The Toxicologist - Society of Toxicology

evidence unconvincing because observed tumors are not well correlated with cytotoxicity
and cell proliferation. OEHHA has proposed PHGs based on linear extrapolation
for all four THMs, yielding values from 0.4 to 5 ppb, versus the current
MCL of 80 ppb for the four chemicals combined. The low hazard levels for all of
these chemicals are a concern because of their ubiquity in drinking water. Public
comments are invited on these assessments and appropriate regulatory levels that
might be derived.
1944 HEALTH RISK OF INTERNAL NICKEL EXPOSURE
FROM MEDICAL DEVICES.
J. Tsuji 1 , K. Hentz 2 and S. Rosenbloom 3 . 1 Exponent, Bellevue, WA, 2 Exponent,
Alexandria, VA and 3 Exponent, Philadelphia, PA.
Nickel is a focus of potential health risks from corrosion of medical devices because
of its use in many medical-grade alloys, the prevalence of nickel allergy in the general
population, and reported tumors in some studies of pure or high nickel-containing
powders or pellets implanted in rodents. This review evaluates the available
evidence for assessing the potential health effects of nickel released from medical
devices. Nickel is generally of low toxicity for consumer exposures, resulting primarily
in dermatitis in sensitive individuals from skin contact (about 8-10% of women
and 1-2% of men). Oral exposures may also cause contact dermatitis, although typically
only in previously sensitized individuals. Nickel oral dosing studies indicate
that most sensitive individuals would react to a 1 mg/day systemic dose (adjusted
for oral absorption); whereas, only 1% of sensitive individuals would react to approximately
0.1 mg/day, which is within background exposures from diet and
water. Tolerance can develop from repeated oral dosing in previously sensitive people
(absorbed dose of 0.2 to 0.6 mg/day). Patch testing before and after implantation
of medical devices also indicates patients may become more sensitive or less
sensitive to nickel. The incidence of nickel allergy from medical devices appears to
be less than the incidence of nickel sensitivity in the general population. Medical
devices, in most cases, are likely not releasing sufficient nickel to cause such reactions.
Systemic nickel exposure may also be less allergenic than by other routes.
Although pure nickel or non-medical device alloys with more than 67-68% nickel
may cause tumors when implanted in rodents, administered doses are high (e.g.,
250 mg/kg). By contrast, carcinogenicity has not been indicated by nickel-containing
medical devices in humans or in dogs. Nickel releases from medical devices in
humans are much lower and elevated exposures are transient. These factors combined
with the primarily high-dose mode of action of soluble nickel indicate low
risk of carcinogenicity from nickel in medical devices.
1945 ATSDR’S CHRONIC INHALATION MINIMAL RISK
LEVEL (MRL) FOR VANADIUM.
L. Ingerman 1 , J. Taylor 2 and L. Cseh 2 . 1 Environmental Science, SRC (formerly
Syracuse Research Corporation), North Syracuse, NY and 2 Agency for Toxic Substances
and Disease Registry, Atlanta, GA. Sponsor: G. Diamond.
Vanadium is primarily used in the production of rust-resistant, spring, and highspeed
tool steels; vanadium pentoxide is used in ceramics. ATSDR recently re-evaluated
the toxicity of vanadium and released an updated toxicological profile for
public comment in October 2009. Although the general population is primarily exposed
to vanadium via the diet, urban populations, especially in the Northeast, are
exposed to elevated vanadium oxide levels in the air. Limited occupational exposure
data suggest that the respiratory tract is the most sensitive target of toxicity of inhaled
vanadium. Studies in rats and mice exposed to vanadium pentoxide support
these findings. Chronic exposure to vanadium pentoxide resulted in several respiratory
tract effects (e.g., alveolar and bronchiolar epithelial hyperplasia, chronic laryngeal
inflammation, epiglottis epithelial degeneration, and goblet cell hyperplasia
in nasal epithelium) in rats exposed to ≥0.28 mg V/m3 6 hr/d, 5 d/wk (NTP
2002). Similar lung and larynx effects were observed in mice exposed to ≥0.56 mg
V/m3. Benchmark dose analyses of incidence data for 5 respiratory effects observed
in male rats were conducted to identify the point of departure for deriving a
chronic inhalation MRL for vanadium. The lowest BMDL10 values ranged from
0.04 to 0.16 mg V/m3. Human equivalent concentrations (HEC) were estimated
by multiplying duration adjusted BMDL10 values by the regional deposited dose
ratio (RDDR) for the respiratory tract area of concern. The HECs were 0.0008,
0.017, 0.005, 0.003, and 0.012 mg V/m3 for alveolar epithelial hyperplasia, bronchiolar
epithelial hyperplasia, laryngeal inflammation, epiglottis epithelial degeneration,
and nasal goblet cell hyperplasia, respectively. The HEC of 0.003 mg V/m3
for degeneration of epiglottis epithelium was selected as the point of departure for
the MRL. This value was divided by an uncertainty factor of 30 (3 for animal to
human extrapolation and 10 for human variability) resulting in a chronic inhalation
MRL of 0.0001 mg V/m3.
1946 EVALUATION OF RECENT INFORMATION ON
CARCINOGENICITY OF PERCHLOROETHYLENE
(PCE)IN HUMANS.
L. A. Beyer, L. R. Rhomberg and B. D. Beck. Gradient, Cambridge, MA.
EPA’s recent evaluation of PCE states that “Overall, the epidemiologic evidence has
associated [PCE] exposure with excess risk for a number of cancers, although a
causal association has yet to be definitively established.” A number of endpoints
that were positive in animals studies were considered relevant to humans: liver tumors
in mice, mononuclear cell leukemia (MCL) in rats, kidney cancers in male
rats, and brain (glioma) in male rats. In contrast, positive findings in human populations
have been inconsistent, even in populations receiving the highest exposures
to PCE (e.g., drycleaners). We conducted an independent analysis of the epidemiology
studies, concluding that they demonstrate little consistent evidence of carcinogenic
risks, and further, that many of the cancers found are known to be associated
with confounders such as smoking and alcohol consumption. Moreover, the
results of the epidemiology studies are not concordant with those found in animal
bioassays. Our analysis of the animal bioassays identified a number of limitations
that call into question the relevance or reliability of the findings. The animal bioassay
results comprise species/strain specific tumors that (1) are not increased by PCE
in other species or strains; (2) have high background tumor levels in the strains
showing response (with the exception of rat kidney tumors); (3) have especially
high responses in the control groups; and (4) whose relevance to humans is debated.
The mode-of-action (MOA) information, while incomplete, reveals important
differences in how rodents and humans metabolize PCE, which help explain
the differences in cancers (types and rates) seen in humans and rodents. In addition,
MOA considerations affect the shape of plausible dose-response curves. We conclude
that overall, the evidence does not support PCE being a human carcinogen.
1947 PEAK AND DECLINE OF CANCER RATES AT OLD AGE.
C. Harding, F. Pompei, E. E. Lee, D. Burmistrov, M. N. Bassily and R. Wilson.
Jefferson Laboratories, Department of Physics, Harvard University, Cambridge, MA.
Increased age is regularly linked with heightened cancer risk, but modern research
suggests a flattening around age 80. Here, new data is reported on all major cancer
sites in elderly men and women. We find that age-specific cancer incidence rates,
mortality rates, and prevalence proportions often reach a maximum at very old age,
and subsequently decline. These results were calculated for a single population
comprising 9.5% of the United States over the period 1998-2002. We further report
that the age of peak cancer incidence (normally around 80) is consistent over
the period 1979-2003. Generally, it appears that centenarians are asymptomatic or
unsusceptible to developing new cancers. Data was taken from the Surveillance,
Epidemiology, and End Results cancer registries, with old age population figures
derived from censuses, post-censal estimates, and life tables. The age-specific pattern
of cancer rates is commonly used to test theories of carcinogenesis. We examine
several biological and non-biological reasons for the apparent turnover in cancer
rates, including heterogeneous susceptibility to cancer, general senescence, and
error in census population figures. We model rising and falling cancer rates with a
beta curve obtained by appending an empirical, linearly decreasing factor to the
well known Armitage-Doll multistage model. Old age survival data may reveal important
details of the relationship between aging and cancer. Additionally, because
this relationship may be causal, we suggest that some medical, diet, and lifestyle interventions
restricting carcinogenesis ought to be examined for possible effects on
longevity.
1948 STUDY ON THE INHIBITION OF
PROTOPORPHYRINOGEN OXIDASE (PPO) FROM
RATS, MICE, RABBITS, AND HUMANS.
A. Doi 1 , T. Bernshausen 2 , E. Fabian 2 , R. Niggeweg 2 , C. Werner 2 , R.
Landsiedel 2 and B. van Ravenzwaay 2 . 1 Toxicology, BASF, Research Triangle Park,
NC and 2 Experimental Toxicology and Ecology, BASF SE, Ludwigshafen, Germany.
Protoporphyrinogen oxidase (PPO) catalyzes the last common step in the biosynthesis
of heme and chlorophyll, a key pathway for both plants and mammals.
Accordingly, herbicides that target the PPO enzyme may exert toxic effects in mammalian
species. This study aimed to investigate the relative inhibitory effects of the
PPO inhibitor Kixor® on PPO activity in liver mitochondrial fractions obtained
from rats, mice, rabbits and humans. Mitochondria fractions were prepared and
characterized according to the activity of marker enzymes. Measurements of PPO
activities of liver mitochondrial preparations were based on the spectrofluorometric
detection of protoporphyrin formation over time. PPO activities were linear to the
amount of mitochondria homogenate, and varied across species, with human mitochondria
fractions showing lower PPO activity per mg of protein, followed by the
rabbit, mouse and rat. The PPO activity using 20 μg mitochondrial protein of
414 SOT 2010 ANNUAL MEETING