National Toxicology Program (NTP) Proposed Revised Criteria for Listing Substances in the Biennial Report on Carcinogens (BRC) and Notice of Meeting of the NTP Board of Scientific Counselors

[Federal Register Volume 60, Number 110 (Thursday, June 8, 1995)]

[Notices]

[Pages 30434-30436]

From the Federal Register Online via the Government Publishing Office [www.gpo.gov]

[FR Doc No: 95-13874]

[[Page 30433]]

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Part V

Department of Health and Human Services

_______________________________________________________________________

Public Health Service

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National Toxicology Program (NTP) Proposed Revised Criteria for Listing

Substances in the Biennial Report on Carcinogens (BRC) and Notice of

Meeting of the NTP Board of Scientific Counselors

Federal Register / Vol. 60, No. 110 / Thursday, June 8, 1995 /

Notices

[[Page 30434]]

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Public Health Service

National Toxicology Program (NTP) Proposed Revised Criteria for

Listing Substances in the Biennial Report on Carcinogens (BRC) and

Notice of Meeting of the NTP Board of Scientific Counselors

Background

A public meeting of the NTP Board of Scientific Counselors' ad hoc

Working Group to Review the Criteria for Listing Substances in the

Biennial Report on Carcinogens (BRC) was held on April 24 and 25, 1995,

at the Washington Hilton and Towers Hotel, 1919 Connecticut Avenue NW.,

Washington DC. The purpose of the meeting was to receive public

comments on the current criteria for listing substances in the BRC, and

to review and make recommendations on these criteria. The issues

addressed by this ad hoc group were: (1) The adequacy of existing

criteria for listing substances in future Reports; and (2) the

incorporation of mechanistic data as part of the criteria for listing

substances in future Reports which may include the consideration of

sensitive sub-populations as well as procedures to upgrade or downgrade

the evaluation of the results of animal bioassay or epidemiology

studies. A background and discussion document prepared by the NTP for

use by the ad hoc working group and also for review and comment by the

public, is available upon request. Copies of this document can be

obtained by contacting the NTP Liaison Office at NIEHS, P.O. Box 12233,

Research Triangle Park, NC 27709, or by FAX to (919) 541-0295.

This meeting was the first step in the review of the criteria and

was open to the public. The meeting began with a plenary session which

provided background on the BRC and a public comment session. The

working group then broke into three breakout groups, with each breakout

group addressing the same above listed issues. The final session of the

meeting was a plenary session at which time each breakout group

reported on their deliberations. The chairperson, rapporteur, and

facilitator of the three breakout groups completed draft reports of

their group's discussions and recommendations and submitted it to the

Chairperson of the ad hoc working group. The Chairperson, working with

NIEHS/NTP staff, completed a draft summary report of the criteria

review meeting which subsequently was sent to all ad hoc working group

members for editing and corrections. A copy of the revised summary

report is printed below. Also printed below are the current and

proposed revised criteria developed by the NIEHS/NTP based on the input

of the NTP Board of Scientific Counselors' ad hoc working group.

Action-Request for Public Input on the Proposed Revised Criteria

The NTP seeks comments and views on the proposed revised criteria

which follows. Public input concerning the proposed revised criteria

for listing a substance in the BRC is important to the review process

and is encouraged. A further opportunity for comment will be provided

during a meeting of the NTP Board of Scientific Counselors in the NIEHS

Conference Center, Building 101, South Campus, National Institute of

Environmental Health Sciences, 111 Alexander Drive, Research Triangle

Park, North Carolina, on June 29 , 1995. The primary agenda topic for

this meeting concerns the summary report and recommendations of the ad

hoc working group of the NTP Board from their review of the criteria

for listing substances in the BRC on April 24 and 25, 1995. This

meeting is open to the public, and public input concerning the criteria

for listing a substance in the Biennial Report on Carcinogens is

encouraged. Formal oral comments during the NTP Board meeting will be

limited to five minutes to permit maximum participation. Written

comments accompanying oral statements are encouraged. To assure

consideration by the Board at this meeting, written comments must be

submitted to Dr. Larry G. Hart, Executive Secretary for the NTP Board

of Scientific Counselors and received by June 23, 1995. Registration to

attend is not required; however, to ensure adequate seating, we ask

that those planning to attend let us know. To register, submit written

comments or announce intention to make oral comments on the criteria

review report, receive information on the agenda, or be put on the

mailing list for summary minutes subsequent to the meeting, please

contact: Dr. L. G. Hart, P.O. Box 12233, Research Triangle Park, NC

27709; telephone: (919) 541-3971; FAX: (919) 541-0719.

Dated: May 30, 1995.

Kenneth Olden,

Director, National Toxicology Program.

Attachments

Summary Report of the Meeting of the National Toxicology Program's

Board of Scientific Counselors' Ad Hoc Working Group To Review the

Criteria for Listing Substances in the Biennial Report on Carcinogens,

Washington Hilton and Towers Hotel, Washington, D.C., April 24 and 25,

1995

Background

The Biennial Report on Carcinogens is prepared in response to

Section 301(b)(4) of the Public Health Service Act which stipulates

that the Secretary of the Department of Health and Human Services

shall publish a report which contains a list of all substances (i)

which either are known to be human carcinogens or may reasonably be

anticipated to be human carcinogens; and (ii) to which a significant

number of persons residing in the United States are exposed. This

responsibility has been delegated by the Secretary to the Director,

National Toxicology Program (NTP). Dr. Ken Olden, Director of the

National Institute of Environmental Health Sciences (NIEHS) and the

National Toxicology Program, has initiated a review of the BRC to

broaden input to its preparation, broaden the scope of scientific

review associated with the Report, and provide review of the

criteria used for inclusion of substances in the BRC.

An ad hoc working group of the NTP Board of Scientific

Counselors was established to receive public comments on the

existing criteria and review and make recommendations on the

criteria for listing substances in the BRC. This ad hoc working

group had a balance of expertise and views and included

representatives from Academia; Industry; Labor; Federal, State and

Local Agencies; and Private Organizations. The working group

reviewed the criteria in an open, public meeting in Washington, D.C.

on April 24 & 25, 1995.

Meeting Summary

The ad hoc working group was chaired by NTP Board of Scientific

Counselors member Dr. Arnold Brown of the University of Wisconsin.

The working group was divided into three breakout groups to allow

for a more in depth discussion of the criteria and the public

comments received. Each of the breakout groups were asked to address

the following issues in their review of the criteria:

(a) The adequacy of existing criteria for listing substances in

future Reports; and

(b) The incorporation of mechanistic data as part of the

criteria for listing substances in future Reports that may include

the consideration of sensitive sub-populations as well as procedures

to upgrade or downgrade the evaluation of the results of animal

bioassay or epidemiology studies.

Plenary Session I was chaired by Dr. George Lucier, Director,

Environmental Toxicology Program, NIEHS/NTP and allowed for opening

and background presentations by Dr. Kenneth Olden, Director, NIEHS

and NTP, Dr. C. W. Jameson, NIEHS/NTP, and Dr. Marilyn Wind, CPSC

(NTP Executive Committee BRC Working Group representative). Dr.

Lucier then gave the charge to the ad hoc working group to

[[Page 30435]] address the two issues outlined above in their review

of the criteria and identify areas of consensus, areas of debate,

and the knowledge gaps that create the debate. Dr. Lucier then

turned the meeting over to Dr. Brown.

Plenary Session II was devoted to the presentation of public

comments concerning the BRC criteria. Written comments had been

received from the following individuals/organizations and

distributed to the ad hoc Working Group prior to the meeting:

North American Insulation Manufacturers Association

Chlorobenzene Producers Association

Dr. Stephen DeVito, US EPA

Dr. E. E. McConnell

Public comments were made during Plenary Session II by the

following individuals:

Dr. Charles Axten--NAIMA

Dr. Nathan Karch--Karch & Associates

Dr. Matthew Bogdanffy--Haskell Laboratory

Dr. James Sherman--Chlorobenzene Producers Association

Dr. Myra Karstadt--Center for Science in the Public Interest

Dr. Frank Mirer--United Auto Workers

Dr. E. E. McConnell--Private Consultant

Comments made during the public comment period ranged from

recommending retention of the current criteria with no change, to

revising the existing criteria to require the incorporation of

available mechanistic data. (A copy of the written public statements

provided by the above listed individuals is available upon written

request to the NTP Liaison Office, NIEHS, P.O. Box 12233, MD A3-01,

Research Triangle Park, NC 27709-2233). Following the public comment

session, Dr. Brown directed that each breakout group was to meet

individually and, based on the charge given to the ad hoc Working

Group by Dr. Lucier, address the BRC criteria.

Upon completion of the discussions of the three breakout groups,

the full ad hoc Working Group reconvened in the final Plenary III

session. Each breakout group made a report on their deliberations

and recommendations.

Each breakout group had addressed the two issues outlined in the

charge given by Dr. Lucier. Breakout group 1 stated in their report

that the existing criteria were found not to be adequate and

suggested revision of the criteria to include use of available

mechanistic data that is relevant for improving hazard

identification. The report from breakout group 2 stated there was

unanimity from their members that the criteria should be updated and

that mechanistic data should be utilized in the listing process.

Group 2 recommended significant revisions to the existing criteria

including the incorporation of additional listing categories.

Breakout group 3 report stated that their members were of the

general consensus that the current criteria are adequate for the

stated purpose of the BRC, however minor revisions and

clairifications to the existing criteria were considered to be

appropriate. In summary, it was the recommendation of breakout

groups 1 & 3 that the existing two categories of the current

criteria for listing substances in the BRC should remain with

revisions to category 2 to allow for all scientific evidence to be

considered. This will allow for the best scientific judgment to be

used in consideration of substances for listing in the BRC. Breakout

group 2 recommended a more significant expansion of the current

criteria which included the incorporation of additional listing

categories of ``presumptive evidence of carcinogenic activity'' and

``laboratory animal carcinogen presumed not to be a human

carcinogen''.

Based on the reports from the three breakout groups and the

ensuing discussions during the final plenary session of the entire

ad hoc Working Group, the NIEHS/NTP determined that, while there was

not complete agreement concerning the adequacy of the current

criteria for listing substances in the BRC, it was the general

consensus of the entire ad hoc Working Group that the existing

criteria should be revised and clarified. The recommended revisions

are to permit consideration of more mechanistic information in

listing substances in the BRC. As indicated in the three breakout

group reports, the area of debate was how extensive the

modifications should be. The discussions during Plenary Session III

indicated that the majority of the ad hoc Working Group members felt

the revised criteria should maintain the current 2 categories with

revisions to assure that all scientific evidence is considered to

allow for the best scientific judgment. It was also apparent from

these discussions that there was consensus that the BRC is a hazard

identification document and not to be used as a quantitative risk

assessment for the listed substances. It is based on these

considerations and recommendations that the NIEHS/NTP has proposed

revised criteria for listing substances in the BRC. These proposed

revisions are consistent with the discussion and recommendations of

the majority of the ad hoc Working Group and the current legislation

regarding the Biennial Report on Carcinogens. These proposed revised

criteria will be available to the public for review and comment and

presented to the NTP Board of Scientific Counselors at their June

29, 1995, meeting. The Board will review the report and

recommendations; receive public comment on the report; and develop

Board recommendations concerning the selection criteria. Further

review will include the PHS Environmental Health Policy Committee

and the NTP Executive Committee.

The ad hoc Working Group made several additional general

recommendations concerning the Biennial Report on Carcinogens. These

included recommending that a formal mechanism be established for the

re-evaluation of substances previously listed in the BRC to

determine if listing is still warranted. As a result of this

recommendation, the NTP will evaluate the current procedures for de-

listing a substance and, if necessary, revise it. It was also

recommended by the Working Group that the NTP should stimulate

discussion (e.g., workshops, discussion papers) on the use of

mechanistic data in hazard identification. The recent NTP workshop

on ``Mechanism-Based Toxicology in Cancer Risk Assessment:

Implications for Research, Regulation and Legislation'' held January

11-13, 1995, and the upcoming Workshop on Validation and Regulatory

Acceptance of Alternative Test Methods'' planned for October 30-

November 1, 1995 are examples of how this recommendation will be

acted upon. The NTP plans to continue these types of activities in

the future.

Current BRC Criteria

For the purpose of the BRC, the degrees of evidence are as

follows:

1. Known To Be Carcinogens

There is sufficient evidence of carcinogenicity from studies in

humans that indicates a causal relationship between the agent and

human cancer.

2. Reasonably Anticipated To Be Carcinogens

a. There is limited evidence of carcinogenicity from studies in

humans, which indicates that causal interpretation is credible, but

that alternative explanations, such as chance, bias or confounding,

could not adequately be excluded, or

b. There is sufficient evidence of carcinogenicity from studies

in experimental animals that indicates that there is an increased

incidence of malignant tumors: (a) in multiple species or strains,

or (b) in multiple experiments (preferably with different routes of

administration or using different dose levels), or (c) to an unusual

degree with regard to incidence, site or type of tumor, or age at

onset. Additional evidence may be provided by data concerning dose-

response effects, as well as information on mutagenicity or chemical

structure.

Proposed Revised BRC Criteria

For the purpose of the BRC, the degrees of evidence are as

follows:

1. Known To Be Human Carcinogens

There is sufficient evidence of carcinogenicity from studies in

humans that indicates a causal relationship between the substance

and human cancer.

2. Reasonably Anticipated To Be Human Carcinogens

a. There is limited evidence of carcinogenicity from studies in

humans which indicate that causal interpretation is credible but

that alternative explanations such as chance, bias or confounding

could not adequately be excluded, or

b. There is sufficient evidence of carcinogenicity from studies

in experimental animals that indicates there is an increased

incidence of malignant and/or combined benign and malignant tumors:

(1) in multiple species or at multiple tissue sites, or (2) by

multiple routes of exposure, or (3) to an unusual degree with regard

to incidence, site or type of tumor or age at onset.

Conclusions regarding carcinogenicity in humans or experimental

animals should be based on scientific judgment. Consideration may be

given to relevant information on dose response, route of exposure,

chemical structure, sensitive sub populations, genetic effects or

other data relating to mechanism of action, and/or factors that may

be unique to a given substance. There may be substances for which

there is less than sufficient [[Page 30436]] evidence of

carcinogenicity in humans or laboratory animals but for which there

are compelling data indicating that the substance could reasonably

be anticipated to cause cancer in humans. Conversely, there may be

substances for which there is sufficient evidence of carcinogenicity

in laboratory animals but there are compelling data indicating that

the agent acts through mechanisms which do not operate in humans and

would therefore reasonably be anticipated not to cause cancer in

humans.

National Toxicology Program Board of Scientific Counselors' Ad Hoc

Working Group for the Review of the Criteria for Listing Substances in

the Biennial Report on Carcinogens

List of Ad Hoc Working Group Members

Dr. Arnold Brown(Chairman)--University of Wisconsin Medical School

Dr. Bill Allaben--FDA/NCTR

Dr. Carl Barrett--NIEHS

Dr. Eula Bingham--Univ. of Cincinnati

Dr. John Dement--Duke University Medical Center

Dr. Norman Drinkwater--McArdle Laboratory , Univ. of Wisconsin

Dr. Kathleen Dixon--Univ. of Cincinnati, Dept. of Environ. Health

Dr. Gerard Egan--Exxon Biomedical Sciences Inc.

Dr. Clay Frederick--Rohm & Haas

Dr. Thomas Goldsworthy--Chemical Industry Institute of Toxicology

Dr. Bryan Hardin--NIOSH

Dr. David Longfellow--NCI

Dr. Judith MacGregor--Toxicology Consulting Services

Dr. Roger McClellan--Chemical Industry Institute of Toxicology

Dr. Karen Medville--Cornell University

Dr. James Melius--Center to Protect Workers' Rights

Dr. Beth Mileson--NC State Department of Health

Dr. Franklin Mirer--International Union, UAW

Dr. Rafael Moure--University of Massachusetts / Lowell

Dr. Gunter Oberdorster--Univ. of Rochester, Dept. Env. Medicine

Dr. Jean Parker--EPA/ORD

Dr. Janet Phoenix--Environmental Health Center, Washington, DC

Dr. Resha Putzrath--Georgetown Risk Group, Washington, DC

Dr. David Rall--Asst. Surgeon General, USPHS (Ret.)

Dr. Larry Roslinski--Ford Motor Company

Mr. Sheldon Samuels--Workplace Health Fund

Dr. Regina Santella--Columbia University, Dept. Environ. Sciences

Dr. Loretta Schuman--OSHA

Dr. Ellen Silbergeld--Environmental Defense Fund and the U of MD

Dr. Thomas Sinks--Nat'l Center for Env. Health, CDC

Dr. Thomas Slaga--Univ. of Texas, M.D. Anderson Cancer Center

Ms. Yee Wan--Stevens ATSDR

Dr. Donald Stevenson--Former Director of Toxicology, Shell Oil Co.

Dr. Lorenzo Tomatis--Former Director, IARC

Dr. Harri Vainio--Institute of Occupational Health, Finland

Dr. Vanessa Vu--EPA/OPPTS

Dr. Bailus Walker--Howard University

Dr. Cheryl Walker--Univ. of Texas, M.D. Anderson Cancer Center

Dr. Jerry Ward--National Cancer Institute

Dr. Marilyn Wind--CPSC

Dr. Sidney Wolfe--Public Citizens Group, Washington, DC

Dr. Hiroshi Yamasaki--IARC

Dr. Lauren Zeise--State of California EPA

[FR Doc. 95-13874 Filed 6-7-95; 8:45 am]

BILLING CODE 4140-01-P