The Toxicologist - Society of Toxicology

1939 MODE OF ACTION FOR THE CANCER RISK
ASSESSMENT OF INGESTED HEXAVALENT CHROMIUM:
IDENTIFYING AND RESOLVING DATA GAPS.
C. Thompson 1 , D. Proctor 2 , L. Haws 2 and M. A. Harris 1 . 1 ToxStrategies, Inc.,
Katy, TX and 2 ToxStrategies, Austin, TX.
A recent NTP study observed tumors in the oral cavity and small intestine of rats
and mice, respectively, following chronic exposure to hexavalent chromium
[Cr(VI)] in drinking water at 20 to 180 mg/L. These data have been used for health
risk assessment, through application of a linear model and surface area scaling, to
estimate risk at environmental exposures occurring at levels approximately one million
times lower than those tested in animals. In the absence of mode of action
(MOA) data, it has been assumed, because Cr(VI) is genotoxic, that the tumors observed
in animals are due to a mutagenic MOA. However, it is also plausible that
Cr(VI) does not cause cancer at environmentally relevant exposures because necessary
key events require much higher doses. As such, our goal was to develop a MOA
framework to identify key events and data gaps. MOAs are likely tissue- and dosedependent,
and key events may contribute to more than one MOA. Key events
identified include: 1) competing kinetic processes of absorption and extracellular
reduction, 2) intracellular reduction of Cr(VI) to Cr(III), 3) oxidative stress, 4) sustained
inflammation, 5) oxidative DNA damage, adduct formation or Cr inter- or
intra-strand crosslinks, and 6) tumor formation. Other elements of the MOA
framework include cytotoxicity, apoptosis, and disruption of the normal Cr (III)
homeostasis. Our Cr(VI) MOA/human relevance framework indicates missing data
in several critical areas. Specifically, information on dose-response in the low dose
range and temporal sequencing of key events do not exist for measures of oxidative
stress, inflammation and other key events. Further, the tissue doses at which many
key events occur are entirely lacking and are important for quantifying interspecies
variability. Using our MOA/human relevance framework, critical data gaps have
been identified and a research plan constructed to provide mechanistic and dosimetric
information necessary for human health risk assessment.
1940 WATER QUALITY IN WYOMING LIVESTOCK AND
WILDLIFE.
B. L. Wise. University of Wyoming, Laramie, WY. Sponsor: M. Raisbeck.
Although there is a considerable body of data regarding water quality and the impacts
of various contaminants in cattle, horses, sheep, deer, elk and pronghorn, the
last concerted attempt to compile it into a simplified set of recommendations in the
US was in 1974. As part of an ongoing effort, we have examined Cd, Cr, Cu, B and
Pb. Data was collected by searching the usual bibliographic databases (e.g. Medline,
Web of Science, etc.). If peer-reviewed literature was inadequate for a given element,
regional diagnostic labs and wildlife agencies were solicited for unpublished
reports, etc. Since quantitative, experimental data for large mammalian wildlife is
sparse, estimates are derived via comparative physiology with domestic species.
Estimates of the NOAEL and LOAEL were established from the literature and a
reference dose for each species, class and toxic endpoint. The maximum tolerable
water concentration (without uncertainty factors) was then calculated from the
geometric mean of the NOAEL and LOAEL for the most sensitive species.
Cadmium has three possible adverse effects in our species of interest: acute toxicity,
chronic toxicity, and residues in edible tissues. Limited data suggest that Cd is only
moderately acutely toxic in ruminants (LOAEL of 1.27 mg Cd/kg BW/day); however,
the very slow elimination of Cd means that, in relatively long-lived animals,
very tiny doses (life time exposure to 10 mg/L) may result in nephropathy. Based
upon biotransfer rates of 9.0 X 10-5 and 1.7 X 10-5 for kidney and liver, respectively,
and a practical lifespan of 7 years for range cattle, violative residues could be
achieved in kidney with water concentrations as low as .156 mg/l. A similar value
(3.95 mg Cd/L) was calculated for red meat Cr data in livestock was limited to case
reports of spontaneous poisoning. Chromium (III) appears to be near non-toxic,
whereas Cr (VI) is much more toxic (50-70 mg/kg BW) to species of interest.
Although sheep are notably more sensitive to chronic Cu poisoning than other
species, they consume considerably less water. Thus, the MTC calculated for cattle
and sheep were very similar 4.5 and 4.125 mg Cu/L respectively.
1941 ASSESSMENT OF THE ORAL CANCER POTENCY OF
HEXAVALENT CHROMIUM (CR+6).
A. H. Stern and G. B. Post. Office of Science, New Jersey Department
Environmental Protection, Trenton, NJ.
Cr+6 has long been recognized as an inhalation carcinogen to humans. However,
despite some suggestive evidence from laboratory animal and human epidemiological
studies, until recently there has been no definitive evidence of the potential for
Cr+6 to act as a carcinogen by ingestion. The 2007 National Toxicology Program
(NTP) chronic drinking water bioassay of Cr+6 provides clear evidence of carcinogenicity
by ingestion in both sexes of mice (small intestine) and rats (oral mucosa).
Mice were selected as the key species for derivation of the cancer potency because of
the greater sensitivity of their response than rats. Male mice were chosen for quantitative
dose-response modeling because of the greater coherence of their dose-response
than in female mice. We estimated the oral human cancer potency of Cr+6
from the NTP data on small intestine tumors in the male mice by using benchmark
dose modeling to calculate the point-of-departure followed by linear extrapolation
as per the 2005 U.S. EPA Guidelines for Carcinogen Risk Assessment. The resulting
human cancer potency was estimated to be 0.5 (mg/kg/day)-1. We considered
the relevance of these data to human environmental exposures particularly with respect
to the capacity of the mouse and human stomachs to reduce Cr+6 to the essentially
non-toxic Cr+3 form. Based on several different but complementary approaches,
we concluded that the ability of Cr+6 to escape reduction in the stomach
is due largely to the rapid kinetics of absorption and stomach emptying rather than
to exceedance of the reduction capacity at the doses used in the study. We therefore
conclude that the cancer potency calculated from the NTP study data is relevant to
humans exposed at these and lower doses.
1942 MODE-OF-ACTION PROPOSAL FOR ORAL
HEXAVALENT CHROMIUM CARCINOGENESIS.
M. Nascarella, A. S. Lewis and B. D. Beck. Gradient, Cambridge, MA.
A recent chronic bioassay conducted by the National Toxicology Program (NTP)
found that oral exposure to hexavalent chromium (CrVI) in drinking water caused
duodenal adenomas in male mice at 90 mg CrVI/L and in female mice at 60 mg
CrVI/L. We present an analysis suggesting that the mode of action for CrVI carcinogenesis
in mice likely involves regenerative cell growth secondary to tissue injury.
Thus, the proposed key event would be the initial tissue injury, and the mode
of action is expected to exhibit a threshold dose-response. Support for this mode of
action is based on results from a chronic NTP bioassay showing diffuse epithelial
hyperplasia of the duodenum in male and female mice at all doses, with the proliferative
response occurring at doses lower than those associated with tumors. Also, a
3 month NTP study showed increased diffuse epithelial hyperplasia in the duodenum
of mice, providing temporal concordance between these hyperplastic responses
and eventual tumor formation. Multiple lines of evidence from the scientific
literature provide evidence that chromosomal damage from drinking water
exposure of CrVI is unlikely. For example, in the case of the NTP genetic toxicology
study, in two different studies there was no statistically significant increase in in
vivo chromosomal damage in the identical mouse strain that was used in the
chronic bioassay. (It should be noted that an increase in chromosomal damage was
observed in a study involving male mice from another strain.) There is also evidence
supporting our proposal from a recent study that found no increased DNA damage
in the duodenum of mice following chronic oral exposure sub-tumorigenic doses of
CrVI in drinking water. Thus, we conclude that the preliminary evidence supports
a non-linear dose-response model for CrVI, although additional MOA analyses
would be important.
1943 DEVELOPMENT OF PUBLIC HEALTH GOALS (PHGS)
FOR HEXAVALENT CHROMIUM AND
TRIHALOMETHANES IN DRINKING WATER.
R. A. Howd, R. Sedman, Y. Wang and A. M. Fan. Office of Environmental Health
Hazard Assessment, Cal/EPA, Oakland, CA.
The California Safe Drinking Water Act requires OEHHA to develop PHGs for
chemicals in drinking water based only on protection of public health. These PHG
values are used by the California Department of Public Health for development of
California-specific Maximum Contaminant Levels (MCLs), which also consider
cost and technical feasibility. PHGs are comparable to the MCLGs developed by
U.S. EPA, except that for carcinogens OEHHA provides a specific guidance value
based on a one in a million risk level, while U.S. EPA sets a value of zero. Two recent
risk assessments that involve cancer evaluations are highlighted here.
Hexavalent chromium (Cr6) presents particular complexity because of uncertainty
over its oral toxicity, due to rapid reduction to the trivalent form (Cr3) in vivo.
Recent NTP bioassays found significant increases in gastrointestinal tumors in both
mice and rats. Linear multistage extrapolation of the male mouse intestinal tumor
data provides a cancer potency value of 0.6 (mg/kg-day)-1, and a proposed PHG of
0.06 ppb. This value is much lower than the current MCLs of 50 ppb (California)
and 100 ppb (U.S. EPA). For trihalomethanes, tumor increases are found in rodent
bioassays for chloroform, bromoform, bromodichloromethane, and dibromochloromethane.
Cancer risk extrapolation involves particular uncertainty for
chloroform; it has been proposed that tumors are secondary to cytotoxicity, and
thus would not occur at low drinking water concentrations. OEHHA considers this
SOT 2010 ANNUAL MEETING 413