United States
kS^laMIjk Environmental Protection
^J^iniiil m11 Agency
EPA/690/R-09/009F
Final
9-08-2009
Provisional Peer-Reviewed Toxicity Values for
2-Chloroacetaldehyde
(CASRN 107-20-0)
Superfund Health Risk Technical Support Center
National Center for Environmental Assessment
Office of Research and Development
U.S. Environmental Protection Agency
Cincinnati, OH 45268

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Commonly Used Abbreviations
BMD
Benchmark Dose
IRIS
Integrated Risk Information System
IUR
inhalation unit risk
LOAEL
lowest-observed-adverse-effect level
LOAELadj
LOAEL adjusted to continuous exposure duration
LOAELhec
LOAEL adjusted for dosimetric differences across species to a human
NOAEL
no-ob served-adverse-effect level
NOAELadj
NOAEL adjusted to continuous exposure duration
NOAELhec
NOAEL adjusted for dosimetric differences across species to a human
NOEL
no-ob served-effect level
OSF
oral slope factor
p-IUR
provisional inhalation unit risk
p-OSF
provisional oral slope factor
p-RfC
provisional inhalation reference concentration
p-RfD
provisional oral reference dose
RfC
inhalation reference concentration
RfD
oral reference dose
UF
uncertainty factor
UFa
animal to human uncertainty factor
UFC
composite uncertainty factor
UFd
incomplete to complete database uncertainty factor
UFh
interhuman uncertainty factor
UFl
LOAEL to NOAEL uncertainty factor
UFS
subchronic to chronic uncertainty factor
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PROVISIONAL PEER-REVIEWED TOXICITY VALUES FOR
2-CHLOROACETALDEHYDE (CASRN 107-20-0)
Background
On December 5, 2003, the U.S. Environmental Protection Agency's (U.S. EPA) Office of
Superfund Remediation and Technology Innovation (OSRTI) revised its hierarchy of human
health toxicity values for Superfund risk assessments, establishing the following three tiers as the
new hierarchy:
1)	U.S. EPA's Integrated Risk Information System (IRIS).
2)	Provisional Peer-Reviewed Toxicity Values (PPRTVs) used in U.S. EPA's Superfund
Program.
3)	Other (peer-reviewed) toxicity values, including
~	Minimal Risk Levels produced by the Agency for Toxic Substances and Disease
Registry (ATSDR),
~	California Environmental Protection Agency (CalEPA) values, and
~	EPA Health Effects Assessment Summary Table (HEAST) values.
A PPRTV is defined as a toxicity value derived for use in the Superfund Program when
such a value is not available in U.S. EPA's IRIS. PPRTVs are developed according to a
Standard Operating Procedure (SOP) and are derived after a review of the relevant scientific
literature using the same methods, sources of data, and Agency guidance for value derivation
generally used by the U.S. EPA IRIS Program. All provisional toxicity values receive internal
review by two U.S. EPA scientists and external peer review by three independently selected
scientific experts. PPRTVs differ from IRIS values in that PPRTVs do not receive the
multiprogram consensus review provided for IRIS values. This is because IRIS values are
generally intended to be used in all U.S. EPA programs, while PPRTVs are developed
specifically for the Superfund Program.
Because new information becomes available and scientific methods improve over time,
PPRTVs are reviewed on a 5-year basis and updated into the active database. Once an IRIS
value for a specific chemical becomes available for Agency review, the analogous PPRTV for
that same chemical is retired. It should also be noted that some PPRTV documents conclude that
a PPRTV cannot be derived based on inadequate data.
Disclaimers
Users of this document should first check to see if any IRIS values exist for the chemical
of concern before proceeding to use a PPRTV. If no IRIS value is available, staff in the regional
Superfund and Resource Conservation and Recovery Act (RCRA) program offices are advised to
carefully review the information provided in this document to ensure that the PPRTVs used are
appropriate for the types of exposures and circumstances at the Superfund site or RCRA facility
in question. PPRTVs are periodically updated; therefore, users should ensure that the values
contained in the PPRTV are current at the time of use.
It is important to remember that a provisional value alone tells very little about the
adverse effects of a chemical or the quality of evidence on which the value is based. Therefore,
users are strongly encouraged to read the entire PPRTV document and understand the strengths
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and limitations of the derived provisional values. PPRTVs are developed by the U.S. EPA
Office of Research and Development's National Center for Environmental Assessment,
Superfund Health Risk Technical Support Center for OSRTI. Other U.S. EPA programs or
external parties who may choose of their own initiative to use these PPRTVs are advised that
Superfund resources will not generally be used to respond to challenges of PPRTVs used in a
context outside of the Superfund Program.
Questions Regarding PPRTVs
Questions regarding the contents of the PPRTVs and their appropriate use (e.g., on
chemicals not covered, or whether chemicals have pending IRIS toxicity values) may be directed
to the U.S. EPA Office of Research and Development's National Center for Environmental
Assessment, Superfund Health Risk Technical Support Center (513-569-7300), or OSRTI.
INTRODUCTION
2-Chloroacetaldehyde (CAA) is a metabolite of the human carcinogen vinyl chloride.
The empirical formula for CAA is C2H3OCI, and Figure 1 shows the chemical structure.
Figure 1. Chemical Structure Diagram for 2-Chloroacetaldehyde
The U.S. EPA has not derived RfDs, RfCs, or estimates of carcinogenic potency or risk
for CAA. No values are posted on IRIS (U.S. EPA, 2008a), the Drinking Water Standards and
Health Advisories list (U.S. EPA, 2006), or the Health Effects Assessment Summary Tables
(HEAST) (U.S. EPA, 1997). Relevant documents in the Chemical Assessments and Related
Activities (CARA) list (U.S. EPA, 1991, 1994) include a Health and Environmental Effects
Profile (HEEP) (U.S. EPA, 1986) and a Health and Environmental Effects Document (HEED)
(U.S. EPA, 1988). However, both of these documents conclude that no adequate data were
available to derive quantitative estimates of noncarcinogenic or carcinogenic risk. The HEEP
(U.S. EPA, 1986) and HEED (U.S. EPA, 1988) assign CAA to weight-of-evidence Group D for
cancer.
U.S. EPA (2008b) lists interim Acute Exposure Guidelines (AEGLs) for CAA for use in
the event of a sudden, unexpected release. The AEGL1 values (sensory irritation threshold)
range from an 8-hour value of 0.22 ppm (0.7 mg/m ) to a 10-minute value of 2.3 ppm
(7.4 mg/m3). The AEGL2 values (incapacitation) range from an 8-hour value of 0.39 ppm
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3	3
(1.25 mg/m ) to a 10-minute value of 9.8 ppm (31.5 mg/m ). The AEGL3 values (death or
serious, irreversible health effects) range from an 8-hour value of 1.8 ppm (5.8 mg/m3) to a
"3
10-minute value of 44 ppm (141 mg/m ).
There are occupational exposure limits for 2-chloroacetaldehyde. The American
Conference of Governmental Industrial Hygienists (ACGIH, 2007) has adopted a Short-Term
Exposure Limit (STEL) ceiling of 1 ppm (3 mg/m3) for CAA. This value is intended to
minimize the potential for ocular and upper respiratory tract irritation in exposed workers
(ACGIH, 2007). The National Institute of Occupational Safety and Health (NIOSH, 2008)
"3
recommends a ceiling limit of 1 ppm (3 mg/m ) for CAA based on the same effects. The
Occupational Safety and Health Administration (OSHA, 2008) also lists a ceiling limit of 1 ppm
(3 mg/m3) for CAA.
The National Toxicology Program (NTP, 2008) has not assessed the toxicity or
carcinogenicity of CAA, and this compound is not included in the 11th Report on Carcinogens
(NTP, 2005). CAA has not been the subject of a monograph by the International Agency for
Research on Cancer (IARC, 2008) or a toxicological profile by ATSDR (2008).
CalEPA (2002, 2008a,b) has not derived exposure levels for chronic toxicity or carcinogenic
potency for CAA.
To identify toxicological information pertinent to the derivation of provisional toxicity
values for CAA, literature searches were conducted on October 29, 2008 using the following
databases: MEDLINE, TOXLINE, BIOSIS (1999-October 2008), Chemical Abstracts
(1999-October 2008), TSCATS1/2, CCRIS, DART, GENETOX, HSDB, RTECS, and Current
Contents (April 2007-October 2008). An additional literature search was conducted on
July 14, 2009 of MEDLINE. Except where noted, the literature searches were not limited by
date.
REVIEW OF PERTINENT DATA
Human Studies
No relevant data were located regarding the toxicity of CAA to humans following
inhalation or oral exposure.
Animal Studies
Oral Exposure
Designed primarily as a cancer bioassay of three different chlorinated water
contaminants, Daniel et al. (1992) exposed 40 male B6C3F1 mice for 104 weeks to drinking
water containing CAA at 0.1 g/L (equivalent to 17 mg/kg-day, as determined by study authors).
Untreated control animals (23 in one group, from which interim euthanasias were conducted, and
10 in a second group) received distilled water. Interim sacrifices of five animals per group were
conducted at 30 and 60 weeks of exposure. Complete necropsy and microscopic examination
were performed. There were no statistically significant treatment-related effects on survival or
body weight. There were no changes in spleen, kidneys, or testes weights, or histopathological
changes in any tissue except the liver. Absolute and relative liver weights were slightly
increased at the 30-week sacrifice but did not maintain statistical significance by 104 weeks
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(p > 0.10). At terminal sacrifice (104 weeks), hepatocellular necrosis was noted in 7/26 (27%)
treated animals, compared to 1/20 (5%) in controls; mild cytoplasmic vacuolization, cytomegaly,
and cytoplasmic alteration were also reported. Additionally, a significant increase in the
incidence of liver tumors was found. The prevalence of liver neoplasms at terminal sacrifice was
statistically significantly (p < 0.03) increased over controls, with carcinomas in 8/26 (31%) and
adenomas in 2/26 (8%), as well as preneoplastic lesions (hyperplastic nodules) in 2/26 (8%). In
control animals, carcinomas, adenomas, and nodules occurred in 2/20, 1/20, and 0/20,
respectively. At the 60-week sacrifice, there were 1/5 treated animals with hepatocellular
carcinoma, compared with 0/5 controls. No carcinomas, adenomas, or hyperplastic nodules were
reported in animals sacrificed at Week 30.
Van Duuren et al. (1979) observed no significant increase in forestomach or internal
tumors in Ha:ICR Swiss mice (30/sex) treated with 0.25 mg of CAA in water by intragastric
intubation once per week for up to 636 days, compared with vehicle (30/sex) and untreated
(60 males, 100 females) controls. Based on a reference body weight of 0.036 kg for mice in a
chronic study (U.S. EPA, 1988), this corresponds to an average weekly dose of approximately
7 mg/kg in the treated mice.
Inhalation Exposure
No subchronic or chronic inhalation studies are available for derivation of an RfC or
inhalation unit risk for CAA.
Other Studies
Other Routes
Lawrence et al. (1972) conducted studies of repeated intraperitoneal (i.p.) injection of
CAA in rats. Male Sprague-Dawley rats were treated with CAA by i.p. injection at 0.001879 or
0.003758 mL/kg daily for 30 days or 0.00032, 0.0008, 0.0016, or 0.0032 mL/kg 3 times weekly
for 12 weeks. Effects were seen primarily in the high-dose group in the 30-day study and the
two highest dose groups in the 12-week study, and were similar in the two studies: reduced body
weight gain; decreased red blood cell count, hemoglobin, and hematocrit; and histopathological
lesions in the lungs (increased severity of bronchopneumonia and changes in respiratory
epithelium relative to controls).
Van Duuren et al. (1979) reported negative results in cancer bioassays of CAA conducted
in groups of 30 female Ha:ICR Swiss mice by dermal application (1 mg/mouse in 0.1-mL
acetone, 3 times weekly, for 581 days) or subcutaneous injection (0.25 mg in water, once
weekly, for 630 days) compared with vehicle (30/group) and untreated (100/group) controls.
CAA also gave negative results as an initiator in a dermal initiation-promotion protocol with
PMA (phorbol myristate acetate) as the promoter (Van Duuren et al., 1979).
Genotoxicity
CAA has been demonstrated to be mutagenic in a variety of in vitro assays using both
prokaryotes and eukaryotes with and without metabolic activation (Bignami et al., 1980;
Rannug et al., 1976; McCann et al., 1975; Malaveille et al., 1975; Phillips et al., 1980;
Garro and Phillips, 1980; Hussain and Osterman-Golkar, 1984; Perrard, 1985;
Lorprieno et al., 1977; Huberman et al., 1975; Rosenkranz, 1977; Jacobsen et al., 1989;
Mroczkowska et al., 1993; Kohwi-Shigematsu and Nelson, 1988; Matsuda et al., 1995;
Chiang et al., 1997; Tudek et al., 1999; Chang et al., 1992; Kandala et al., 1990). In human cell
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lines, CAA was found to modify a specific site within the regulatory sequence of the human
cytomegalovirus intermediate early (IE) gene (Kohwi-Shigematsu and Nelson, 1988), the supF
gene of mutant plasmids transfected into human fibroblast cells (Matsuda et al., 1995), sites in
the hypoxanthine (guanine) phosphoribosyl-transferase (hprt) locus of human B-lymphoblastoid
cells (Chiang et al., 1997), and adenine, cytosine, and guanine bases in the human
p53 tumor-suppressor gene contained in pSP65 plasmids grown in Escherichia coli strain DH5a
(Tudek et al., 1999). The formation of CAA-induced DNA adducts, leading to the occurrence of
mutations, has been confirmed (Jacobsen et al., 1989; Tudek et al., 1999). CAA induced
promutagenic exocyclic etheno DNA adducts (e.g., l,N6-ethenodeoxyadenosine) in human
B-lymphoid cells (Zielinski and Hergenhahn, 2001). CAA treatment caused dose-dependent
increases in etheno DNA adducts (l,N6-ethenodeoxyadenosine, 3,N4-ethenodeoxycytidine, and
l,N2-ethenodeoxyguanosine) and small increases in strand breaks and abasic sites in the supF
gene of the pSP189 plasmid (Kim et al., 2007). The location of CAA-induced DNA adducts in
supF target genes corresponds well with mutation data showing that mutations occur at many
different base positions along the supF target (Choi and Pfeifer, 2004). The mutational spectra
obtained with the supF target genes showed a preponderance of C/G to T/A transitions and C/G
to A/T transversions (Choi and Pfeifer, 2004). In the human p53 gene, CAA-induced DNA
damage was concentrated in sequences that showed secondary structure perturbations inhibiting
DNA synthesis, which are mutation hot spots in the human p53 gene (Kowalczyk et al., 2006).
Combined, these in vitro studies demonstrating possible mutagenicity for CAA do not correlate
with the limited in vivo studies.
DERIVATION OF SUBCHRONIC AND CHRONIC PROVISIONAL ORAL
RfD VALUES FOR 2-CHLOROACETALDEHYDE
Because of the lack of human oral data and the inadequacy of the animal oral data, p-RfD
values for CAA cannot be derived. The cancer bioassay study performed by Daniel et al. (1992)
is limited in its application to noncancer risk assessment for two reasons: first, this study utilized
only a single dose level; secondly, administration of CAA resulted in carcinogenic effects in the
liver, which makes it difficult to distinguish between liver effects that may be precancerous and
effects that may be distinct from the carcinogenic process.
DERIVATION OF SUBCHRONIC AND CHRONIC PROVISIONAL INHALATION
RfC VALUES FOR 2-CHLOROACETALDEHYDE
Provisional RfC values for CAA cannot be derived because of the lack of suitable human
or animal inhalation data.
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PROVISIONAL CARCINOGENICITY ASSESSMENT
FOR 2-CHLOROACETALDEHYDE
Weight-of-Evidence Descriptor
No data were located regarding the carcinogenicity of CAA in humans.
Daniel et al. (1992) found a significant increase in liver tumors in male mice treated with CAA
for 2 years. However, only a single dose level was tested. Female mice were not assessed in this
study. A series of studies performed by Van Duuren et al. (1979) in mice exposed by intragastric
injection, subcutaneous injection, or dermal application were negative but were not adequate
cancer bioassays. Genotoxicity data show that CAA is mutagenic in both bacteria and human
cells. Under the 2005 Guidelines for Carcinogen Risk Assessment (U.S. EPA, 2005), there is
"Suggestive Evidence of Carcinogenic Potential for 2-chloroacetaldehyde, " based on a positive
response in a limited animal bioassay and strong evidence of mutagenicity.
Quantitative Estimates of Carcinogenic Risk
Oral Exposure
Oral data are limited and include a single dose level study (Daniel et al., 1992) that can
be used to derive a quantitative estimate of cancer risk for CAA. Because the cancer descriptor
for this chemical is "Suggestive Evidence of Carcinogenic Potential," a screening p-OSF is
provided in an appendix, which may be useful in certain instances. Please see the attached
Appendix for details.
Inhalation Exposure
No inhalation studies are available to develop an inhalation unit risk estimate (IUR).
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reactive metabolites, chloroethylene oxide and chloroacetaldehyde, in a metabolically competent
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Choi, J.-H. and G.P. Pfeifer. 2004. DNA damage and mutations produced by
chloroacetaldehyde in a CpG-methylated target gene. Mutat. Res. 568:245-256.
Daniel, F.B., A.B. DeAngelo, J. A. Stober et al. 1992. Hepatocarcinogenicity of chloral hydrate,
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Garro, A.J. and R.A. Phillips. 1980. Detection of mutagen-induced lesions in isolated DNA by
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Hussain, S. and S. Osterman-Golkar. 1984. Dose-response relationships for mutations induced
in E. coli by some model compounds. With an addendum: Reaction kinetics in water of
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Jacobsen, J.S., C.P. Perkins, J.T. Callahan et al. 1989. Mechanisms of mutagenesis by
chloroacetaldehyde. Genetics. 121:213-222.
Kandala, J.C., J.E.K. Mrema, A. DeAngelo et al. 1990. 2-Chloroacetaldehyde and
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Comm. 167:457-463.
Kim, M.Y., X. Zhou, J.C. Delaney et al. 2007. AlkB influences the chloroacetaldehyde-induced
mutation spectra and toxicity in the pSP189 supF shuttle vector. Chem. Res. Toxicol.
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Kohwi-Shigematsu, T. and J.A. Nelson. 1988. The chemical carcinogen, chloroacetaldehyde,
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immediate early gene in vivo. Mol. Carcinogen. 1:20-25.
Kowalczyk, P., J.M. Ciesla, M. Saparbaev et al. 2006. Sequence-specificp53 gene damage by
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Lawrence, W.H., E.O. Dillingham, J.E. Turner et al. 1972. Toxicity Profile of
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Matsuda, T., T. Yagi, M. Kawanishi et al. 1995. Molecular analysis of mutations induced by
2-chloroacetaldehyde, the ultimate carcinogenic form of vinyl chloride, in human cells using
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McCann, J., V. Simmon, D. Streitweiser et al. 1975. Mutagenicity of chloroacetaldehyde, a
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72(8):3190-3193.
Mroczkowska, M.M., I.K. Kolasa and J.T. Kusmierek. 1993. Chloroacetaldehyde-induced
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adaptive response to alkylating agents. Mutagenesis. 8:341-348.
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NTP (National Toxicology Program). 2005. 11th Report on Carcinogens. U.S. Department of
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Rannug, U., R. Geothe and C.A. Wachmeister. 1976. The mutagenicity of chloroethylene
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Tudek, B., P. Kowalczyk and J.M. Ciesla. 1999. Localization of chloroacetaldehyde-induced
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Anal. Chem. 370:97-100.
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APPENDIX A. DERIVATION OF A SCREENING ORAL SLOPE FACTOR
FOR 2-CHLOROACETALDEHYDE (CASRN 107-20-0)
For reasons noted in the main PPRTV document, it is inappropriate to derive provisional
toxicity values for 2-Chloroacetaldehyde (CAA). However, information is available for this
chemical which, although insufficient to support derivation of a provisional toxicity value, under
current guidelines, may be of limited use to risk assessors. In such cases, the Superfund Health
Risk Technical Support Center summarizes available information in an Appendix and develops a
"Screening Value." Appendices receive the same level of internal and external scientific peer
review as the PPRTV documents to ensure their appropriateness within the limitations detailed in
the document. Users of screening toxicity values in an appendix to a PPRTV assessment should
understand that there is considerably more uncertainty associated with the derivation of an
appendix screening toxicity value than for a value presented in the body of the assessment.
Questions or concerns about the appropriate use of Screening Values should be directed to the
Superfund Health Risk Technical Support Center.
Oral data are limited but can be used to derive a quantitative estimate of cancer risk for
CAA. Male mice exhibited increased incidences of hepatocellular tumors in a cancer bioassay
that included a single dose level (Daniel et al., 1992). While it is undesirable to utilize a
single-dose study for quantitative estimates of cancer risk, the U.S. EPA attempts to estimate the
cancer oral slope factor (OSF) when at all possible and has used a linear extrapolation from a
single dose in prior provisional cancer slope factor derivations. Additionally, while there is
strong evidence of mutagenicity in a variety of in vitro tests, due to design deficiencies (i.e.,
single dose level) in the in vivo cancer bioassay, the mode of action of 2-chloroacetaldehyde
cannot be clearly defined as mutagenic. Because the mode of action of CAA is not defined, the
linear quantitative methodology was applied.
Table A-l shows the dose-response data used in the quantitative cancer assessment. The
dose in the Daniel et al. (1992) mouse study was first converted to a human equivalent dose
(HED) by adjusting for differences in body weight between humans and mice. In accordance
with U.S. EPA (2005) Guidelines for Carcinogen Risk Assessment, a factor of BW3 4 was used
for cross-species scaling. For doses expressed per unit body weight (mg/kg or mg/kg-day), the
relationship is reciprocal, and the human dose (mg/kg) is obtained by multiplying the animal
dose (mg/kg) by the ratio of animal :human body weight raised to the 1/4 power. Because the
mice were exposed to drinking water containing 0.1 g/L CAA (equivalent to 17 mg/kg-day) for
104 weeks, no adjustment for discontinuous exposure or less-than-lifetime administration is
necessary. The equation used to calculate the HED is shown below, and the HED is presented in
Table A-l.
HED = Dose x (W/70 kg)1/4
where
Dose = average daily animal dose (mg/kg-day)
W = average mouse body weight during the study (kg)
70 kg = reference human body weight (U.S. EPA, 1988)
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Table A-l. Dose-Response Data for Liver Tumors in Male Mice Treated with
2-Chloroacetaldehyde in the Drinking Water for 104 Weeks"
Animal Dose
(mg/kg-day)
Average
Body
Weightb
(kg)
Human
Equivalent
Dose (HED)
(mg/kg-day)
Incidence of Carcinomas
Incidence of Carcinomas and
Adenomas (Combined)
60 wks
104 wks
60 +104 wks
60 wks
104 wks
60 +104 wks
0
NA
0
0/5
2/20
2/25
0/5
3/20
3/25
17
0.0241
2.32
1/5
8/26
9/31
1/5
10/26
11/31
"Daniel etal. (1992).
Calculated from initial and final body-weight measurements made during the study.
Dose-response modeling of the data in Table A-l was performed to obtain a point of
departure (POD) for a quantitative assessment of cancer risk. The POD is an estimated dose
(expressed in human-equivalent terms) near the lower end of the observed range that marks the
starting point for extrapolation to lower doses. There are several ways to analyze the data from
Daniel et al. (1992); each possible approach was modeled and compared. Hepatocellular
adenomas and carcinomas combined and carcinomas alone were modeled based on incidence at
104 weeks. Additionally, the combined incidence at the 60- and 104-week sacrifices for
carcinomas alone and adenomas and carcinomas combined was modeled. Appendix A provides
details of the modeling effort. Modeling results were similar for all four data sets. The
BMDLiohed (lower bound on human equivalent dose estimated to produce a 10% increase in
tumor incidence over background) was estimated using the U.S. EPA (2000) benchmark dose
(BMD) methodology and benchmark response (BMR) of 10% extra risk. The lowest
BMDLiohed was 0.37 mg/kg-day for combined hepatocellular adenomas and carcinomas in male
mice sacrificed at 104 weeks.
The BMDLiohed of 0.37 mg/kg-day was selected as the POD for derivation of the p-OSF.
In order to linearly extrapolate cancer risks from the BMDLiohed to the origin, the p-OSF was
calculated as the ratio BMR/BMDLiohf.p (0.1 0.37 mg/kg-day), as follows:
p-OSF = BMR BMDLiohed
= 0.1 0.37 mg/kg-day
= 0.27 or 2.7 x 10"1 (mg/kg-day)"1
Given that the limited data available (only one treated dose level in the key study) constrained
the model shape and precluded application of statistical methods to assess model fit, this p-OSF
is highly uncertain.
The p-OSF for CAA should not be used with exposures exceeding the POD
(BMDLiohed = 0.37 mg/kg-day) because the slope is not linear at higher doses. Above the POD,
the fitted dose-response model better characterizes what is known about the carcinogenicity of
CAA. Table A-2 shows the doses associated with specific levels of cancer risk based on the
p-OSF estimated herein.
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Table A-2. Doses of CAA Associated with Specific Levels of Cancer Risk
Risk Level
Dose (mg/kg-day)
10"4
0.0004
10"5
0.00004
10"6
0.000004
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APPENDIX B. DETAILS OF BENCHMARK DOSE MODELING
FOR ORAL SLOPE FACTOR
Model Fitting Procedure for Cancer Incidence Data:
The model-fitting procedure for dichotomous cancer incidence data is as follows. The
multistage-cancer model in the U.S. EPA benchmark dose modeling software (BMDS) is fit to
the incidence data using the "extra risk" option. The multistage model is run for all polynomial
degrees up to n-1 (where n is the number of dose groups including control); the degree
polynomial with the lowest AIC is selected. Goodness-of-fit is assessed by the % test; adequate
fit is indicated by ap-value greater than 0.1. In accordance with U.S. EPA (2000) Benchmark
Dose Technical Guidance Document, benchmark doses (BMDs) and lower bounds on the BMD
(BMDLs) associated with a benchmark response (BMR) of 10% extra risk are calculated.
Model Fitting Results for Liver Tumors in Male Mice (Daniel et al., 1992):
Table B-l shows the dose-response data on liver tumor incidence in male mice treated
with 2-chloroacetaldehyde in drinking water for 104 weeks (Daniel et al., 1992). Hepatocellular
adenomas and/or carcinomas were observed in the mice at both the 60-week interim sacrifice and
terminal 104-week sacrifice. Therefore, modeling was performed for 4 separate data sets:
(1) combined adenomas and carcinomas in male mice sacrificed at 104 weeks, (2) combined
adenomas and carcinomas in male mice sacrificed at 60 or 104 weeks, (3) carcinomas alone in
male mice sacrificed at 104 weeks, and (4) carcinomas alone in male mice sacrificed at 60 or
104 weeks.
Table B-l. Model Predictions for Liver Tumors in Male Mice"
Model
Degrees
of
Freedom
x2
X2 Goodness of
Fit
/>-Valucb
AIC
BMDxohed
(mg/kg-day)
BMDLxohed
(mg/kg-day)
104 weeks only (degree = 1)°
Carcinomas
0
0
NA
49.10
0.93
0.45
Carcinomas and
Adenomas
0
0
NA
55.55
0.76
0.37
Pooled (60 + 104 weeks) (degree = 1)°
Carcinomas
0
0
NA
55.29
0.94
0.49
Carcinomas and
Adenomas
0
0
NA
61.23
0.79
0.42
"Daniel etal. (1992)
bValues <0.10 fail to meet conventional goodness-of-fit criteria
°Only the 1-degree polynomial was run due to the use of only 2 dose groups in the study. Betas restricted to > 0.
NA = Not Available
The incidence and human equivalent dose data were modeled according to the procedure
outlined above using BMDS version 2.1 with default parameter restrictions. Due to the use of
only a single treated group in the study, only the 1-degree model was run. With only a single
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treated group and a background incidence above zero (i.e., a two-parameter model and two dose
groups), there were insufficient degrees of freedom available to assess model fit for any of these
data sets. Therefore, although BMDio and BMDLio values were calculated, they should be
considered to be highly uncertain.
Table B-l and Figures B-l through B-4 present the modeling results. Modeling results
were similar for all four data sets. The lowest BMDLiohed was 0.37 mg/kg-day for combined
hepatocellular adenomas and carcinomas in male mice sacrificed at 104 weeks.
Multistage Cancer Model with 0.95 Confidence Level
Dose
18:11 02/27 2009
Figure B-l. Fit of Multistage (1-Degree) Model to Data on Hepatocellular Carcinomas in
Male Mice at 104 Weeks (Daniel et al., 1992)
BMDs and BMDLs indicated are human equivalent doses associated with an extra risk of 10% and are in units
of mg/kg-day.
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Multistage Cancer Model with 0.95 Confidence Level
Dose
18:18 02/27 2009
Figure B-2. Fit of Multistage (1-Degree) Model to Data on Hepatocellular Carcinomas or
Adenomas (Combined) in Male Mice at 104 Weeks (Daniel et al., 1992)
BMDs and BMDLs indicated are human equivalent doses associated with an extra risk of 10% and are in units
of mg/kg-day.
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Multistage Cancer Model with 0.95 Confidence Level
Dose
18:20 02/27 2009
Figure B-3. Fit of Multistage (1-Degree) Model to Data on Hepatocellular Carcinomas in
Male Mice at 60 and 104 Weeks (Daniel et al., 1992)
BMDs and BMDLs indicated are human equivalent doses associated with an extra risk of 10% and are in units
of mg/kg-day.
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Multistage Cancer Model with 0.95 Confidence Level
Dose
18:22 02/27 2009
Figure B-4. Fit of Multistage (1-Degree) Model to Data on Hepatocellular Carcinomas or
Adenomas (Combined) in Male Mice at 60 and 104 Weeks (Daniel et al., 1992)
BMDs and BMDLs indicated are human equivalent doses associated with an extra risk of 10% and are in units
of mg/kg-day.
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