The Toxicologist - Society of Toxicology

NPC and sinonasal cancer in neighboring tissues of the URT and other sites of first
contact with inhaled exposure, these collective results support a broader pattern of
carcinogenicity within the URT.
1947 EVIDENCE-BASED ANALYSIS DEFINING A
FORMALDEHYDE VAPOR CONCENTRATION NOEL
FOR IRRITANT RESPONSES IN HUMANS.
J. K. Britt 1 , N. Halmes 2 , B. Kerger 3 and R. C. James 1 . 1 TERRA, Inc., Tallahassee,
FL, 2 Halmes & Associates, Centennial, CO and 3 HSRI, Inc., Tallahassee, FL.
The available scientific literature contains a broad range of human studies suggesting
a range of levels at which formaldehyde may begin to induce eye or upper respiratory
irritation. This study attempts to resolve the current uncertainty by an
analysis derived via methods developed for reaching an evidence-based medical/toxicological
conclusion. A literature search was conducted to identify all potentially
relevant studies. The literature has shown that subjective symptoms of irritation are
affected by mood (negative affect), the individual’s pre-conceived or naïve interpretation
of the possible hazard associated with an odor, and that eye irritation is the
most sensitive endpoint. Studies were rated and ranked according to preselected experimental
design components that included these considerations. Studies that inadequately
addressed certain rating components were eliminated altogether. Not
surprisingly, experimental studies with carefully controlled exposures, using physiologic
responses to derive objective measurements, and carefully controlled for confounding
ranked and rated the highest and provided the best available evidence.
The present evidence-based analysis identified a NOEL for eye irritation of 0.6
ppm formaldehyde and a LOEL of 1.0 ppm with a unidentified threshold falling
somewhere between these two levels. If subjective symptom measurements, which
comprised the majority of the studies, were considered separately, and a well tolerated
subjective interpretation of the exposure was the desired measurement outcome
then a somewhat higher level near 1.0 ppm would represent the likely No
Observable Adverse Effect Level.
1948 WEIGHT-OF-EVIDENCE EVALUATION OF A
PLAUSIBLE MODE OF ACTION FOR
LEUKEMOGENESIS FROM INHALATION EXPOSURE
TO FORMALDEHYDE.
L. Bailey, A. K. Hamade and L. R. Rhomberg. Gradient, Cambridge, MA.
We conducted a weight-of-evidence evaluation to assess the plausibility of three
modes of action that have been proposed for formaldehyde (FA) leukemogenesis: 1)
FA directly targeting bone marrow; 2) FA targeting nasal stem cells in the nasal-associated
lymphoid tissue (NALT); or 3) FA targeting circulating hematopoietic
stem cells (HSC), with later incorporation of nasal stem cells or HSCs into bone
marrow. We determined whether the concentrations of FA that would be necessary
to exceed endogenous levels in tissue are relevant to typical human exposures, and
whether these concentrations would cause irritation. We determined whether the
available evidence is consistent with FA-induced genotoxicity directly in the bone
marrow, NALT, or circulating HSCs, and whether the types of DNA damage observed
in FA genotoxicity studies are consistent with typical DNA damage associated
with leukemias. And finally, we examined the likelihood that damaged circulating
stem cells home back to healthy bone marrow to induce leukemia. We found
that under typical human exposure concentrations, FA’s reactivity precludes its
movement past the immediate respiratory epithelia following inhalation, precluding
its ability to cause DNA damage in the NALT or circulating HSCs. We found
that higher FA exposures (necessary to exceed endogenous levels) would likely be
associated with a high degree of irritation. We found these results to be consistent
with our further observation that cytogenetic effects typically reported in support
of potential distant-site FA toxicity were inconsistent, potentially confounded by
other exposures, not specific to leukemias, and typically reported in human peripheral
blood lymphocytes which should not be presumed to equate with circulating
HSCs. Finally, we found that there are many questions regarding HSC homing to
bone marrow under homeostatic conditions. We conclude that the current weight
of evidence, considering metabolism, distribution, genotoxicity, and HSC homing
provides little support for the proposed modes of action for FA leukemogenesis.
1949 DOES FORMALDEHYDE CAUSE HEMATOTOXICITY? A
WEIGHT-OF-EVIDENCE EVALUATION OF
HEMATOTOXICITY STUDIES IN HUMANS AND
ANIMALS IN THE CONTEXT OF LEUKEMOGENICITY.
A. Hamade, L. A. Bailey and L. R. Rhomberg. Toxicology, Gradient, Cambridge, MA.
We conducted a weight-of-evidence evaluation to assess the plausibility of recently
proposed hypotheses that suggested potential hematotoxic and leukemogenic properties
for formaldehyde. First, we evaluated studies in humans that assessed hema-
tology outcomes in subjects occupationally exposed to formaldehyde. We found no
indication from these studies that formaldehyde is hematotoxic. Some studies have
shown some evidence of changes in hematology in occupationally exposed populations;
however, not all details of these studies are available, the studies provide
mixed evidence of effects, and some studies report statistically significant outcomes
even at concentrations that may be exceeded in some public spaces. Even when
some studies show evidence of hematology changes, the changes are not clinically
significant and may be explained by mechanisms independent of bone marrow toxicity.
Second, we evaluated hematotoxicity studies in animals. We found generally
no convincing evidence that formaldehyde, even at very high exposure concentrations,
could cause hematotoxicity. Moreover, our evaluation revealed that animal
studies do not show evidence of leukemia induction by formaldehyde exposure, a
conclusion that seriously weakens the argument for its induction in humans. Only
one study reports formaldehyde-associated leukemia in animals, and this study has
serious faults that discredit its outcomes. Third, we examined the hematotoxic effects
of established leukemogens, such as benzene and cyclophosphamide, and
found that these agents invariably induce bone marrow toxicity and hematotoxicity,
suggesting that if formaldehyde causes leukemia in humans, it is likely independent
of hematotoxicity, which would be inconsistent with any mechanism currently
known for leukemogenesis. In conclusion, we did not find convincing evidence
that formaldehyde is hematotoxic in animals or humans.
1950 IS MTBE GENOTOXIC OR MUTAGENIC?
M. Seeley, L. A. Beyer and B. D. Beck. Gradient Corporation, Cambridge, MA.
Due to prior use as a fuel oxygenate, methyl-tert-butyl-ether (MTBE) has been
found in groundwater, where it presents a concern for potential human health risks,
primarily cancer. There is no evidence that MTBE causes cancer in humans.
Increased cancer incidence has been observed in several animal cancer bioassays,
but only at exposure levels several orders of magnitude greater than potential exposures
to MTBE in groundwater. The mode-of-action and nature of the dose-response
for MTBE carcinogenesis is currently a matter of scientific debate, with important
ramifications for establishing permissible concentrations of MTBE in
groundwater. Key to that debate is whether MTBE is genotoxic or mutagenic, in
that evidence of mutagenicity would be potentially supportive of a no threshold
dose-response model. We therefore conducted a weight-of-evidence analysis of
MTBE genotoxicity assays, including those from both published studies, and unpublished
studies discussed in regulatory documents. We identified 13 in vivo and
28 in vitro assays, including mutagenicity assays (24) as well as “indicator” assays
(17) (i.e. tests, such as sister chromatid exchange assays, that reflect genotoxicity,
but do not confirm mutagenicity). Importantly, none of the in vivo, and only one
in vitro mutagenicity assay yielded a positive result with MTBE; subsequent evaluations
indicate this result was due to exogenous formation of formaldehyde, specific
to the conditions of the in vitro assay, rather than intrinsic mutagenicity of MTBE.
Based on a critical analysis of the 12 indicator assays that provided some evidence of
DNA damage under certain conditions, we identified important limitations for
these assays, including minimal nature of the response, lack of a clear dose-response,
problems with study design, methodological issues, as well as differences
between in vitro and in vivo metabolism of MTBE. We conclude that the weight of
the evidence indicates that MTBE is unlikely to be genotoxic or mutagenic. Thus
margins-of-exposure analyses are more appropriate than linear no-threshold models
for use in quantification of MTBE cancer risks
1951 METHYL TERTIARY BUTYL ETHER (MTBE): TWO-
YEAR DRINKING WATER STUDY IN WISTAR RATS.
E. Bermudez 1 , D. K. Layko 1 , G. A. Willson 2 and D. E. Dodd 1 . 1 The Hamner
Institutes for Health Sciences, Research Triangle Park, NC and 2 Experimental
Pathology Laboratories, Inc., Research Triangle Park, NC .
To improve the human health risk assessment of MTBE in drinking water, male
and female Wistar rats (50/sex/group) were exposed to drinking water, ad libitum,
containing various concentrations of MTBE, 7 d/wk, for 2 yr. MTBE drinking
water concentrations were 0 (control), 0.5, 3, and 7.5 mg/mL for male rats, and 0,
0.5, 3, and 15 mg/mL for female rats. Endpoints included clinical observations,
body weights, food and water consumption, gross necropsy, organ weights, and tissue
histopathology. Body weights and food consumption were unaffected by exposure,
but water consumption was reduced in all MTBE-exposed groups (e.g., 77,
71 and 69% of the control for the 0.5, 3 and 7.5 mg/mL male groups, respectively).
Statistical analyses of animal survival indicated no differences in survival between
control and MTBE groups. Following 24 months of MTBE exposure, statistically
significant increases in left and right kidney weights were observed in male and female
rats of all MTBE exposure groups. Microscopically, a statistically significant
increase in the incidence and severity of chronic progressive nephropathy (CPN), a
SOT 2011 ANNUAL MEETING 417