Federal Register: May 24, 2002 (Volume 67, Number 101)
DOCID: FR Doc 02-13059
DEPARTMENT OF HEALTH AND HUMAN SERVICES
Public Health Service
NOTICE: NOTICES
ACTION: Meetings:
SUBJECT CATEGORY:
National Toxicology Program (NTP); Availability of Data From Preliminary Studies and Proposed Study Protocols for Cancer Bioassays of Hexavalent Chromium in Rats and Mice; Request for Public Comment and Notice of Public Meeting
DOCUMENT SUMMARY:
Summary
Hexavalent chromium (CAS number 18540299) was nominated to the NTP for study of its potential toxicity and carcinogenicity when administered to animals in drinking water (see Federal Register: May 7, 2001, Vol. 66, No. 88, pages 2303723039). Members of the California legislative delegation, the California Environmental Protection Agency, and the California Health and Human Services Agency nominated hexavalent chromium to the NTP for study. The basis for the nomination is a document prepared by the California Environmental Protection Agency's (EPA) Office of Environmental Health Hazard Assessment titled ``Public Health Goal for Chromium in Drinking Water'', a copy of which is available on the NTP's Web site http://ntpserver.niehs.nih.gov (see NTP Studies of Hexavalent Chromium Compounds under What's New?).
The purpose of this notice is to announce:
(1) The availability of data from studies designed to assess the
absorption of chromium by rats, mice and guinea pigs receiving
hexavalent chromium, as sodium dichromate dihydrate, in drinking water;
(2) The design and availability of data from 90day oral toxicity
studies in rats and mice receiving hexavalent chromium in drinking water;
(3) A proposed design for 2year rodent cancer studies of hexavalent chromium in drinking water;
(4) A public meeting to discuss these data and the proposed design for 2year studies; and
(5) A request for public comments on these data and the proposed design for the 2year studies.
Public Meeting
A public meeting will be held July 24, 2002 in the Rodbell Auditorium, Rall Building, South Campus, National Institute of Environmental Health Sciences (NIEHS), 111 T.W. Alexander Drive, Research Triangle Park, North Carolina. The meeting will begin at 8:30 AM and is open to the public. Attendance at this meeting is limited only by the space available. Individuals who plan to attend are asked to register with the NTP executive secretary (see contact information below). The names of those registered to attend will be given to the NIEHS Security Office in order to gain access to the campus. Persons attending who have not preregistered may be asked to provide pertinent information about the meeting, i.e., title or host of meeting before gaining access to the campus. All visitors will need to be prepared to show 2 forms of identification (ID), i.e., driver's license and one of the following: company ID, government ID, or university ID. Also those planning to attend who need special assistance are asked to notify the NTP executive secretary in advance of the meeting (see contact information below).
A tentative agenda is provided below and includes opportunity for
oral public comment. A scientific panel of experts (``the Panel'') will
discuss the data, to date, obtained from NTP studies of hexavalent
chromium administered as sodium dichromate dihydrate and the proposed
study design for 2year rodent cancer studies (see below, NTP Studies).
The agenda and roster of the Panel will be available prior to the
meeting on the NTP Web site (http://ntpserver.niehs.nih.gov) and upon
request to the executive secretary at the address given below.
Following the meeting, summary minutes will be available electronically
on the NTP Web site and in hardcopy upon request to the executive secretary.
Tentative Agenda
8:30 AM
Welcome and introductions
8:40 AM
Overview of the NTP
Hexavalent chromium nomination
NTP studies on hexavalent chromium
Proposed design for 2year studies
Public comments
Noon
Lunch
1:00 PM
Presentation of remarks by scientific expert panel
General discussion
3:30 PM
Adjourn
Request for Public Comment
The NTP meeting on hexavalent chromium is open to the public and
public comment is welcome on the data from the 21day and 90day
studies, the proposed NTP 2year study plans, and any other issues
related to the evaluation of the toxicity and carcinogenicity of
hexavalent chromium in drinking water. Time will be provided at the
meeting for oral public comments and persons requesting time for an
oral presentation are asked to contact the NTP Executive Secretary Dr.
Mary S. Wolfe, (P.O. Box 12233, MD A301, Research Triangle Park, NC 27709, phone: 9195410530, fax: 9195410295, email:
liaison@starbase.niehs.nih.gov). Persons registering to make oral
comments are asked to provide contact information, including name,
affiliation, mailing address, phone, fax, email, and supporting
organization (if any). Each speaker is also asked to provide, if
possible, a written copy of the statement by July 15, 2002, to enable
review by the Panel and NTP staff prior to the meeting. The written
statement can supplement and may expand the oral presentation. At least
seven minutes will be allotted to each speaker, and if time permits,
may be extended to ten minutes. Each organization is allowed one time
slot for an oral presentation. Registration for making public comments
will also be available onsite. If registering onsite to speak and
reading comments from printed copy, the speaker is asked to provide 15 copies of the statement. These copies
[[Page 36621]]
will be distributed to the Panel and NTP staff and will be used to supplement the record.
Written comments, in lieu of an oral presentation, are also welcome. The comments should include contact information, including name, affiliation, mailing address, phone, fax, email, and sponsoring organization (if any) and preferably be received by July 15, 2002, to enable review by the Panel and NTP staff prior to the meeting as well as to supplement the record.
NTP Studies
Hexavalent chromium (CAS number 18540299) was nominated to the NTP for study of its potential toxicity and carcinogenicity when administered to animals in the drinking water. Hexavalent chromium is a known human carcinogen (http://ntpserver.niehs.nih.gov, see Report on Carcinogens). It has been proposed that the reduction of hexavalent chromium to the trivalent form in the gut provides a physiological barrier such that when exposure to hexavalent chromium occurs from drinking water, the absorption of hexavalent chromium would not be sufficient to cause cancer. Public comments received in response to the earlier Federal Register notice (see above) suggested that this reductive mechanism would be expected to be more effective in humans and other animals lacking an anatomical forestomach than in rats and mice that have a forestomach.
To address these considerations, the NTP carried out studies in which rats, mice and guinea pigs (which lack a forestomach) received drinking water containing sodium dichromate dihydrate for 21 days. After that time, the animals were sacrificed and blood, kidney and bone were collected and analyzed for total chromium. The complete protocol and data from these studies are available on the NTP Web site (http:// ntpserver.niehs.nih.gov).
Additionally, the NTP has completed 90day toxicity studies of standard design in which F344/N rats and B6C3F1 mice of both sexes received control water or one of 5 concentrations (62.5, 125, 250, 500, or 1000 mg/L) of hexavalent chromium in their drinking water. The studies included measurements of clinical chemistry indices and the animals received a complete histopathological evaluation. The protocol outline for these studies is also available on the NTP Web site and data from the 90day studies are anticipated to be available on the NTP Web site approximately one month prior to the meeting.
Also available on the NTP Web site is a draft protocol that outlines 2year toxicity and carcinogenicity studies of hexavalent chromium in rats and mice. The NTP will establish the final design for these studies following completion and evaluation of the 90day studies, evaluation of the data for total chromium tissue concentration from the 21day studies, and consideration of input from the Panel, all written received in response to this notice, and oral public comments received at the public meeting.
Background
Chromium is a naturally occurring element, present in several valence states. The most common valence states are trivalent (Chromium III), hexavalent (Chromium VI), and elemental chromium (0). Chromium III is an essential nutrient forming part of a complex known as the glucose tolerance factor. Chromium compounds are stable in the trivalent state and occur in nature most commonly at this oxidation level. Hexavalent chromium compounds are the next most stable forms, although these rarely occur in nature and are typically associated with anthropogenic (human activities) sources.
Hexavalent chromium is more toxic than trivalent chromium, and is absorbed from the gut more readily than trivalent chromium. Hexavalent chromium is an oxidant and it reduces to trivalent chromium, passing through the intermediate reactive V and IV valence states. The toxicity of hexavalent chromium is thought to result from either direct binding of these intermediates to cellular constituents or through the generation of free radicals.
Prolonged inhalation of hexavalent chromium is an established cause of occupational lung cancer in chromate production workers and people engaged in the manufacture of chromate pigments. This finding is supported by inhalation studies in rats and mice that have shown lung tumors following exposure to calcium chromate or sodium dichromate.
Orally administered chromium compounds are relatively poorly
absorbed, with most estimates in the range of 0.5 to 2%. The absorption
of trivalent chromium is approximately one quarter that of the
hexavalent form. Hexavalent chromium reduces to trivalent chromium in
the stomach, and this reduction may potentially limit its systemic
availability. This ``protective'' mechanism is not complete, however,
because studies have shown that orally administered hexavalent
chromium, when given at doses far below those where trivalent chromium
showed no adverse effect, caused liver and kidney toxicity. Other
concerns with hexavalent chromium given orally involve gastrointestinal
effects. Acute gastritis is a common finding in humans who accidentally
or intentionally ingested various hexavalent chromium compounds. Also,
in a study reported in 1968, a small increase in primarily benign
forestomach papillomas was seen in mice exposed to potassium chromate
in the drinking water at 9 mg/kg Chromium VI for three generations over 880 days.
Dated: May 16, 2002.
Kenneth Olden,
Director, National Toxicology Program.
[FR Doc. 0213059 Filed 52302; 8:45 am]
BILLING CODE 414001P
SUMMARY:
National Toxicology Program—; Study protocols for cancer bioassays of hexavalent chromium in rats and mice,
DOCUMENT BODY 2:
Summary
Hexavalent chromium (CAS number 18540299) was nominated to the NTP for study of its potential toxicity and carcinogenicity when administered to animals in drinking water (see Federal Register: May 7, 2001, Vol. 66, No. 88, pages 2303723039). Members of the California legislative delegation, the California Environmental Protection Agency, and the California Health and Human Services Agency nominated hexavalent chromium to the NTP for study. The basis for the nomination is a document prepared by the California Environmental Protection Agency's (EPA) Office of Environmental Health Hazard Assessment titled ``Public Health Goal for Chromium in Drinking Water'', a copy of which is available on the NTP's Web site http://ntpserver.niehs.nih.gov (see NTP Studies of Hexavalent Chromium Compounds under What's New?).
The purpose of this notice is to announce:
(1) The availability of data from studies designed to assess the
absorption of chromium by rats, mice and guinea pigs receiving
hexavalent chromium, as sodium dichromate dihydrate, in drinking water;
(2) The design and availability of data from 90day oral toxicity
studies in rats and mice receiving hexavalent chromium in drinking water;
(3) A proposed design for 2year rodent cancer studies of hexavalent chromium in drinking water;
(4) A public meeting to discuss these data and the proposed design for 2year studies; and
(5) A request for public comments on these data and the proposed design for the 2year studies.
Public Meeting
A public meeting will be held July 24, 2002 in the Rodbell Auditorium, Rall Building, South Campus, National Institute of Environmental Health Sciences (NIEHS), 111 T.W. Alexander Drive, Research Triangle Park, North Carolina. The meeting will begin at 8:30 AM and is open to the public. Attendance at this meeting is limited only by the space available. Individuals who plan to attend are asked to register with the NTP executive secretary (see contact information below). The names of those registered to attend will be given to the NIEHS Security Office in order to gain access to the campus. Persons attending who have not preregistered may be asked to provide pertinent information about the meeting, i.e., title or host of meeting before gaining access to the campus. All visitors will need to be prepared to show 2 forms of identification (ID), i.e., driver's license and one of the following: company ID, government ID, or university ID. Also those planning to attend who need special assistance are asked to notify the NTP executive secretary in advance of the meeting (see contact information below).
A tentative agenda is provided below and includes opportunity for
oral public comment. A scientific panel of experts (``the Panel'') will
discuss the data, to date, obtained from NTP studies of hexavalent
chromium administered as sodium dichromate dihydrate and the proposed
study design for 2year rodent cancer studies (see below, NTP Studies).
The agenda and roster of the Panel will be available prior to the
meeting on the NTP Web site (http://ntpserver.niehs.nih.gov) and upon
request to the executive secretary at the address given below.
Following the meeting, summary minutes will be available electronically
on the NTP Web site and in hardcopy upon request to the executive secretary.
Tentative Agenda
8:30 AM
Welcome and introductions
8:40 AM
Overview of the NTP
Hexavalent chromium nomination
NTP studies on hexavalent chromium
Proposed design for 2year studies
Public comments
Noon
Lunch
1:00 PM
Presentation of remarks by scientific expert panel
General discussion
3:30 PM
Adjourn
Request for Public Comment
The NTP meeting on hexavalent chromium is open to the public and
public comment is welcome on the data from the 21day and 90day
studies, the proposed NTP 2year study plans, and any other issues
related to the evaluation of the toxicity and carcinogenicity of
hexavalent chromium in drinking water. Time will be provided at the
meeting for oral public comments and persons requesting time for an
oral presentation are asked to contact the NTP Executive Secretary Dr.
Mary S. Wolfe, (P.O. Box 12233, MD A301, Research Triangle Park, NC 27709, phone: 9195410530, fax: 9195410295, email:
liaison@starbase.niehs.nih.gov). Persons registering to make oral
comments are asked to provide contact information, including name,
affiliation, mailing address, phone, fax, email, and supporting
organization (if any). Each speaker is also asked to provide, if
possible, a written copy of the statement by July 15, 2002, to enable
review by the Panel and NTP staff prior to the meeting. The written
statement can supplement and may expand the oral presentation. At least
seven minutes will be allotted to each speaker, and if time permits,
may be extended to ten minutes. Each organization is allowed one time
slot for an oral presentation. Registration for making public comments
will also be available onsite. If registering onsite to speak and
reading comments from printed copy, the speaker is asked to provide 15 copies of the statement. These copies
[[Page 36621]]
will be distributed to the Panel and NTP staff and will be used to supplement the record.
Written comments, in lieu of an oral presentation, are also welcome. The comments should include contact information, including name, affiliation, mailing address, phone, fax, email, and sponsoring organization (if any) and preferably be received by July 15, 2002, to enable review by the Panel and NTP staff prior to the meeting as well as to supplement the record.
NTP Studies
Hexavalent chromium (CAS number 18540299) was nominated to the NTP for study of its potential toxicity and carcinogenicity when administered to animals in the drinking water. Hexavalent chromium is a known human carcinogen (http://ntpserver.niehs.nih.gov, see Report on Carcinogens). It has been proposed that the reduction of hexavalent chromium to the trivalent form in the gut provides a physiological barrier such that when exposure to hexavalent chromium occurs from drinking water, the absorption of hexavalent chromium would not be sufficient to cause cancer. Public comments received in response to the earlier Federal Register notice (see above) suggested that this reductive mechanism would be expected to be more effective in humans and other animals lacking an anatomical forestomach than in rats and mice that have a forestomach.
To address these considerations, the NTP carried out studies in which rats, mice and guinea pigs (which lack a forestomach) received drinking water containing sodium dichromate dihydrate for 21 days. After that time, the animals were sacrificed and blood, kidney and bone were collected and analyzed for total chromium. The complete protocol and data from these studies are available on the NTP Web site (http:// ntpserver.niehs.nih.gov).
Additionally, the NTP has completed 90day toxicity studies of standard design in which F344/N rats and B6C3F1 mice of both sexes received control water or one of 5 concentrations (62.5, 125, 250, 500, or 1000 mg/L) of hexavalent chromium in their drinking water. The studies included measurements of clinical chemistry indices and the animals received a complete histopathological evaluation. The protocol outline for these studies is also available on the NTP Web site and data from the 90day studies are anticipated to be available on the NTP Web site approximately one month prior to the meeting.
Also available on the NTP Web site is a draft protocol that outlines 2year toxicity and carcinogenicity studies of hexavalent chromium in rats and mice. The NTP will establish the final design for these studies following completion and evaluation of the 90day studies, evaluation of the data for total chromium tissue concentration from the 21day studies, and consideration of input from the Panel, all written received in response to this notice, and oral public comments received at the public meeting.
Background
Chromium is a naturally occurring element, present in several valence states. The most common valence states are trivalent (Chromium III), hexavalent (Chromium VI), and elemental chromium (0). Chromium III is an essential nutrient forming part of a complex known as the glucose tolerance factor. Chromium compounds are stable in the trivalent state and occur in nature most commonly at this oxidation level. Hexavalent chromium compounds are the next most stable forms, although these rarely occur in nature and are typically associated with anthropogenic (human activities) sources.
Hexavalent chromium is more toxic than trivalent chromium, and is absorbed from the gut more readily than trivalent chromium. Hexavalent chromium is an oxidant and it reduces to trivalent chromium, passing through the intermediate reactive V and IV valence states. The toxicity of hexavalent chromium is thought to result from either direct binding of these intermediates to cellular constituents or through the generation of free radicals.
Prolonged inhalation of hexavalent chromium is an established cause of occupational lung cancer in chromate production workers and people engaged in the manufacture of chromate pigments. This finding is supported by inhalation studies in rats and mice that have shown lung tumors following exposure to calcium chromate or sodium dichromate.
Orally administered chromium compounds are relatively poorly
absorbed, with most estimates in the range of 0.5 to 2%. The absorption
of trivalent chromium is approximately one quarter that of the
hexavalent form. Hexavalent chromium reduces to trivalent chromium in
the stomach, and this reduction may potentially limit its systemic
availability. This ``protective'' mechanism is not complete, however,
because studies have shown that orally administered hexavalent
chromium, when given at doses far below those where trivalent chromium
showed no adverse effect, caused liver and kidney toxicity. Other
concerns with hexavalent chromium given orally involve gastrointestinal
effects. Acute gastritis is a common finding in humans who accidentally
or intentionally ingested various hexavalent chromium compounds. Also,
in a study reported in 1968, a small increase in primarily benign
forestomach papillomas was seen in mice exposed to potassium chromate
in the drinking water at 9 mg/kg Chromium VI for three generations over 880 days.
Dated: May 16, 2002.
Kenneth Olden,
Director, National Toxicology Program.
[FR Doc. 0213059 Filed 52302; 8:45 am]
BILLING CODE 414001P