Peer Review of Toxicological Review of Soluble Nickel Salts
A draft assessment of soluble nickel salts that relied upon the U.S. EPA
risk assessment method underwent an independent peer review on January
13 and 14 by a panel of expert scientists and risk assessors meeting at
the University of Cincinnati College of Medicine. The panel discussed
the underlying epidemiological and toxicological data and evaluated the
risk assessment conclusions regarding carcinogenicity and non-cancer
endpoints. Staff of Toxicology Excellence for Risk Assessment (TERA),
and additional experts from Syracuse Research Corporation, Bailey
Research Associates, and Mabbett & Associates developed the draft
document. The U.S. EPA Office of Water and the Metal Finishing
Association of Southern California sponsored development of the text.
Health Canada provided funding for the peer review. Because TERA staff
wrote large portions of the document, a group from the TERA Board of
Trustees independently selected the panel of experts. The review panel
included: Dr. P. Michael Bolger, Food and Drug Administration; Dr. James
J. Collins, Solutia, Inc.; Dr. M. Joseph Fedoruk, University of
California Irvine; Dr. Ernest Foulkes, University of Cincinnati; Dr.
Ernest Mastromatteo, University of Toronto; Dr. Ann G. Schwartz,
Allegheny University of the Health Sciences; and Dr. Alan H. Stern, New
Jersey Department of Environmental Protection. Dr. Joyce M. Donohue,
U.S. Environmental Protection Agency; Donna J. Sivulka, private
consultant; and Dr. John S. Wheeler, Agency for Toxic Substances and
Disease Registry participated as non-voting discussants.
The panel reviewed the document, as well as a number of comments on the
document and TERA responses to those comments. The panel reached the
conclusion that the narrative statement developed under U.S. EPAs 1996
proposed cancer guidelines for the carcinogenicity of soluble nickel
salts should state that the carcinogenicity of soluble nickel via both
the oral and inhalation routes cannot be determined. For the inhalation
route this assessment was based on an evaluation of the extensive but
equivocal epidemiology database, together with the negative NTP
bioassays in rats and mice. Limited knowledge of the mode of action of
soluble nickel salts also contributed to the choice of classification.
For the oral route, the choice of narrative statement was based on
negative but deficient oral animal studies. In light of the decision
that a qualitative determination of the carcinogenicity of soluble
nickel could not be determined, the panel also decided that the
carcinogenicity of soluble nickel via the oral and inhalation routes
could not be quantified.
For the noncancer endpoints, the panel agreed that the best choice of
study for the oral reference dose (RfD) was Vyskocil et al., 1994,
although there were a number of limitations to this data which result in
low confidence in the RfD. The critical effect in the study was
albuminuria, with a LOAEL of 6.9 mg/kg-day. A composite uncertainty
factor of 1000 was used, resulting in a RfD of 7E-3 mg/kg-day.
For the inhalation route, a reference concentration (RfC) was derived
from the NTP (1996) study of nickel sulfate in rats. The critical
effect was lung fibrosis in male rats. The NOAEL was 0.027 mg Ni/cu.m.
After duration adjustments and conducting dosimetric adjustments for
particle deposition according to the U. S. EPAs RfC methodology, the
NOAEL human equivalent concentration (HEC) was 0.0021 mg/cu.m. A
benchmark concentration (HEC) of 0.017 mg/cu.m. was also calculated.
Because extensive occupational exposure experience shows that rats are
more sensitive than humans are, and because of the use of dosimetry to
estimate the equivalent human dose, the uncertainty factor for
interspecies extrapolation was 1. An uncertainty factor of 10 was used
for intrahuman variability, resulting in a composite factor of 10. The
use of these factors resulted in a RfC of 2E-4 mg/cu.m. An alternative
RfC developed with data from a human epidemiology study by Muir et al.,
1993 was considered. However, in light of numerous uncertainties in the
study, the panel thought the NTP study preferable but asked the authors
to include the Muir derived RfC in the document for comparison purposes.
The draft document will be revised to reflect the comments from the
panel and the approved risk values (RfC and RfD) will be included on the
ITER database (http://www.tera.org/iter). The ITER database contains
chronic risk values from a number of organizations presented in a format
that allows the user to compare the bases of the different values.
This independent peer review was organized by Toxicology Excellence for
Risk Assessment (TERA); a non-profit corporation dedicated to the best
use of toxicity data for risk assessment. The meeting was open to the
public with a number of observers from government, academia, and
industry present. A summary of the meeting will be made available in
February on the Internet at http://www.tera.org/peer. This site also
provides more information about TERA and the peer review program.
Contact Jacqueline Patterson [(513) 521-7426 or email
patterson at tera.org.]