17, 1991. At that time, a list of priority data needs for 38 priority hazardous substances frequently found at waste sites 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). The 38 substances, each of which is found on ATSDR's Priority List of Hazardous Substances (66 FR 54014, October 25, 2001), are aldrin/dieldrin, arsenic, benzene, beryllium, cadmium, carbon tetrachloride, chloroethane, chloroform, chromium, cyanide, p,p'-DDT,DDE,DDD, di(2-ethylhexyl) phthalate, lead, mercury, methylene chloride, nickel, polychlorinated biphenyl compounds (PCBs), polycyclic aromatic hydrocarbons (PAHs--includes 15 substances), selenium, tetrachloroethylene, toluene, trichloroethylene, vinyl chloride, and zinc. On July 30, 1997, priority data needs for 12 additional hazardous substances frequently found at waste sites were determined and announced in the Federal Register (62 FR 40820). The 12 substances, each of which is included in ATSDR's Priority List of Hazardous Substances, are chlordane, 1,2-dibromo-3-chloropropane, di-n-butyl phthalate, disulfoton, endrin (includes endrin aldehyde), endosulfan (alpha-, beta-, and endosulfan sulfate), heptachlor (includes heptachlor epoxide), hexachlorobutadiene, hexachlorocyclohexane (alpha-, beta-, delta- and gamma-), manganese, methoxychlor, and toxaphene. Recently, priority data needs for 10 additional hazardous substances frequently found at waste sites were determined and announced in the Federal Register (66 FR 42659). The 10 substances, each of which is included in ATSDR's Priority List of Hazardous Substances, are asbestos, benzidine, chlorinated dibenzo-p-dioxins, 1,2-dibromoethane, 1,2-dichloroethane, 1,1-dichloroethane, ethylbenzene, pentachlorophenol, 1,1,2,2-tetrachloroethane, and total xylenes. ATSDR invited the public to comment on the priority data needs for these substances during a period of 90 days. ATSDR is responding to the comments, and a final list of priority data needs will be published in the Federal Register in the near future. To date, 190 priority data needs have been identified for the first 50 hazardous substances (Table 1). ATSDR fills these data needs through U.S. Environmental Protection Agency (EPA) regulatory mechanisms (test rules), private-sector voluntarism, and the direct use of CERCLA funds. Additional data needs are being addressed through collaboration with the National Toxicology Program (NTP), by ATSDR's Great Lakes Human Health Effects Research Program, and other agency programs. Currently, 101 priority data needs associated with the first 50 substances are being addressed via these mechanisms, and 62 priority data needs have been filled. Priority data needs documents describing ATSDR's rationale for prioritizing research needs for each substance are available. 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 identified in this Notice by indicating their interest through submission of a letter of intent to ATSDR (see ADDRESSES section of this Notice). A Tri-Agency Superfund Applied Research Committee (TASARC) composed of scientists from ATSDR, NTP, and the EPA, will review all proposed voluntary research efforts.DATES: ATSDR provides updates on the status of its Substance-Specific Applied Research Program approximately every 3 years. ATSDR considers the voluntary research effort to be important to the continuing implementation of the SSARP. Therefore, the agency strongly encourages private-sector organizations to volunteer at any time to conduct research to fill data needs until ATSDR announces that other research mechanisms are in place to address those specific data needs.ADDRESSES: Private-sector organizations interested in volunteering to conduct research can write to Dr. William Cibulas, Chief, Research Implementation Branch, Division of Toxicology, ATSDR, 1600 Clifton Road, NE., Mailstop E-29, Atlanta, Georgia 30333, e-mail: wcibulas@cdc.gov. Information about pertinent ongoing or completed research that may fill priority data needs cited in this Notice should be similarly addressed. Other Requirements: Projects that involve the collection of information from 10 or more individuals and funded by cooperative agreement will be subject to review by the Office of Management and Budget (OMB) under the Paperwork Reduction Act.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: (404) 498-0715, fax: (404) 498-0092. This notice will also be available on ATSDR's website at http://www.atsdr.cdc.gov or you may call the ATSDR Information Center at 1-888-422-8737.SUPPLEMENTARY INFORMATION:Background CERCLA as amended by SARA (42 U.S.C. 9604(i)) requires that ATSDR (1) jointly with the EPA, develop and prioritize a list of hazardous substances found at National Priorities List (NPL) sites, (2) prepare toxicological profiles for these substances, and (3) assure the initiation of a research program to address identified data needs associated with the substances. Before starting such a program, ATSDR will consider recommendations of the Interagency Testing Committee on the type of research that should be done. This committee was established under Section 4(e) of the Toxic Substances Control Act of 1976 [15 U.S.C. 2604(e)](TSCA). The major goals of the ATSDR SSARP are (1) to address the substance-specific information needs of the public and scientific community, and (2) to supply information necessary to improve the database used to conduct comprehensive public health assessments of populations living near hazardous waste sites. We anticipate that the information will help to establish linkages between levels of contaminants in the environment and levels in human tissue and organs[[Page 4837]]associated with adverse health effects. Once such links have been established, strategies to mitigate potentially harmful exposures can be developed. This program will also provide data that can be generalized to other substances or areas of science, including risk assessment of chemicals, thus creating a scientific information base for addressing a broader range of data needs. 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 addition, ATSDR is a member of NTP's 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. CERCLA section 104(i)(5)(D) 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 substance in question,'' as required in TSCA and the Federal Insecticide, Fungicide, and Rodenticide Act of 1972 (7 U.S.C. 136 et seq.) (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 the regulatory mechanisms referenced (TSCA/FIFRA), private-sector voluntarism, and the direct use of CERCLA funds. The TASARC, composed of scientists from ATSDR, NTP, and EPA, has been set up to: (1) Advise ATSDR on the assignment of priorities for mechanisms to address data needs, (2) Coordinate knowledge of research activities to avoid duplication of research in other programs and under other authorities, (3) Advise ATSDR on issues of science related to substance-specific data needs, and (4) Maintain a scheduled forum that provides an overall review of the ATSDR SSARP. TASARC has met 10 times since the initiation of the SSARP. It has guided referral of data needs to EPA and the associated development of test rules through TSCA. In addition, it has endorsed the proposals of several private-sector organizations to conduct voluntary research. Furthermore, TASARC has become a forum for other federal agencies to bring forth their research agendas. For example, it has coordinated research efforts on hazardous pollutants with the Office of Air and Radiation, EPA. TASARC has developed testing guidelines for immunotoxicity; and has endorsed the use of decision-support methodologies such as physiologically based pharmacokinetic (PBPK) modeling and benchmark-dose modeling, where appropriate. Additional data needs are being addressed through collaborative research efforts with NTP, by ATSDR's Great Lakes Human Health Effects Research Program, and other agency programs. To date, 101 priority data needs associated with the first 50 substances (Table 1) are being addressed via these mechanisms.Criteria for Evaluating Status of Priority Data Needs To update the activities covered under the SSARP, criteria for evaluating the status of the priority data needs were developed. Based on these criteria and the review of the current literature, a priority data need can be filled, or unchanged. In the event a priority data need is considered filled, it does not necessarily mean that the study has been completed and that ATSDR has accepted the data. It does, however, indicate that the agency no longer considers it a priority to initiate additional studies at this time. The criteria for evaluating the status of the priority data needs are described below.General Criteria A priority data need is filled: If it has been referred to one of the implementation mechanisms and research has been initiated, or If an updated ATSDR toxicological profile or other recent review document contains relevant new (peer-reviewed and publicly available) studies since the finalization of the priority data needs document; and it is generally agreed that a priority data need no longer exists. A priority data need remains unchanged: If no mechanism or information has been identified to address the priority data need, or If the priority data need is included in the ATSDR/EPA test rule under development, or is associated with a pilot substance in EPA's Voluntary Children's Chemical Evaluation Program.Specific Criteria Since the 1999 SSARP update in the Federal Register, ATSDR has developed specific criteria for two categories of data needs described below. Epidemiologic studies--A priority data need is filled if multiple new studies assessing key health end points are available in ATSDR's updated toxicological profile and/or ongoing studies have been identified, e.g., human health studies supported by ATSDR's Great Lakes Human Health Effects Research Program or the Minority Health Professions Foundation Research Program. In some cases, ATSDR indicates that it will continue to evaluate new data as they become available to determine whether additional studies are needed. Exposure levels in humans--A priority data need is filled if (a) there are current and adequate biomonitoring data for exposed populations associated with health effects (from published or ongoing studies), or (b) there are reference range data (e.g., National Health and Nutrition Examination Survey (NHANES)) or generally agreed upon background population levels. In the latter case, ATSDR acknowledges that reference concentration data can support exposure and health assessments at waste sites, but the agency also continues to recognize the importance of collecting additional data on uniquely exposed populations at waste sites. It should be noted that the status of the priority data needs may change in future updates of the SSARP as new information becomes available. Further, during the literature review, new studies may be identified suggesting other effects of concern, such as those related to endocrine disruptors and children's health, which have not been included in the original list of priority data needs. In such cases, additional priority data needs may be added to the research agenda. For example, for both tetrachloroethylene and trichloroethylene, the priority data need for developmental neurotoxicity study is now listed separately from the priority data need for one-species developmental toxicity (see Table 1). Therefore, the total number of priority data needs changed accordingly, i.e., from a total of 188 reported in the Federal Register notice in 1999 (64 FR 2760) to 190 in the current update notice. Also, research needs previously considered filled might be reassigned as priority data needs, e.g., if a previously derived Minimal Risk Level (MRL), a[[Page 4838]]health guidance value, was withdrawn from the updated ATSDR toxicological profile. Finally, a priority data need previously associated with an implementation mechanism, may no longer be addressed via that mechanism (or any other mechanism) if the study being conducted to fill the specific priority data need is discontinued. Based on the above criteria, 62 priority data needs have been filled.Update of Activities in the SSARP An update of the activities associated with the mechanisms for implementing the ATSDR Substance-Specific Applied Research Program (SSARP) is discussed below. Publications and reports of research completed under the various implementation mechanisms are available by writing to ATSDR (see ADDRESSES section of this Notice).A. TSCA/FIFRA In developing and implementing the SSARP, ATSDR, NTP, and EPA have identified a subset of priority data needs for substances of mutual interest to the federal programs. These data needs are being addressed through a program of toxicologic testing under TSCA according to established procedures and guidelines. On several occasions when ATSDR identified priority data needs for oral exposure, other agencies needed inhalation data. In response, ATSDR is considering proposals to conduct inhalation studies in conjunction with physiologically based pharmacokinetic (PBPK) studies in lieu of oral studies. ATSDR expects that inhalation data derived from these studies can be used with PBPK modeling to address its oral toxicity data needs. Currently, an EPA/ATSDR test rule, under development, includes eight ATSDR substances, i.e., benzene, chloroethane, cyanide (hydrogen cyanide and sodium cyanide), methylene chloride, tetrachloroethylene, toluene and trichloroethylene, and addresses 18 ATSDR priority data needs (Table 2). The test rule is presently undergoing ATSDR and EPA final review. We anticipate it will be available for public comment in the near future. TASARC has established an interagency task force on metals and has conducted a survey to assess federal agencies' needs for testing metals. Currently, the task force has agreed to examine at least seven metals included in the ATSDR's SSARP (arsenic, beryllium, chromium, manganese, mercury, nickel, and selenium, associated with 22 priority data needs) (Table 2). The EPA will solicit testing proposals for these metals and pursue test rule development for these metals at a later date.B. Private-Sector Voluntarism On February 7, 1992, as part of the Substance-Specific Applied Research Program (SSARP), ATSDR announced a set of proposed procedures for conducting voluntary research (57 FR 4758). Revisions based on public comments were published on November 16, 1992 (57 FR 54160). Private-sector organizations were encouraged to volunteer to conduct research to fill specific priority data needs at no expense to ATSDR. To date, ATSDR has established agreements with the American Chemistry Council (ACC) [formerly the Chemical Manufacturers Association (CMA)], the General Electric Company (GE), and the Halogenated Solvents Industry Alliance, Inc. (HSIA) to conduct substance-specific research (Table 2). Through the voluntary research efforts of these organizations, at least 16 research needs for polychlorinated biphenyl compounds [PCBs], methylene chloride, tetrachloroethylene, trichloroethylene, and vinyl chloride are being addressed (Table 2).American Chemistry Council (ACC) Formerly the Chemical Manufacturers Association (CMA) In 1996, ATSDR entered into a memorandum of understanding (MOU) with ACC covering two studies, ``Vinyl chloride: Combined inhalation two-generation reproduction and developmental toxicity study in CD rats.'' In November 2000, ATSDR accepted the final reports of the studies.General Electric Company (GE) In 1995, ATSDR entered into an MOU with SSARP covering two studies on PCBs: (1) ``An assessment of the chronic toxicity and oncogenicity of Aroclors 1016, 1242, 1254, and 1260 administered in diet to rats,'' including ``PCB congener analyses,'' and (2) ``Metabolite detection as a tool for determining naturally occurring aerobic PCB biodegradation.'' While the above studies do not address ATSDR's priority data needs for PCBs, they do address other agency research needs for these substances. The agency accepted the final report for the chronic toxicity and oncogenicity of the four aroclors in October 1997,and the final report for the aerobic biodegradation study in July 1999.Halogenated Solvents Industry Alliance (HSIA) In 1995, ATSDR entered into an MOU with HSIA covering studies to address three priority data needs for methylene chloride. The studies, ``Addressing priority data needs for methylene chloride with physiologically based pharmacokinetic modeling,'' evaluated acute- and subchronic-duration toxicity and developmental toxicity via oral exposure. The data were obtained using physiologically based pharmacokinetic modeling. The final report for these studies was accepted by the agency in February 1997. In September 1999, HSIA entered into a second MOU with ATSDR to conduct a study, ``Methylene chloride: 28 day inhalation toxicity study in the rat to assess potential immunotoxicity.'' The agency accepted the final report for the study in November 2000. HSIA is in the process of obtaining oral data from the inhalation study using PBPK modeling. This is because ATSDR has determined ingestion of contaminated environmental media to be the primary exposure route at hazardous waste sites. HSIA intends to conduct similar immunotoxicity studies for tetrachloroethylene and trichloroethylene. In February 2000, ATSDR signed a third MOU with HSIA, which conducted a study, ``Trichloroethylene: Inhalation Developmental Toxicity Study in CD Rats.'' The agency accepted the final report of the study in September 2001. As in the case of the methylene chloride immunotoxicity study described above, HSIA intends to obtain developmental toxicity data for oral exposure using PBPK modeling. Also, HSIA plans to perform similar developmental toxicity studies for tetrachloroethylene. Finally, ATSDR and HSIA are continuing discussion to address additional priority data needs for trichloroethylene and tetrachloroethylene in conjunction with EPA's pilot studies for its Voluntary Children's Chemical Evaluation Program. In addition to the substance-specific MOUs described above, in March 2001, ATSDR also signed an MOU with the Electric Power Research Institute, Inc. (EPRI) on ``Verification of Techniques for Assessing the Effects of Neurotoxicants on Neurodevelopment in Children.'' The objective of the study is to validate a battery of neurodevelopmental tests for use in assessing the effects of prenatal or postnatal exposure to developmental neurotoxicants. The study includes an evaluation of a broad spectrum of[[Page 4839]]functions; therefore, the validation of these tests will be useful for further assessing the developmental neurotoxicity of some of the ATSDR priority substances such as the PCBs, methylmercury, and lead. In addition to the private sector support (EPRI), ATSDR is coordinating a federal effort (via interagency agreements with EPA, Food and Drug Administration [FDA] and NIEHS) to support the study.C. CERCLA-Funded Research (Minority Health Professions Foundation Research Program) During FY 1992, ATSDR announced a $4 million cooperative agreement program with the Minority Health Professions Foundation (MHPF) to support substance-specific investigations. A not-for-profit Internal Revenue Code 501(c)(3) organization, the MHPF comprises 11 minority health professions schools. Its primary mission is to research health problems that disproportionately affect poor and minority citizens. The purpose of this cooperative agreement is to address substance-specific data needs for priority hazardous substances identified by ATSDR. In addition, this agreement strengthens the environmental health research opportunities for scientists and students at MHPF member institutions and enhances existing disciplinary capacities to conduct research in toxicology and environmental health. In the first 5-year project period that concluded during FY 1997, nine priority data needs for 21 priority hazardous substances and 22 other research needs for these and other substances were addressed. The MHPF has developed a report, ``Environmental Health and Toxicology Research Program: Meeting Environmental Health Challenges Through Research, Education, and Service,'' that describes the research findings and other successes from the first 5 years of the program. New research initiated in the second 5-year project period includes studies to address 10 additional priority data needs for chlordane, 1,2-dibromo-3-chloropropane, di-n-butyl phthalate, lead, manganese, the polycyclic aromatic hydrocarbons (PAHs), zinc, and eight other research needs. To date, the MHPF activities have resulted in the publication of 50 manuscripts in peer-reviewed journals. The institutions receiving awards and their current respective research projects that fill identified research needs are listed in Table 2.D. National Toxicology Program (NTP) Section 104(i)(5) of CERCLA directs the administrator of ATSDR (in consultation with the administrator of EPA and agencies and programs of the Public Health Service) to assess whether adequate information on the health effects of priority hazardous substances found at NPL sites is available. Where adequate information is not available, ATSDR, in cooperation with the National Toxicology Program (NTP), is required to assure the initiation of a program of research designed to determine these health effects (and techniques for developing methods to determine such health effects). ATSDR has been collaborating with NTP to address priority data needs of mutual interest, including (1) di-n-butyl phthalate: dose-response data in animals for acute-duration exposure via oral exposure route, (2) carbon tetrachloride: immunotoxicology study via oral exposure, and (3) heptachlor: reproductive toxicity study via oral exposure (Table 2).E. Great Lakes Human Health Effects Research Program Some of the priority data needs identified in the SSARP have been independently identified as research needs through the ATSDR Great Lakes Human Health Effects Research Program, a separate research program. In support of the Great Lakes Critical Programs Act of 1990, ATSDR announced in FY 1992 the availability of $2 million for a grant program to conduct research on the potential for short- and long-term adverse health effects from consumption of contaminated fish from the Great Lakes basin. Research undertaken through this program is intended to build on and amplify the results of past and ongoing fish consumption research in the Great Lakes basin. The ATSDR-supported research projects focus on known high-risk populations to define further the human health consequences of exposure to persistent toxic substances (PTSs) identified in the Great Lakes basin. These at-risk populations include sport anglers; African Americans, Asians and other non-English speaking populations; pregnant women; fetuses, nursing infants, and children of mothers who consume contaminated Great Lakes sport fish; the elderly, and the urban poor. To date, the research activities of the ATSDR Great Lakes research program have resulted in 55 publications in peer-reviewed journals. Currently, 14 priority data needs for 24 priority hazardous substances (including 15 PAHs) identified in the SSARP are being addressed through this program. The institutions receiving awards and their respective studies are listed in Table 2.F. Other ATSDR Programs In its role as a public health agency addressing environmental health, ATSDR may collect human data to validate substance-specific exposure and toxicity findings. The need for additional information on levels of contaminants in humans has been identified, and remains as a priority data need for 49 of the first 50 priority substances (Table 1). ATSDR will obtain this information through exposure and health effects studies, and through establishing and using substance-specific subregistries of people within the agency's National Exposure Registry who have potentially been exposed to these substances. The list of the 50 priority hazardous substances in the SSARP was forwarded to ATSDR's Exposure and Disease Registry Branch (EDRB), Division of Health Studies, for consideration as potential candidates for subregistries of exposed persons, based on criteria described in its 1994 document, ``National Exposure Registry: Policies and Procedures Manual (Revised),'' Agency for Toxic Substances and Disease Registry, Public Health Service, U.S. Department of Health and Human Services, Atlanta, Georgia, NTIS Publication No. PB95-154571. To date, of the first 50 priority substances in the SSARP, ATSDR has established subregistries for benzene, chromium, and trichloroethylene. Arsenic, cadmium, and lead are not considered to be in the pool of candidate substances for an exposure registry at this time, and, therefore, are not considered priority data needs. This decision will be reevaluated as more information on the chemicals and exposure sites become available. All other substances in the SSARP (Table 1) remain in the candidate pool and therefore continue to be classified as priority data needs. They will be considered for selection as primary contaminants during each selection process.G. Conclusion The results of the research conducted via the SSARP are expected to provide information necessary to improve the database used to conduct comprehensive public health assessments of populations living near hazardous waste sites. The information will enable the agency to establish linkages between levels of contaminants in the environment and levels in human tissue and organs associated with adverse health effects, ultimately helping to determine methods for interdicting exposure and mitigating toxicity. This program will also provide[[Page 4840]]data that can be generalized to other substances or areas of science, including risk assessment of chemicals, thus creating a scientific information base for addressing a broader range of data needs. The agency plans to provide an update on the status of this research program approximately every 3 years. Dated: January 25, 2002.Georgi Jones,Director, Office of Policy and External Affairs, Agency for Toxic Substances and Disease Registry. Table 1.--ATSDR's Substance-Specific Priority Data Needs for 50 Priority Hazardous Substances---------------------------------------------------------------------------------------------------------------- Status change Substances PDN ID \1\ PDN description Program \2\ \3\ Comments \4\----------------------------------------------------------------------------------------------------------------Aldrin/Dieldrin............... 1A Dose-response .............. Filled....... An MRL was data in animals derived in the for intermediate- 2000 updated duration oral toxicological exposure. profile. 1B Bioavailability from soil. 1C Exposure levels .............. ............. This priority in humans living data need, near hazardous previously waste sites and addressed in a other study in the populations, Great Lakes such as exposed research workers. program, is no longer investigated in that study. 1D Potential ATSDR......... candidate for subregistry of exposed persons.Arsenic....................... 2A Comparative EPA. ................ toxicokinetic studies to determine if an appropriate animal species can be identified. 2B Half-lives in EPA........... surface water, groundwater. 2C Bioavailability EPA........... from soil. 2D Exposure levels G. Lakes...... Filled....... Background level in humans living data are near hazardous available in waste sites and ATSDR's 1993 other toxicological populations, profile, and at such as exposed least seven workers. ATSDR studies that evaluated urine arsenic levels and potential adverse health effects are available. Also, additional studies are available in ATSDR's 2000 updated toxicological profile.Benzene....................... 3A Dose-response EPA........... data in animals for acute- and intermediate- duration oral exposure. The subchronic study should include an extended reproductive organ histopathology. 3B Two-species EPA........... ............. Previously developmental planned study toxicity study in the MHPF via oral research exposure. program to address this priority data need was canceled. 3C Neurotoxicology EPA........... battery of tests via oral exposure. 3D Epidemiologic .............. Filled....... Based on an studies on the evaluation of health effects the data in of benzene ATSDR's 1997 (Special updated emphasis end toxicological points include profile. ATSDR immunotoxicity). will continue to evaluate new data as they become available to determine if additional studies are needed. 3E Exposure levels .............. Filled....... Reference range in humans living concentrations near hazardous are available waste sites and (Ashley et al. other 1992, 1994; populations, Needham et al. such as exposed 1995), and at workers. least one ATSDR study that evaluated blood benzene levels and potential adverse health effects is available. ATSDR acknowledges that reference concentration data can support exposure and health assessments at waste sites, but the agency also continues to recognize the importance of collecting additional data on uniquely exposed populations at waste sites.[[Page 4841]]Beryllium..................... 4A Dose-response EPA........... data in animals for acute- and intermediate- duration inhalation exposures. The subchronic study should include extended reproductive organ histopathology. 4B Two-species EPA........... developmental toxicity study via inhalation exposure. 4C Environmental EPA........... fate in air; factors affecting bioavailability in air. 4D Analytical .............. Filled....... Based on an methods to evaluation of determine the data in environmental ATSDR's 2000 speciation. updated toxicological profile. 4E Immunotoxicology EPA........... battery of tests following oral exposure. 4F Exposure levels .............. Filled....... Reference range in humans living concentrations near hazardous in urine are waste sites and available other (Paschal et al. populations, 1998). ATSDR such as exposed acknowledges workers. that reference concentration data can support exposure and health assessments at waste sites, but the agency also continues to recognize the importance of collecting additional data on uniquely exposed populations at waste sites. 4G Potential ATSDR......... candidate for subregistry of exposed persons.Cadmium....................... 5A Analytical .............. Filled....... Based on an methods for evaluation of biological the data in tissues and ATSDR's 1999 fluids and updated environmental toxicological media. profile. 5B Exposure levels G. Lakes...... Filled....... Referent in humans living population near hazardous urine cadmium waste sites and levels are other available populations, (NHANES III), such as exposed and at least workers. nine ATSDR studies that evaluated blood and urine cadmium levels and potential adverse health effects are available.Carbon tetrachloride.......... 6A Dose-response data in animals for chronic oral exposure. The study should include extended reproductive organ and nervous tissue histopathology. 6B Immunotoxicology NTP........... Filled....... NTP dose-finding battery of tests study and one via oral new study in exposure. ATSDR's 1994 updated toxicological profile addressed the priority data need. 6C Half-life in soil .............. Filled....... One new study in ATSDR's 1994 updated toxicological profile provided information on half-life in soil. 6D Exposure levels .............. Filled....... Reference range in humans living concentrations near hazardous in blood are waste sites and available other (Ashley et al. populations, 1992, 1994; such as exposed Needham et al. workers. 1995). ATSDR acknowledges that reference concentration data can support exposure and health assessments at waste sites, but the agency also continues to recognize the importance of collecting additional data on uniquely exposed populations at waste sites.[[Page 4842]] 6E Potential ATSDR......... candidate for subregistry of exposed persons.Chlordane..................... 7A Oral MHPF.......... Filled....... Availability of multigenerationa NTP........... ongoing study l studies to in the MHPF evaluate research reproductive program and toxicity. anticipated initiation of an NTP study in 2002. 7B Bioavailability studies following ingestion of contaminated media. 7C Exposure levels in humans living near hazardous waste sites and other populations potentially exposed to chlordane. 7D Potential ATSDR......... candidate for subregistry of exposed persons.Chloroethane.................. 8A Dose-response EPA........... data in animals for acute- and intermediate- duration oral exposures. The subchronic study should include an evaluation of immune and nervous system tissues, and extended reproductive organ histopathology. 8B Dose-response EPA........... data in animals for chronic inhalation exposures. The study should include an evaluation of nervous system tissues. 8C Potential ATSDR......... candidate for subregistry of exposed persons.Chloroform.................... 9A Dose-response .............. Filled....... An MRL was data in animals derived in for intermediate- ATSDR's 1997 duration oral updated exposure. toxicological profile. 9B Epidemiologic .............. Filled....... Based on an studies on the evaluation of health effects the data in of chloroform ATSDR's 1997 (Special updated emphasis end toxicological points include profile. ATSDR cancer, will continue neurotoxicity, to evaluate new reproductive and data as they developmental become toxicity, available to hepatotoxicity, determine if and renal additional toxicity). studies are needed. 9C Exposure levels .............. Filled....... Reference range in humans living concentrations near hazardous in blood are waste sites and available other (Ashley et al. populations, 1992, 1994; and such as exposed Needham et al. workers. 1995). ATSDR acknowledges that reference concentration data can support exposure and health assessments at waste sites, but the agency also continues to recognize the importance of collecting additional data on uniquely exposed populations at waste sites.[[Page 4843]] 9D Potential ATSDR......... candidate for subregistry of exposed persons.Chromium...................... 10A Dose-response EPA........... data in animals for acute- duration exposure to chromium (VI) and (III) via oral exposure and for intermediate- duration exposure to chromium (VI) via oral exposure. 10B Multigeneration EPA........... reproductive toxicity study via oral exposure to chromium (III) and (VI). 10C Immunotoxicology EPA........... battery of tests following oral exposure to chromium (III) and (VI). 10D Two-species EPA........... developmental toxicity study via oral exposure to chromium (III) and (VI). 10E Exposure levels G. Lakes...... Filled....... Reference range in humans living concentrations near hazardous in urine are waste sites and available other (Paschal et al. populations, 1998). Also, at such as exposed least two ATSDR workers. studies that evaluated urine chromium levels and potential adverse health effects are available. In addition, this PDN is being addressed in a study in the Great Lakes research program.Cyanide....................... 11A Dose-response EPA........... data in animals for acute- and intermediate- duration exposures via inhalation. The subchronic study should include extended reproductive organ histopathology and evaluation of neurobehavioral and neuropathologica l end points. 11B Two-species EPA........... developmental toxicity study via oral exposure. 11C Evaluation of the .............. Filled....... A study environmental addressing the fate of cyanide priority data in soil. need was submitted by industry to EPA in response to EPA's solicitation for proposals for test rule making. Scientists from EPA and ATSDR reviewed the study and considered that this research need is no longer a priority. 11D Exposure levels in humans living near hazardous waste sites and other populations, such as exposed workers. 11E Potential ATSDR......... candidate for subregistry of exposed persons.1,2-dibromo-3-chloropro pane.. 12A Dose-response data in animals for acute- duration exposure via the oral route (including reproductive organ histopathology). 12B Dose-response data in animals for chronic- duration exposure via the oral route (including reproductive organ histopathology). 12C Two-species developmental toxicity study via oral exposure.[[Page 4844]] 12D Immunotoxicology .............. ............. Previously testing battery planned study via oral in the MHPF exposure. research program to address this priority data need was canceled. 12E Neurotoxicology .............. ............. Previously testing battery planned study via oral in the MHPF exposure. research program to address this priority data need was canceled. 12F Exposure levels in humans living near hazardous waste sites and other exposed populations, such as exposed workers. 12G Potential ATSDR......... candidate for subregistry of exposed persons.DDT........................... 13A Dose-response data in animals for chronic- duration oral exposure. 13B Comparative toxicokinetic study (across routes/species). 13C Bioavailability and bioaccumulation from soil. 13D Epidemiologic G. Lakes...... Filled....... Multiple new studies on the studies in health of DDT, ATSDR's 2000 DDD, and DDE updated (Special toxicological emphasis end profile and points include five ongoing immunotoxicity, studies in the and reproductive Great Lakes and research developmental program are toxicity. available. 13E Exposure levels G. Lakes...... in humans living near hazardous waste sites and other populations, such as exposed workers. 13F Potential ATSDR......... candidate for subregistry of exposed persons.Di(2-ethyl-hexyl)phthalate.... 14A Epidemiologic studies on the health effects of DEHP (Special emphasis end points include cancer). 14B Dose-response .............. ............. This research data in animals need is for acute- and reassigned as a intermediate- priority data duration oral need because of exposures. The the data in subchronic study ATSDR's 2000 should include updated an extended toxicological histopathologic profile. evaluation of Specifically, the immunologic the previously and neurologic developed MRL systems. for acute- duration (1993 toxicological profile) was withdrawn, and a provisional MRL for intermediate- duration was derived replacing the previously established one. 14C Multigeneration .............. ............. This research reproductive need is toxicity study reassigned as a via oral priority data exposure. need based on an evaluation of the data in ATSDR's 2000 updated toxicological profile. Also, the NTP Center for the Evaluation of Risks to Human Reproduction Expert Panel Report (October 2000) has identified critical data needs for reproductive toxicity 14D Comparative .............. ............. The NTP Center toxicokinetic for the studies (Studies Evaluation of designed to Risks to Human examine how Reproduction primates Expert Panel metabolize and Report (October distribute DEHP 2000) has also as compared with identified rodents via oral critical data exposure). needs for toxicokinetic information. 14E Exposure levels in humans living near hazardous waste sites and other populations, such as exposed workers. 14F Potential ATSDR......... candidate for subregistry of exposed persons.[[Page 4845]]Di-n-butyl phthalate.......... 15A Dose-response NTP........... Filled....... NTP completed a data in animals 14-day study. for acute- duration exposure via the oral route. 15B Dose-response data in animals for chronic- duration exposure via the oral route. 15C Carcinogenicity studies via oral exposure. 15D In vivo MHPF.......... Filled....... Availability of genotoxicity ongoing studies studies. in the MHPF research program. 15E Immunotoxicology .............. ............. Previously studies via oral planned study exposure. in the MHPF research program to address this priority data need was canceled. 15F Neurotoxicity .............. ............. Previously studies via oral planned study exposure. in the MHPF research program to address this priority data need was canceled. 15G Exposure levels in humans living near hazardous waste sites and other populations, such as exposed workers. 15H Environmental fate of di-n- butyl phthalate in environmental media. 15I Bioavailability in contaminated environmental media near hazardous waste sites. 15J Potential ATSDR......... candidate for subregistry of exposed persons.Disulfoton.................... 16A Immunotoxicology testing battery following oral exposure. 16B Exposure levels of disulfoton in tissues/fluids for populations living near hazardous waste sites and other populations, such as exposed workers. 16C Disulfoton should ATSDR......... be considered as a potential candidate for a subregistry of exposed persons.Endosulfan (,, and sulfate). oral exposure. 17B Data on sensitive neurologic end point following oral exposure. 17C Exposure levels in humans living near hazardous waste sites and other populations, such as exposed workers. 17D Data on the bioavailability of endosulfan from soil. 17E Potential ATSDR......... candidate for subregistry of exposed persons.Endrin/endrin aldehyde........ 18A Dose-response animal data for acute oral exposure to endrin. 18B Multigeneration NTP........... reproductive toxicity studies via oral exposure to endrin. 18C Accurately describe the toxicokinetics of endrin and its degradation products and identify the animal species to be used as the most appropriate model for human exposure. 18D Exposure levels for endrin and its degradation products in humans living near hazardous waste sites.[[Page 4846]] 18E Accurately describe the environmental fate of endrin, including environmental breakdown products and rates, media half-lives, and chemical and physical properties of the breakdown products that help predict mobility and volatility. 18F Potential ATSDR......... candidate for subregistry of exposed persons.Heptachlor/heptachlor epoxide. 19A Dose-response animal data for acute- and intermediate- duration oral exposures, including immunopathology. 19B Multigeneration NTP........... Filled....... Availability of reproductive publication toxicity studies ``The effects via the oral of perinatal/ route of juvenile exposure. heptachlor exposure on adult immune and reproductive system function in rats'' by Smialowicz et al. (2001), Toxicological Sciences 61:164- 75. 19C Two-species developmental toxicity studies via the oral route of exposure. 19D Exposure levels in humans living near hazardous waste sites and other populations, such as exposed workers. 19E Bioavailability from contaminated air, water, and soil and bioaccumulation potential. 19F Potential ATSDR......... candidate for subregistry of exposed persons.Hexachloro-butadiene.......... 20A Dose-response data in animals for acute- duration exposure via the oral route. 20B Exposure levels in humans living near hazardous waste sites and other populations, such as exposed workers. 20C Environmental fate studies that determine the extent to which hexachlorobutadi ene volatilizes from soil, and studies that determine the reactions and rates which drive degradation in soil. 20D Bioavailability studies in soil and plants. 20E Potential ATSDR. candidate for subregistry of exposed person.Hexachloro-cyclohexane (, , , and data for chronic- derived in ). duration oral ATSDR's 1999 exposure. updated toxicological profile. 21B Mechanistic studies on the neurotoxicity, hepatotoxicity, reproductive toxicity, and immunotoxicity of hexachlorocycloh exane. 21C Exposure levels .............. Filled....... Reference range in humans living concentrations near hazardous in blood are waste sites and available. other ATSDR populations, acknowledges such as exposed that reference workers. concentration data can support exposure and health assessments at waste sites, but the agency also continues to recognize the importance of collecting additional data on uniquely exposed populations at waste sites.[[Page 4847]] 21D Potential ATSDR. candidate for subregistry of exposed persons.Lead.......................... 22A Mechanistic MHPF.......... Filled....... Multiple new studies on the studies (13 neurotoxic publications effects of lead. from the MHPF research program + numerous new published studies in ATSDR's 1999 updated toxicological profile) are available. 22B Analytical MHPF.......... Filled....... A publication methods for from the MHPF tissue levels. research program and numerous studies in ATSDR's 1999 toxicological profile are available. 22C Exposure levels MHPF.......... Filled....... Referent in humans living G. Lakes...... population near hazardous blood and urine waste sites and lead levels are other available populations, (NHANES III; such as exposed Paschal et al. workers. 1998), and at least 19 ATSDR studies that evaluated blood lead levels and potential adverse health effects are available.Manganese..................... 23A Dose-response MHPF.......... Filled....... Availability of data for acute- EPA........... ongoing studies and intermediate- in the MHPF duration oral research exposures (the program. subchronic study should include reproductive histopathology and an evaluation of immunologic parameters including manganese effects on plaque-forming cells (SRBC), surface markers (D4:D8 ratio), and delayed hypersensitivity reactions). 23B Toxicokinetic MHPF.......... Filled....... Avaialbiltiy of studies on EPA........... ongoing studies animals to in the MHPF investigate research uptake and program. absorption, relative uptake of differing manganese compounds, metabolism of manganese, and interaction of manganese with other substances following oral exposure. 23C Epidemiological .............. Filled....... Based on studies on the evaluation of health effects the data in of manganese ATSDR's 2000 (Special updated emphasis end toxicological points include profile. ATSDR neurologic, will continue reproductive, to evaluate new developmental, data as they immunologic, and become cancer). available to determine if additional studies are needed. 23D Exposure levels in humans living near hazardous waste sites and other populations, such as exposed workers. 23E Relative EPA. bioavailability of different manganese compounds and bioavialability of manganese from soil.Mercury....................... 24A Multigeneration MHPF.......... Filled....... Three reproductive publications toxicity study from the MHPF via oral research exposure. program are available. 24B Dose-response EPA........... Filled....... An MRL was data in animals derived in for chronic- ATSDR's 1999 duration oral updated exposure. toxicological profile. 24C Immunotoxicology EPA. battery of tests via oral exposure.[[Page 4848]] 24D Exposure levels G. Lakes...... Filled....... Background in humans living levels data are near hazardous available in waste sites and ATSDR's 1997 other updated populations, toxicological such as exposed profile, and workers. multiple studies that evaluated blood, urine, and hair mercury levels and potential adverse health effects are available (Five ATSDR studies + at least eight ongoing studies of the Great Lakes research program). 24E Potential ATSDR. candidate for subregistry of exposed persons.Methoxychlor.................. 25A Evaluate .............. Filled....... Based on an neurologic evaluation of effects after the data in long-term, low- ATSDR's 2000 level oral updated exposure. toxicological profile. 25B Exposure levels of methoxychlor and primary metabolities in humans living near hazardous waste sites and in those individuals with the potential to ingest it. 25C Evaluate the fate, transport, and levels of the degradation products of methoxychlor in soil. 25D Potential ATSDR. candidate for subregistry of exposed persons.Methylene chloride............ 26A Dose-response EPA........... Filled....... ATSDR accepted data in animals Vol Res....... HSIA's toxicity for acute- and study for acute- intermediate- and duration oral intermediate- exposure. The exposure