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United States Office of Chemical Safety and
Environmental Protection Agency Pollution Prevention
Risk Evaluation for
Methylene Chloride
Supplemental File:
Methylene Chloride Benchmark Dose and PBPK Modeling Report
CASRN: 75-09-2
H
H
..mCl
CI
October 2019, DRAFT
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This supplemental file includes both updated BMD and PBPK modeling results for cancer (and non-cancer
liver toxicity endpoints from Aiso et al. (2014) (PART A, beginning on page 3) and an excerpt of the BMD and
PBPK modeling results from the IRIS Assessment Document from 2011 (U.S. EPA, 2011) for non-cancer liver
toxicity endpoints from Nitschke et al. (1988) (PART B, beginning on page 140).
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PART A:
Methylene Chloride Benchmark Dose and PBPK Modeling
Report
May 31, 2019
[Date submitted by ORD to OPPT]
National Center for Environmental Assessment
Office of Research and Development
U.S. Environmental Protection Agency
Washington, DC
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DISCLAIMER
This document is a preliminary draft for review purposes only. This information is distributed
solely for the purpose of pre-dissemination review under applicable information quality guidelines. It has
not been formally disseminated by EPA. It does not represent and should not be construed to represent
any Agency determination or policy. Mention of trade names or commercial products does not constitute
endorsement or recommendation for use.
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CONTENTS
1. Background 6
2. Summary of BMD Modeling Approach 7
3. Summary of BMD Modeling Results 10
4. Summary of PBPK Analyses 12
5. BMD Modeling for Aiso et al. (2014) Male Rats 16
5.1. Subcutis (Fibroma/Fibrosarcoma) 16
5.2. Mammary Gland (Fibroadenoma/Adenoma) 22
5.3. Mammary Gland (Fibroadenoma/Adenoma/Adenocarcinoma) 28
5.4. Subcutis (Fibroma/Fibrosarcoma) or Mammary Gland (Fibroadenoma/Adenoma) 34
5.5. Subcutis or Mammary Gland (Fibroadenoma/Adenoma/Adenocarcinoma) 44
6. BMD Modeling for Aiso et al. (2014) Female Rats 54
6.1. Mammary Gland (Fibroadenoma/Adenoma/Adenocarcinoma) 54
6.2. Liver Acidophilic Cell Foci 60
6.3. Liver Basophilic Cell Foci 64
7. BMD Modeling for Aiso et al. (2014) Male Mice 68
7.1. Liver (Hepatocellular Adenoma/Hepatocellular Carcinoma) 68
7.2. Lung (Bronchiolar-Alveolar Adenoma/Bronchiolar-Alveolar Carcinoma) 74
7.3. Liver or Lung Tumor 80
7.4. Lung Terminal Bronchiole Hyperplasia 90
8. BMD Modeling for Aiso et al. (2014) Female Mice 94
8.1. Liver (Hepatocellular Adenoma/Hepatocellular Carcinoma) 94
8.2. Lung (Bronchiolar-Alveolar Adenoma/Bronchiolar-Alveolar Carcinoma) 100
8.3. Liver or Lung Tumor 104
8.4. Lung Terminal Bronchiole Hyperplasia 114
9. BMD Modeling for NTP (1986) Male Mice 118
9.1. Liver (Hepatocellular Carcinoma or Adenoma) 118
9.2. Lung (Bronchoalveolar Carcinoma or Adenoma) 124
9.3. Liver or Lung Tumor 128
Appendix A: OCSPP Request to ORD NCEA 134
Appendix B: OCSPP Justification for Endpoints Not Chosen 137
Appendix C: Model Selection Considerations for POD Computation 137
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1. Background
OCSPP requested that NCEA ran PBPK and benchmark dose (BMD) models, including all
dichotomous models that are available in BMDS 3.1, to estimate risk from methylene chloride
(dichloromethane, DCM) for select endpoints from the Aiso et al (2014) and NTP (1986) cancer
inhalation studies. The specific endpoints selected by OCSPP are identified in Appendix A,
Tables 1 and 2 of the OCSPP request. The justifications provided by OCSPP for the exclusion of
certain endpoints from the Aiso et al. (2014) study are provided in Appendix B.
Subsequently to the initial OCSPP request (Appendices A and B), OCSPP requested that
ORD NCEA assess the combined risk of tumor when multiple tumors were observed in the same
study. This was done by applying the BMDS 3.1 multi-tumor (MS Combo) model to the tumors
identified in Appendix A, Tables 1 and 2 that occurred in the same study, same sex. As described
in the BMDS 3 .1 User Guide, the multi-tumor (MS Combo) model uses the individual
Multistage models fits to the individual tumors to estimate the risk of getting one or more of the
tumors being analyzed.
As noted in Section 6 of the BMDS 3 .1 User Guide, the multi-tumor (MS Combo) model
assumes that the tumors are statistically independent of one another, and that this assumption is
generally considered appropriate unless there is "substantial biological evidence to indicate that
the tumor types are not independent—conditional on model parameter values." NCEA has not
evaluated the appropriateness of this assumption specifically for the tumors evaluated in this
report.
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2. Summary of BMD Modeling Approach
As requested by OCSPP, all BMDS 3.1 dichotomous models that use likelihood optimization
and profile likelihood-based confidence intervals were used in this analysis. Standard and non-
standard forms of these models (defined below) were run separately in BMDS 3.1 so that auto-
generated model selection recommendations accurately reflect current EPA model selection
procedures (EPA. 2012. EPA. 2014) (See Appendix C). BMDS 3.1 models that use Bayesian
fitting procedures and Bayesian model averaging were not applied in this work.
Standard BMDS 3.1 Models1 Applied to All Individual Endpoints2:
• Gamma-restricted (gam-r)
• Log-Logistic-restricted (lnl-r)
• Multistage-restricted (mst-r); from degree = 1 to degree = # dose groups - 1
• Weibull-restricted (wei-r)
• Dichotomous Hill-unrestricted (dhl-ur)
• Logistic (log)
• Log-Probit-unrestricted (lnp-ur)
• Probit (pro)
Non-Standard BMDS 3.1 Models1 Applied to All Individual Endpoints:
• Dichotomous Hill-restricted (dhl-r)
• LogProbit-restricted (lnp-r)
• Gamma-unrestricted (gam-ur)
• Log-Logistic-unrestricted (lnl-ur)
• Multistage-unrestricted (mst-ur)
• Weibull-unrestricted (wei-ur)
Models Applied by BMDS 3.1 Multi-tumor (MS Combo) Model for Estimating Combined Risk
• Multistage (restricted); from degree = 1 to degree = # dose groups - 2
1 The set of standard models are identified in accordance with EPA BMD technical guidance (EPA, 2012) and the
default dichotomous models in BMDS 3.1. Non-standard models are the remaining (non-default) dichotomous
models available in BMDS 3.1.
2 Consistent with EPA cancer (EPA, 2005) and BMD (EPA, 2012) guidance, ORD NCEA prefers to only apply the
Multistage model to cancer endpoints. In this case, all BMDS 3.1 dichotomous models were applied to both cancer
and noncancer datasets at the request of OCSPP (see Appendix A).
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General Model Options Used for Individual Endpoint and Combined Risk (MS Combo)
Analyses:
• Risk Type: Extra Risk
• BMR: 0.1 (10%)
• Confidence Level: 0.95
• Background: Estimated
• Model Restrictions: Restrictions for BMDS 3.1 models are defined in the BMDS 3.1
User Guide and are applied in accordance with EPA BMD Technical Guidance (EPA.
2012).
Model Selection
For each individual endpoint BMD analysis, a model was selected from among the preferred
standard set of models (noting instances where consideration of non-standard models may be
justified) in accordance with EPA BMD Technical Guidance (EPA. 2012) (see Appendix C). This
model is hereafter referred to as "Selected, Full Model Suite." For cancer (tumor) endpoints,3 a
model was first chosen in accordance with EPA's technical guidance for choosing the appropriate
stage of a multistage model for cancer modeling (EPA. 2014).4 This model is hereafter referred to as
"Selected, Multistage." EPA BMD Technical Guidance (EPA. 2012) was then used to compare the
"Selected, Multistage" model to other standard dichotomous models that were applied to the cancer
(tumor) endpoint to identify a "Selected, Full Model Suite" model for the cancer (tumor) endpoint.
The "Selected, Multistage" models for the cancer (tumor) endpoints were the Multistage model
forms used in the multi-tumor combined risk (MS Combo) analyses.
Dose Metrics Used in Dose-response Analyses (see PBPK report for details on each dose metric)
Liver Glutathione S-Transferase dose (Li-GST) (mg DCM metabolized via GST pathway /
Liter of liver tissue / day) for the analysis of liver tumor responses reported by Aiso et al. (2014)
for male and female mice and by NTP (1986) for male mice.
Lung Glutathione S-Transferase dose (Lu-GST) (mg DCM metabolized via GST pathway
/Liter of lung tissue /day) for the analysis of lung tumor responses reported by Aiso et al. (2014)
for male and female mice and by NTP (1986) for male mice, and for the analysis of terminal
bronchiole hyperplasia responses reported by Aiso et al. (2014) for male and female mice.
Whole Body Glutathione S-Transferase dose (WB-GST) (mg dichloromethane metabolized via
GST pathway in lung and liver/kg-day) for multi-tumor (MS Combo) analysis of combined risk
3 Consistent with OCSPP instructions (Table 1), the Aiso et al. (2014) female rat acidophilic and basophilic cell foci
endpoints have been treated as "Non-Neoplastic Foci" for the purposes of individual endpoint analysis and model
selection (as was the lung hyperplasia endpoint) and were not evaluated for combined risk using the BMDS multi-
tumor (MS_Combo) model. The Aiso et al (2014) paper treats these lesions as "preneoplastic."
4 Consistent with this guidance, only Multistage degrees up to the number of dose groups (n) - 2 were considered
for cancer (tumor) endpoints. For the noncancer endpoints (i.e., the cell foci and hyperplasia endpoints), results for
Multistage models with degrees up to n -1 are considered (EPA, 2012).
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of lung or liver tumors reported by Aiso et al. (2014) for male and female mice and by NTP
(1986) for male mice.
Slowly perfused AUC(DCM) (SP-AUC) (mg DCM - hour / Liter of Slowly Perfused Tissue) for
the analysis of tumors of the mammary gland region reported by Aiso et al. (2014) for male and
female rats and for multi-tumor (MS Combo) estimation of combined risk of mammary gland
and subcutis (in mammary gland region) tumors reported by Aiso et al. (2014) for male rats.
Liver Cytochrome P450 dose (Li-CYP) (mg DCM metabolized via CYP pathway /Liter of lung
tissue /day) for the analysis of liver acidophilic cell foci and basophilic cell foci reported by Aiso
et al. (2014) for male and female rats.
Endpoint Selection for BMP Modeling
NCEA has modeled the endpoints chosen in accordance with the statistical justification provided
by OCSPP (Appendix B) for the choice of endpoints to be modelled. There it is stated that some
endpoints were not chosen, despite significant trend tests, because of no dose with a significant
difference from controls based on a pairwise statistical comparison of treated to control. NCEA
recommends that selection be based primarily on trend testing, noting that trend tests are to be
particularly preferred over pairwise tests in the context of less common health effects.
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3. Summary of BMD Modeling Results
Sec.
Endpoint
Dose
Metric1
Selected, Full
Model Suite/
Selected, Full
Model Suite
Selected,
Multistage/MS Combo2
delected,
Multistage
BMD io
BMDLio
BMD io
BMDLio
3
Aiso et al. (2014) - Male Rats
3.1
Subcutis
SP-
AUC
lnp-ur/mst2-r
142.3
27.626
156.13
106.730
3.2
Mammary Gland (F/A)
SP-
AUC
log/mstl-
r
352.95
266.06
373.53
205.35
3.3
Mammary Gland (F/A/AC)
SP-
AUC
Log/mstl-
r
374.83
267.16
440.28
222.31
3.4
Subcutis or Mammary Gland (F/A)
SP-
AUC
MS_Combo (Subcutis: mst2-r;
F/A: mstl-r)
110.11
78.802
3.5
Subcutis or Mammary Gland
(F/A/AC)
SP-
AUC
MS_Combo (Subcutis: mst2-r; F/A: mstl-r)
115.26
81.265
4
Aiso et al. (2014) - Female Rats
4.1
Mammary Gland (F/A/AC)
SP-
AUC
pro/mstl-
r
271.35
166.68
247.23
123.70
4.2
Acidophilic Cell Foci
Li-CYP
gam-r
732.62
645.50
4.3
Basophilic Cell Foci
Li-CYP
log
136.40
114.20
5
Aiso et al. (2014) - Male Mia
5.1
Liver
Li-GST
lnl-r/mst2
¦r
754.63
413.06
956.50
593.21
Lu-
GST
5.2
Lung
pro/mstl-
r
136.66
115.93
70.936
55.91
5.3
Liver or Lung Tumor
WB-
GST
MS_Combo (Liver: mst2-r; Lung: mstl-r)
10.938
8.2167
5.4
TB Hyperplasia
Lu-
GST
gam
487.13
324.61
6
Aiso et al. (2014) - Female Mice
6.1
Liver
Li-GST
Pro/mst2-r
1595.1
1332.8
1408.7
762.3
6.2
Lung
Lu-
GST
mst2-r/mst2-r
371.9
223.47
371.9
223.47
6.3
Liver or Lung Tumor
WB-
GST
MS_Combo (Liver: mst2-r; Lung: mst2-r)
44.901
25.302
6.4
TB Hyperplasia
Lu-
GST
mst3-r/mst3-r
648.4247
411.2842
648.4247
411.2842
7
NTP (1986) - Male Mice
7.1
Liver Tumor
Li-GST
pro-r/mstl
-r
1072.4
740.82
914.22
544.51
7.2
Lung Tumor
Lu-
GST
mstl-r/mstl-r
61.67445
48.6464
61.67445
48.6464
7.3
Liver or Lung Tumor
WB-
GST
MS_Combo (Liver: mstl-r; Lung: mstl-r)
9.764454
7.752931
1 See Section 2 for abbreviation definitions; As described in Section 2, BMDs were derived from the standard set of models as
defined in the EPA BMD technical guidance and as identified in BMDS 3.1 as defaults. Since the standard approach gave
adequate results for all endpoints, non-standard models were not considered for BMD derivations.
2 As described Section 2, "Model Selection," the "Selected, Multistage" models were selected in accordance with EPA's
guidance for choosing the appropriate stage of a multistage model for cancer modeling ("EPA. 2014). These criteria are
implemented automatically when MS_Combo is used with the "autoselect" option (MS_Combo also supports manual
specification of multistage degree).
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F=Fibroadenoma, A=Adenoma, AC=Adenocarcinoma, TB=Terminal Bronchiole
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4. Summary of PBPK Analyses
The DCM PBPK model as adapted and applied in the 2011 IRIS Toxicological Review was used
for the additional analyses of the NTP bioassay and the newer Aiso et al. (2104) bioassay.
Briefly, with the model parameterized for mice or rats, internal doses were calculated for the
inhalation exposures used in the bioassays. BW values for each species, sex, exposure, and
study were set: for NTP the values used for the 2011 IRIS Toxicol ogical Review were applied
and the end-of-exposure values reported in Aiso et al. (2014) were used for that study. The dose
metrics listed in the previous section for the various endpoints were calculated and used in the
BMD modeling.
With the model parameterized for humans, the corresponding internal doses for a fixed exposure
level (1 |ig/m3) were calculated to estimate human cancer risk. For non-cancer endpoints the
inhalation concentration was calculated such that the human internal dose matched the human
BMDLio (scaled from animal values); i.e., the human equivalent concentration (HEC). Further,
the human parameter script allows the parameters to be sampled from distributions for the
population being evaluated, in this case women and men 18-65 years of age. This population
sampling includes the polymorphism known to occur for the enzyme glutathione S-transferase
(GST) thetat-1 (GST-T1); individuals can either have two active GST-T1 alleles (referred to as
"+/+"), one active and one inactive allele (+/-), or two inactive alleles (-/-). The activity
distribution for the corresponding metabolic step in the +/- population is one half that of the +/+
population, and in GST-T1 -/- individuals the activity is zero.
For each individual in the simulated or virtual population, the internal dose was estimated and
the mean of the resulting distribution calculated, allowing for the calculation of a population
mean risk level (cancer evaluation). Similarly, a population sample of HEC values was
estimated; in this case the 1st percentile of the distribution is selected to assure that the HEC
(after application of other relevant uncertainty factors) is protective of the population as a whole.
In particular, using the 1st percentile of the non-cancer HEC values obviates the need for an intra-
human uncertainty factor for pharmacokinetics (PK), but a factor of 3 for pharmacodynamic
(PD) variability should still be applied, along with a factor of 3 for animal-human PD
differences.
Prior to model application, to check that the model code was still functioning as it did for the
2011 Toxicol ogical Review, we attempted to reproduce rat and mouse internal doses for the NTP
bioassay (i.e., using the same parameters and exposure levels). However, some numerical
instability was found, particularly for the mouse simulations (integration warnings occurred).
Although these only involved model variables becoming very slightly negative (~ 10"8), they
were corrected by restricting the integration step size to 10"4 h. Integration warnings still
occurred with this correction, but blood and tissue concentrations did not become negative and
restricting the step size further did not alter the dose metric calculations up to 4 significant
figures.
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The resulting rat and mouse internal doses differed slightly from those reported in the 2011 IRIS
review, but differences were less than 0.1%, so this was considered a reasonable validation of the
computational model.
Simulations with the human model parameters did not have numerical warnings and it was found
that when the same random seed was used, Monte Carlo (MC) sampling for human distributions
were reproducible across 3 separate computers/operators.
As outlined above, several modifications to the analysis of human dosimetry were made, from
the analysis performed for the 2011 Toxicological Review, at OCSPP's request:
> The analyses were conducted for workplace exposures; hence the scripts were modified to sample
from individuals 18-65 years of age and exposure was assumed to occur 8 h/d, 5 d/w.
> Analyses were primarily conducted for all GST-T1 genotypes in the population (i.e., using the
estimated prevalence of the polymorphism in the U.S. population) but results for GST-T1
mediated cancer risks are also provided for the +/+ sub-population (which has the highest risk).
The 20% of the population who are -/- are effectively at zero risk when a GST metric is used
(liver-specific GST metabolism, lung-specific GST metabolism, or whole-body GST
metabolism), since they produce no DCM-GST metabolites.
> For non-cancer endpoints the population PBPK approach calls for calculating the human
equivalent concentration (HEC) for each person, then calculating the 1st percentile of that
distribution to obtain a value expected to be protective of the whole population. This was done
for acidophilic and basophilic cell foci in female rats, where liver-specific CYP metabolism is the
dose metric.
> However, for non-cancer lung lesions in the mouse lung (terminal bronchiole hyperplasia), the
GST pathway is thought to be causative, so is the preferred metric. However, the HEC for a
GST-T1 -/- individual would be effectively infinite, since they produce none of the metabolite,
making it impossible to obtain a meaningful result. GST -/- individuals are predicted to be 20%
of the general population. Therefore, these HEC calculations will be restricted to GST-T1 +/+
and +/- individuals, but instead of calculating the 1st percentile of their HEC distribution, the
percentile used will be 1%/(100% - 20%) = 1.25%. If 1.25% of the +/+ and +/- populations have
internal doses below the BMDL~,10 at a given exposure level, then 99% of the overall population
will be protected.
Other details of the risk calculations are provided in footnotes to the table of results, just
below.
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Methylene Chloride Benchmark Dose Report
BMD modeling results and tumor risk factors/HECs determined for 10% extra risk, various endpoints and BMD
models
Internal
dose metric3
Sex,
Species
Endpoint
(Asio study, unless
"(NIP)")
BMD
modelb
Animal
BMDLi,;,a'c
Human
BMDLioad
Human
tumor risk
factor6
Mean huma
dose from
expos
Mixed
population
n internal
1 jig/m3
urea
GST +/+
Resulting h
unit risk (
0
Mixed
population
uman inhalation
g/m3)1 or HEC
ng/m,)t
GST +/+
Male rat
Subcutis
lnp-ur
27.626
27.626
3.62 x 10"3
5.76 x 10"8
mst2-r
106.73
106.73
9.37 x 10"4
1.49 x 10"8
Mammary Gland
(F/A)
log
266.06
266.06
3.76 x 10"4
5.98 x 10"9
mstl-r
205.35
205.35
4.87 x 10"4
7.74 x 10"9
Mammary Gland
log
267.16
267.16
3.74 x 10"4
5.95 x 10"9
(F/A/AC)
mstl-r
222.31
222.31
4.50 x 10"4
7.15 x 10"9
Slowly
perfused
AUC (DCM)
1
.59 x 10"5
Not
significantly
different
Not significantly
different from
Subcutis or
Mammary Gland
multi-
tumor
78.802
78.802
1.27 x 10"3
2.02 x 10"8
m)
from mixed
population
mixed population
Subcutis or
Mammary Gland
(F/A/AC)
multi-
tumor
81.265
81.265
1.23 x 10"3
1.96 x 10"8
Female
rat
Subcutis or
Mammary Gland
(F/A/AC)
pro
166.68
166.68
6.00 x 10"4
9.54 x 10"9
mstl-r
123.7
123.7
8.08 x 10"4
1.29 x 10"8
Liver CYP
metabolism
Female
rat
Acidophilic cell foci
gam-r
645.5
157.4
n/a
n/a
98.2 mg/m3
Basophilic cell foci
log
114.2
27.85
n/a
17.3 mg/m3
Liver GST
Male
mice
Liver tumor
lnl-r
413.06
59.01
1.70 x 10"3
6.65 x 10"7
1.17 x 10-
6
1.13 x 10"9
1.98 x 10"9
mst2-r
593.21
84.74
1.18 x 10"3
7.58 x 10"10
1.38 x 10"9
Liver tumor (NTP)
lnl-r
740.82
105.8
9.45 x 10"4
6.28 x 10"10
1.11 x 10"9
mstl-r
544.51
77.79
1.29 x 10"3
8.55 x 10"10
1.50 x 10"9
Female
mice
Liver tumor
pro
1332.8
190.40
5.25 x 10"4
3.49 x 10"10
6.14 x 10"10
mst2-r
762.31
108.90
9.18 x 10"4
6.11 x 10"10
1.07 x 10"9
This document is a draft for review purposes only and does not constitute Agency policy.
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Methylene Chloride Benchmark Dose Report
BMD modeling results and tumor risk factors/HECs determined for 10% extra risk, various endpoints and BMD
models
Internal
dose metric3
Sex,
Species
Endpoint
(Asio study, unless
"(NIP)")
BMD
modelb
Animal
BMDLio3
Human
BMDLio"
Human
tumor risk
factor6
Mean human internal
dose from 1 jig/m3
exposure3
Mixed
population
GST +/+
Resulting human inhalation unit
risk( g/m3)1 or HEC (mg/m')'
Mixed
population
GST +/+
Lung GST
Male
mice
Lung tumor
pro
115.93
16.56
6.04 x 10"3
2.65 x 10"
4.68 x 10"
mstl-r
55.91
7.987
1.25 x 10":
4.39 x 10"8
7.75 x 10"8
5.50 x 10"
9.70 x 10"
Lung tumor (NTP)
mstl-r
48.646
6.949
1.44 x 10"2
6.32 x 10"
1.12 x 10"!
Female
mice
Lung tumor
mst2-r
223.47
31.92
3.13 x 10"3
TB hyperplasia
mst3-r
411.28
58.75
n/a
4.39 x 10"8
7.75 x 10"8
1.38 x lQ-io
2.43 x 1Q-10
7.75 x 104 mg/m3
5.73 x 104 mg/m3
Whole body
GST
Male
mice
Liver or lung tumor
8.217
1.174
5.52 x 10"2
1.30 x 10"!
2.28 x 10"!
Liver or lung (NTP)
multi-tumor
7.753
1.108
9.03 x 10"2
1.53 x 10"8
2.68 x 10"8
1.38 x 10"!
2.42 x 10"!
Female
mice
Liver or lung tumor
25.302
3.615
2.77 x 10"2
4.23 x 10"10
7.41 x 10"10
3 Tissue-specific dose-units = mg diclilorometliane metabolized via GST pathway/L tissue (liver or lung)/day; whole-body dose units = mg dicliloromethane
metabolized via GST pathway in lung and liver/kg-day; AUC(DCM) = mg-li/L tissue; all metrics are daily averages given a - week exposure per bioassay
conditions (animal dosimetry) or 8 h/d, 5 d/w workplace exposure scenario (human dosimetry).
b See BMD modeling report for model definitions and details.
0 Animal BMDLio refers to the BMD-model-predicted mouse or rat internal dose and its 95% lower confidence limit, associated with a 10% extra risk for the
incidence of tumors; units are those for the identified dose metric, described in footnote "a".
d When the dose metric is the rate of production of the presumed toxic metabolite (mg/kg/d), allometric scaling is applied to adjust for the fact that humans are
expected to detoxify the metabolite more slowly than mice and rats. A mouse BMDLio is divided by (BWhuman/BWmouse)"25 = 7 and a rat BMDLio divided by
(BWhuman/BW rat)" 25 - 4.1. When the metric is the concentration (AUC) of a chemical, no adjustment is made. Units are the same as for the Animal BMDLio.
e Diclilorometliane tumor risk factor (extra risk per unit internal dose) derived by dividing the BMR (0.1) by the allometric-scaled human BMDLio. Units are
l/(BMDLio units) for corresponding tissues/endpoints.
f Human inhalation risk is the product of the mean internal dose and the tumor risk factor. HEC is the 1st percentile of a distribution obtained by determining the
exposure concentration for each individual in a simulated population that is predicted to yield an internal dose equal to the (internal) Human BMDLio; with use of
the 1st percentile the intra-human uncertainty factor can be reduced from a standard value of 10 to 3, to account for remaining variability in pharmacodynamic
sensitivity.
This document is a draft for review purposes only and does not constitute Agency policy.
15
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Methylene Chloride Benchmark Dose Report
5. BMP Modeling for Aiso et al. (2014) Male Rats
5.1. Subcutis (Fibroma/Fibrosarcoma)
Slowly perfused AUC(DCM)
N
Incidence
0
50
1
93.33
50
4
196.4
50
8
403.4
50
12
Summary of BMDS 3.1 Modeling Results for Male Rat Subcutis
fibroma/fibrosarcoma of Mammary Gland Region vs Slowly Perfused AUC(DCM)
(Aiso et al., 2014)
Standard Models
Restriction**
*
10% Extra Risk
P Value
AIC
BMDS Recommends
BMDS Recommendation Notes
BMD
BMDL
Gamma
Restricted
156.13
106.73
0.91319
140.9343
Viable
- Alternate
Log-Logistic
Restricted
147.17
96.484
0.94833
140.8606
Viable
- Alternate
Multistage Degree 2*
Restricted
156.13
106.730
0.91319
140.9343
Selected, Multistage
Multistaee-cancer euidance CEP A 2014)
Multistage Degree 1
(Quantal Linear)
Restricted
156.13
106.731
0.91319
140.9343
Viable
- Alternate
Weibull
Restricted
156.13
106.73
0.91319
140.9343
Viable
- Alternate
Dichotomous Hill
LTnrestricted
138.03
27.686
NA
144.7558
Questionable
BMDL 3x lower than lowest non-zero dose
d.f.=0, saturated model (Goodness of fit test
Logistic
NA
246.95
197.55
0.36954
142.8886
Viable
- Alternate
Log-Probit**
LTnrestricted
142.3
27.626
0.79923
142.8201
Selected, Full Model
Suite
Lowest BMDL
BMDL 3x lower than lowest non-zero dose
Probit
NA
233.52
184.66
0.42664
142.5548
Viable
- Alternate
Non-Standard
Models
Dichotomous Hill
Restricted
137.99
2.5892
NA
144.7558
Questionable
BMD/BMDL ratio > 20
BMD/BMDL ratio > 5
BMDL 3x lower than lowest non-zero dose
BMDL lOx lower than lowest non-zero dose
d.f.=0, saturated model (Goodness of fit test
cannot be calculated)
Log-Probit
Restricted
217.41
157.08
0.33052
143.036
Viable
- Alternate
Gamma
LTnrestricted
144.28
22.716
0.72859
142.8754
Viable
- Alternate
Lowest BMDL
Log-Logistic
LTnrestricted
143.44
24.99
0.75334
142.854
Viable
- Alternate
BMD/BMDL ratio > 5
BMDL 3x lower than lowest non-zero dose
Multistage Degree 3
LTnrestricted
141.76
48.088
NA
144.7558
Questionable
d.f.=0, saturated model (Goodness of fit test
cannot be calculated)
Multistage Degree 2
LTnrestricted
139.38
69.79
0.7815
142.8332
Viable
- Alternate
Multistage Degree 1
LTnrestricted
156.13
106.73
0.91319
140.9343
Viable
- Alternate
Weibull
LTnrestricted
143.85
23.673
0.7325
3
142.872
Viable - Alternate
BMD/BMDL ratio > 5
BMDL 3x lower than lowest non-zero dose
* Selected, Multistage (Yellow); residuals for doses 0, 93.33,196.4, and 403.4 were -0.056061617, -0.023081873, 0.350885593, and -0.234147449, respectively.
**Selected, Full Model Suite (Green); residuals for doses 0, 93.33, 196.4, and 403.4 were 0.012874656, -0.128373844, 0.201154994, and -0.087060503, respectively.
***Restrictions defined in the BMDS 3.1 User Guide; CF = Computation failed; NA = Not Applicable
This document is a draft for review purposes only and does not constitute Agency policy.
16
DRAFT-DO NOT CITE OR QUOTE
-------
Methylene Chloride Benchmark Dose Report
0.3
0.25
0.2
(D
tn
0&5
tn
(D
al
0.1
0.05
BMDS 3.1 Standard Model Plots for Male Rat Subcutis
fibroma/fibrosarcoma of Mammary Gland Region vs Slowly perfused
AUC(DCM)(Aiso et alv 2014)
50
100
150
200
Dose
250
300
350
400
¦Frequentist Gamma Estimated Probability
¦Frequentist Multistage Degree 3 Estimated Probability
¦Frequentist Multistage Degree 1 Estimated Probability
¦ Frequentist Dichotomous Hill Estimated Probability
¦Frequentist Log-Probit Estimated Probability
¦Frequentist Log-Logistic Estimated Probability
Frequentist Multistage Degree 2 Estimated Probability
¦Frequentist Weibull Estimated Probability
¦ Frequentist Logistic Estimated Probability
¦Frequentist Probit Estimated Probability
This document is a draft for review purposes only and does not constitute Agency policy.
17
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User Input
Methylene Chloride Benchmark Dose Report
Selected, Multistage - Multistage 2 Restricted; Extra Risk, BMR =0.1
Info
Model
Multistage degree 2 vl .0
Data set
Name
Aiso Male Rat Subcutis
(fibroma/ fibro sarcoma)
Formula
P[dose] = g + (l-g)*[l-exp(-
bl*doseAl)l
Options
Risk Type
BMR
Confidence
Level
Background
Extra Risk
0.1
0.95
Estimated
Model Data
Dependent
Variable
Independent
Variable
Total # of
Observation
Slowly perfused
AUC(DCM)
[Tumor Incidence]
Model Results
Benchmark Dose
BMD
156.1284704
BMDL
106.7298415
BMDU
285.6542832
AIC
140.9342972
P-value
0.913190507
D.O.F.
2
Chi2
0.181621518
Slope Factor
0.000936945
Model Parameters
# of Parameters
3
Variable
Estimate
Background (g)
0.021140922
Betal
0.000674832
Beta2
0
Goodness of Fit
Dose
Estimated
Probability
Expected
Observed
Size
Scaled
Residual
0
0.021140922
1.05704609
1
50
-0.0561
93.33
0.080890193
4.04450965
4
50
-0.0231
196.4
0.142646218
7.1323109
8
50
0.35089
403.4
0.25442153
12.7210765
12
50
-0.2341
Analysis of Deviance
Model
Log Likelihood
# of Parameters
Deviance
Test d.f.
P Value
Full Model
-68.3779146
0
_
_
_
Fitted Model
-68.4671486
2
0.178468
2
0.91463
Reduced Model
-75.3540323
1
13.95224
3
0.00297
This document is a draft for review purposes only and does not constitute Agency policy.
18
DRAFT-DO NOT CITE OR QUOTE
-------
Methylene Chloride Benchmark Dose Report
Male Rat Subcutis (fibroma/fibrosarcoma) (Aiso et al., 2014) vs Slowly
Perfused AUC - Multistage (Restricted) Degree 2 Model with BMR of
10% Extra Risk for BMD and 0.95 Lower Confidence Limit for BMDL
0.3
0.25
0.2
I 0.15
to
(D
CC
0.05
50
100
150
200
Dose
250
300
350
400
— — Estimated Probability«
• Data
«Response at BMD
BMD
• Linear Extrapolation
¦ BMDL
This document is a draft for review purposes only and does not constitute Agency policy.
19
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-------
Methylene Chloride Benchmark Dose Report
Selected, Full Model Suite - LogProbit (Unrestricted) - Extra Risk, BMR = 0.1
User Input
Info
Model
Log-Probit vl.O
Data set
Name
Aiso Male Rat Subcutis
(frbroma/frbrosarcoma)
Formula
P[dose] = g+(l-g) *
CumNorm(a+b*Log(Dose))
Options
Risk Type
BMR
Confidence
Level
Background
Extra Risk
0.1
0.95
Estimated
Model Data
Dependent
Variable
Independent
Variable
Total # of
Observation
Slowly perfused
AUC(DCM)
[Tumor Incidence]
Model Results
Benchmark Dose
BMD
142.2953605
BMDL
27.62612894
BMDU
272.2029592
AIC
142.8201328
P-value
0.799233465
D.O.F.
1
Chi2
0.064688463
Slope Factor
0.00361976
Model Parameters
# of Parameters
3
Variable
Estimate
Background (g)
0.019746682
a
-3.86519696
b
0.521116367
Goodness of Fit
Dose
Estimated
Probability
Expected
Observed
Size
Scaled
Residual
0
0.019746682
0.98733408
1
50
0.01287
93.33
0.085064792
4.25323961
4
50
-0.1284
196.4
0.149846454
7.4923227
8
50
0.20115
403.4
0.245297496
12.2648748
12
50
-0.0871
Analysis of Deviance
Model
Log Likelihood
# of Parameters
Deviance
Test d.f.
P Value
Full Model
-68.3779146
0
-
-
-
Fitted Model
-68.4100664
3
0.064304
1
0.79982
Reduced Model
-75.3540323
1
13.95224
3
0.00297
This document is a draft for review purposes only and does not constitute Agency policy.
20
DRAFT-DO NOT CITE OR QUOTE
-------
Methylene Chloride Benchmark Dose Report
0.3
0.25
0.2
m
tn
° 0.15
LO
CD
DC
0.1
0.05
0
Male Rat Subcutis (fibroma/fibrosarcoma) (Aiso et al., 2014) vs Slowly
Perfused AUC Log-Probit (Unrestricted) Model with BMR of 10% Extra
Risk for the BMD and 0.95 Lower Confidence Limit for the BMDL
---
•
50 100 150 200 250 300 350 400
Dose
— Estimated Probability Response at BMD • Data BMD BMDL
This document is a draft for review purposes only and does not constitute Agency policy.
21
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-------
Methylene Chloride Benchmark Dose Report
5.2. Mammary Gland (Fibroadenoma/Adenoma)
Slowly perfused AUC(DCM)
N
Incidence
0
50
2
93.33
50
2
196.4
50
3
403.4
50
8
Summary of BMDS 3.1 Modeling Results for Male Rat Mammary Gland
(Fibroadenoma/Adenoma) vs Slowly Perfused AUC(DCM) (Aiso et al., 2014)
Standard Models
Restriction**
10% Extra Risk
P Value
AIC
BMDS Recommends
BMDS Recommendation Notes
*
BMD
BMDL
Gamma
Restricted
364.06
228.26
0.94651
106.2571
Viable - Alternate
Log-Logistic
Restricted
365.05
226.8
0.9371
106.2588
Viable - Alternate
Multistage Degree 2*
Restricted
358.17
227.01
0.96695
104.3196
Viable - Alternate
Multistage Degree 1
(Quantal Linear)*
Restricted
373.53
205.35
0.60372
105.2816
Selected, Multistage
Multistaee-cancer euidance (EPA. 2014)
Weibull
Restricted
366.05
228.37
0.9338
106.2595
Viable - Alternate
Dichotomous Hill
LTnrestricted
365.05
226.8
NA
108.2588
Questionable
d.f.=0, saturated model (Goodness of fit test
cannot be calculated)
Logistic**
NA
352.95
266.06
0.88061
104.4998
Selected, Full Model
Suite
Lowest AIC****
BMD computation failed; lower limit
includes zero
BMDL not estimated
Goodness of fit p-value <0.1
Goodness of fit p-value < 0.05
Log-Probit
LTnrestricted
7E+07
0
0.00756
112.5538
LTnusable
IResidual for Dose Grout) Near BMDI > 2
BMD higher than maximum dose
Probit
NA
350.46
254.8
0.84549
104.5806
Viable - Alternate
Non-Standard
Models
Dichotomous Hill
Restricted
288.9
196.59
NA
108.2526
Questionable
d.f.=0, saturated model (Goodness of fit test
cannot be calculated)
Log-Probit
Restricted
1E+08
0
0.00756
112.5538
LTnusable
BMD computation failed; lower limit
includes zero
BMDL not estimated
Goodness of fit p-value <0.1
Goodness of fit p-value < 0.05
Residual for Dose Group Near BMD > 2
BMD higher than maximum dose
Gamma
LTnrestricted
364.06
228.26
0.94651
106.2571
Viable - Alternate
Log-Logistic
LTnrestricted
365.05
226.8
0.9371
106.2588
Viable - Alternate
Multistage Degree 3
LTnrestricted
365.01
195.33
NA
108.2526
Questionable
d.f.=0, saturated model (Goodness of fit test
cannot be calculated)
Multistage Degree 2
LTnrestricted
364.68
228.27
0.99225
106.2527
Viable - Alternate
Multistage Degree 1
LTnrestricted
373.53
205.35
0.60372
105.2816
Viable - Alternate
Weibull
LTnrestricted
366.06
228.38
0.9338
106.2595
Viable - Alternate
*Selected, Multistage (Yellow); residuals for doses 0, 93.33,196.4, and 403.4 were 0.428673711, -0.463013542, -0.56695839, and 0.538250382, respectively.
**Selected, Full Model Suite (Green); residuals for doses 0, 93.33, 196.4, and 403.4 were 0.371049352, -0.188859404, -0.260432602, and 0.114455242, respectively.
***Restrictions defined in the BMDS 3.1 User Guide
****Note that while Multistage 2 has a lower AIC, it was not the selected Multistage model in accordance with Multistage selection criteria (EPA. 2014)
This document is a draft for review purposes only and does not constitute Agency policy.
22
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-------
Methylene Chloride Benchmark Dose Report
0.2
0.18
0.16
0.14
0.12
-------
User Input
Methylene Chloride Benchmark Dose Report
Selected, Multistage - Multistage 1 Restricted; Extra Risk, BMR =0.1
Info
Model
Multistage degree 1 vl.O
Data set
Name
Mammary Gland
(F ibroadenoma/Adenoma)
Formula
P[dose] = g + (l-g)*[l-exp(-
bl*dose"l)l
Options
Risk Type
BMR
Confidence
Level
Background
Extra Risk
0.1
0.95
Estimated
Model Data
Dependent
Variable
Independent
Variable
Total # of
Observation
Slowly perfused
AUC(DCM)
[Tumor Incidence]
Model Results
Benchmark Dose
BMD
373.526323
BMDL
205.347909
BMDU
Infinity
AIC
105.2815672
P-value
0.603717449
D.O.F.
2
Chi2
1.00929798
Slope Factor
0.000486978
Model Parameters
# of Parameters
2
Variable
Estimate
Background (g)
0.029707391
Betal
0.00028207
Goodness of Fit
Dose
Estimated
Probability
Expected
Observed
Size
Scaled
Residual
0
0.029707391
1.48536956
2
50
0.42867
93.33
0.054917614
2.74588068
2
50
-0.463
196.4
0.081998371
4.09991855
3
50
-0.567
403.4
0.134064258
6.70321289
8
50
0.53825
Analysis of Deviance
Model
Log Likelihood
# of Parameters
Deviance
Test d.f.
P Value
Full Model
-50.1262849
0
_
_
_
Fitted Model
-50.6407836
2
1.028997
2
0.5978
Reduced Model
-53.2768927
1
6.301216
3
0.09784
This document is a draft for review purposes only and does not constitute Agency policy.
24
DRAFT-DO NOT CITE OR QUOTE
-------
Methylene Chloride Benchmark Dose Report
Male Rat Mammary Gland (fibroadenoma/adenoma) (Aiso et al., 2014) vs
Slowly perfused AUC(DCM) -
Multistage Degree 1 Model with BMR of 10%
Extra Risk for the BMD and 0.95 Lower Confidence Limit for the BMDL
0.2
0.18
0.16
0.14
0.12
m
LO
1 0.1
to
(D
C£
0.08
0.06
m
i
0.02
0
0 50 100 150 200 250 300 350
400
Dose
— Estimated Probability^—
Response at BMD —
Linear Extrapolation
a
This document is a draft for review purposes only and does not constitute Agency policy.
25
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-------
User Input
Methylene Chloride Benchmark Dose Report
Selected, Full Model Suite - Logistic - Extra Risk, BMR = 0.1
Info
Model
Logistic vl.O
Data set
Name
Mammary Gland
(F ibroadenoma/Adenoma)
Formula
P[dose] = l/[l+exp(-a-b*dose)]
Options
Risk Type
BMR
Confidence
Level
Background
Extra Risk
0.1
0.95
Estimated
Model Data
Dependent
Variable
Independent
Variable
Total # of
Observation
[Tumor Incidence]
Model Results
Benchmark Dose
BMD
352.9483762
BMDL
266.0600548
BMDU
763.0199094
AIC
104.499798
P-value
0.8806145
D.O.F.
2
Chi2
0.254270639
Model Parameters
# of Parameters
3
Variable
Estimate
a
-3.44504194
b
0.004319944
Goodness of Fit
Dose
Estimated
Probability
Expected
Observed
Size
Scaled
Residual
0
0.030917064
1.54585318
2
50
0.37105
93.33
0.045570136
2.27850679
2
50
-0.1889
196.4
0.06935724
3.46786198
3
50
-0.2604
403.4
0.154155128
7.70775638
8
50
0.11446
Analysis of Deviance
Model
Log Likelihood
# of Parameters
Deviance
Test d.f.
P Value
Full Model
-50.1262849
0
_
_
_
Fitted Model
-50.249899
2
0.247228
2
0.88372
Reduced Model
-53.2768927
1
6.301216
3
0.09784
This document is a draft for review purposes only and does not constitute Agency policy.
26
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-------
Methylene Chloride Benchmark Dose Report
0.2
0.19
0.18
0.17
0.16
0.15
0.14
0.13
0.12
-------
Methylene Chloride Benchmark Dose Report
5.3. Mammary Gland (Fibroadenoma/Adenoma/Adenocarcinoma)
Slowly Perfused AUC(DCM)
N
Incidence
0
50
3
93.33
50
2
196.4
50
3
403.4
50
8
Summary of BMDS 3.1 Modeling Results for Male Rat Mammary Gland
Fibroadenoma/Adenoma/Adenocarcinoma of Mammary Gland Region (Aiso et al.,
2014)
Standard Models
Restriction**
*
10% Extra Risk
P Value
AIC
BMDS Recommends
BMDS Recommendation Notes
BMD
BMDL
Gamma
Restricted
384.84
256.66
0.64092
112.376
Viable - Alternate
Log-Logistic
Restricted
386.6
255.7
0.63837
112.38
Viable - Alternate
Multistage Degree 2
Restricted
379.36
255.01
0.77427
110.6585
Viable - Alternate
Multistage Degree 1
(Quantal Linear)*
Restricted
440.28
222.31
0.43113
111.8755
Selected, Multistage
Multistaee-cancer guidance fEPA. 2014)
BMD higher than maximum dose
Weibull
Restricted
387.21
257.66
0.63796
112.3806
Viable - Alternate
Dichotomous Hill
LTnrestricted
386.55
255.7
NA
114.38
Questionable
d.f.=0, saturated model (Goodness of fit test
cannot be calculated)
Logistic**
NA
374.83
267.16
0.60803
111.117
Selected, Full Model
Suite
Lowest AIC****
Log-Probit
LTnrestricted
398.85
248.42
0.60733
112.4316
Viable - Alternate
Probit
NA
377.87
257.81
0.57841
111.2227
Viable - Alternate
Non-Standard
Models
Dichotomous Hill
Restricted
385.04
200.37
NA
114.3787
Questionable
d.f.=0, saturated model (Goodness of fit test
cannot be calculated)
Log-Probit
Restricted
382.52
259.78
0.6436
112.3716
Viable - Alternate
Gamma
LTnrestricted
384.68
256.66
0.64074
112.376
Viable - Alternate
Log-Logistic
LTnrestricted
386.58
255.71
0.63836
112.38
Viable - Alternate
Multistage Degree 3
LTnrestricted
391.45
210.95
NA
114.1549
Questionable
d.f.=0, saturated model (Goodness of fit test
cannot be calculated)
Multistage Degree 2
LTnrestricted
389.98
267.91
0.84764
112.1921
Viable - Alternate
Multistage Degree 1
LTnrestricted
440.28
222.31
0.43113
111.8755
Viable - Alternate
BMD higher than maximum dose
Weibull
LTnrestricted
387.21
257.66
0.63796
112.3806
Viable - Alternate
*Selected, Multistage (Yellow); residuals for doses 0, 93.33,196.4, and 403.4 were 0.642295022, -0.668909011, -0.65159258, and 0.63098188, respectively.
**Selected, Full Model Suite (Green); residuals for doses 0, 93.33, 196.4, and 403.4 were 0.725402568, -0.458166157, -0.452330816, and 0.233107389, respectively.
***Restrictions defined in the BMDS 3.1 User Guide
****Note that while Multistage 2 has a lower AIC, it was not the selected Multistage model in accordance with Multistage selection criteria (EPA, 2014)
This document is a draft for review purposes only and does not constitute Agency policy.
28
DRAFT-DO NOT CITE OR QUOTE
-------
Methylene Chloride Benchmark Dose Report
BMDS 3.1 Standard Model Plots for Male Rat Mammary Gland
(fibroadenoma/adenoma/adenocarcinoma) vs Slowly perfused AUC(DCM)
(Aiso et al., 2014)
0.2
0.18
0.16
0.14
0.12
I 0.1
LO
CD
DC
0.08
0.06
0.04
0.02
0
50
100
150
200
Dose
250
300
350
400
¦Frequentist Gamma Estimated Probability
¦Frequentist Multistage Degree 3 Estimated Probability
¦Frequentist Multistage Degree 1 Estimated Probability -
¦ Frequentist Dichotomous Hill Estimated Probability
¦Frequentist Log-Probit Estimated Probability
¦Frequentist Log-Logistic Estimated Probability
Frequentist Multistage Degree 2 Estimated Probability
¦Frequentist Weibull Estimated Probability
¦ Frequentist Logistic Estimated Probability
¦Frequentist Probit Estimated Probability
This document is a draft for review purposes only and does not constitute Agency policy.
29
DRAFT-DO NOT CITE OR QUOTE
-------
Methylene Chloride Benchmark Dose Report
Selected, Multistage - Multistage 1 Restricted; Extra Risk, BMR =0.1
User Input
Info
Options
Model Data
Model
Multistage degree 1 vl.O
Risk Type
Extra Risk
Dependent
Variable
Slowly Perfused
AUC(DCM)
Data set
Name
Mammary Gland
(F ibroadenoma/Adenoma/A
denocarcinoma)
BMR
0.1
Independent
Variable
|Tumor Incidence!
Confidence
0 95
Formula
P[dose] = g + (l-g)*[l-exp(-
bl*doseAl)l
Background
Estimated
Total # ot
Observation
4
Model Results
Benchmark Dose
BMD
440.2811477
BMDL
222.3136192
BMDU
Infinity
AIC
111.875539
P-value
0.431129577
D.O.F.
2
Chi2
1.682693184
Slope Factor
0.000449815
Model Parameters
# of Parameters
2
Variable
Estimate
Background (g)
0.041817531
Betal
0.000239303
Goodness of Fit
Dose
Estimated
Probability
Expected
Observed
Size
Scaled
Residual
0
0.041817531
2.09087655
3
50
0.6423
93.33
0.062980496
3.1490248
2
50
-0.6689
196.4
0.085809333
4.29046666
3
50
-0.6516
403.4
0.129991071
6.49955353
8
50
0.63098
Analysis of Deviance
Model
Log Likelihood
# of Parameters
Deviance
Test d.f.
P Value
Full Model
-53.0774536
0
_
_
_
Fitted Model
-53.9377695
2
1.720632
2
0.42303
Reduced Model
-55.7538744
1
5.352841
3
0.14771
This document is a draft for review purposes only and does not constitute Agency policy.
30
DRAFT-DO NOT CITE OR QUOTE
-------
Methylene Chloride Benchmark Dose Report
Male Rat Mammary Gland (fibroadenoma/ adenoma/adenocarcinoma)
(Aiso et al., 2014) vs Slowly perfused AUC(DCM) - Multistage Degree 1
Model with BMR of 10% Extra Risk for the BMD and 0.95 Lower Confidence
Limit for the BMDL
0.2
0.18
0.16
0.14
0.12
-------
User Input
Methylene Chloride Benchmark Dose Report
Selected, Full Model Suite - Logistic - Extra Risk, BMR = 0.1
Info
Model
Logistic vl.O
Data set
Name
Mammary Gland
(F ibroadenoma/Adenoma/A
denocarcinoma)
Formula
P[dose] = l/[l+exp(-a-b*dose)]
Options
Risk Type
BMR
Confidence
Level
Background
Extra Risk
0.1
0.95
Estimated
Model Data
Dependent
Variable
Independent
Variable
Total # of
Observation
Slowly Perfused
AUC(DCM)
[Tumor Incidence]
Model Results
Benchmark Dose
BMD
374.8279749
BMDL
267.1555314
BMDU
Infinity
AIC
111.1169774
P-value
0.608028412
D.O.F.
2
Chi2
0.995067334
Model Parameters
# of Parameters
2
Variable
Estimate
a
-3.18021631
b
0.003550063
Goodness of Fit
Dose
Estimated
Probability
Expected
Observed
Size
Scaled
Residual
0
0.039917043
1.99585217
3
50
0.7254
93.33
0.054738778
2.73693889
2
50
-0.4582
196.4
0.077059711
3.85298554
3
50
-0.4523
403.4
0.14828436
7.414218
8
50
0.23311
Analysis of Deviance
Model
Log Likelihood
# of Parameters
Deviance
Test d.f.
P Value
Full Model
-53.0774536
0
_
_
_
Fitted Model
-53.5584887
2
0.96207
2
0.61814
Reduced Model
-55.7538744
1
5.352841
3
0.14771
This document is a draft for review purposes only and does not constitute Agency policy.
32
DRAFT-DO NOT CITE OR QUOTE
-------
Methylene Chloride Benchmark Dose Report
0.2
0.18
0.16
0.14
0.12
m
LO
1 0.1
tn
(D
C£
0.08
Male Rat Mammary Gland (fibroadenoma/
adenoma/adenocarcinoma) (Aiso et al., 2014) vs Slowly perfused
AUC(DCM) - Logistic Model with BMR of 10% Extra Risk for the BMD
and 0.95 Lower Confidence Limit for the BMDL
*
y
0.04
0.02
0
50 100 150 200 250 300 350 400
Dose
— — — Estimated Probability Response at BMD • Data BMD BMDL
This document is a draft for review purposes only and does not constitute Agency policy.
33
DRAFT-DO NOT CITE OR QUOTE
-------
Methylene Chloride Benchmark Dose Report
5.4. Subcutis (Fibroma/Fibrosarcoma) or Mammary Gland
(Fibroadenoma/Adenoma)
Aiso Male Rat Subcutis (fibroma/fibrosarcoma of mammary gland region)
Slowly perfused AUC(DCM)
N
Incidence
0
50
1
93.33
50
4
196.4
50
8
403.4
50
12
Aiso Male Rat Mammary Gland (fibroadenoma/adenoma)
Slowly perfused AUC(DCM)
N
Incidence
0
50
2
93.33
50
2
196.4
50
3
403.4
50
8
Summary of BMDS 3.1 Multi-tumor (MSCombo) Modeling Results for Male Rat
Subcutis (fibroma/fibrosarcoma of mammary gland region) and Mammary Gland
(fibroadenoma/adenoma) vs. Slowly perfused AUC(DCM) (Aiso et al., 2014)
Models*
Dataset
10% Extra Risk
Slope
P Value
AIC
BMDS Recommendation Notes
BMD
BMDL
Factor
Multi-tumor
(MS Combo)
Combined
Risk
110.11
78.802
1.27e"3
NA
NA
-
Multistage Degree 1
Mammary
Gland
373.53
205.35
4.87e4
0.60372
105.2816
Multistaee-cancer guidance (EPA. 2014)
Multistage Degree 2
Subcutis
156.13
106.73
9.37e4
0.91319
140.9343
Multistage-cancer guidance (EPA. 2014)
*Multistage models used in the BMDS multi-tumor (MS Combo) model are restricted as described in the BMDS 3.1 User Guide. The selected Multistage model
was chosen from among all relevant model runs (see detailed results for all relevant Multistage degrees below) in accordance with EPA's technical guidance for
choosing the appropriate stage of a multistage model for cancer modeling (EPA. 2014).
This document is a draft for review purposes only and does not constitute Agency policy.
34
DRAFT-DO NOT CITE OR QUOTE
-------
Methylene Chloride Benchmark Dose Report
Selected Multistage model plots for subcutis (orange) and mammary
gland (blue) tumors vs slowly perfused AUC(DCM) in male rats that
inhaled methylene chloride in Aiso et al. (2014) 2-year study
0.3
0.25
0.2
0.1
0.05
0
50
100
150
200
250
300
350
400
Dose
Frequentist Multistage Degree 1 Estimated Probability
Frequentist Multistage Degree 2 Estimated Probability
Multi-tumor (MSCombo) Results for Male Rat Subcutis (fibroma/fibrosarcoma of
mammary gland region) and Mammary Gland (fibroadenoma/adenoma) vs. Slowly
perfused AUC(DCM) (Aiso et al., 2014)
User Input
Model Results
Info
Benchmark Dose
Model
Multi-tumor v 1.0
BMD
110.10601
BMDL
78.801884
Model Options
BMDU
198.32585
Risk Type
Extra Risk
Slope Factor
0.001269
BMR
0.1
Confidence
Level
0.95
Combined Log-Likelihood
-119.1079322
Background
Estimated
Combined Log-Likelihood
Constant
106.0887573
This document is a draft for review purposes only and does not constitute Agency policy.
35
DRAFT-DO NOT CITE OR QUOTE
-------
Methylene Chloride Benchmark Dose Report
Male Rat Mammary Gland (fibroadenoma/adenoma) - Multistage 1 Restricted
(Selected Multistage Degree); Extra Risk, BMR = 0.1
User Input
Info
Options
Model Data
Model
Multistage degree 1 vl.O
Risk Type
Extra Risk
Dependent
Variable
Slowly perfused
AUC(DCM)
Data set
Name
Mammary Gland
(fibroadenoma/ adenoma) -
Male Rats
BMR
Confidence
Level
Background
0.1
0.95
Estimated
Independent
Variable
[Tumor Incidencel
Formula
P[dose] = g + (l-g)*[l-exp(-
bl*dose" 1)1
Total # of
Observation
4
Model Results
Benchmark Dose
BMD
373.526323
BMDL
205.347909
BMDU
Infinity
AIC
105.2815672
P-value
0.603717449
D.O.F.
2
Chi2
1.00929798
Slope Factor
0.000486978
Model Parameters
# of Parameters
2
Variable
Estimate
Background (g)
0.029707391
Betal
0.00028207
Goodness of Fit
Dose
Estimated
Probability
Expected
Observed
Size
Scaled
Residual
0
0.029707391
1.48536956
2
50
0.42867
93.33
0.054917614
2.74588068
2
50
-0.463
196.4
0.081998371
4.09991855
3
50
-0.567
403.4
0.134064258
6.70321289
8
50
0.53825
Analysis of Deviance
Model
Log Likelihood
# of Parameters
Deviance
Test d.f.
P Value
Full Model
-50.1262849
0
_
_
_
Fitted Model
-50.6407836
2
1.028997
2
0.5978
Reduced Model
-53.2768927
1
6.301216
3
0.09784
This document is a draft for review purposes only and does not constitute Agency policy.
36
DRAFT-DO NOT CITE OR QUOTE
-------
Methylene Chloride Benchmark Dose Report
Male Rat Mammary Gland (fibroadenoma/adenoma) (Aiso et al.,
2014) vs Slowly Perfused AUC Multistage Degree 1 with BMR of 10%
Extra Risk for the BMD, 0.95 Lower Confidence Limit for the BMDL
0.2
0.18
0.16
0.14
m
0.12
m
LO
1 0.1
tn
(D
C£
0.08
0.06
0
---
0.02
0
50 100 150 20C
250 300 350
400
Dose
— Estimated Probability^—
Response at BMD —
Linear Extrapolation
a
Data
BMD
BMDL
This document is a draft for review purposes only and does not constitute Agency policy.
37
DRAFT-DO NOT CITE OR QUOTE
-------
Methylene Chloride Benchmark Dose Report
Male Rat Mammary Gland (fibroadenoma/adenoma) - Multistage 2
Restricted; Extra Risk, BMR = 0.1
User Input
Info
Options
Model Data
Model
Multistage degree 2 vl .0
Mammary Gland
(fibroadenoma/adenoma)
Male Rat
Data set
Name
P[dose] = g + (1-g)*
exp(-bl*doseAl-
b2*doseA2)]
Formula
Dependent
Variable
Independent
Variable
Observation
Slowly perfused
AUC(DCM)
Risk Type
BMR
Confidence
Level
Background
Extra Risk
Estimated
0.95
Model Results
Benchmark Dose
BMD
358.1716141
BMDL
227.0120986
BMDU
890.3526015
AIC
104.3196334
P-value
0.96694809
D.O.F.
2
Chi2
0.067220934
Slope Factor
0.000440505
Model Parameters
# of Parameters
3
Variable
Estimate
Background (g)
0.035640591
Betal
0
Beta2
8.21288E-07
Goodness of Fit
Dose
Estimated
Probability
Expected
Observed
Size
Scaled
Residual
0
0.035640591
1.78202957
2
50
0.16627
93.33
0.042514829
2.12574143
2
50
_
0.0881
196.4
0.065712188
3.28560941
3
50
-0.163
403.4
0.156285175
7.81425874
8
50
0.07234
Analysis of Deviance
Model
Log Likelihood
# of Parameters
Deviance
Test d.f.
P Value
Full Model
-50.1262849
0
_
_
_
Fitted Model
-50.1598167
2
0.067064
2
0.96702
Reduced Model
-53.2768927
1
6.301216
3
0.09784
This document is a draft for review purposes only and does not constitute Agency policy.
38
DRAFT-DO NOT CITE OR QUOTE
-------
Methylene Chloride Benchmark Dose Report
Male Rat Mammary Gland (fibroadenoma/adenoma) (Aiso et al., 2014)
vs Slowly Perfused AUC - Multistage Degree 2 Model with BMR of 10%
Extra Risk for the BMD and 0.95 Lower Confidence Limit for the BMDL
0.2
0.18
0.16
0.14
0.12
0.08
0.06
0.04
0.02
0
50
100
150
200
250
300
350
400
Dose
— — — Estimated Probability Response at BMD Linear Extrapolation
• Data BMD BMDL
This document is a draft for review purposes only and does not constitute Agency policy.
39
DRAFT-DO NOT CITE OR QUOTE
-------
Methylene Chloride Benchmark Dose Report
Male Rat Subcutis (fibroma/fibrosarcoma) - Multistage 1 Restricted; Extra Risk, BMR = 0.1
User Input
Info
Model
Multistage degree 1 vl.O
Dataset Name
Subcutis - Male Rats
Formula
P[dose] = g + (l-g)*[l-exp(-
bl*dose"l)l
Options
Risk Type
BMR
Confidence
Level
Background
Extra Risk
0.1
0.95
Estimated
Model Data
Dependent
Variable
Independent
Variable
Total # of
Observation
Slowly perfused
AUC(DCM)
[Tumor Incidence]
Model Results
Benchmark Dose
BMD
156.1277934
BMDL
106.7309355
BMDU
275.9726206
AIC
140.9342972
P-value
0.913190559
D.O.F.
2
Chi2
0.181621405
Slope Factor
0.000936935
Model Parameters
# of Parameters
3
Variable
Estimate
Background (g)
0.021140508
Betal
0.000674835
Beta2
0
Goodness of Fit
Dose
Estimated
Probability
Expected
Observed
Size
Scaled
Residual
0
0.021140508
1.05702542
1
50
-0.0561
93.33
0.080890056
4.0445028
4
50
-0.0231
196.4
0.142646349
7.13231744
8
50
0.35089
403.4
0.254422095
12.7211048
12
50
-0.2341
Analysis of Deviance
Model
Log Likelihood
# of Parameters
Deviance
Test d.f.
P Value
Full Model
-68.3779146
0
-
-
-
Fitted Model
-68.4671486
2
0.178468
2
0.91463
Reduced Model
-75.3540323
1
13.95224
3
0.00297
This document is a draft for review purposes only and does not constitute Agency policy.
40
DRAFT-DO NOT CITE OR QUOTE
-------
Methylene Chloride Benchmark Dose Report
Male Rat Subcutis (fibroma/fibrosarcoma) (Aiso et al., 2014) vs
Slowly Perfused AUC - Multistage Degree 1 with BMR of 10% Extra
Risk for the BMD and 0.95 Lower Confidence Limit for the BMDL
0.3
0.25
0.2
0.1
0.05
0
50
100
150
200
250
300
350
400
Dose
— — — Estimated Probability Response at BMD Linear Extrapolation
• Data BMD BMDL
This document is a draft for review purposes only and does not constitute Agency policy.
41
DRAFT-DO NOT CITE OR QUOTE
-------
Methylene Chloride Benchmark Dose Report
Male Rat Subcutis (fibroma/fibrosarcoma) - Multistage 2 Restricted (Selected Multistage
Degree); Extra Risk, BMR = 0.1
User Input
Info
Model
Multistage degree 2 vl .0
Dataset Name
Subcutis - Male Rats
Formula
P[dose] = g + (l-g)*[l-exp(-
b 1 *dose" 1 -b2*dose" 2)1
Options
Risk Type
BMR
Confidence
Level
Background
Extra Risk
0.1
0.95
Estimated
Model Data
Dependent
Variable
Independent
Variable
Total # of
Observation
Slowly perfused
AUC(DCM)
[Tumor Incidence]
Model Results
Benchmark Dose
BMD
156.1284704
BMDL
106.7298415
BMDU
285.6542832
AIC
140.9342972
P-value
0.913190507
D.O.F.
2
Chi2
0.181621518
Slope Factor
0.000936945
Model Parameters
# of Parameters
3
Variable
Estimate
Background (g)
0.021140922
Betal
0.000674832
Beta2
0
Goodness of Fit
Dose
Estimated
Probability
Expected
Observed
Size
Scaled
Residual
0
0.021140922
1.05704609
1
50
-0.0561
93.33
0.080890193
4.04450965
4
50
-0.0231
196.4
0.142646218
7.1323109
8
50
0.35089
403.4
0.25442153
12.7210765
12
50
-0.2341
Analysis of Deviance
Model
Log Likelihood
# of Parameters
Deviance
Test d.f.
P Value
Full Model
-68.3779146
0
-
-
-
Fitted Model
-68.4671486
2
0.178468
2
0.91463
Reduced Model
-75.3540323
1
13.95224
3
0.00297
This document is a draft for review purposes only and does not constitute Agency policy.
42
DRAFT-DO NOT CITE OR QUOTE
-------
Methylene Chloride Benchmark Dose Report
Male Rat Subcutis (fibroma/fibrosarcoma) (Aiso et al., 2014) vs
Slowly Perfused AUC - Multistage Degree 2 with BMR of 10% Extra
Risk for the BMD and 0.95 Lower Confidence Limit for the BMDL
0.3
0.25
0.2
0.1
0.05
0
50
100
150
200
250
300
350
400
Dose
— — — Estimated Probability Response at BMD Linear Extrapolation
• Data BMD BMDL
This document is a draft for review purposes only and does not constitute Agency policy.
43
DRAFT-DO NOT CITE OR QUOTE
-------
Methylene Chloride Benchmark Dose Report
5.5. Subcutis or Mammary Gland (Fibroadenoma/Adenoma/Adenocarcinoma)
Aiso Male Rat Subcutis (fibroma/fibrosarcoma of mammary gland region)
Slowly perfused AUC(DCM)
N
Incidence
0
50
1
93.33
50
4
196.4
50
8
403.4
50
12
Aiso Male Rat Mammary Gland (fibroadenoma/adenoma/adenocarcinoma)
Slowly perfused AUC(DCM)
N
Incidence
0
50
3
93.33
50
2
196.4
50
3
403.4
50
8
Summary of BMDS 3.1 Multi-tumor (MSCombo) Results for Male Rat Subcutis
(fibroma/fibrosarcoma of mammary gland region) and Mammary Gland
(fibroadenoma/adenoma/adenocarcinoma) vs. Slowly perfused AUC(DCM) (Aiso et al.,
2014)
Models*
Dataset
10% Extra Risk
Slope
Factor
P Value
AIC
BMDS Recommendation Notes
BMD
BMDL
Multi-tumor
(MS Combo)
Combined Risk
115.26
81.265
1.23e"3
NA
NA
-
Multistage Degree 1
Mammary Gland
440.28
222.31
4.50e"4
0.43113
111.8755
Multistaee-cancer guidance (EPA. 2014)
BMD higher than maximum dose
Multistage Degree 2
Subcutis
156.13
106.73
9.37e"4
0.91319
140.9343
Multistage-cancer guidance (EPA 2014)
*Multistage models used in the BMDS multi-tumor (MS Combo) model are restricted as described in the BMDS 3.1 User Guide. The selected Multistage model was
chosen from among all relevant model runs (see detailed results for all relevant Multistage degrees below) in accordance with EPA's technical guidance for choosing
the appropriate stage of a multistage model for cancer modeling.
This document is a draft for review purposes only and does not constitute Agency policy.
44
DRAFT-DO NOT CITE OR QUOTE
-------
Methylene Chloride Benchmark Dose Report
0.3
0.25
0.2
(u
LO
g. 0.15
LO
CD
DC
0.1
0.05
Selected Multistage model plots for subcutis (orange) and mammary
gland (blue) tumors vs slowly perfused AUC(DCM) in male rats that
inhaled methylene chloride in Aiso et al. (2014) 2-year study
0
50 100 150 200 250 300 350 400
Dose
Frequentist Multistage Degree 1 Estimated Probability
Frequentist Multistage Degree 2 Estimated Probability
Multi-tumor (MSCombo) Results for Male Rat Subcutis (fibroma/fibrosarcoma of
mammary gland region) and Mammary Gland (fibroadenoma/adenoma/adenocarcinoma) vs.
Slowly perfused AUC(DCM) (Aiso et al., 2014)
User Input
Model Results
Info
Benchmark Dose
Model
Multi-tumor v 1.0
BMD
115.25711
BMDL
81.265248
Model Options
BMDU
211.11693
Risk Type
Extra Risk
Slope Factor
0.0012305
BMR
0.1
Confidence
Level
0.95
Combined Log-Likelihood
-122.4049181
Background
Estimated
Combined Log-Likelihood
Constant
108.861346
This document is a draft for review purposes only and does not constitute Agency policy.
45
DRAFT-DO NOT CITE OR QUOTE
-------
Methylene Chloride Benchmark Dose Report
Male Rat Mammary Gland (fibroadenoma/adenoma/adenocarcinoma) - Multistage 1 Restricted
(Selected Multistage Degree); Extra Risk, BMR =0.1
User Input
Info
Options
Model Data
Model
Multistage degree 1 vl.O
Risk Type
Extra Risk
Dependent
Variable
Slowly perfused
AUC(DCM)
Dataset Name
Mammary Gland
(fibroadenoma/ adenoma/adenocarc
inoma) - Male Rats
BMR
0.1
Independent
Variable
[Tumor Incidence!
Confidence
Level
0.95
Formula
P[dose] = g + (l-g)*[l-exp(-
bl*dose"l)l
Total # of
Observation
4
Background
Estimated
Model Results
Benchmark Dose
BMD
440.2811477
BMDL
222.3136192
BMDU
Infinity
AIC
111.875539
P-value
0.431129577
D.O.F.
2
Chi2
1.682693184
Slope Factor
0.000449815
Model Parameters
# of Parameters
3
Variable
Estimate
Background (g)
0.041817531
Betal
0.000239303
Beta2
0
Goodness of Fit
Dose
Estimated
Probability
Expected
Observed
Size
Scaled
Residual
0
0.041817531
2.09087655
3
50
0.6423
93.33
0.062980496
3.1490248
2
50
-0.6689
196.4
0.085809333
4.29046666
3
50
-0.6516
403.4
0.129991071
6.49955353
8
50
0.63098
Analysis of Deviance
Model
Log Likelihood
# of Parameters
Deviance
Test d.f.
P Value
Full Model
-53.0774536
0
-
-
-
Fitted Model
-53.9377695
2
1.720632
2
0.42303
Reduced Model
-55.7538744
1
5.352841
3
0.14771
This document is a draft for review purposes only and does not constitute Agency policy.
46
DRAFT-DO NOT CITE OR QUOTE
-------
Methylene Chloride Benchmark Dose Report
Male Rat Mammary Gland (fibroadenoma/adenoma/
adenocarcinoma) (Aiso et al., 2014) vs Slowly Perfused AUC -
Multistage Degree 1 with BMR of 10% Extra Risk for the BMD
0.2
0.18
0.16
and 0.95 Lower Confidence Limit for the BMDL
0 14
0.12
m
LO
1 0.1
tn
(D
C£
0.08
0.04
0.02
0
50 100 150 200
250 300 350 400
450
Dose
Estimated Probability"
Response at BMD
• Linear Extrapolation
•
Data
— BMD
«BMDL
This document is a draft for review purposes only and does not constitute Agency policy.
47
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Methylene Chloride Benchmark Dose Report
Male Rat Mammary Gland (fibroadenoma/adenoma/adenocarcinoma) - Multistage 2 Restricted;
Extra Risk, BMR = 0.1
User Input
Info
Options
Model Data
Model
Multistage degree 2 vl .0
Risk Type
Extra Risk
Dependent
Variable
Slowly perfused
AUC(DCM)
Dataset Name
Mammary Gland
(fibroadenoma/ adenoma/adenocarc
inoma) - Male Rat
BMR
0.1
Independent
Variable
[Tumor Incidence!
Confidence
Level
0.95
Formula
P[dose] = g + (l-g)*[l-exp(-
b 1 *dose" 1 -b2*dose" 2)1
Total # of
Observation
4
Background
Estimated
Model Results
Benchmark Dose
BMD
379.3582184
BMDL
255.0118006
BMDU
Infinity
AIC
110.6584528
P-value
0.774267398
D.O.F.
2
Chi2
0.511675979
Slope Factor
0.000392139
Model Parameters
# of Parameters
3
Variable
Estimate
Background (g)
0.045087926
Betal
0
Beta2
7.32114E-07
Goodness of Fit
Dose
Estimated
Probability
Expected
Observed
Size
Scaled
Residual
0
0.045087926
2.2543963
3
50
0.50817
93.33
0.051158095
2.55790475
2
50
-0.3581
196.4
0.071677261
3.58386305
3
50
-0.3201
403.4
0.152338684
7.61693422
8
50
0.15076
Analysis of Deviance
Model
Log Likelihood
# of Parameters
Deviance
Test d.f.
P Value
Full Model
-53.0774536
0
-
-
-
Fitted Model
-53.3292264
2
0.503546
2
0.77742
Reduced Model
-55.7538744
1
5.352841
3
0.14771
This document is a draft for review purposes only and does not constitute Agency policy.
48
DRAFT-DO NOT CITE OR QUOTE
-------
Methylene Chloride Benchmark Dose Report
Male Rat Mammary Gland (fibroadenoma/adenoma/
adenocarcinoma) (Aiso et al., 2014) vs Slowly Perfused AUC -
Multistage Degree 2 with BMR of 10% Extra Risk for the BMD
0.2
0.18
0.16
and 0.95 Lower Confidence Limit for the BMDL
0.12
(D
tn
1 0.1
tn
(D
C£
0.08
0.04
0.02
0
50 100 150 200 250 300 350
400
Dose
Estimated Probability^™
^ Response at BMD —
Linear Extrapolation
•
Data
— BMD
BMDL
This document is a draft for review purposes only and does not constitute Agency policy.
49
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Methylene Chloride Benchmark Dose Report
Male Rat Subcutis (fibroma/fibrosarcoma) - Multistage 1 Restricted; Extra Risk, BMR = 0.1
User Input
Info
Model
Multistage degree 1 vl.O
Dataset Name
Subcutis - Male Rats
Formula
P[dose] = g + (l-g)*[l-exp(-
bl*dose"l)l
Options
Risk Type
BMR
Confidence
Level
Background
Extra Risk
0.1
0.95
Estimated
Model Data
Dependent
Variable
Independent
Variable
Total # of
Observation
Slowly perfused
AUC(DCM)
[Tumor Incidence]
Model Results
Benchmark Dose
BMD
156.1277934
BMDL
106.7309355
BMDU
275.9726206
AIC
140.9342972
P-value
0.913190559
D.O.F.
2
Chi2
0.181621405
Slope Factor
0.000936935
Model Parameters
# of Parameters
3
Variable
Estimate
Background (g)
0.021140508
Betal
0.000674835
Beta2
0
Goodness of Fit
Dose
Estimated
Probability
Expected
Observed
Size
Scaled
Residual
0
0.021140508
1.05702542
1
50
-0.0561
93.33
0.080890056
4.0445028
4
50
-0.0231
196.4
0.142646349
7.13231744
8
50
0.35089
403.4
0.254422095
12.7211048
12
50
-0.2341
Analysis of Deviance
Model
Log Likelihood
# of Parameters
Deviance
Test d.f.
P Value
Full Model
-68.3779146
0
-
-
-
Fitted Model
-68.4671486
2
0.178468
2
0.91463
Reduced Model
-75.3540323
1
13.95224
3
0.00297
This document is a draft for review purposes only and does not constitute Agency policy.
50
DRAFT-DO NOT CITE OR QUOTE
-------
Methylene Chloride Benchmark Dose Report
Male Rat Subcutis (fibroma/fibrosarcoma) (Aiso, 2014) vs Slowly
Perfused AUC - Multistage Degree 1 with BMR of 10% Extra Risk
for the BMD and 0.95 Lower Confidence Limit for the BMDL
0.3
0.25
0.2
0.1
0.05
0
50
100
150
200
250
300
350
400
Dose
— — — Estimated Probability Response at BMD Linear Extrapolation
• Data BMD BMDL
This document is a draft for review purposes only and does not constitute Agency policy.
51
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Methylene Chloride Benchmark Dose Report
Male Rat Subcutis (fibroma/fibrosarcoma) - Multistage 2 Restricted (Selected Multistage
Degree); Extra Risk, BMR = 0.1
User Input
Info
Model
Multistage degree 2 vl .0
Dataset Name
Subcutis - Male Rats
Formula
P[dose] = g + (l-g)*[l-exp(-
b 1 *dose" 1 -b2*dose" 2)1
Options
Risk Type
BMR
Confidence
Level
Background
Extra Risk
0.1
0.95
Estimated
Model Data
Dependent
Variable
Independent
Variable
Total # of
Observation
Slowly perfused
AUC(DCM)
[Tumor Incidence]
Model Results
Benchmark Dose
BMD
156.1284704
BMDL
106.7298415
BMDU
285.6542832
AIC
140.9342972
P-value
0.913190507
D.O.F.
2
Chi2
0.181621518
Slope Factor
0.000936945
Model Parameters
# of Parameters
3
Variable
Estimate
Background (g)
0.021140922
Betal
0.000674832
Beta2
0
Goodness of Fit
Dose
Estimated
Probability
Expected
Observed
Size
Scaled
Residual
0
0.021140922
1.05704609
1
50
-0.0561
93.33
0.080890193
4.04450965
4
50
-0.0231
196.4
0.142646218
7.1323109
8
50
0.35089
403.4
0.25442153
12.7210765
12
50
-0.2341
Analysis of Deviance
Model
Log Likelihood
# of Parameters
Deviance
Test d.f.
P Value
Full Model
-68.3779146
0
-
-
-
Fitted Model
-68.4671486
2
0.178468
2
0.91463
Reduced Model
-75.3540323
1
13.95224
3
0.00297
This document is a draft for review purposes only and does not constitute Agency policy.
52
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Methylene Chloride Benchmark Dose Report
0.3
0.25
0.2
m
LO
g. 0.15
LO
CD
DC
Male Rat Subcutis (fibroma/fibrosarcoma) (Aiso et al., 2014) vs
Slowly Perfused AUC - Multistage Degree 2 with BMR of 10% Extra
Risk for the BMD and 0.95 Lower Confidence Limit for the BMDL
•
•
0.1
0.05
4
0
50 100
15C
200 250 300 350 400
Dose
•
Estimated Probability^™
Data
- Response at BMD —
BMD
Linear Extrapolation
BMDL
This document is a draft for review purposes only and does not constitute Agency policy.
53
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Methylene Chloride Benchmark Dose Report
6. BMP Modeling for Aiso et al. (2014) Female Rats
6.1. Mammary Gland (Fibroadenoma/Adenoma/Adenocarcinoma)
Slowly Perfused AUC(DCM)
N
Incidence
0
50
7
93.29
50
9
196.3
50
10
402.9
50
14
Summary of BMDS 3.1 Modeling Results for Female Rat Mammary Gland
Fibroadenoma/Adenoma/Adenocarcinoma (Aiso et al., 2014)
Standard Models
Restriction**
10% Extra Risk
P Value
AIC
BMDS Recommends
BMDS Recommendation Notes
*
BMD
BMDL
Gamma
Restricted
252.38
123.73
0.83726
203.01348
Viable - Alternate
Log-Logistic
Restricted
251.92
112.12
0.83049
203.01710
Viable - Alternate
Multistage Degree 2
Restricted
259.85
123.79
0.84732
203.00822
Viable - Alternate
Multistage Degree 1
(Quantal Linear)*
Restricted
247.23
123.70
0.97846
201.01500
Selected, Multistage
Multistaee-cancer euidance fEPA. 2014)
Weibull
Restricted
253.00
123.74
0.83797
203.01308
Viable - Alternate
BMD computation failed; lower limit
Dichotomous Hill
LTnrestricted
251.92
0
NA
205.01710
LTnusable
includes zero; BMDL not estimated
d.f.=0, saturated model (Goodness of fit test
cannot be calculated)
Logistic
NA
275.68
173.88
0.97832
201.01485
Viable - Alternate
Log-Probit
LTnrestricted
391.50
0
0.41963
203.63506
LTnusable
BMD computation failed; lower limit
includes zero; BMDL not estimated
Probit**
NA
271.35
166.68
0.97985
201.01173
Selected, Full Model
Suite
Lowest AIC
Non-Standard
Models
Dichotomous Hill
Restricted
251.94
112.12
NA
205.01710
Questionable
d.f.=0, saturated model (Goodness of fit test
cannot be calculated)
Log-Probit
Restricted
391.75
186.71
0.41963
203.63507
Viable - Alternate
BMD/BMDL ratio > 20
Gamma
LTnrestricted
251.76
11.125
0.83726
203.01350
Questionable
BMD/BMDL ratio > 5
BMDL 3x lower than lowest non-zero dose
Log-Logistic
LTnrestricted
251.92
0
0.83049
203.01710
LTnusable
BMD computation failed; lower limit
includes zero; BMDL not estimated
BMD/BMDL ratio > 5
Multistage Degree 3
LTnrestricted
303.92
28.637
NA
204.97127
Questionable
BMDL 3x lower than lowest non-zero dose
d.f.=0, saturated model (Goodness of fit test
cannot be calculated)
Multistage Degree 2
LTnrestricted
259.90
70.927
0.84731
203.00822
Viable - Alternate
Multistage Degree 1
LTnrestricted
247.15
123.70
0.97846
201.01500
Viable - Alternate
Weibull
LTnrestricted
253.20
0
0.83798
203.01308
LTnusable
BMD computation failed; lower limit
includes zero; BMDL not estimated
* Selected, Multistage (Yellow); residuals for doses 0, 93.29, 196.3, and 402.9 were -0.010239177, 0.111846652, -0.164713519, and 0.061617456, respectively.
**Selected, Full Model Suite (Green); residuals for doses 0, 93.29, 196.3, and 402.9 were -0.092589223, 0.164652106-0.070902629, and -0.001870175, respectively.
***Restrictions defined in the BMDS 3.1 User Guide; NA = Not Applicable
This document is a draft for review purposes only and does not constitute Agency policy.
54
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-------
Methylene Chloride Benchmark Dose Report
0.3
0.25
0.2
I 0.15
to
(D
C£
0.1
0.05
BMDS 3.1 Standard Model Plots for Female Rat Mammary Gland
(Fibroadenoma/Adenoma/Adenocarcinoma) vs Slowly perfused
AUC(DCM) (Aisoetal., 2014)
50
100
150
200
Dose
250
300
350
400
¦Frequentist Dichotomous Hill Estimated Probability
¦ Frequentist Gamma Estimated Probability
¦Frequentist Multistage Degree 3 Estimated Probability -
¦Frequentist Multistage Degree 1 Estimated Probability -
¦Frequentist Log-Probit Estimated Probability
Frequentist Log-Logistic Estimated Probability
¦Frequentist Multistage Degree 2 Estimated Probability
¦Frequentist Weibull Estimated Probability
This document is a draft for review purposes only and does not constitute Agency policy.
55
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Methylene Chloride Benchmark Dose Report
Selected, Multistage - Multistage 1 Restricted; Extra Risk, BMR =0.1
Info
Options
Model Data
Model
Multistage degree 1 vl.O
Risk Type
Extra Risk
Dependent
Variable
Slowly perfused
AUC(DCM)
Data set
Name
Aiso Female Rat Mammary
Gland (Fibroadenoma/Adenoma/
Adenocarcinoma)
BMR
0.1
Independent
Variable
[Tumor Incidence!
Confidence
Level
0.95
Formula
P[dose] = g + (l-g)*[l-exp(-
bl*doseAl)l
Total # of
Observation
4
Background
Estimated
Model Results
Benchmark Dose
BMD
247.2325655
BMDL
123.7009246
BMDU
Infinity
AIC
201.0149992
P-value
0.978464391
D.O.F.
2
Chi2
0.043541769
Slope Factor
0.000808401
Model Parameters
# of Parameters
3
Variable
Estimate
Background (g)
0.140503205
Betal
0.00042616
Goodness of Fit
Dose
Estimated
Probability
Expected
Observed
Size
Scaled
Residual
0
0.140503205
7.025160271
7
50
-0.010239
93.29
0.174003388
8.700169384
9
50
0.1118467
196.3
0.209479192
10.47395962
10
50
-0.164714
402.9
0.27610423
13.8052115
14
50
0.0616175
Analysis of Deviance
Model
Log Likelihood
# of Parameters
Deviance
Test d.f.
P Value
Full Model
-98.48563564
0
_
_
_
Fitted Model
-98.50749962
2
0.04372796
2
0.9783733
Reduced Model
-100.0804847
1
3.18969813
3
0.363292
This document is a draft for review purposes only and does not constitute Agency policy.
56
DRAFT-DO NOT CITE OR QUOTE
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Methylene Chloride Benchmark Dose Report
Female Rat Mammary Gland (Fibroadenoma/Adenoma/
Adenocarcinoma) (Aiso et al., 2014) vs Slowly Perfused AUC -
Multistage Degree 1 Model with BMR of 10% Extra Risk for the BMD
and 0.95 Lower Confidence Limit for the BMDL
0.3
0.25
•
0
0.2
Response
o
i-*
ui
0.1
0.05
0
50 100
150 200 250 300 350 400
Dose
— Estimated Probability^—
Response at BMD —
Linear Extrapolation
a
Data
BMD
BMDL
This document is a draft for review purposes only and does not constitute Agency policy.
57
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User Input
Methylene Chloride Benchmark Dose Report
Selected, Full Model Suite - Probit - Extra Risk, BMR = 0.1
Info
Model
Probit vl.O
Data set
Name
Aiso Female Rat Mammary
Gland (Fibroadenoma/Adenoma/
Adenocarcinoma)
Formula
P[dose] =
CumNorm(a+b*Dose)
Options
Risk Type
BMR
Confidence
Level
Background
Extra Risk
0.1
0.95
Estimated
Model Data
Dependent
Variable
Independent
Variable
Total # of
Observation
Slowly perfused
AUC(DCM)
[Tumor Incidence]
Model Results
Benchmark Dose
BMD
271.3350125
BMDL
166.6839944
BMDU
Infinity
AIC
201.0117292
P-value
0.979848922
D.O.F.
2
Chi2
0.04071376
Slope Factor
271.3350125
Model Parameters
# of Parameters
3
Variable
Estimate
a
-1.059855271
b
0.001184826
Goodness of Fit
Dose
Estimated
Probability
Expected
Observed
Size
Scaled
Residual
0
0.144605224
7.230261182
7
50
-0.092589
93.29
0.171228226
8.561411293
9
50
0.1646521
196.3
0.20404093
10.20204651
10
50
-0.070903
402.9
0.280118768
14.00593839
14
50
-0.00187
Analysis of Deviance
Model
Log Likelihood
# of Parameters
Deviance
Test d.f.
P Value
Full Model
-98.48563564
0
_
_
_
Fitted Model
-98.50586461
2
0.04045793
2
0.9799743
Reduced Model
-100.0804847
1
3.18969813
3
0.363292
This document is a draft for review purposes only and does not constitute Agency policy.
58
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Methylene Chloride Benchmark Dose Report
0.3
0.25
0.2
(D
to
g. 0.15
LO
CD
DC
0.1
0.05
0
0 50 100 150 200 250 300 350 400
Dose
— — — Estimated Probability Response at BMD • Data BMD BMDL
Female Rat Mammary Gland (Fibroadenoma/Adenoma/
Adenocarcinoma) (Aiso et al., 2014) vs Slowly Perfused AUC - Probit
Model with BMR of 10% Extra Risk for the BMD and 0.95 Lower
Confidence Limit for the BMDL
This document is a draft for review purposes only and does not constitute Agency policy.
59
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Methylene Chloride Benchmark Dose Report
6.2. Liver Acidophilic Cell Foci
Liver CYP dose
N
Incidence
0
50
3
786.8
50
8
846
50
14
925.7
50
23
Summary of BMDS 3.1 Results for Female Rat Liver Acidophilic Cell Foci (Aiso et al.,
2014)
Standard Models
Restrict.**
10% Extra Risk
P Value
AIC
BMDS Recommends
BMDS Recommendation Notes
BMD
BMDL
Gamma*
Restricted
732.62
645.50
0.56828
200.11723
Selected, Full Model
Suite
Lowest AIC
Log-Logistic
Restricted
775.29
676.75
0.80528
201.01418
Viable
- Alternate
Multistage Degree 3
Restricted
596.40
362.39
0.09585
203.82564
Questionable
Goodness of fit p-value <0.1
Multistage Degree 2
Restricted
499.87
254.05
0.04010
205.60272
Questionable
Goodness of fit p-value <0.1
Goodness of fit p-value < 0.05
BMDL 3x lower than lowest non-zero dose
Multistage Degree 1
(Quantal Linear)
Restricted
297.12
219.94
0.01435
207.65468
Questionable
Goodness of fit p-value <0.1
Goodness of fit p-value < 0.05
BMDL 3x lower than lowest non-zero dose
Weibull
Restricted
771.46
665.19
0.74279
201.06111
Viable
- Alternate
Dichotomous Hill
LTnrestricted
775.15
676.82
NA
203.01388
Questionable
d.f.=0, saturated model (Goodness of fit test
cannot be calculated)
Logistic
NA
478.95
403.17
0.04372
205.40117
Questionable
Goodness of fit p-value <0.1
Goodness of fit p-value < 0.05
Log-Probit
LTnrestricted
778.75
687.49
0.86786
200.98110
Viable
-
Alternate
Probit
NA
443.88
374.89
0.03421
205.92483
Questionable
Goodness of fit p-value <0.1
Goodness of fit p-value < 0.05
Non-Standard
Models
Dichotomous Hill
Restricted
782.89
678.91
NA
202.95345
Questionable
d.f.=0, saturated model (Goodness of fit test
cannot be calculated)
Log-Probit
Restricted
778.75
687.49
0.86786
200.98110
Viable
- Alternate
Gamma
LTnrestricted
732.62
645.49
0.56828
200.11723
Viable
- Alternate
Log-Logistic
LTnrestricted
775.25
676.75
0.80529
201.01418
Viable
- Alternate
Multistage Degree 3
LTnrestricted
783.55
12.570
NA
202.95345
Questionable
BMD/BMDL ratio > 20
BMD/BMDL ratio > 5
BMDL 3x lower than lowest non-zero dose
BMDL lOx lower than lowest non-zero dose
d.f.=0, saturated model (Goodness of fit test
cannot be calculated)
Multistage Degree 2
LTnrestricted
785.48
706.31
0.86464
200.98261
Viable
- Alternate
Multistage Degree 1
LTnrestricted
297.13
219.94
0.01435
207.65468
Questionable
Goodness of fit p-value <0.1
Goodness of fit p-value < 0.05
BMDL 3x lower than lowest non-zero dose
Weibull
LTnrestricted
771.45
665.18
0.74279
201.06111
Viable
- Alternate
* Selected, Full Model Suite (Green); residuals for doses 0, 786.8, 846, and 925.7 were 0.215521983, -0.795365045, -0.087537521, and 0.66601925, respectively.
**Restrictions defined in the BMDS 3.1 User Guide; NA = Not Applicable
This document is a draft for review purposes only and does not constitute Agency policy.
60
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Methylene Chloride Benchmark Dose Report
BMDS 3.1 Standard Models, Female Rat Acidophilic cell foci vs Liver
CYP Dose (Aiso et al., 2014)
0.5
0.45
0.4
0.35
0.3
I 0.25
LO
CD
DC
0.2
0.15
0.1
0.05
100
200
300
400
500
600
700
800
900
Dose
¦Frequentist Gamma Estimated Probability
¦Frequentist Multistage Degree 3 Estimated Probability
¦ Frequentist Multistage Degree 1 Estimated Probability -
¦Frequentist Dichotomous Hill Estimated Probability
¦Frequentist Log-Probit Estimated Probability
¦Frequentist Log-Logistic Estimated Probability
Frequentist Multistage Degree 2 Estimated Probability
¦ Frequentist Weibull Estimated Probability
¦Frequentist Logistic Estimated Probability
¦Frequentist Probit Estimated Probability
This document is a draft for review purposes only and does not constitute Agency policy.
61
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Methylene Chloride Benchmark Dose Report
Selected, Full Model Suite - Gamma (Restricted) - Extra Risk, BMR = 0.1
User Input
Info
Model
Gamma vl .0
Data set
Name
Aiso Female Rat Liver
Acidophilic Cell Foci
Formula
P[dose]= g+(l-
g) *CumGamma fb *dose,al
Options
Risk Type
BMR
Confidence
Level
Background
Extra Risk
0.1
0.95
Estimated
Model Data
Dependent
Variable
Independent
Variable
Total # of
Observation
Liver CYP Dose
[Tumor Incidence]
Model Results
Benchmark Dose
BMD
732.6188725
BMDL
645.4953642
BMDU
780.2931446
AIC
200.1172284
P-value
0.568274974
D.O.F.
2
Chi2
1.130299738
Model Parameters
# of Parameters
3
Variable
Estimate
Background (g)
0.053161763
a
20
b
0.019826491
Goodness of Fit
Dose
Estimated
Probability
Expected
Observed
Size
Scaled
Residual
0
0.053161763
2.658088146
3
50
0.215522
786.8
0.205445588
10.27227941
8
50
-0.795365
846
0.285591848
14.27959239
14
50
-0.087538
925.7
0.413613552
20.68067758
23
50
0.6660192
Analysis of Deviance
Model
Log Likelihood
# of Parameters
Deviance
Test d.f.
P Value
Full Model
-97.47672389
0
_
_
_
Fitted Model
-98.05861422
2
1.16378066
2
0.558841
Reduced Model
-110.2159856
1
25.4785235
3
<0.0001
This document is a draft for review purposes only and does not constitute Agency policy.
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Methylene Chloride Benchmark Dose Report
Liver Acidophilic cell foci (Aiso et al., 2014) vs Liver CYP Dose -
Gamma Model with BMR of 10% Extra Risk for the BMD and 0.95
Lower Confidence Limit for the BMDL
0.5
0.45
0.4
0.35
0.3
0.2
0.15
0.1
0.05
0
100
200
300
400
500
600
700
800
900
Dose
Estimated Probability Response at BMD • Data BMD BMDL
This document is a draft for review purposes only and does not constitute Agency policy.
63
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Methylene Chloride Benchmark Dose Report
6.3. Liver Basophilic Cell Foci
Liver CYP dose
N
Incidence
0
50
18
786.8
50
37
846
50
40
925.7
50
36
Summary of BMDS 3.1 Results for Female Rat Liver Basophilic Cell Foci (Aiso et al.,
2014)
Standard Models
Restriction**
10% Extra Risk
P Value
AIC
BMDS Recommends
BMDS Recommendation Notes
BMD
BMDL
Gamma
Restricted
94.924
72.238
0.49100
237.40193
Questionable
BMD 3x lower than lowest non-zero dose
BMDL 3x lower than lowest non-zero dose
BMDL lOx lower than lowest non-zero dose
Log-Logistic
Restricted
59.469
38.027
0.54988
237.18500
Questionable
BMD 3x lower than lowest non-zero dose
BMDL 3x lower than lowest non-zero dose
BMD lOx lower than lowest non-zero dose
BMDL lOx lower than lowest non-zero dose
Multistage Degree 3
Restricted
94.925
72.238
0.49100
237.40193
Questionable
BMD 3x lower than lowest non-zero dose
BMDL 3x lower than lowest non-zero dose
BMDL lOx lower than lowest non-zero dose
Multistage Degree 2
Restricted
94.925
72.237
0.49100
237.40193
Questionable
BMD 3x lower than lowest non-zero dose
BMDL 3x lower than lowest non-zero dose
BMDL lOx lower than lowest non-zero dose
Multistage Degree 1
(Quantal Linear)
Restricted
94.925
72.235
0.49100
237.40193
Viable - Alternate
BMD 3x lower than lowest non-zero dose
BMDL 3x lower than lowest non-zero dose
BMDL lOx lower than lowest non-zero dose
Weibull
Restricted
94.924
72.238
0.49100
237.40193
Questionable
BMD 3x lower than lowest non-zero dose
BMDL 3x lower than lowest non-zero dose
BMDL lOx lower than lowest non-zero dose
Dichotomous Hill
LTnrestricted
CF
CF
CF
CF
Logistic*
NA
136.40
114.20
0.43147
237.6487
Selected, Full Model
Suite
Lowest AIC
BMD 3x lower than lowest non-zero dose
BMDL 3x lower than lowest non-zero dos
Log-Probit
LTnrestricted
CF
CF
CF
CF
Probit
NA
137.52
116.44
0.41968
237.7033
Viable - Alternate
BMD 3x lower than lowest non-zero dose
BMDL 3x lower than lowest non-zero dose
Non-Standard Models
Dichotomous Hill
Restricted
3.37E-6
0
0.33414
238.93484
LTnusable
BMD lower limit includes 0; BMDL not estimated
BMD 3x lower than lowest non-zero dose
BMD lOx lower than lowest non-zero dose
Log-Probit
Restricted
177.39
134.88
0.48467
237.42358
Viable - Alternate
BMD 3x lower than lowest non-zero dose
BMDL 3x lower than lowest non-zero dose
Gamma
LTnrestricted
0.0931
0.0415
0.59427
237.03875
Questionable
BMD 3x lower than lowest non-zero dose
BMDL 3x lower than lowest non-zero dose
BMD lOx lower than lowest non-zero dose
BMDL lOx lower than lowest non-zero dose
Log-Logistic
LTnrestricted
591.91
8.1697
0.55116
238.34446
Questionable
BMD/BMDL ratio > 20
BMD/BMDL ratio > 5
BMDL 3x lower than lowest non-zero dose
BMDL lOx lower than lowest non-zero dose
Multistage Degree 3
LTnrestricted
34.560
14.395
0.37934
238.77240
Questionable
BMD 3x lower than lowest non-zero dose
BMDL 3x lower than lowest non-zero dose
BMD lOx lower than lowest non-zero dose
BMDL lOx lower than lowest non-zero dose
Multistage Degree 2
LTnrestricted
94.925
72.2360
7
0.49100
237.40193
Questionable
BMD 3x lower than lowest non-zero dose
BMDL 3x lower than lowest non-zero dose
BMDL lOx lower than lowest non-zero dose
Multistage Degree 1
LTnrestricted
-9999
0
0.62726
236.93484
LTnusable
BMD computation failed; BMDL not estimated
Weibull
LTnrestricted
3.37E-6
0
0.33414
238.93484
LTnusable
BMD lower limit includes 0; BMDL not estimated
BMD 3x lower than lowest non-zero dose
BMD lOx lower than lowest non-zero dose
*Selected, Full Model Suite (Green); residuals for doses 0, 786.8, 846, and 925.7 were -0.092410996, 0.204561516, 0.826796158, and -0.973209778, respectively.
**Restrictions defined in the BMDS 3.1 User Guide; CF = Computation Failed; NA = Not Applicable
This document is a draft for review purposes only and does not constitute Agency policy.
64
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Methylene Chloride Benchmark Dose Report
0.8
0.7
0.6
0.5
I 0.4
to
(D
C£
0.3
0.2
0.1
BMDS 3.1 Standard Model Plots for Female Rat Liver Basophilic cell
foci vs Liver CYP Dose (Aiso et al., 2014)
100
200
300
400
500
600
700
800
900
Dose
¦Frequentist Gamma Estimated Probability
¦Frequentist Multistage Degree 3 Estimated Probability
¦Frequentist Multistage Degree 1 Estimated Probability -
¦Frequentist Logistic Estimated Probability
¦Frequentist Log-Logistic Estimated Probability
Frequentist Multistage Degree 2 Estimated Probability
¦Frequentist Weibull Estimated Probability
¦Frequentist Probit Estimated Probability
This document is a draft for review purposes only and does not constitute Agency policy.
65
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User Input
Methylene Chloride Benchmark Dose Report
Selected, Full Model Suite - Logistic - Extra Risk, BMR = 0.1
Info
Model
Log-Probit vl .0
Data set
Name
Aiso Female Rat Liver
Basophilic Cell Foci
Formula
P[dose] = l/[l+exp(-a-b*dose)]
Options
Risk Type
BMR
Confidence
Level
Background
Extra Risk
0.1
0.95
Estimated
Model Data
Dependent
Variable
Independent
Variable
Total # of
Observation
Liver CYP Dose
[Tumor Incidence]
Model Results
Benchmark Dose
BMD
136.4021223
BMDL
114.2007853
BMDU
172.2573305
AIC
237.6487326
P-value
0.431470049
D.O.F.
2
Chi2
1.681114366
Model Parameters
# of Parameters
2
Variable
Estimate
a
-0.548138135
b
0.001942254
Goodness of Fit
Dose
Estimated
Probability
Expected
Observed
Size
Scaled
Residual
0
0.366296484
18.31482418
18
50
-0.092411
786.8
0.727113618
36.3556809
37
50
0.2045615
846
0.74932371
37.46618549
40
50
0.8267962
925.7
0.777266327
38.86331634
36
50
-0.97321
Analysis of Deviance
Model
Log Likelihood
# of Parameters
Deviance
Test d.f.
P Value
Full Model
-115.9915426
0
_
_
_
Fitted Model
-116.8243663
2
1.66564729
2
0.4348198
Reduced Model
-128.8592752
1
25.735465
3
<0.0001
This document is a draft for review purposes only and does not constitute Agency policy.
66
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Methylene Chloride Benchmark Dose Report
Female Rat Liver Basophilic cell foci (Aiso et al., 2014) vs Liver CYP
Dose - Logistic Model with BMR of 10% Extra Risk for the BMD and
0.95 Lower Confidence Limit for the BMDL
0.9
0.8
0.7
0.6
(u
LO
I 0.5
LO
CD
DC
0.4
0.3
0.2
0.1
0
C
•
. *
f---
100 200 300 400 500 600 700 800 900
Dose
— — — Estimated Probability Response at BMD • Data BMD BMDL
This document is a draft for review purposes only and does not constitute Agency policy.
67
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Methylene Chloride Benchmark Dose Report
7. BMP Modeling for Aiso et al. (2014) Male Mice
7.1. Liver (Hepatocellular Adenoma/Hepatocellular Carcinoma)
Liver GST dose
TNI
[Incidence]
0
50
15
1029
50
20
2213
50
25
4902
50
29
Summary of BMDS 3.1 Modeling Results for Male Mice Liver (Hepatocellular
Adenoma/Hepatocellular Carcinoma) (Aiso et al., 2014)
Standard Models
Restrict.***
10% Extra Risk
P Value
AIC
BMDS Recommends
BMDS Recommendation Notes
BMD
BMDL
Gamma
Restricted
956.50
593.22
0.80407
270.16723
Viable - Alternate
Log-Logistic*
Restricted
754.63
413.06
0.91435
269.91025
Selected, Full Model Suite
Lowest AIC
Multistage Degree 2**
Restricted
956.50
593.21
0.80407
270.16723
Selected, Multistage
Multistaee-cancer euidance (EPA. 2014)
Multistage Degree 1
(Quantal Linear)
Restricted
956.58
593.21
0.80407
270.16723
Viable - Alternate
Weibull
Restricted
956.50
593.22
0.80407
270.16723
Viable - Alternate
BMD failed; lower limit includes zero;
Dichotomous Hill
LTnrestricted
770.44
0
NA
273.73152
LTnusable
BMDL not estimated
d.f.=0 (cannot apply Goodness of fit test)
Logistic
NA
1269.5
899.68
0.65243
270.58795
Viable - Alternate
Log-Probit
LTnrestricted
586.23
0
0.79534
271.79881
LTnusable
BMD failed; lower limit includes zero
BMDL not estimated
Probit
NA
1256.8
891.02
0.65701
270.57370
Viable - Alternate
Non-Standard Models
BMD/BMDL ratio > 20
BMD/BMDL ratio > 5
Dichotomous Hill
Restricted
770.40
0.0169
NA
273.73152
Questionable
BMDL 3x lower than lowest non-zero dose
BMDL lOx lower than lowest non-zero dose
d.f.=0 (cannot apply Goodness of fit test)
Log-Probit
Restricted
1694.8
1086.6
0.47506
271.22362
Viable - Alternate
BMD/BMDL ratio > 20
Gamma
LTnrestricted
462.72
2.6093
0.73184
271.84901
Questionable
BMD/BMDL ratio > 5
BMDL 3x lower than lowest non-zero dose
BMDL lOx lower than lowest non-zero dose
Log-Logistic
LTnrestricted
532.29
0
0.77261
271.81505
LTnusable
BMD failed; lower limit includes zero
BMDL not estimated
Multistage Degree 3
LTnrestricted
719.61
163.72
NA
273.73152
Questionable
BMDL 3x lower than lowest non-zero dose
d.f.=0 (cannot apply Goodness of fit test)
Multistage Degree 2
LTnrestricted
609.60
287.19
0.87753
271.75529
Viable - Alternate
Multistage Degree 1
LTnrestricted
956.52
593.21
0.80407
270.16723
Viable - Alternate
Weibull
LTnrestricted
480.61
0
0.74356
271.83861
LTnusable
BMD failed; lower limit includes zero
BMDL not estimated
* Selected, Full Model Suite (Green); residuals for doses 0, 1029, 2213, and 4902 were -0.107305354, 0.026275785, 0.321177338, and -0.252428629, respectively.
**Selected, Multistage (Yellow); residuals for doses 0, 1029, 2213, and 4902 were -0.278519227, 0.124691166, 0.484655839, and -0.328825131, respectively.
***Restrictions defined in the BMDS 3.1 User Guide; NA = Not Applicable
This document is a draft for review purposes only and does not constitute Agency policy.
68
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Methylene Chloride Benchmark Dose Report
0.7
0.6
0.5
0.4
C
o
Q.
to
(D
al
0.3
0.2
0.1
BMDS 3.1 Standard Model Plots for Male Mice Liver (Hepatocellular
Adenoma/Hepatocellular Carcinoma) (Aiso et al., 2014) vs Liver GST
Dose
500
1000
1500
2000
2500
Dose
3000
3500
4000
4500
¦Frequentist Gamma Estimated Probability
¦Frequentist Multistage Degree 3 Estimated Probability
¦Frequentist Multistage Degree 1 Estimated Probability -
¦Frequentist Dichotomous Hill Estimated Probability
¦Frequentist Log-Probit Estimated Probability
¦Frequentist Log-Logistic Estimated Probability
Frequentist Multistage Degree 2 Estimated Probability
¦Frequentist Weibull Estimated Probability
¦Frequentist Logistic Estimated Probability
¦Frequentist Probit Estimated Probability
This document is a draft for review purposes only and does not constitute Agency policy.
69
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Methylene Chloride Benchmark Dose Report
Selected, Multistage - Multistage 2 Restricted; Extra Risk, BMR =0.1
User Input
Info
Options
Model Data
Model
Multistage degree 2 vl .0
Risk Type
Extra Risk
Dependent
Variable
Liver GST Dose
Data set
Name
Aiso et al. (2014) Male
Mice Liver (Hepatocellular
Adenoma/ Carcinoma)
BMR
0.1
Independent
Variable
[Tumor Incidence!
Confidence
0 95
Formula
P[dose] = g + (l-g)*[l-exp(-
b 1 *do seA1 -b2 *do seA2 )1
Background
Estimated
Total # of
Observation
4
Model Results
Benchmark Dose
BMD
956.5003924
BMDL
593.2107703
BMDU
2941.314946
AIC
270.1672319
P-value
0.804069921
D.O.F.
2
Chi2
0.436138096
Slope Factor
0.000168574
Model Parameters
# of Parameters
3
Variable
Estimate
Background (g)
0.318348595
Betal
0.000110152
Beta2
0
Goodness of Fit
Dose
Estimated
Probability
Expected
Observed
Size
Scaled
Residual
0
0.318348595
15.9174297
15
50
-0.2785
1029
0.391393516
19.5696758
20
50
0.12469
2213
0.465809873
23.2904936
25
50
0.48466
4902
0.602755145
30.1377572
29
50
-0.3288
Analysis of Deviance
Model
Log Likelihood
# of Parameters
Deviance
Test d.f.
P Value
Full Model
-132.865757
0
_
_
_
Fitted Model
-133.083616
2
0.435717
2
0.80424
Reduced Model
-137.416984
1
9.102453
3
0.02796
This document is a draft for review purposes only and does not constitute Agency policy.
70
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Methylene Chloride Benchmark Dose Report
0.6
0.5
0.4
I 0.3
to
(D
C£
Aiso et al. (2014) Male Mice Liver (Hepatocellular Adenoma/
Carcinoma) vs Liver GST Dose - Multistage 2, BMR of 10% Extra Risk
for BMD, 0.95 Lower Confidence Limit for BMDL
0.2
0.1
0 500 1000 1500 2000 2500 3000 3500 4000 4500
Dose
— — Estimated Probability Response at BMD
• Data BMD
• Linear Extrapolation
¦ BMDL
This document is a draft for review purposes only and does not constitute Agency policy.
71
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Methylene Chloride Benchmark Dose Report
Selected, Full Model Suite - Log-Logistic (Restricted) - Extra Risk, BMR = 0.1
Info
Options
Model Data
Model
Log-Logistic vl.O
Risk Type
Extra Risk
Dependent
Variable
Liver GST Dose
Data set
Name
Aiso et al. (2014) Male
Mice Liver (Hepatocellular
Adenoma/ Carcinoma)
BMR
0.1
Independent
Variable
[Tumor Incidence!
Confidence
0 95
Formula
P[dose] = g+(l-g)/[l+exp(-a-
b*Log(dose))l
Background
Estimated
Total # of
Observation
4
Model Results
Benchmark Dose
BMD
754.627573
BMDL
413.0555392
BMDU
2812.916208
AIC
269.9102517
P-value
0.914351713
D.O.F.
2
Chi2
0.179079951
Model Parameters
# of Parameters
3
Variable
Estimate
Background (g)
0.306999581
a
-8.82344892
b
1
Goodness of Fit
Dose
Estimated
Probability
Expected
Observed
Size
Scaled
Residual
0
0.306999581
15.349979
15
50
-0.1073
1029
0.398180953
19.9090477
20
50
0.02628
2213
0.477312724
23.8656362
25
50
0.32118
4902
0.597506701
29.8753351
29
50
-0.2524
Analysis of Deviance
Model
Log Likelihood
# of Parameters
Deviance
Test d.f.
P Value
Full Model
-132.865757
0
_
_
_
Fitted Model
-132.955126
2
0.178737
2
0.91451
Reduced Model
-137.416984
1
9.102453
3
0.02796
This document is a draft for review purposes only and does not constitute Agency policy.
72
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Methylene Chloride Benchmark Dose Report
0.6
0.5
0.4
(D
to
c
Aiso et al. (2014) Male Mice Hepatocellular Adenoma/ Carcinoma vs
Liver GST Dose - Log-Logistic Model with BMR of 10% Extra Risk for
the BMD and 0.95 Lower Confidence Limit for the BMDL
•
-
Wr
V
\
\
\
v.
*
Q_ U.D 1
tn
(D
ctl
0.2
0.1
0
C
500 1000 1500 2000 2500 3000 3500 4000 4500
Dose
— — — Estimated Probability Response at BMD • Data BMD BMDL
This document is a draft for review purposes only and does not constitute Agency policy.
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Methylene Chloride Benchmark Dose Report
7.2. Lung (Bronchiolar-Alveolar Adenoma/Bronchiolar-Alveolar Carcinoma)
Lung GST dose
TNI
[Incidence]
0
50
8
209.8
50
17
444.6
50
26
978.1
50
42
Summary of BMDS 3.1 Modeling Results for Male Mice Lung (Bronchiolar-
Alveolar Adenoma/Bronchiolar-Alveolar Carcinoma) vs Lung GST (Aiso et al.,
2014)
Standard Models
Restriction**
*
10% Extra Risk
P Value
AIC
BMDS Recommends
BMDS Recommendation Notes
BMD
BMDL
Gamma
Restricted
124.71
58.666
0.7187
227.4017
Viable - Alternate
BMDL 3x lower than lowest non-zero dose
Log-Logistic
Restricted
147.21
67.859
0.48672
227.7546
Viable - Alternate
BMDL 3x lower than lowest non-zero dose
Multistage Degree 2
Restricted
102.86
59.031
0.90626
227.2861
Viable - Alternate
BMDL 3x lower than lowest non-zero dose
Multistage Degree 1
(Quantal Linear)*
Restricted
70.936
55.91
0.56748
226.4326
Selected, Multistage
Multistaee-cancer euidance fEPA. 2014)
BMDL 3x lower than lowest non-zero dose
Weibull
Restricted
118.56
58.831
0.78247
227.3483
Viable - Alternate
BMDL 3x lower than lowest non-zero dose
Dichotomous Hill
LTnrestricted
147.22
67.858
0.48672
227.7546
Viable - Alternate
BMDL 3x lower than lowest non-zero dose
Logistic
NA
140.66
117.27
0.7658
225.8138
Viable - Alternate
Log-Probit
LTnrestricted
151.94
74.246
0.47274
227.7862
Viable - Alternate
Probit**
NA
136.66
115.93
0.76894
225.8046
Selected, Full Model
Suite
Lowest AIC
Non-Standard
Models
Dichotomous Hill
Restricted
147.22
67.858
0.48672
227.7546
Viable - Alternate
BMDL 3x lower than lowest non-zero dose
Log-Probit
Restricted
151.94
102.69
0.47274
227.7862
Viable - Alternate
Gamma
LTnrestricted
124.71
41.956
0.7187
227.4017
Viable - Alternate
BMDL 3x lower than lowest non-zero dose
Log-Logistic
LTnrestricted
147.25
67.859
0.48672
227.7546
Viable - Alternate
BMDL 3x lower than lowest non-zero dose
Multistage Degree 3
LTnrestricted
94.442
32.031
NA
229.2722
Questionable
BMDL 3x lower than lowest non-zero dose
d.f.=0, saturated model (Goodness of fit test
cannot be calculated)
Multistage Degree 2
LTnrestricted
102.86
56.921
0.90626
227.2861
Viable - Alternate
BMDL 3x lower than lowest non-zero dose
Multistage Degree 1
LTnrestricted
70.936
55.91
0.56748
226.4326
Viable - Alternate
BMDL 3x lower than lowest non-zero dose
Weibull
LTnrestricted
118.56
46.611
0.78247
227.3483
Viable - Alternate
BMDL 3x lower than lowest non-zero dose
*Selected, Multistage (Yellow); residuals for doses 0, 209.8, 444,6, and 978.1 were 0.312670191, -0.489892085, -0.54059179, and 0.709290841, respectively.
**Selected, Full Model Suite (Green); residuals for doses 0, 209.8, 444,6, and 978.1 were -0.492233766, 0.330089147, 0.323276987, and -0.264073236, respectively.
***Restrictions defined in the BMDS 3.1 User Guide; NA = Not Applicable
This document is a draft for review purposes only and does not constitute Agency policy.
74
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Methylene Chloride Benchmark Dose Report
0.9
0.8
0.7
0.6
I 0.5
LO
CD
DC
0.4
0.3
0.2
0.1
BMDS 3.1 Standard Model Plots for Male Mice Lung (Bronchiolar-
Alveolar Adenoma/Bronchiolar-Alveolar Carcinoma) (Aiso et al., 2014)
vs Lung GST
100
200
300
400
500
Dose
600
700
800
900
¦Frequentist Gamma Estimated Probability
¦Frequentist Multistage Degree 3 Estimated Probability
¦Frequentist Multistage Degree 1 Estimated Probability -
¦ Frequentist Dichotomous Hill Estimated Probability
¦Frequentist Log-Probit Estimated Probability
¦Frequentist Log-Logistic Estimated Probability
Frequentist Multistage Degree 2 Estimated Probability
¦Frequentist Weibull Estimated Probability
¦ Frequentist Logistic Estimated Probability
¦Frequentist Probit Estimated Probability
This document is a draft for review purposes only and does not constitute Agency policy.
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Methylene Chloride Benchmark Dose Report
Selected, Multistage - Multistage 1 Restricted; Extra Risk, BMR =0.1
User Input
Info
Model
Data set
Name
Formula
Multistage degree 1 vl.O
Aiso et al. (2014) Male
Mice Lung (Bronchiolar-
Alveolar
Adenoma/Bronchiolar-
Alveolar Carcinoma)
P[dose] = g + (l-g)*[l-exp(-
bl*doseAl)l
Options
Risk Type
Extra Risk
BMR
0.1
Confidence
Level
0.95
Background
Estimated
Model Data
Dependent
Variable
Lung GST Dose
Independent
Variable
[Tumor Incidence!
Total # of
Observation
4
Model Results
Benchmark Dose
BMD
70.93641143
BMDL
55.90961925
BMDU
94.01120627
AIC
226.4325854
P-value
0.567482742
D.O.F.
2
Chi2
1.133089883
Slope Factor
0.001788601
Model Parameters
# of Parameters
2
Variable
Estimate
Background (g)
0.144455052
Betal
0.001485281
Goodness of Fit
Dose
Estimated
Probability
Expected
Observed
Size
Scaled
Residual
0
0.144455052
7.22275262
8
50
0.31267
209.8
0.373513865
18.6756933
17
50
-0.4899
444.6
0.557967846
27.8983923
26
50
-0.5406
978.1
0.799866404
39.9933202
42
50
0.70929
Analysis of Deviance
Model
Log Likelihood
# of Parameters
Deviance
Test d.f.
P Value
Full Model
-110.63611
0
_
_
_
Fitted Model
-111.216293
2
1.160365
2
0.5598
Reduced Model
-138.139035
1
55.00585
3
<0.0001
This document is a draft for review purposes only and does not constitute Agency policy.
76
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Methylene Chloride Benchmark Dose Report
Aiso et al. (2014) Male Mice Lung (Bronchiolar-Alveolar
Adenoma/Bronchiolar-Alveolar Carcinoma) vs Lung GST - Multistage
Degree 1 Model, BMR of 10% Extra Risk for the BMD and 0.95 Lower
Confidence Limit for the BMDL
•
\
\
\
\
1
1
1
1
1
\
\
\
\
\
s'
•
—7
y
0 100 200 300 400 500 600 700 800 900
Dose
— — — Estimated Probability Response at BMD Linear Extrapolation
• Data BMD BMDL
This document is a draft for review purposes only and does not constitute Agency policy.
11
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Methylene Chloride Benchmark Dose Report
Selected, Full Model Suite - Probit - Extra Risk, BMR =0.1
User Input
Info
Model
Data set
Name
Formula
Log-Probit vl .0
Aiso et al. (2014) Male
Mice Lung (Bronchiolar-
Alveolar
Adenoma/Bronchiolar-
Alveolar Carcinoma)
P[dose]:
CumNorm(a+b*Dose)
Options
Risk Type
Extra Risk
BMR
0.1
Confidence
Level
0.95
Background
Estimated
Model Results
Benchmark Dose
BMD
136.6643728
BMDL
115.9251001
BMDU
162.0151938
AIC
225.8046015
P-value
0.768935795
D.O.F.
2
Chi2
0.52549561
Model Data
Dependent
Variable
Lung GST Dose
Independent
Variable
[Tumor Incidencel
Total # of
Observation
4
Model Parameters
# of Parameters
2
Variable
Estimate
a
-0.88844355
b
0.001982181
Goodness of Fit
Dose
Estimated
Probability
Expected
Observed
Size
Scaled
Residual
0
0.187151105
9.35755524
8
50
-0.4922
209.8
0.318255716
15.9127858
17
50
0.33009
444.6
0.497141239
24.8570619
26
50
0.32328
978.1
0.853216241
42.660812
42
50
-0.2641
Analysis of Deviance
Model
Log Likelihood
# of Parameters
Deviance
Test d.f.
P Value
Full Model
-110.63611
0
_
_
_
Fitted Model
-110.902301
2
0.532381
2
0.76629
Reduced Model
-138.139035
1
55.00585
3
<0.0001
This document is a draft for review purposes only and does not constitute Agency policy.
78
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Methylene Chloride Benchmark Dose Report
Aiso et al. (2014) Male Mice Lung (Bronchiolar-Alveolar
Adenoma/Bronchiolar-Alveolar Carcinoma) vs Lung GST - Probit
Model, BMR of 10% Extra Risk for the BMD and 0.95 Lower
Confidence Limit for the BMDL
0.9
0.8
0.7
0.6
m
LO
I 0.5
LO
CD
DC
0.4
0.3
0.2
0.1
0
'/
V
\
\
\
\
« "
»
100 200 300 400 500 600 700 800 900
Dose
— — — Estimated Probability Response at BMD • Data BMD BMDL
This document is a draft for review purposes only and does not constitute Agency policy.
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Methylene Chloride Benchmark Dose Report
7.3. Liver or Lung Tumor
Aiso et al. (2014) Male Mouse Liver (Hepatocellular Adenoma/Carcinoma)
Whole body GST dose
[N]
[Incidence]
0
50
15
43.65
50
20
93.77
50
25
207.6
50
29
Aiso et al. (2014) Male Mouse Lung (Bronchiolar-Alveolar
Adenoma/Carcinoma)
Whole body GST dose
[N]
[Incidence]
0
50
8
43.65
50
17
93.77
50
26
207.6
50
42
Summary of BMDS 3.1 Multi-tumor (MSCombo) Modeling Results for Male
Mouse Liver and Lung vs. Whole Body GST Dose (Aiso et al., 2014)
Models*
Dataset
10% Extra Risk
Slope
P Value
AIC
BMDS Recommendation Notes
BMD
BMDL
Factor
Multi-tumor
(MS Combo)
Combined Risk
10.938
8.2167
1.22e-2
NA
NA
| -
Multistage Degree 2
Liver Tumors
40.505
25.123
3.98e-3
0.80461
270.1659
Multistaee-cancer euidance fEPA. 2014)
Multistage Degree 1
Lung Tumors
14.985
11.804
8.47e-3
0.59028
226.3507
Multistaee-cancer euidance fEPA. 2014)
BMDL 3x lower than lowest non-zero dose
*Multistage models used in the BMDS multi-tumor (MS Combo) model are restricted as described in the BMDS 3.1 User Guide. The selected Multistage model
was chosen from among all relevant model runs (see detailed results for all relevant Multistage degrees below) in accordance with EPA's technical guidance for
choosing the appropriate stage of a multistage model for cancer modeling (Aiso, 2014).
This document is a draft for review purposes only and does not constitute Agency policy.
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Methylene Chloride Benchmark Dose Report
Selected Multistage model plots for Liver (blue) and Lung (orange) vs.
Whole Body GST in Male Mice that inhaled methylene chloride in
Aiso et al. (2014) 2-year study
1
0.9
0.8
0.7
a) 0.6
tn
I 0.5
tn
(D
^ 0.4
0.3
0.2
0.1
0
50 100 150 200
Dose
-Frequentist Multistage Degree 2 Estimated Probability Frequentist Multistage Degree 1 Estimated Probability
Multi-tumor (MS Combo) Results for Combined Risk of Male Mouse Liver
(Hepatocellular Adenoma/Carcinoma) and Lung (Bronchiolar-Alveolar
Adenoma/Carcinoma) vs. Whole Body GST Dose (Aiso et al., 2014)
User Input
Model Results
Info
Model
Multi-tumor v 1.0
Model Options
Risk Type
Extra Risk
BMR
0.1
Confidence
Level
0.95
Background
Estimated
Benchmark Dose
BMD
10.93812
BMDL
8.2166986
BMDU
15.868682
Slope Factor
0.0121703
Combined Log-Likelihood
-244.2583144
Combined Log-Likelihood
Constant
226.7895073
This document is a draft for review purposes only and does not constitute Agency policy.
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Methylene Chloride Benchmark Dose Report
Male Mouse Liver (Hepatocellular Adenoma/Carcinoma)- Multistage 1 Restricted; Extra Risk,
BMR = 0.1
User Input
Info
Options
Model Data
Model
Multistage degree 1 vl.O
Risk Type
Extra Risk
Dependent
Variable
Whole Body GST
Male Mouse Liver
(Hepatocellular
Adenoma/Carcinoma)
BMR
0.1
Data set
Independent
Variable
Name
Confidence
Level
0.95
[Tumor Incidence!
P[dose] = g + (l-g)*[l-exp(-
bl*dose" 1)1
Total # of
Observation
Formula
Background
Estimated
4
Model Results
Benchmark Dose
BMD
40.51379621
BMDL
25.12342007
BMDU
94.63866854
AIC
270.1658827
P-value
0.804615103
D.O.F.
2
Chi2
0.434782497
Slope Factor
0.00398035
Model Parameters
# of Parameters
2
Variable
Estimate
Background (g)
0.318340384
Betal
0.002600608
Goodness of Fit
Dose
Estimated
Probability
Expected
Observed
Size
Scaled
Residual
0
0.318340384
15.91701921
15
50
-0.278397
43.65
0.391489673
19.57448367
20
50
0.1232926
93.77
0.465852833
23.29264167
25
50
0.484044
207.6
0.602718877
30.13594386
29
50
-0.328296
Analysis of Deviance
Model
Log Likelihood
# of Parameters
Deviance
Test d.f.
P Value
Full Model
-132.8657575
0
_
_
_
Fitted Model
-133.0829414
2
0.43436774
2
0.804782
Reduced Model
-137.4169841
1
9.10245313
3
0.0279593
This document is a draft for review purposes only and does not constitute Agency policy.
82
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Methylene Chloride Benchmark Dose Report
Male Mouse Liver (Hepatocellular Adenoma/Carcinoma) (Aiso et al.,
2014) vs Whole Body GST - Multistage Degree 1 with BMR of 10%
Extra Risk for the BMD and 0.95 Lower Confidence Limit for the BMDL
0.6
0.5
0.4
-------
Methylene Chloride Benchmark Dose Report
Male Mouse Liver (Hepatocellular Adenoma/Carcinoma) - Multistage 2 Restricted (Selected
Multistage Degree); Extra Risk, BMR =0.1
Info
Model
Multistage degree 2 vl .0
Data set
Name
Male Mouse Liver
(Hepatocellular
Adenoma/Carcinoma)
Formula
P[dose] = g + (l-g)*[l-
exp(-bl*doseAl-
b2*doseA2)l
Options
Risk Type
Extra Risk
BMR
0.1
Confidence
Level
0.95
Background
Estimated
Model Data
Dependent
Variable
Whole Body GST Dose
Independent
Variable
[Tumor Incidence!
Total # of
Observation
4
Model Results
Benchmark Dose
BMD
40.50540747
BMDL
25.12334901
BMDU
124.5617822
AIC
270.1658817
P-value
0.804611589
D.O.F.
2
Chi2
0.434791233
Slope Factor
0.003980361
Model Parameters
# of Parameters
3
Variable
Estimate
Background (g)
0.318285763
Betal
0.002601147
Beta2
0
Goodness of Fit
Dose
Estimated
Probability
Expected
Observed
Size
Scaled
Residual
0
0.318285763
15.91428813
15
50
-0.27758
43.65
0.39145522
19.57276099
20
50
0.1237937
93.77
0.46583701
23.29185049
25
50
0.4842694
207.6
0.602731464
30.13657321
29
50
-0.32848
Analysis of Deviance
Model
Log Likelihood
# of Parameters
Deviance
Test d.f.
P Value
Full Model
-132.8657575
0
_
_
_
Fitted Model
-133.0829409
2
0.43436674
2
0.8047824
Reduced Model
-137.4169841
1
9.10245313
3
0.0279593
This document is a draft for review purposes only and does not constitute Agency policy.
84
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Methylene Chloride Benchmark Dose Report
Male Mouse Liver (Hepatocellular Adenoma/Carcinoma) (Aiso et al.,
2014) vs Whole Body GST - Multistage Degree 2 with BMR of 10%
Extra Risk for the BMD and 0.95 Lower Confidence Limit for the BMDL
0.6
0.5
0.4
-------
Methylene Chloride Benchmark Dose Report
Male Mouse Lung (Bronchiolar-Alveolar Adenoma/Carcinoma) - Multistage 1 Restricted
(Selected Multistage Degree); Extra Risk, BMR =0.1
Info
Model
Multistage degree 1 vl.O
Data set
Name
Aiso et al. (2014) Male
Mouse Lung (Bronchiolar-
Alveolar
Adenoma/Carcinoma)
Formula
P[dose] = g + (l-g)*[l-
exp(-bl*doseAl)l
Options
Risk Type
Extra Risk
BMR
0.1
Confidence
Level
0.95
Background
Estimated
Model Data
Dependent
Variable
Whole Body GST Dose
Independent
Variable
[Tumor Incidence!
Total # of
Observation
4
Model Results
Benchmark Dose
BMD
14.9845282
BMDL
11.80389197
BMDU
19.87149393
AIC
226.3507471
P-value
0.590282056
D.O.F.
2
Chi2
1.054309591
Slope Factor
0.008471782
Model Parameters
# of Parameters
2
Variable
Estimate
Background (g)
0.145037511
Betal
0.007031287
Goodness of Fit
Dose
Estimated
Probability
Expected
Observed
Size
Scaled
Residual
0
0.145037511
7.251875556
8
50
0.300452
43.65
0.370993289
18.54966446
17
50
-0.453672
93.77
0.557812575
27.89062875
26
50
-0.538361
207.6
0.801386157
40.06930785
42
50
0.6843879
Analysis of Deviance
Model
Log Likelihood
# of Parameters
Deviance
Test d.f.
P Value
Full Model
-110.6361102
0
_
_
_
Fitted Model
-111.1753736
2
1.07852675
2
0.5831777
Reduced Model
-138.1390352
1
55.0058499
3
<0.0001
This document is a draft for review purposes only and does not constitute Agency policy.
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Methylene Chloride Benchmark Dose Report
Male Mouse Lung (Bronchiolar-Alveolar Adenoma/ Carcinoma) (Aiso
et al., 2014) vs Whole Body GST - Multistage Degree 1, BMR of 10%
Extra Risk for BMD and 0.95 Lower Confidence Limit for BMDL
4
\
\
\
\
\
\
\
\
\
\
\
\
\
¦
~
~
/•
/
\
\
\
<
/
0.9
0.8
0.7
0.6
I 0.5
LO
CD
DC
0.4
0.3
0.2
0.1
50
100
Dose
150
200
— — Estimated Probability
• Data
• Response at BMD
BMD
«Linear Extrapolation
¦ BMDL
This document is a draft for review purposes only and does not constitute Agency policy.
87
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Methylene Chloride Benchmark Dose Report
Male Mouse Lung (Bronchiolar-Alveolar Adenoma/Carcinoma) - Multistage 2 Restricted; Extra
Risk, BMR= 0.1
User Input
Info
Options
Model Data
Model
Multistage degree 2 vl .0
Risk Type
Extra Risk
Dependent
Variable
Independent
Variable
Whole Body GST
Dose
[Tumor Incidencel
Dataset Name
Aiso et al. (2014) Male Mouse
Lung (Bronchiolar-Alveolar
Adenoma/ C arcinoma)
BMR
0.1
Confidence
0 95
Formula
P[dose] = g + (l-g)*[l-exp(-
bl *doseAl-b2*doseA2)l
Background
Estimated
Total # of
Observation
4
Model Results
Benchmark Dose
BMD
21.4029062
BMDL
12.40675232
BMDU
48.5177516
AIC
227.2897899
P-value
0.894475331
D.O.F.
1
Chi2
0.017594297
Slope Factor
0.008060127
Model Parameters
# of Parameters
3
Variable
Estimate
Background (g)
0.161228481
Betal
0.004576058
Beta2
1.6197E-05
Goodness of Fit
Dose
Estimated
Probability
Expected
Observed
Size
Scaled
Residual
0
0.161228481
8.061424049
8
50
-0.023622
43.65
0.333971155
16.69855776
17
50
0.0903895
93.77
0.526370885
26.31854426
26
50
-0.090223
207.6
0.838598333
41.92991665
42
50
0.0269401
Analysis of Deviance
Model
Log Likelihood
# of Parameters
Deviance
Test d.f.
P Value
Full Model
-110.6361102
0
_
_
_
Fitted Model
-110.644895
3
0.01756954
1
0.8945492
Reduced Model
-138.1390352
1
55.0058499
3
<0.0001
This document is a draft for review purposes only and does not constitute Agency policy.
88
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Methylene Chloride Benchmark Dose Report
Male Mouse Lung (Bronchiolar-Alveolar Adenoma/Carcinoma) (Aiso et
al., 2014) vs Whole Body GST - Multistage Degree 2 with BMR of 10%
Extra Risk for the BMD and 0.95 Lower Confidence Limit for the BMDL
%
\
\
\
\
\
\
\
\
''
*
/'
0.9
0.8
0.7
0.6
I 0.5
LO
CD
DC
0.4
0.3
0.2
0.1
50
100
Dose
150
200
— — Estimated Probability
• Data
• Response at BMD
BMD
• Linear Extrapolation
«BMDL
This document is a draft for review purposes only and does not constitute Agency policy.
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Methylene Chloride Benchmark Dose Report
7.4. Lung Terminal Bronchiole Hyperplasia
Lung GST dose
TNI
[Incidence]
0
50
0
209.8
50
1
444.6
50
5
978.1
50
13
Summary of BMDS 3.1 Modeling Results for Male Mouse Terminal Bronchiole
Hyperplasia vs Lung GST Dose (Aiso et al., 2014)
Standard Models
Restriction**
10% Extra Risk
P Value
AIC
BMDS Recommends
BMDS Recommendation Notes
BMD
BMDL
Gamma*
Restricted
487.13
324.61
0.90863
103.8117
Selected, Full Model
Suite
Lowest AIC
Log-Logistic
Restricted
484.91
322.18
0.66742
105.8058
Viable
- Alternate
Multistage Degree 3
Restricted
505.45
319.43
0.83894
103.9745
Viable
- Alternate
Multistage Degree 2
Restricted
505.44
319.43
0.55341
105.9745
Viable
- Alternate
Multistage Degree 1
(Quantal Linear)
Restricted
409.03
286.57
0.47162
105.4225
Viable
- Alternate
Weibull
Restricted
491.72
323.09
0.62769
105.8579
Viable
- Alternate
Dichotomous Hill
LTnrestricted
444.82
309.41
NA
107.6179
Questionable
d.f.=0, saturated model (Goodness of fit test
cannot be calculated)
Logistic
NA
648.76
543.11
0.31824
106.4429
Viable
- Alternate
BMD failed; lower limit includes zero
BMDL not estimated
Log-Probit
LTnrestricted
2E+08
0
<0.0001
131.5823
LTnusable
Goodness of fit p-value <0.1
Goodness of fit p-value < 0.05
Residual for Dose Group Near BMD > 2
BMD higher than maximum dose
Residual at control > 2
Probit
NA
612.08
507.25
0.40875
105.8043
Viable
- Alternate
Non-Standard
Models
Dichotomous Hill
Restricted
444.6
309.41
NA
107.61790
Questionable
d.f.=0 (Goodness of fit cannot be calculated)
Log-Probit
Restricted
937813
0
<0.0001
131.58234
LTnusable
BMD failed; lower limit includes zero
BMDL not estimated
Goodness of fit p-value <0.1
Goodness of fit p-value < 0.05
Residual for Dose Group Near BMD > 2
BMD higher than maximum dose
Residual at control > 2
Gamma
LTnrestricted
487.12
324.43
0.90863
103.81169
Viable
- Alternate
Log-Logistic
LTnrestricted
484.91
322.18
0.66742
105.80578
Viable
- Alternate
Multistage Degree 3
LTnrestricted
444.43
321.21
NA
107.61791
Questionable
d.f.=0 (Goodness of fit cannot be calculated)
Multistage Degree 2
LTnrestricted
505.44
317.30
0.83894
103.97450
Viable
- Alternate
Multistage Degree 1
LTnrestricted
409.03
286.57
0.47162
105.42253
Viable
- Alternate
Weibull
LTnrestricted
491.70
322.73
0.62771
105.85787
Viable
- Alternate
*Selected, Full Model Suite (Green); residuals for doses 0, 209.8, 444,6, and 978.1 were -0.000872639, -0.273690741, 0.325572248, and -0.103637637, respectively.
**Restrictions defined in the BMDS 3.1 User Guide; NA = Not Applicable
This document is a draft for review purposes only and does not constitute Agency policy.
90
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Methylene Chloride Benchmark Dose Report
BMDS 3.1 Standard Model Plots for Male Mouse Terminal Bronchiole
Hyperplasia vs Lung GST Dose (Aiso et al., 2014)
0.3
0.25
0.2
I 0.15
LO
CD
DC
0.1
0.05
100
200
300
400
500
Dose
600
700
800
900
¦Frequentist Gamma Estimated Probability
¦Frequentist Multistage Degree 3 Estimated Probability
¦Frequentist Multistage Degree 1 Estimated Probability -
¦ Frequentist Dichotomous Hill Estimated Probability
¦Frequentist Log-Probit Estimated Probability
¦Frequentist Log-Logistic Estimated Probability
Frequentist Multistage Degree 2 Estimated Probability
¦Frequentist Weibull Estimated Probability
¦ Frequentist Logistic Estimated Probability
¦Frequentist Probit Estimated Probability
This document is a draft for review purposes only and does not constitute Agency policy.
91
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Methylene Chloride Benchmark Dose Report
Selected, Full Model Suite - Gamma (Restricted) - Extra Risk, BMR = 0.1
Info
Options
Model Data
Model
Gamma vl .0
Risk Type
Extra Risk
Dependent
Variable
Lung GST Dose
Data set
Name
Aiso et al. (2014) Male
Mouse Terminal Bronchiole
Hyperplasia
BMR
0.1
Independent
Variable
[Tumor Incidence!
Confidence
0 95
Formula
P[dose]= g+(l-
g) *CumGamma [b *dose,al
Background
Estimated
Total # of
Observation
4
Model Results
Benchmark Dose
BMD
487.1280354
BMDL
324.6110673
BMDU
634.974297
AIC
103.8116931
P-value
0.908625087
D.O.F.
2
Chi2
0.191645431
Model Parameters
# of Parameters
3
Variable
Estimate
Background (g)
1.523E-08
a
1.764256328
b
0.000849385
Goodness of Fit
Dose
Estimated
Probability
Expected
Observed
Size
Scaled
Residual
0
1.523E-08
7.615E-07
0
50
-0.0009
209.8
0.026180174
1.30900868
1
50
-0.2737
444.6
0.08702202
4.35110099
5
50
0.32557
978.1
0.266479937
13.3239968
13
50
-0.1036
Analysis of Deviance
Model
Log Likelihood
# of Parameters
Deviance
Test d.f.
P Value
Full Model
-49.8089503
0
_
_
_
Fitted Model
-49.9058465
2
0.193792
2
0.90765
Reduced Model
-62.79117
1
25.96444
3
<0.0001
This document is a draft for review purposes only and does not constitute Agency policy.
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Methylene Chloride Benchmark Dose Report
0.3
0.25
0.2
m
LO
° 0.15
tn
(D
C£
0.1
0.05
Aiso et al. (2014) Male Mouse Terminal Bronchiole Hyperplasia vs
Lung GST - Gamma Model with BMR of 10% Extra Risk for the BMD
and 0.95 Lower Confidence Limit for the BMDL
/•
/
/
/
/
/
/
/
/
/
/
t
/
/
/
/
/
/
/
/
/
/
-
/
/
~
~
/
~
~
~
~
~
*
*
K
\
i \
\
\
V
~
y
100 200 300 400 500 600 700 800 900
Dose
— — — Estimated Probability Response at BMD • Data BMD BMDL
This document is a draft for review purposes only and does not constitute Agency policy.
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Methylene Chloride Benchmark Dose Report
8. BMP Modeling for Aiso et al. (2014) Female Mice
8.1. Liver (Hepatocellular Adenoma/Hepatocellular Carcinoma)
Liver GST dose
[N]
[Incidence]
0
50
2
1127
49
8
2435
49
9
5203
50
30
Summary of BMDS 3.1 Modeling Results for Female Mouse Liver (Hepatocellular
Adenoma/Hepatocellular Carcinoma) vs Liver GST Dose (Aiso et al., 2014)
Standard Models
Restrict.***
10% Extra Risk
P Value
AIC
BMDS Recommends
BMDS Recommendation Notes
BMD
BMDL
Gamma
Restricted
1446.2
706.01
0.08571
183.39119
Questionable
Goodness of fit p-value <0.1
Log-Logistic
Restricted
1598.8
778.77
0.06904
183.66883
Questionable
Goodness of fit p-value <0.1
Multistage Degree
2*
Restricted
1408.7
762.31
0.13986
182.61744
Selected, Multistage
Multistage Degree 1
(Quantal Linear)
Restricted
807.21
621.21
0.09583
183.43529
Questionable
Goodness of fit p-value <0.1
Weibull
Restricted
1509.9
736.61
0.10410
183.03450
Viable - Alternate
Dichotomous Hill
LTnrestricted
1598.8
778.77
NA
185.66883
Questionable
d.f.=0, saturated model (Goodness of fit test
cannot be calculated)
Logistic
NA
1732.7
1440.0
0.37410
180.34516
Viable - Alternate
Log-Probit
LTnrestricted
1496.2
772.70
0.04600
184.41190
Questionable
Goodness of fit p-value <0.1
Goodness of fit p-value < 0.05
Probit**
NA
1595.1
1332.8
0.37801
180.32441
Selected, Full Model
Suite
Lowest AIC
Non-Standard
Models
Dichotomous Hill
Restricted
1598.8
778.77
0.06904
183.66883
Questionable
Goodness of fit p-value <0.1
Log-Probit
Restricted
1495.6
1075.0
0.04600
184.41189
Questionable
Goodness of fit p-value <0.1
Goodness of fit p-value < 0.05
Gamma
LTnrestricted
1446.3
689.33
0.08571
183.39119
Questionable
Goodness of fit p-value <0.1
Log-Logistic
LTnrestricted
1599.2
778.77
0.06904
183.66883
Questionable
Goodness of fit p-value <0.1
Multistage Degree 3
LTnrestricted
673.69
248.13
NA
182.44800
Questionable
BMDL 3x lower than lowest non-zero dose
d.f.=0 (Goodness of fit cannot be calculated)
Multistage Degree 2
LTnrestricted
1408.4
762.31
0.13986
182.61744
Viable - Alternate
Multistage Degree 1
LTnrestricted
807.21
621.21
0.09583
183.43529
Questionable
Goodness of fit p-value <0.1
Weibull
LTnrestricted
1509.9
736.07
0.10411
183.03450
Viable - Alternate
*Selected, Multistage (Yellow); residuals for doses 0,1127, 2435, and 5203 were -0.255660408, 0.981438585, -1.050357536, and 0.324699593, respectively.
**Selected, Full Model Suite (Green); residuals for doses 0, 1127, 2435, and 5203 were -0.581452723,1.103963499, -0.61310587, and 0.087362998, respectively.
***Restrictions defined in the BMDS 3.1 User Guide; NA = Not Applicable
This document is a draft for review purposes only and does not constitute Agency policy.
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Methylene Chloride Benchmark Dose Report
0.7
0.6
0.5
0.4
C
o
Q.
to
(D
CC
0.3
0.2
0.1
BMDS 3.1 Standard Model Plots for Liver (Hepatocellular
Adenoma/Hepatocellular Carcinoma) vs Liver GST (Aiso et al., 2014)
1000
2000
3000
4000
5000
Dose
¦Frequentist Gamma Estimated Probability
¦Frequentist Multistage Degree 3 Estimated Probability
¦Frequentist Multistage Degree 1 Estimated Probability -
¦Frequentist Dichotomous Hill Estimated Probability
¦Frequentist Log-Probit Estimated Probability
¦Frequentist Log-Logistic Estimated Probability
Frequentist Multistage Degree 2 Estimated Probability
¦Frequentist Weibull Estimated Probability
¦Frequentist Logistic Estimated Probability
¦Frequentist Probit Estimated Probability
This document is a draft for review purposes only and does not constitute Agency policy.
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Methylene Chloride Benchmark Dose Report
Selected, Multistage - Multistage 2 Restricted; Extra Risk, BMR =0.1
User Input
Info
Model
Data set
Name
Formula
Multistage degree 2 vl .0
Aiso et al. (2014) Female
Mouse Liver
(Hepatocellular
Adenoma/Hepatocellular
Carcinoma)
P[dose] = g + (l-g)*[l-exp(-
b1*do seA1 -b2 *do seA2)]
Options
Risk Type
Extra Risk
BMR
0.1
Confidence
Level
0.95
Background
Estimated
Model Data
Dependent
Variable
Liver GST Dose
Independent
Variable
[Tumor Incidence!
Total # of
Observation
4
Model Results
Benchmark Dose
BMD
1408.701273
BMDL
762.3062298
BMDU
2170.280873
AIC
182.6174393
P-value
0.13985562
D.O.F.
1
Chi2
2.179547016
Slope Factor
0.000131181
Model Parameters
# of Parameters
3
Variable
Estimate
Background (g)
0.047407152
Betal
4.44581E-05
Beta2
2.15337E-08
Goodness of Fit
Dose
Estimated
Probability
Expected
Observed
Size
Scaled
Residual
0
0.047407152
2.370357576
2
50
-0.246468
1127
0.118405041
5.801846992
8
49
0.9719417
2435
0.247610695
12.13292403
9
49
-1.036921
5203
0.578032473
28.90162363
30
50
0.3145217
Analysis of Deviance
Model
Log Likelihood
# of Parameters
Deviance
Test d.f.
P Value
Full Model
-87.22399352
0
_
_
_
Fitted Model
-88.30871965
3
2.16945225
1
0.1407764
Reduced Model
-110.7896779
1
47.1313687
3
<0.0001
This document is a draft for review purposes only and does not constitute Agency policy.
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Methylene Chloride Benchmark Dose Report
Aiso et al. (2014) Female Mouse Liver Tumor vs Liver GST - Multistage
(Restricted) Degree 2 Model, BMR of 10% Extra Risk for BMD and 0.95 Lower
Confidence Limit for BMDL
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
0
1000
2000
3000
4000
5000
Dose
— — — Estimated Probability Response at BMD Linear Extrapolation
• Data BMD BMDL
This document is a draft for review purposes only and does not constitute Agency policy.
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Methylene Chloride Benchmark Dose Report
Selected, Full Model Suite - Probit - Extra Risk, BMR =0.1
User Input
Info
Model
Data set
Name
Formula
Probit vl .0
Aiso et al. (2014) Female
Mouse Liver
(Hepatocellular
Adenoma/Hepatocellular
Carcinoma)
P[dose]:
CumNorm(a+b*Dose)
Options
Risk Type
Extra Risk
BMR
0.1
Confidence
Level
0.95
Background
Estimated
Model Results
Benchmark Dose
BMD
1595.107529
BMDL
1332.777247
BMDU
1907.524552
AIC
180.3244078
P-value
0.37800892
D.O.F.
2
Chi2
1.945674973
Model Data
Dependent
Variable
Liver GST Dose
Independent
Variable
[Tumor Incidencel
Total # of
Observation
4
Model Parameters
# of Parameters
2
Variable
Estimate
a
-1.599925117
b
0.00035145
Goodness of Fit
Dose
Estimated
Probability
Expected
Observed
Size
Scaled
Residual
0
0.054807598
2.740379913
2
50
-0.460033
1127
0.114325487
5.601948877
8
49
1.0765936
2435
0.228394439
11.19132752
9
49
-0.745708
5203
0.590436635
29.52183177
30
50
0.1375145
Analysis of Deviance
Model
Log Likelihood
# of Parameters
Deviance
Test d.f.
P Value
Full Model
-87.600959
-87.22399352
0
_
_
Fitted Model
-88.5357146
-88.1622039
2
1.87642075
2
Reduced Model
-111.355023
-110.7896779
1
47.1313687
3
This document is a draft for review purposes only and does not constitute Agency policy.
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Methylene Chloride Benchmark Dose Report
0.7
0.6
0.5
0.4
(u
LO
£
O
Q.
LO
CD
^ 0.3
0.2
0.1
t
0
Aiso et al. (2014) Female Mouse Liver (Hepatocellular
Adenoma/Hepatocellular Carcinoma) vs Liver GST - Probit Model, BMR
of 10% Extra Risk for BMD and 0.95 Lower Confidence Limit for BMDL
~
7
s
*
*
*
X
r
•
::::::: 2000 3000 4000 5000
Dose
— — — Estimated Probability Response at BMD • Data BMD BMDL
This document is a draft for review purposes only and does not constitute Agency policy.
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Methylene Chloride Benchmark Dose Report
8.2. Lung (Bronchiolar-Alveolar Adenoma/Bronchiolar-Alveolar Carcinoma)
Lung GST dose
TNI
[Incidence]
0
50
5
229.8
50
5
489.3
49
12
1038
50
30
Summary of BMDS 3.1 Modeling Results for Female Mice Lung (Bronchiolar-
Alveolar Adenoma/Bronchiolar-Alveolar Carcinoma) vs lung GST Dose (Aiso et al.,
2014)
Standard Models
Restriction*
*
10% Extra Risk
P Value
AIC
BMDS Recommends
BMDS Recommendation Notes
BMD
BMDL
Gamma
Restricted
401.07
240.69
0.66795
193.05738
Viable
- Alternate
Log-Logistic
Restricted
399.76
247.30
0.66396
193.06230
Viable
- Alternate
Multistage Degree
2*
Restricted
371.93
223.47
0.83445
191.24117
Selected, Multistage
and Selected, Full
Model Suite
Multistase-cancer euidance (EPA. 2014):
Lowest AIC
Multistage Degree 1
(Quantal Linear)
Restricted
174.79
131.52
0.04565
197.41738
Questionable
Goodness of fit p-value <0.1
Goodness of fit p-value < 0.05
Weibull
Restricted
395.77
233.52
0.57702
193.18852
Viable
- Alternate
Dichotomous Hill
LTnrestricted
438.65
252.35
NA
194.87252
Questionable
d.f.=0, saturated model (Goodness of fit test
cannot be calculated)
Logistic
NA
325.53
271.12
0.62543
191.81268
Viable
- Alternate
Log-Probit
LTnrestricted
881.06
165.24
0.01917
198.04778
Questionable
Goodness of fit p-value <0.1
Goodness of fit p-value < 0.05
BMD/BMDL ratio > 5
Probit
NA
300.72
251.83
0.53476
192.10948
Viable
- Alternate
Non-Standard
Models
Dichotomous Hill
Restricted
460.87
252.46
NA
194.87047
Questionable
d.f.=0 (Goodness of fit cannot be calculated)
Log-Probit
Restricted
404.99
256.99
0.79485
192.93864
Viable
- Alternate
Gamma
LTnrestricted
401.10
240.69
0.66794
193.05738
Viable
- Alternate
Log-Logistic
LTnrestricted
399.74
247.30
0.66396
193.06230
Viable
- Alternate
Multistage Degree 3
LTnrestricted
408.34
198.94
NA
194.87051
Questionable
d.f.=0 (Goodness of fit cannot be calculated)
Multistage Degree 2
LTnrestricted
415.78
227.89
0.64104
193.08908
Viable
- Alternate
Multistage Degree 1
LTnrestricted
174.79
131.51
0.04565
197.41738
Questionable
Goodness of fit p-value <0.1
Goodness of fit p-value < 0.05
Weibull
LTnrestricted
395.70
233.52
0.57703
193.18852
Viable
- Alternate
* Selected, Multistage & Selected, Full Model Suite (Green); residuals for doses 0, 229.8, 489.3, and 1038 are 0.353291028, -0.472348654, 0.038830428, and 0.056725116,
respectively.
**Restrictions defined in the BMDS 3.1 User Guide; NA = Not Applicable
This document is a draft for review purposes only and does not constitute Agency policy.
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Methylene Chloride Benchmark Dose Report
0.7
0.6
0.5
oj 0-4
to
c
o
Q.
to
O)
^ 0.3
0.2
0.1
BMDS 3.1 Standard Model Plots for Female Mice Lung (Bronchiolar-Alveolar
Adenoma/Bronchiolar-Alveolar Carcinoma) vs Lung GST (Aiso et al., 2014)
200
400
600
800
1000
Dose
¦Frequentist Gamma Estimated Probability
¦Frequentist Multistage Degree 3 Estimated Probability
¦Frequentist Multistage Degree 1 Estimated Probability -
¦ Frequentist Dichotomous Hill Estimated Probability
¦Frequentist Log-Probit Estimated Probability
¦Frequentist Log-Logistic Estimated Probability
Frequentist Multistage Degree 2 Estimated Probability
¦Frequentist Weibull Estimated Probability
¦ Frequentist Logistic Estimated Probability
¦Frequentist Probit Estimated Probability
This document is a draft for review purposes only and does not constitute Agency policy.
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Methylene Chloride Benchmark Dose Report
Selected, Multistage & Selected, Full Model Suite - Multistage 2 Restricted; Extra Risk, BMR
0.1
User Input
Info
Model
Data set
Name
Formula
Multistage degree 2 vl .0
Female Mice Lung
(Bronchiolar-Alveolar
Adenoma/Bronchiolar-
Alveolar Care.) (Aiso et al.,
2014)
P[dose] = g + (l-g)*[l-exp(-
b1*do seA1 -b2 *do seA2 )1
Options
Risk Type
Extra Risk
BMR
0.1
Confidence
Level
0.95
Background
Estimated
Model Data
Dependent
Variable
Lung GST Dose
Independent
Variable
[Tumor Incidencel
Total # of
Observation
4
Model Results
Benchmark Dose
BMD
371.9343533
BMDL
223.4690891
BMDU
447.743515
AIC
191.2411713
P-value
0.834454353
D.O.F.
2
Chi2
0.361954474
Slope Factor
0.000447489
Model Parameters
# of Parameters
3
Variable
Estimate
Background (g)
0.086540256
Betal
0
Beta2
7.61632E-07
Goodness of Fit
Dose
Estimated
Probability
Expected
Observed
Size
Scaled
Residual
0
0.086540256
4.327012821
5
50
0.3385073
229.8
0.122550852
6.127542608
5
50
-0.486271
489.3
0.238801991
11.70129755
12
49
0.1000859
1038
0.597931185
29.89655926
30
50
0.0298353
Analysis of Deviance
Model
Log Likelihood
# of Parameters
Deviance
Test d.f.
P Value
Full Model
-93.43523273
0
_
_
_
Fitted Model
-93.62058567
2
0.37070588
2
0.830811
Reduced Model
-114.3093965
1
41.7483275
3
<0.0001
This document is a draft for review purposes only and does not constitute Agency policy.
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Methylene Chloride Benchmark Dose Report
Female Mice Lung (Bronchiolar-Alveolar Adenoma/Bronchiolar-Alveolar
Carcinoma) vs Lung GST (Aiso et al., 2014)
- Multistage (Restricted)
Degree 2 Model with BMR of 10% Extra Risk for the BMD and 0.95
0.7
0.6
0.5
-------
Methylene Chloride Benchmark Dose Report
8.3. Liver or Lung Tumor
Female Mouse Liver (Hepatocellular Adenoma/Carcinoma) (Aiso et al.,
2014)
Whole body GST dose
[N]
[Incidence]
0
50
2
47.79
49
8
103.2
49
9
220.4
50
30
Female Mouse Lung (Bronc
liolar-Alveo
al., 2014)
ar Adenoma/Carcinoma) (Aiso et
Whole body GST dose
[N]
[Incidence]
0
50
5
47.79
50
5
103.2
49
12
220.4
50
30
Summary of BMDS 3.1 Multi-tumor (MSCombo) Modeling Results for Female
Mouse Liver (Hepatocellular Adenoma/Carcinoma) and Lung (Bronchiolar-
Alveolar Adenoma/Carcinoma) vs. Whole Body GST Dose (Aiso et al., 2014)
Models*
Dataset
10% Extra Risk
Slope
P Value
AIC
BMDS Recommendation Notes
BMD
BMDL
Factor
Multi-tumor
(MS Combo)
Combined
Risk
44.90091
25.30172
3.95e-3
NA
NA
-
Multistage Degree 2
Liver Tumors
59.71416
32.3186
3.09e-3
0.139811
182.6181
Multistaee-cancer guidance (EPA 2014)
Multistage Degree 2
Lung Tumors
78.8968
46.73242
2.14e-3
0.843905
191.2181
Multistage-cancer guidance (EPA 2014)
*Multistage models used in the BMDS multi-tumor (MS Combo) model are restricted as described in the BMDS 3.1 User Guide. The selected Multistage model
was chosen from among all relevant model runs (see detailed results for all relevant Multistage degrees below) in accordance with EPA's technical guidance for
choosing the appropriate stage of a multistage model for cancer modeling.
This document is a draft for review purposes only and does not constitute Agency policy.
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Methylene Chloride Benchmark Dose Report
1
Selected Multistage plots for Female Mouse Liver (blue) and Lung
(orange) tumors vs. Whole Body GST (Aiso et al., 2014)
1
0.9
0.8
0.7
a) 0.6
tn
I 0.5
tn
(D
^ 0.4
0.3
0.2
0.1
0
50 100 150 200
Dose
-Frequentist Multistage Degree 2 Estimated Probability Frequentist Multistage Degree 2 Estimated Probability
Multi-tumor (MS Combo) Results for Female Mouse Liver (Hepatocellular
Adenoma/Carcinoma) and Lung (Bronchiolar-Alveolar Adenoma/Carcinoma) vs.
Whole Body GST Dose (Aiso et al., 2014)
User Input
Model Results
Info
Benchmark Dose
Model
Multi-tumor v 1.0
BMD
44.90090916
BMDL
25.30171599
Model Options
BMDU
62.0867887
Risk Type
Extra Risk
Slope Factor
0.003952301
BMR
0.1
Confidence
Level
0.95
Combined Log-Likelihood
-181.918071
Background
Estimated
Combined Log-Likelihood
Constant
165.8293306
This document is a draft for review purposes only and does not constitute Agency policy.
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Methylene Chloride Benchmark Dose Report
Female Mouse Liver (Hepatocellular Adenoma/Carcinoma) (Aiso et al., 2014) - Multistage 1
Restricted; Extra Risk, BMR = 0.1
User Input
Info
Options
Model Data
Model
Multistage degree 1 vl.O
Risk Type
Extra Risk
Dependent
Female Mouse Liver
BMR
0.1
Variable
Whole Body GST
Data set
(Hepatocellular
Adenoma/Care.) (Aiso et al.,
2014)
Independent
Variable
Name
Confidence
Level
0.95
[Tumor Incidence!
Total # of
Observation
Formula
P[dose] = g + (l-g)*[l-exp(-
bl*dose" 1)1
Background
Estimated
4
Model Results
Benchmark Dose
BMD
34.20378883
BMDL
26.32253773
BMDU
46.65003073
AIC
183.4415706
P-value
0.095541486
D.O.F.
2
Chi2
4.696389425
Slope Factor
0.003799026
Model Parameters
# of Parameters
2
Variable
Estimate
Background (g)
0.03310213
Betal
0.003080376
Goodness of Fit
Dose
Estimated
Probability
Expected
Observed
Size
Scaled
Residual
0
0.03310213
1.655106503
2
50
0.2726351
47.79
0.165459123
8.107497027
8
49
-0.041327
103.2
0.296408371
14.52401019
9
49
-1.728028
220.4
0.509621228
25.48106138
30
50
1.2783856
Analysis of Deviance
Model
Log Likelihood
# of Parameters
Deviance
Test d.f.
P Value
Full Model
-87.22399352
0
_
_
_
Fitted Model
-89.72078532
2
4.99358359
2
0.0823488
Reduced Model
-110.7896779
1
47.1313687
3
<0.0001
This document is a draft for review purposes only and does not constitute Agency policy.
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-------
Methylene Chloride Benchmark Dose Report
Female Mouse Liver (Hepatocellular Adenoma/ Carcinoma) (Aiso et
al., 2014) vs. Whole Body GST Dose - Multistage Degree 1 with BMR
of 10% Extra Risk for BMD and 0.95 Lower Confidence Limit for BMDL
0.7
0.6
0.5
„ 0.4
to
c
Q.
tn
^ 0.3
0.2
*
•
0.1
J*
0
0
50 100 150 200
Dose
-
Estimated Probability Response at BMD Linear Extrapolation
•
Data
BMD BMDL
This document is a draft for review purposes only and does not constitute Agency policy.
107
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Methylene Chloride Benchmark Dose Report
Female Mouse Liver (Hepatocellular Adenoma/Carcinoma) (Aiso et al., 2014) - Multistage 2
Restricted (Selected Multistage Degree); Extra Risk, BMR =0.1
Info
Model
Multistage degree 2 vl .0
Data set
Name
Female Mouse Liver
(Hepatocellular
Adenoma/Carcinoma) (Aiso
et al., 2014)
Formula
P[dose] = g + (l-g)*[l-
exp(-bl*doseAl-
b2*doseA2)l
Options
Risk Type
Extra Risk
BMR
0.1
Confidence
Level
0.95
Background
Estimated
Model Data
Dependent
Variable
Whole Body GST
Independent
Variable
[Tumor Incidencel
Total # of
Observation
4
Model Results
Benchmark Dose
BMD
59.71415711
BMDL
32.3186036
BMDU
91.9425009
AIC
182.6180846
P-value
0.139811174
D.O.F.
1
Chi2
2.18003619
Slope Factor
0.003094193
Model Parameters
# of Parameters
3
Variable
Estimate
Background (g)
0.047397565
Betal
0.001047255
Beta2
1.20099E-05
Goodness of Fit
Dose
Estimated
Probability
Expected
Observed
Size
Scaled
Residual
0
0.047397565
2.369878248
2
50
-0.246173
47.79
0.118416103
5.802389055
8
49
0.9716628
103.2
0.247641509
12.13443395
9
49
-1.037378
220.4
0.57800676
28.90033801
30
50
0.3148872
Analysis of Deviance
Model
Log Likelihood
# of Parameters
Deviance
Test d.f.
P Value
Full Model
-87.22399352
0
_
_
_
Fitted Model
-88.30904231
3
2.17009758
1
0.1407173
Reduced Model
-110.7896779
1
47.1313687
3
<0.0001
This document is a draft for review purposes only and does not constitute Agency policy.
108
DRAFT-DO NOT CITE OR QUOTE
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Methylene Chloride Benchmark Dose Report
Female Mouse Liver (Hepatocellular Adenoma/ Carcinoma) (Aiso et
al., 2014) vs. Whole Body GST Dose - Multistage Degree 2, BMR of
10% Extra Risk for BMD & 0.95 Lower Confidence Limit for BMDL
0.7
0.6
0.5
0.2
0.1
0
50
100
150
200
Dose
— — — Estimated Probability Response at BMD Linear Extrapolation
• Data BMD BMDL
This document is a draft for review purposes only and does not constitute Agency policy.
109
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Methylene Chloride Benchmark Dose Report
Female Mouse Lung (Bronchiolar-Alveolar Adenoma/Carcinoma) vs. Whole Body GST Dose
(Aiso et al., 2014) - Multistage 1 Restricted; Extra Risk, BMR = 0.1
Info
Model
Multistage degree 1 vl.O
Data set
Name
Female Lung (Bronchiolar-
Alveolar Adenoma/
Carcinoma) (Aiso et al.,
2014)
Formula
P[dose] = g + (l-g)*[l-
exp(-bl*doseAl)l
Options
Risk Type
Extra Risk
BMR
0.1
Confidence
Level
0.95
Background
Estimated
Model Data
Dependent
Variable
Whole Body GST
Independent
Variable
[Tumor Incidence!
Total # of
Observation
4
Model Results
Benchmark Dose
BMD
36.91414083
BMDL
27.77338153
BMDU
52.26999119
AIC
197.2451823
P-value
0.04932767
D.O.F.
2
Chi2
6.018540187
Slope Factor
0.00360057
Model Parameters
# of Parameters
2
Variable
Estimate
Background (g)
0.068115075
Betal
0.002854205
Goodness of Fit
Dose
Estimated
Probability
Expected
Observed
Size
Scaled
Residual
0
0.068115075
3.405753745
5
50
0.8948858
47.79
0.186938387
9.34691934
5
50
-1.576833
103.2
0.305872676
14.98776114
12
49
-0.926313
220.4
0.503222315
25.16111576
30
50
1.3686716
Analysis of Deviance
Model
Log Likelihood
# of Parameters
Deviance
Test d.f.
P Value
Full Model
-93.43523273
0
_
_
_
Fitted Model
-96.62259117
2
6.37471688
2
0.0412808
Reduced Model
-114.3093965
1
41.7483275
3
<0.0001
This document is a draft for review purposes only and does not constitute Agency policy.
110
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-------
Methylene Chloride Benchmark Dose Report
Female Mouse Lung (Bronchiolar-Alveolar Adenoma/ Carcinoma) (Aiso
et al., 2014) vs. Whole Body GST Dose - Multistage Degree 1, BMR of
10% Extra Risk for BMD and 0.95 Lower Confidence Limit for the BMDL
0.7
0.6
0.5
„ 0.4
to
C
o
tn
(D
^ 0.3
0.2
- -
•
0
50 100 150 200
Dose
•
Estimated Probability Response at BMD Linear Extrapolation
Data BMD BMDL
This document is a draft for review purposes only and does not constitute Agency policy.
Ill
DRAFT-DO NOT CITE OR QUOTE
-------
Methylene Chloride Benchmark Dose Report
Female Mouse Lung (Bronchiolar-Alveolar Adenoma/Carcinoma) vs. Whole Body GST Dose
(Aiso et al., 2014)- Multistage 2 Restricted (Selected Multistage Degree); Extra Risk, BMR =
0.1
User Input
Info
Model
Dataset Name
Formula
Multistage degree 2 vl .0
Female Mouse Lung
(Bronchiolar-Alveolar
Adenoma/Carcinoma) (Aiso et
al., 2014)
P[dose] = g + (l-g)*[l-exp(-
bl *doseAl-b2*doseA2)l
Options
Risk Type
Extra Risk
BMR
0.1
Confidence
Level
0.95
Background
Estimated
Model Data
Dependent
Variable
Whole Body GST
Independent
Variable
[Tumor Incidencel
Total # of
Observation
4
Model Results
Benchmark Dose
BMD
78.89679983
BMDL
46.73241659
BMDU
95.00278902
AIC
191.2180574
P-value
0.843905042
D.O.F.
2
Chi2
0.339430601
Slope Factor
0.002139842
Model Parameters
# of Parameters
3
Variable
Estimate
Background (g)
0.087158217
Betal
0
Beta2
1.69262E-05
Goodness of Fit
Dose
Estimated
Probability
Expected
Observed
Size
Scaled
Residual
0
0.087158217
4.357910841
5
50
0.3219277
47.79
0.12177298
6.088649008
5
50
-0.470787
103.2
0.237734723
11.64900141
12
49
0.1177899
220.4
0.598842769
29.94213844
30
50
0.0166952
Analysis of Deviance
Model
Log Likelihood
# of Parameters
Deviance
Test d.f.
P Value
Full Model
-93.43523273
0
_
_
_
Fitted Model
-93.6090287
2
0.34759193
2
0.8404684
Reduced Model
-114.3093965
1
41.7483275
3
<0.0001
This document is a draft for review purposes only and does not constitute Agency policy.
112
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Methylene Chloride Benchmark Dose Report
Female Mouse Lung (Bronchiolar-Alveolar Adenoma/Carcinoma)
(Aiso et al., 2014) vs. Whole Body GST Multistage Degree 2, BMR of
10% Extra Risk for BMD & 0.95 Lower Confidence Limit for BMDL
0.7
0.6
0.5
-------
Methylene Chloride Benchmark Dose Report
8.4. Lung Terminal Bronchiole Hyperplasia
Lung GST dose
TNI
[Incidence]
0
50
0
229.8
50
3
489.3
49
2
1038
50
9
Summary of BMDS 3.1 Modeling Results for Female Mouse Lung Terminal
Bronchiole Hyperplasia (Aiso et al., 2014)
Standard Models
Restriction*
10% Extra Risk
P Value
AIC
BMDS Recommends
BMDS Recommendation Notes
*
BMD
BMDL
Gamma
Restricted
614.95
408.09
0.41428
92.432770
Viable - Alternate
Log-Logistic
Restricted
608.82
390.73
0.41207
92.477298
Viable - Alternate
Multistage Degree 3*
Restricted
648.42
411.28
0.40258
92.32310
Selected, Full Model
Suite
Lowest AIC
Multistage Degree 2
Restricted
626.79
408.91
0.40391
92.402314
Viable - Alternate
Multistage Degree 1
(Quantal Linear)
Restricted
614.95
408.07
0.41428
92.432770
Viable - Alternate
Weibull
Restricted
614.95
408.09
0.41428
92.432770
Viable - Alternate
BMD/BMDL ratio > 20
Dichotomous Hill
LTnrestricted
608.83
2.9245
0.18299
94.477298
Questionable
BMD/BMDL ratio > 5
BMDL 3x lower than lowest non-zero dose
BMDL lOx lower than lowest non-zero dose
Logistic
NA
823.80
671.04
0.26255
93.711124
Viable - Alternate
BMD failed; lower limit includes zero
Log-Probit
LTnrestricted
993.19
0
0.08892
96.914737
LTnusable
BMDL not estimated
Goodness of fit p-value <0.1
Probit
NA
795.89
633.93
0.26182
93.617017
Viable - Alternate
Non-Standard
Models
Dichotomous Hill
Restricted
608.82
311.91
NA
96.477319
Questionable
d.f.=0 (Goodness of fit cannot be calculated)
Log-Probit
Restricted
993.16
530.81
0.08892
96.914737
Questionable
Goodness of fit p-value <0.1
Gamma
LTnrestricted
612.83
299.97
0.18934
94.425923
Viable - Alternate
BMD/BMDL ratio > 20
Log-Logistic
LTnrestricted
608.80
2.9409
0.41211
92.477298
Questionable
BMD/BMDL ratio > 5
BMDL 3x lower than lowest non-zero dose
BMDL lOx lower than lowest non-zero dose
Multistage Degree 3
LTnrestricted
924.27
127.43
NA
94.548029
Questionable
BMD/BMDL ratio > 5
d.f.=0 (Goodness of fit cannot be calculated)
Multistage Degree 2
LTnrestricted
626.78
342.90
0.40393
92.402314
Viable - Alternate
Multistage Degree 1
LTnrestricted
614.95
408.07
0.41428
92.432770
Viable - Alternate
Weibull
LTnrestricted
613.13
300.46
0.18795
94.429084
Viable - Alternate
* Selected, Full Model Suite (Green); residuals for doses 0, 229.8, 489.3, and 1038 were -0.000872639,1.012433378, -0.883101828, and 0.121805828, respectively.
**Restrictions defined in the BMDS 3.1 User Guide; NA = Not Applicable
This document is a draft for review purposes only and does not constitute Agency policy.
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Methylene Chloride Benchmark Dose Report
0.2
0.18
0.16
0.14
0.12
C
o
Q.
to
(D
CC
0.1
0.08
0.06
0.04
0.02
BMDS 3.1 Standard Model Plots for Female Mouse Lung Terminal
Bronchiole Hyperplasia (Aiso et al., 2014) vs Lung GST Dose
200
400
600
800
1000
Dose
¦Frequentist Gamma Estimated Probability
¦Frequentist Multistage Degree 3 Estimated Probability
¦Frequentist Multistage Degree 1 Estimated Probability
¦Frequentist Dichotomous Hill Estimated Probability
¦Frequentist Log-Probit Estimated Probability
¦Frequentist Log-Logistic Estimated Probability
Frequentist Multistage Degree 2 Estimated Probability
¦Frequentist Weibull Estimated Probability
¦Frequentist Logistic Estimated Probability
¦Frequentist Probit Estimated Probability
This document is a draft for review purposes only and does not constitute Agency policy.
11S
DRAFT-DO NOT CITE OR QUOTE
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Methylene Chloride Benchmark Dose Report
Selected, Full Model Suite - Multistage 3 Restricted; Extra Risk, BMR =0.1
User Input
Info
Model
Data set
Name
Formula
Multistage degree 3 vl.O
Female Mouse Lung
Terminal Bronchiole
Hyperplasia (Aiso et al..
2014) ^
P[dose] = g + (l-g)*[l-exp(-
bl*doseAl-b2*doseA2 -...)]
Options
Risk Type
Extra Risk
BMR
0.1
Confidence
Level
0.95
Background
Estimated
Model Data
Dependent
Variable
Lung GST Dose
Independent
Variable
[Tumor Incidence!
Total # of
Observation
4
Model Results
Benchmark Dose
BMD
648.4247437
BMDL
411.2842164
BMDU
1045.455128
AIC
92.32309959
P-value
0.40257905
D.O.F.
2
Chi2
1.819727605
Slope Factor
0.000243141
Model Parameters
# of Parameters
3
Variable
Estimate
Background (g)
1.523E-08
Betal
0.000149005
Beta2
0
Beta3
3.20643E-11
Goodness of Fit
Dose
Estimated
Probability
Expected
Observed
Size
Scaled
Residual
0
1.523E-08
7.61499E-07
0
50
-0.000873
229.8
0.034037766
1.701888321
3
50
1.0124334
489.3
0.073799454
3.616173253
2
49
-0.883102
1038
0.173477235
8.673861756
9
50
0.1218058
Analysis of Deviance
Model
Log Likelihood
# of Parameters
Deviance
Test d.f.
P Value
Full Model
Full Model
-43.27401353
0
_
_
Fitted Model
Fitted Model
-44.16154979
2
1.77507252
2
Reduced Model
Reduced Model
-50.65502987
1
14.7620327
3
This document is a draft for review purposes only and does not constitute Agency policy.
116
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Methylene Chloride Benchmark Dose Report
Female Mouse Lung Terminal Bronchiole Hyperplasia (Aiso et al., 2014)
vs Lung GST - Multistage (Restricted) Degree 3 Model with BMR of 10%
Extra Risk for BMD and 0.95 Lower Confidence Limit for the BMDL
0.2
0.18
0.16
0.14
0.12
0.08
0.06
0.04
0.02
0
200
400
600
800
1000
Dose
— — — Estimated Probability Response at BMD Linear Extrapolation
• Data BMD BMDL
This document is a draft for review purposes only and does not constitute Agency policy.
117
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Methylene Chloride Benchmark Dose Report
9. BMP Modeling for NTP (1986) Male Mice
9.1. Liver (Hepatocellular Carcinoma or Adenoma)
Liver GST dose
TNI
[Incidence]
0
50
22
2364.7
47
24
4973.5
47
33
Summary of BMDS 3.1 Modeling Results for Male Mouse Liver (Hepatocellular
Carcinoma or Adenoma) (NTP, 1986)
Standard Models
Restriction**
10% Extra Risk
P Value
AIC
BMDS Recommends
BMDS Recommendation Notes
*
BMD
BMDL
Gamma
Restricted
2119.2
577.84
NA
196.97831
Questionable
BMDL 3x lower than lowest non-zero dose
d.f.=Q (Goodness of fit cannot be calculated)
Log-Logistic
Restricted
2123.4
448.45
NA
196.97831
Questionable
BMDL 3x lower than lowest non-zero dose
d.f.=Q (Goodness of fit cannot be calculated)
Multistage Degree 1
(Quantal Linear)*
Restricted
914.22
544.51
0.40410
195.67397
Selected, Multistage
Multistase-cancer guidance (EPA. 2014)
BMDL 3x lower than lowest non-zero dose
Weibull
Restricted
2099.0
577.83
NA
196.97831
Questionable
BMDL 3x lower than lowest non-zero dose
d.f.=Q (Goodness of fit cannot be calculated)
Dichotomous Hill
LTnrestricted
2123.4
25.248
65535
198.97831
Questionable
BMD/BMDL ratio > 20
BMD/BMDL ratio > 5
BMDL lOx lower than lowest non-zero dose
Logistic
NA
1069.2
733.73
0.50852
195.41475
Viable
- Alternate
BMDL 3x lower than lowest non-zero dose
Log-Probit
LTnrestricted
4386.7
0.2925
NA
197.46348
Questionable
BMD/BMDL ratio > 20
BMD/BMDL ratio > 5
BMDL 1 Ox lower than lowest non-zero dose
d.f.=0 (Goodness of fit cannot be calculated)
Probit**
NA
1072.4
740.82
0.51449
195.40253
Selectet
, Full Model
Suite
Lowest AIC
BMDL 3x lower than lowest non-zero dose
Non-Standard
Models
Dichotomous Hill
Restricted
2123.9
448.45
65535
198.97831
Viable
- Alternate
BMDL 3x lower than lowest non-zero dose
Log-Probit
Restricted
4222.0
985.19
NA
197.46348
Questionable
d.f.=0 (Goodness of fit cannot be calculated)
Gamma
LTnrestricted
2123.4
25.248
65535
198.97831
Questionable
BMD/BMDL ratio > 20
BMD/BMDL ratio > 5
BMDL lOx lower than lowest non-zero dose
Log-Logistic
LTnrestricted
2121.9
9.4046
NA
196.97831
Questionable
BMD/BMDL ratio > 20
BMD/BMDL ratio > 5
BMDL 1 Ox lower than lowest non-zero dose
d.f.=0 (Goodness of fit cannot be calculated)
Multistage Degree 3
LTnrestricted
2123.4
25.248
NA
196.97831
Questionable
BMD/BMDL ratio > 20
BMD/BMDL ratio > 5
BMDL lOx lower than lowest non-zero dose
d.f=0 (Goodness of fit cannot be calculated)
Multistage Degree 2
LTnrestricted
2105.0
436.56
NA
196.97831
Questionable
BMDL 3x lower than lowest non-zero dose
d.f.=0 (Goodness of fit cannot be calculated)
Multistage Degree 1
LTnrestricted
914.24
544.51
0.40410
195.67397
Viable - Recommended
BMDL 3x lower than lowest non-zero dose
Lowest AIC
Weibull
LTnrestricted
2099.8
16.210
NA
196.97831
Questionable
BMD/BMDL ratio > 20
BMD/BMDL ratio > 5
BMDL 1 Ox lower than lowest non-zero dose
d.f.=0 (Goodness of fit cannot be calculated)
*Selected, Multistage (Yellow); residuals for doses 0, 2364.7, and 4973.5 were 0.261074977, -0.677561922 and 0.410919726, respectively.
*Selected, Full Model Suite (Green); residuals for doses 0, 2364.7, and 4973.5 were 0.261074977, -0.677561922 and 0.410919726, respectively.
***Restrictions defined in the BMDS 3.1 User Guide; CF = Computation failed; NA = Not Applicable
This document is a draft for review purposes only and does not constitute Agency policy.
118
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Methylene Chloride Benchmark Dose Report
BMDS 3.1 Standard Model Plots for Male Mouse Liver (Hepatocellular
Carcinoma or Adenoma) (NTP, 1986) vs Liver GST Dose
0.8
0.7
0.6
0.5
I 0.4
LO
CD
DC
0.3
0.2
0.1
500
1000
1500
2000
2500
Dose
3000
3500
4000
4500
¦Frequentist Gamma Estimated Probability
¦Frequentist Multistage Degree 2 Estimated Probability
¦Frequentist Weibull Estimated Probability
¦Frequentist Logistic Estimated Probability
¦Frequentist Probit Estimated Probability
¦Frequentist Log-Logistic Estimated Probability
Frequentist Multistage Degree 1 Estimated Probability
¦Frequentist Dichotomous Hill Estimated Probability
¦Frequentist Log-Probit Estimated Probability
This document is a draft for review purposes only and does not constitute Agency policy.
119
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Methylene Chloride Benchmark Dose Report
Selected, Multistage - Multistage 1 Restricted; Extra Risk, BMR =0.1
Info
Options
Model Data
Model
Multistage degree 1 vl.O
Risk Type
Extra Risk
Dependent
Variable
Liver GST Dose
Data set
Name
Male Mouse Liver
(Hepatocellular Carcinoma
or Adenoma) (NTP, 1986)
BMR
0.1
Independent
Variable
[Tumor Incidence!
Confidence
0 95
Formula
P[dose] = g + (l-g)*[l-exp(-
bl*dose"l)l
Background
Estimated
Total # of
Observation
4
Model Results
Benchmark Dose
BMD
914.2177942
BMDL
544.5121572
BMDU
2570.728336
AIC
195.673967
P-value
0.404095465
D.O.F.
1
Chi2
0.696105323
Slope Factor
0.000183651
Model Parameters
# of Parameters
2
Variable
Estimate
Background (g)
0.421766589
Betal
0.000115247
Goodness of Fit
Dose
Estimated
Probability
Expected
Observed
Size
Scaled
Residual
0.421766589
0.421766589
0.421766589
0.421766589
0.421766589
0.421766589
0.000115247
0.000115247
0.000115247
0.000115247
0.000115247
0.000115247
0.421766589
0.421766589
0.421766589
0.421766589
0.421766589
0.421766589
Analysis of Deviance
Model
Log Likelihood
# of Parameters
Deviance
Test d.f.
P Value
Full Model
-95.48915354
0
_
_
_
Fitted Model
-95.83698349
2
0.69565991
1
0.4042459
Reduced Model
-99.13156225
1
7.28481743
2
0.0261892
This document is a draft for review purposes only and does not constitute Agency policy.
120
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Methylene Chloride Benchmark Dose Report
Male Mouse Liver (Hepatocellular Carcinoma or Adenoma) (NTP,
1986) vs Liver GST - Multistage (Restricted) Degree 1 Model, BMR of
0.8
0.7
10% Extra Risk for BMD and 0.95 Lower Confidence Limit for BMDL
0
o o
In CD
*
•
3 «
° 0.4
to
(D
Ctl
poo
j-i k) w
0
0 500 1000 1500 2000 2500 3000 3500 4000 4500
Dose
» —— Estimated Probability^^—
— Response at BMD
Linear Extrapolation
• Data
-BMD
BMDL
This document is a draft for review purposes only and does not constitute Agency policy.
121
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Methylene Chloride Benchmark Dose Report
Selected, Full Model Suite - Probit - Extra Risk, BMR =0.1
Info
Options
Model Data
Model
Log-Probit vl .0
Risk Type
Extra Risk
Dependent
Variable
Liver GST Dose
Data set
Name
Male Mouse Liver
(Hepatocellular Carcinoma
or Adenoma) (NTP, 1986)
BMR
0.1
Independent
Variable
[Tumor Incidence!
Confidence
0 95
Formula
P[dose] =
CumNorm(a+b*Dose)
Background
Estimated
Total # of
Observation
4
Model Results
Benchmark Dose
BMD
1072.373626
BMDL
740.8220139
BMDU
2495.283352
AIC
195.4025344
P-value
0.514485175
D.O.F.
1
Chi2
0.424934224
Model Parameters
# of Parameters
2
Variable
Estimate
a
-0.199206894
b
0.000136525
Goodness of Fit
Dose
Estimated
Probability
Expected
Observed
Size
Scaled
Residual
0
0.421050453
21.05252267
22
50
0.2713916
2364.7
0.549197834
25.81229819
24
47
-0.53128
4973.5
0.684316129
32.16285808
33
47
0.2627215
Analysis of Deviance
Model
Log Likelihood
# of Parameters
Deviance
Test d.f.
P Value
Full Model
Full Model
-95.48915354
0
_
_
Fitted Model
Fitted Model
-95.70126721
2
0.42422735
1
Reduced Model
Reduced Model
-99.13156225
1
7.28481743
2
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0.8
0.7
0.6
0.5
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Methylene Chloride Benchmark Dose Report
9.2. Lung (Bronchoalveolar Carcinoma or Adenoma)
Lung GST dose
TNI
[Incidence]
0
50
5
475.1
47
27
992.4
47
40
Summary of BMDS 3.1 Modeling Results for Male Mouse Lung (NTP, 1986)
Standard Models
Restriction**
10% Extra Risk
P Value
AIC
BMDS Recommends
BMDS Recommendation Notes
BMD
BMDL
Gamma
Restricted
101.13
49.110
NA
142.17847
Questionable
BMD 3x lower than lowest non-zero dose
BMDL 3x lower than lowest non-zero dose
d.f.=0 (Goodness of fit cannot be calculated)
Log-Logistic
Restricted
154.16
29.332
NA
142.17847
Questionable
BMD/BMDL ratio > 5
BMD 3x lower than lowest non-zero dose
BMDL lOx lower than lowest non-zero dose
d.f. =0 (Goodness of fit cannot be calculated)
Multistage Degree 1
(Quantal Linear)*
Restricted
61.674
48.646
0.64077
140.39807
Selected, Multistage and
Full Model Suite
Lowest AIC
BMD 3x lower than lowest non-zero dose
BMDL 3x lower than lowest non-zero dose
Multistage-cancer guidance ("EPA. 2014"):
Weibull
Restricted
91.325
49.103
NA
142.17847
Questionable
BMD 3x lower than lowest non-zero dose
BMDL 3x lower than lowest non-zero dose
d.f =0 (Goodness of fit cannot be calculated)
Dichotomous Hill
LTnrestricted
154.15
25.047
65535
144.17847
Questionable
BMD/BMDL ratio > 5
BMD 3x lower than lowest non-zero dose
BMDL lOx lower than lowest non-zero dose
Logistic
NA
152.67
121.58
0.15323
142.22560
Viable - Alternate
BMD 3x lower than lowest non-zero dose
BMDL 3x lower than lowest non-zero dose
BMD/BMDL ratio > 5
Log-Probit**
LTnrestricted
158.14
26 644
NA
142.17847
BMD 3x lower than lowest non-zero dose
BMDL 1 Ox lower than lowest non-zero dose
d.f =0 (Goodness of fit cannot be calculated)
Probit
NA
146.25
119.58
0.14797
142.2822
Viable - Alternate
BMD 3x lower than lowest non-zero dose
BMDL 3x lower than lowest non-zero dose
Non-Standard Models
Dichotomous Hill
Restricted
159.31
29.331
65535
144.17847
Questionable
BMD/BMDL ratio > 5
BMDL lOx lower than lowest non-zero dose
Log-Probit
Restricted
158.17
90.029
NA
142.17847
Questionable
BMD 3x lower than lowest non-zero dose
BMDL 3x lower than lowest non-zero dose
d.f.=0 (Goodness of fit test cannot be calculated)
Gamma
LTnrestricted
101.15
2.3408
NA
142.17847
Questionable
BMD/BMDL ratio > 20
BMD/BMDL ratio > 5
BMD 3x lower than lowest non-zero dose
BMDL lOx lower than lowest non-zero dose
d.f.=0 (Goodness of fit test cannot be calculated)
Log-Logistic
LTnrestricted
154.16
25.049
NA
142.17847
Questionable
BMD/BMDL ratio > 5
BMD 3x lower than lowest non-zero dose
BMDL lOx lower than lowest non-zero dose
d.f.=0 (Goodness of fit test cannot be calculated)
Multistage Degree 2
LTnrestricted
75.555
39.224
NA
142.17847
Questionable
BMD 3x lower than lowest non-zero dose
BMDL lOx lower than lowest non-zero dose
d.f.=0 (Goodness of fit test cannot be calculated)
Multistage Degree 1
LTnrestricted
61.674
48.647
0.64077
140.39807
Viable - Alternate
BMD 3x lower than lowest non-zero dose
BMDL 3x lower than lowest non-zero dose
Lowest AIC
Weibull
LTnrestricted
91.325
7.3553
NA
142.17847
Questionable
BMD/BMDL ratio > 5
BMD 3x lower than lowest non-zero dose
BMDL lOx lower than lowest non-zero dose
d.f.=0 (Goodness of fit test cannot be calculated)
*Selected, Multistage & Selected, Full Model Suite (Green); residuals for doses 0, 475.1 and 992.4 were 0.047491478, -0.348706833 and 0.306410218, respectively.
**Restrictions defined in the BMDS 3.1 User Guide; CF = Computation failed; NA = Not Applicable
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BMDS 3.1 Standard Model Plots for Male Mouse Lung
(Bronchoalveolar Carcinoma or Adenoma) (NTP, 1986) vs Lung GST
Dose
0.9
0.8
0.7
0.6
I 0.5
LO
CD
DC
0.4
0.3
0.2
0.1
100
200
300
400
500
Dose
600
700
800
900
¦Frequentist Dichotomous Hill Estimated Probability
¦Frequentist Gamma Estimated Probability
¦Frequentist Multistage Degree 2 Estimated Probability -
¦ Frequentist Weibull Estimated Probability
¦Frequentist Log-Probit Estimated Probability
Frequentist Log-Logistic Estimated Probability
¦Frequentist Multistage Degree 1 Estimated Probability
This document is a draft for review purposes only and does not constitute Agency policy.
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Selected, Multistage and Selected, Full Model Suite - Multistage 1 Restricted; Extra Risk, BMR
= 0.1
User Input
Info
Model
Data set
Name
Formula
Multistage degree 1 vl.O
Male Mouse Lung
(Bronchoalveolar
Carcinoma or Adenoma)
(NTP, 1986)
P[dose] = g + (l-g)*[l-exp(-
bl*dose"l)l
Options
Risk Type
Extra Risk
BMR
0.1
Confidence
Level
0.95
Background
Estimated
Model Data
Dependent
Variable
Lung GST Dose
Independent
Variable
[Tumor Incidence!
Total # of
Observation
4
Model Results
Benchmark Dose
BMD
61.67444792
BMDL
48.64640298
BMDU
80.22384093
AIC
140.3980736
P-value
0.640768023
D.O.F.
1
Chi2
0.217739118
Slope Factor
0.00205565
Model Parameters
# of Parameters
2
Variable
Estimate
Background (g)
0.098003115
Betal
0.001708333
Goodness of Fit
Dose
Estimated
Probability
Expected
Observed
Size
Scaled
Residual
0
0.098003115
4.90015573
5
50
0.0474915
475.1
0.599392599
28.17145216
27
47
-0.348707
992.4
0.83445202
39.21924495
40
47
0.3064102
Analysis of Deviance
Model
Log Likelihood
# of Parameters
Deviance
Test d.f.
P Value
Full Model
-68.08923317
0
_
_
_
Fitted Model
-68.19903682
2
0.21960731
1
0.6393393
Reduced Model
-99.813194
1
63.4479217
2
<0.0001
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Male Mouse Lung (Bronchoalveolar Carcinoma or Adenoma) (Aiso,
2014) vs Lung GST - Multistage (Restricted) Degree 1, BMR of 10%
Extra Risk for BMD and 0.95 Lower Confidence Limit for BMDL
0.9
0.8
0.7
0.6
(D
tn
I 0.5
to
(D
al
0.4
0.3
0.2
A
o.i m
0 100 200 300 400 500
Dose
600 700 800 900
— — Estimated Probability
• Data
• Response at BMD
BMD
• Linear Extrapolation
«BMDL
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9.3. Liver or Lung Tumor
Male Mouse Liver (Hepatocellular Carcinoma or Adenoma) (NTP, 1986)
Whole body GST dose
[N]
[Incidence]
0
50
22
100.2
47
24
210.7
47
33
Male Mouse Lung (Bronchoalveolar Carcinoma or Adenoma) (NTP, 1986)
Whole body GST dose
[N]
[Incidence]
0
50
5
100.2
47
27
210.7
47
40
Summary of BMDS 3.1 Multi-tumor (MSCombo) Modeling Results for Male
Mouse Liver (Hepatocellular Carcinoma or Adenoma) and Male Mouse Lung
(Bronchoalveolar Carcinoma or Adenoma) (NTP, 1986) vs Whole Body GST Dose
Models*
Dataset
10% Extra Risk
BMD
BMDL
Slope
Factor
P Value
AIC
BMDS Recommendation Notes
Multi-tumor
(MS Combo)
Combined
Risk
9.764454
7.752931
4.66e-2
NA
NA
NA
Multistage Degree 1
Liver Tumor
38.73476
23.06951
1.93e-3
0.403940
195.6744
Multistage-cancer guidance (EPA. 20141
BMDL 3x lower than lowest non-zero dose
Multistage Degree 1
Lung Tumor
13.05575
10.29661
9.71e-3
0.656862
140.3774
Multistage-cancer guidance (EPA. 20141
BMD 3x lower than lowest non-zero dose
BMDL 3x lower than lowest non-zero dose
*Multistage models used in the BMDS multi-tumor (MS Combo) model are restricted as described in the BMDS 3.1 User Guide. The selected Multistage model
was chosen from among all relevant model runs (see detailed results for all relevant Multistage degrees below) in accordance with EPA's technical guidance for
choosing the appropriate stage of a multistage model for cancer modeling.
This document is a draft for review purposes only and does not constitute Agency policy.
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Selected Multistage model plots for liver (blue) and lung (orange)
tumors vs whole body GST in male mice that inhaled methylene
chloride in NTP (1986) 2-year study
0.9
0.7
0.5
ce 0.4
0.3
0.2
0.1
0
50
100
150
200
Dose
Frequentist Multistage Degree 1 Estimated Probability Frequentist Multistage Degree 1 Estimated Probability
Multi-tumor (MS Combo) Results for Male Mouse Liver (Hepatocellular
Carcinoma or Adenoma) and Male Mouse Lung (Bronchoalveolar Carcinoma or
Adenoma) (NTP, 1986) vs Whole Body GST Dose
User Input
Model Results
Info
Benchmark Dose
Model
Multi-tumor v 1.0
BMD
9.764453771
BMDL
7.752931464
Model Options
BMDU
12.85165147
Risk Type
Extra Risk
Slope Factor
0.012898347
BMR
0.1
Confidence
Level
0.95
Combined Log-Likelihood
-164.0259348
Background
Estimated
Combined Log-Likelihood
Constant
151.5180253
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Male Mouse Liver (Hepatocellular Carcinoma or Adenoma) - Multistage 1 Restricted (Selected
Multistage Degree); Extra Risk, BMR = 0.1
User Input
Info
Options
Model Data
Model
Multistage degree 1 vl.O
Risk Type
Extra Risk
Dependent
Whnlp Rnrlv flST
Data set
Name
Male Mouse Liver
(Hepatocellular Carcinoma or
Adenoma) (NTP. 1986)
BMR
Confidence
Level
Background
0.1
0.95
Estimated
Independent
Variable
[Tumor Incidence!
Formula
P[dose] = g + (l-g)*[l-exp(-
bl*dose" 1)1
Total # of
Observation
4
Model Results
Benchmark Dose
BMD
38.7347609
BMDL
23.06950774
BMDU
108.9198654
AIC
195.6744286
P-value
0.403939629
D.O.F.
1
Chi2
0.696567039
Slope Factor
0.004334726
Model Parameters
# of Parameters
2
Variable
Estimate
Background (g)
0.421778128
Betal
0.002720051
Goodness of Fit
Dose
Estimated
Probability
Expected
Observed
Size
Scaled
Residual
0
0.421778128
21.0889064
22
50
0.2609088
100.2
0.55972102
26.30688795
24
47
-0.677841
210.7
0.67401774
31.67883378
33
47
0.4111269
Analysis of Deviance
Model
Log Likelihood
# of Parameters
Deviance
Test d.f.
P Value
Full Model
-95.48915354
0
_
_
_
Fitted Model
-95.83721432
2
0.69612157
1
0.40409
Reduced Model
-99.13156225
1
7.28481743
2
0.0261892
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Male Mouse Liver (Hepatocellular Carcinoma or Adenoma) (NTP, 1986)
vs Whole Body GST - Multistage Degree 1 Model with BMR of 10% Extra
Risk for the BMD and 0.95 Lower Confidence Limit for the BMDL
0.9
0.8
0.7
0.6
m
LO
I 0.5
•
I
1
I
1
\
1
1
1
I
*
\
\ w
1
I
1
t
t
1
1
1
1
\
——
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Methylene Chloride Benchmark Dose Report
Male Mouse Lung (Bronchoalveolar Carcinoma or Adenoma) (NTP, 1986) - Multistage 1
Restricted (Selected Multistage Degree); Extra Risk, BMR =0.1
Info
Model
Multistage degree 1 vl.O
Data set
Name
Male Mouse Male Mouse
Lung (Bronchoalveolar
Carcinoma or Adenoma)
(NTP, 1986)
Formula
P[dose] = g + (l-g)*[l-
exp(-bl*doseAl)l
Options
Risk Type
Extra Risk
BMR
0.1
Confidence
Level
0.95
Background
Estimated
Model Data
Dependent
Variable
Whole Body GST Dose
Independent
Variable
[Tumor Incidencel
Total # of
Observation
4
Model Results
Benchmark Dose
BMD
13.05575031
BMDL
10.29661058
BMDU
16.98527498
AIC
140.377441
P-value
0.656861654
D.O.F.
1
Chi2
0.197358299
Slope Factor
0.009711934
Model Parameters
# of Parameters
2
Variable
Estimate
Background (g)
0.098079248
Betal
0.008070047
Goodness of Fit
Dose
Estimated
Probability
Expected
Observed
Size
Scaled
Residual
0
0.098079248
4.90396242
5
50
0.045665
100.2
0.598218676
28.11627777
27
47
-0.332123
210.7
0.835293055
39.2587736
40
47
0.2914919
Analysis of Deviance
Model
Log Likelihood
# of Parameters
Deviance
Test d.f.
P Value
Full Model
-68.08923317
0
_
_
_
Fitted Model
-68.18872052
2
0.1989747
1
0.6555497
Reduced Model
-99.813194
1
63.4479217
2
<0.0001
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Male Mouse Lung (Bronchoalveolar Carcinoma or Adenoma) (NTP, 1986)
vs Whole Body GST- Multistage Degree 1 Model with BMR of 10% Extra
Risk for the BMD and 0.95 Lower Confidence Limit for the BMDL
0.9
0.8
0.7
0.6
I 0.5
to
O)
c£
7^
0.4
0.3
0.2
70
o.i m
50
100
Dose
150
200
— — Estimated Probability"
• Data
• Response at BMD
BMD
«Linear Extrapolation
¦ BMDL
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Appendix A: OCSPP Request to ORD NCEA
Request for ORD to
1) run PBPK and BMD models to estimate cancer risk for methylene chloride from Aiso et al (2014), and
2) run PBPK/dichotomous BMD models for the previous inhalation cancer study (NTP, 1986) with the endpoints
from the IRIS assessment
• Use mouse, rat and human PBPK models described in the Toxicological Review of Methylene Chloride
(EPA, 2011) to model dose-response (Andersen et al., 1991; Marino et al., 2006; David et al., 2006) with
any additions of data/parameters used for the models as used in the IRIS Assessment.
• Use the same internal dose metrics as in the Toxicological Review of Methylene Chloride (EPA, 2011).
NTP, 1986 and Aiso 2014 used the same exposure concentration groups (0, 1000, 2000, 4000 ppm in rats
and mice) except NTP 1986 did not have a mice 1000 ppm group. The internal dose metrics were:
o mammary gland tumors used AUC in slowly perfused tissue
o liver tumors used mg DCM metabolized via GST pathway / L liver tissues / day
o lung tumors used mg DCM metabolized vis GST pathway /L lung tissue /day and
o lung and liver tissues used the sum of dichloromethane metabolized via the GST pathway in the
lung plus the liver, normalized to total BW (i.e., [lung GST metabolism (mg/day) + liver GST
metabolism (mg/d)]/kg BW). Units = mg dichloromethane metabolized via GST pathway in lung
and liver/kg-day.
o For non-cancer endpoints (foci), use the rat PBPK model that was used for the RfC in the 2011
IRIS assessment if that is relevant - this was the CYP only model (or if fits to the new non-
cancer data from Aiso are warranted, please feel free to determine which model works best with
the data).
• Aiso et al. (2014): See Table 1 for endpoints and incidence data and Appendix B for reasons certain
endpoints were not chosen.
o CANCER
Endpoints chosen: Preference for positive trend test, significant pairwise differences from
controls, clearest dose-response data of tumors evaluated
o NONCANCER - Pre-Neoplastic Lesions - Foci and Hyperplasia
Endpoints chosen: Preference for increasing d-r or d-r that may have plateaued and sig. pairwise
comparisons, [no trend tests seem to be conducted for these lesions]
• NTP (1986): See Table 2 for endpoints and incidence data
o CANCER
Endpoints chosen: Same as IRIS Assessment
• Run all dichotomous models (including multistage) available with the BMDS (don't run Bayesian model
averaging)
• Use 10% BMR - cancer and non-cancer
o Justification: As stated in the 2011 IRIS assessment (and based on the 2012 BMD technical
guidance) "A BMR of 10% was selected because, in the absence of information regarding the
magnitude of change in a response that is thought to be minimally biologically significant, a
BMR of 10% is generally recommended, as it provides a consistent basis of comparison
across assessments."
This document is a draft for review purposes only and does not constitute Agency policy.
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• For both mice and rats for the cancer endpoints and hyperplasia, model cancer risk for the full population
(including GST+/+, GST+/-, GST-/-). You can present the information also for GST +/+ only individuals.
Table 1: Tumor or Foci Incidence from Aiso et al., 2014
Concentration (ppm)
0
1000
2000
4000
0
1000
2000
4000
Ref.
Number of animals examined
50
50
50
50
50
50
50
50
Rata
Males
Females
Tumors
Subcutis
Combined:
fibroma/fibrosarcoma
1
4
8
12
-
-
-
-
Table 2,
p440
Mammary
gland
Combined:
Fibroadenoma/
adenomac
2
2
3
8
-
-
-
-
Combined:
fibroadenoma/
3
2
3
7
9
10
14
adenoma/
adenocarci
6
noma
Non-Neoplastic Foci
Acidophilic Cell Foci
-
-
-
-
3
8
14
23
Table 3,
p442
Basophilic Cell Foci
-
-
-
-
18
37
40
36
Miceb
Males
Females
Tumors
Lung
Combined: bronchiolar-
alveolar adenoma/
bronchiolar-alveolar
carcinoma
8
17
26
42
5
5
12
30
Table 5,
p444
Liver
Combined: hepatocellular
adenoma/hepatocellular
carcinoma
15
20
25
29
2
8
9
30
Hyperplasia
Number of animals examined
50
50
50
50
50
50
49
50
Table 6,
p445
Terminal bronchiole
0
1
5
13
0
3
2
9
a For rats, the same concentrations are used in this study as the NTP study
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b For mice, there is an extra concentration (1000 ppm) not used in the NTP study
0 Males only were run because the dose-response fit might be better than the combined
fibroadenoma/adenoma/adenocarcinoma even though preference was given to including adenocarcinomas, because all are
considered adverse
Table 2: Male Mouse Tumor Incidence8 from NTP, 1986 (Appendix G.2 in IRIS Assessment)
Concentration (ppm)
0
2000
4000
Number of Animals Examined
50
47
47
Lung
Bronchoalveolar
carcinoma or adenoma
5
27
40
Liver
Hepatocellular carcinoma
or adenoma
22
24
33
a Note that the 2011 IRIS assessment presented an IUR for combined lung and liver tumors
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Appendix B: OCSPP Justification for Endpoints Not
Chosen
The following are tumor types/endpoints for each species that showed positive trend tests but that were not chosen
for modeling from Aiso et al., 2014 for various reasons (e.g., no clear dose-response when looking at incidences
or no pairwise differences compared with controls for individual concentration levels). The species and tumors
types or endpoints that were not modeled and associated reasons are as follows:
s
o Rats
Liver (males)
o Combined hepatocellular adenoma/carcinoma - Unclear dose-response relationship (incidences of
1, 0, 2 and 3 at 0, 1000, 2000 and 4000 ppm, respectively). These showed no statistically
significant pairwise comparisons, and incidences were small.
Uterus (females)
o Endometrial stromal polyps - Unclear dose-response relationship (incidences of 8, 11,6 and 9 at
0, 1000, 2000 and 4000 ppm, respectively), no statistically significant pairwise comparisons
o Combined: endometrial stromal sarcoma, leiomyosarcoma - no statistically significant pairwise
comparisons, tumor incidence difficult to model (incidences of 0, 0, 0 and 3 at 0, 1000, 2000 and
4000 ppm, respectively)
Spleen (females)
o Mononuclear cell leukemia - no statistically significant pairwise comparison at the highest
concentration and the dose-response relationship is not completely clear (incidences of 2, 4, 8 and
7 at 0, 1000, 2000 and 4000 ppm, respectively)
o However, given some association with leukemia in humans, future modeling efforts could include
this tumor type.
Peritoneum (males)
o Mesothelioma - no statistically significant pairwise comparisons, and the dose-response
relationship is not completely clear (incidences of 3, 1, 0 and 7 at 0, 1000, 2000 and 4000 ppm,
respectively)
Subcutis (males)
o Fibroma - not run because preference was given to modeling combined fibroma/fibrosarcoma,
assuming benign tumors may lead to malignant tumors
Mammary gland
o Fibroadenoma (males/females) and combined fibroadenoma/adenoma (females) - not run
because preference was given to modeling combined fibroadenoma/adenoma/adenocarcinoma
because all were assumed to be relevant for cancer. Note; this was also run to compare the trend
with the same combination of tumors from NTP (1986) as modeled in the IRIS assessment, which
evaluated combined tumors; see also footnote to Table 1 of Appendix A in this document.
Acidophilic and basophilic cell foci (males)
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Methylene Chloride Benchmark Dose Report
Dose-response relationship not clear (22, 31, 33, 24 for acidophilic; 13, 36, 21,18 for basophilic)
Bronchiolar-alveolar adenoma and bronchiolar-alveolar carcinoma (males/females) -dose
response curves (separated by tumor type) not considered because it was assumed that benign
tumors may lead to malignant tumors and therefore, combined tumors were considered more
relevant; also didn't include adenosquamous carcinomas because incidence didn't differ when
adding it to other tumor types for females and data were not available for males
Hepatocellular adenoma and hepatocellular carcinoma (males/females) - dose response curves
(separated by tumor type) not considered because it was assumed that benign tumors may lead to
malignant tumors and the combined was therefore considered more relevant; also
hepatoblastomas not added because incidence didn't differ when adding it to other tumor types
for males and data were not available for females
Hemangioma (males) - dose-response not clear and incidence smaller than other liver tumors
Combined hemangioma/hemangiosarcoma (males/females) - no sig. pairwise comparisons,
smaller incidence than other tumors in liver, females had less clear dose-response than for other
tumors
Adrenal gland
o Pheochromocytoma (males) - no statistically significant pairwise comparisons and the dose-
response relationship is not clear (incidences of 1, 0, 1 and 3 at 0, 1000, 2000 and 4000 ppm,
respectively)
All site
o Hemangiomas (males) - The dose-response relationship is not as positive as other tumor types;
However, because there is a significant pairwise change at the highest dose, and the trend is
significant at p < 0.01, EPA can consider running this later if needed.
Hyperplasia
o Bronchiolar-alveolar, alveolar duct (males/females) - no statistical significant pairwise
comparisons
Liver foci
o No statistically significant pairwise comparisons and generally no clear dose-response
Mice
Lung
Liver
o
o
o
This document is a draft for review purposes only and does not constitute Agency policy.
138 DRAFT-DO NOT CITE OR QUOTE
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Methylene Chloride Benchmark Dose Report
Appendix C. Model Selection Considerations for POD Computation
The following approach is recommended for selecting the model(s) to use for computing the BMDL to
serve as the POD for a specific dataset according to EPA Benchmark Dose Guidance (U.S. EPA. 2012a). Some
of these decisions are best performed by or in collaboration with experts in the statistical procedures and potential
pitfalls of this type of analysis.
1) Assess goodness-of-fit, using a value of a > 0.1 to determine a critical value (or a = 0.05 or a = 0.01
if there is reason to use a specific model(s)) rather than fitting a suite of models.
2) Further reject models that apparently do not adequately describe the relevant low-dose portion
of the dose-response relationship, which can be determined by examining residuals and graphs
of the models and data.
3) Because the remaining models have met the recommended default statistical criteria for
adequacy and visually fit the data, any of them theoretically could be used for determining the
BMDL. Criteria 4-6 below, for selecting the BMDL from these remaining models, are
necessarily somewhat arbitrary and are suggested as defaults.
4) If the BMDL estimates from the remaining models are sufficiently close (given the needs of the
assessment) and reflect no particular influence of individual models, then the model with the lowest
AIC may be used to calculate the BMDL for the POD. This criterion is intended to help arrive at a
single BMDL value in an objective, reproducible manner. If two or more models share the lowest
AIC, the simple average or geometric mean of the BMDLs with the lowest AIC may be used. Note
that this is not the same as "model averaging," which involves weighing a fuller set of adequately
fitting models. In addition, such an average has drawbacks, including the fact that it is not a 95%
lower bound on the average BMD; it is just the average of the particular BMDLs under
consideration (i.e., the average loses the statistical properties of the individual estimates).
5) If the BMDL estimates from the remaining models are not sufficiently close, some model
dependence of the estimate can be assumed. Expert statistical judgment may help at this
point to judge whether model uncertainty is too great to rely on some or all of the results.
If the range of results is judged to be reasonable, there is no clear remaining biological or
statistical basis on which to choose among them, and the lowest BMDL may be selected
as a reasonable conservative estimate. Additional analysis and discussion might include
consideration of additional models, the examination of the parameter values for the
models used or an evaluation of the BMDs to determine if the same pattern exists as for
the BMDLs. Discussion of the decision procedure should always be provided.
6) In some cases, modeling attempts may not yield useful results. When this occurs and the
most biologically relevant effect is from a study considered adequate but not amenable to
modeling, the NOAEL (or LOAEL) could be used as the POD. The modeling issues that
arose should be discussed in the assessment, along with the impacts of any related data
limitations on the results from the alternate NOAEL/LOAEL approach.
This document is a draft for review purposes only and does not constitute Agency policy.
139 DRAFT-DO NOT CITE OR QUOTE
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PART B:
Excerpt of BMD Modeling
from 2011 IRIS Assessment
(U.S. EPA, 2011)
140
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F.2. INHALATION RfC: BMD MODELING OF LIVER LESION INCIDENCE DATA
FOR RATS EXPOSED TO DICHLOROMETHANE VIA INHALATION FOR 2 YEARS
(Nitschke et al., 1988a)
BMD and BMDL refer to the model-predicted dose (and its lower 95% confidence limit)
associated with 10% extra risk for the incidence of hepatic vacuolation in female F344 rats
exposed to dichloromethane via inhalation for 2 years (Nitschke et al.. 1988a) (Table F-3).
Table F-3. Incidence data for liver lesions (hepatic vacuolation) and internal
liver doses based on various metrics in female Sprague-Dawley rats exposed
to dichloromethane via inhalation for 2 years (Nitschke et al., 1988a)
Rat internal liver doseb
Sex
Exposure
(ppm)
Liver lesion
incidence"
CYP
GST
GST and
CYP
Parent
AUC
Male
0
22/70 (31)
Not modeled because results from male rats were not provided for the
50 and 200 ppm groups
50
Not reported
Not modeled because results for middle two doses were not reported
200
Not reported
500
28/70 (40)
Female
0
41/70 (59%)
0
0
0
0
(BW =
229 g)
50
42/70 (60%)
6.17
291.4
1.18
2o5. J
200
41/70 (58%)
665.3
93.2
758.5
17.8
500
782.1
1
68.6
53/70 (76%)
360.0
1,142.
"Number affected divided by total sample size.
internal doses were estimated using a rat PBPK model using exposures reported by study authors (50 ppm =
174 mg/m3, 200 ppm = 695 mg/m3, and 500 ppm = 1,737 mg/m3) and are weighted-average daily values for 1 week
of exposure at 6 hours/day, 5 days/week. CYP dose is in units of mg dichloromethane metabolized via CYP
pathway/L tissue/day; GST dose is in units of mg dichloromethane metabolized via GST pathway/L tissue/day;
GST and CYP dose is in units of mg dichloromethane metabolized via CYP and GST pathways/L tissue/day; and
Parent AUC dose is in units of mg dichloromethane x hours)/L tissue.
Significantly (p < 0.05) different from control with Fisher's exact test.
Source: Nitschke et al. (1988a).
All available dichotomous models in the BMDS (version 2.0) were fit to male and female
rat internal tissue doses of dichloromethane metabolized by the CYP pathway and incidences for
animals with these liver lesions observed at the time of death (Table F-4). The log-probit model
was the best fitting model for the female incidence data based on lowest AIC value among
models with adequate fit (U.S. EPA. 2000c). (If two or more models share the lowest AIC,
BMDLio values from these models may be averaged to obtain a POD. However, this average is
no longer a lower confidence bound that provides the stated coverage, and thus should be
referred to only as an average of BMDLio values. U.S. EPA does not support averaging BMDLs
in situations in which AIC values are similar, but not identical, because the level of stated
F-5
141
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coverage is lost and no consensus exists regarding a specific cut-off between similar and
dissimilar AIC values.)
Table F-4. BMD modeling results for incidence of liver lesions in female
Sprague-Dawley rats exposed to dichloromethane by inhalation for 2 years,
based on liver specific CYP metabolism metric (mg dichloromethane
metabolized via CYP pathway/L liver tissue/day)
Model3
BMD10
BMDL10
x2
goodness of fit
/j-valuc
AIC
Gamma3
622.10
227.29
0.48
367.24
Logistic
278.31
152.41
0.14
369.77
Log-logistica
706.50
506.84
0.94
365.90
Multistage (3)a
513.50
155.06
0.25
368.54
Probit
279.23
154.52
0.14
369.76
Log-probita'b
737.93
531.82
0.98
365.82
Weibull3
715.15
494.87
0.95
365.88
aThese models in U.S. EPA BMDS version 2.0 were fit to the rat dose-response data shown in Table 5-5 by using
internal dose metrics calculated with the rat PBPK model. Gamma and Weibull models restrict power >1; log-
logistic and log-probit models restrict to slope >1, multistage model restrict betas >0; lowest degree polynomial
with an adequate fit reported (degree of polynomial in parentheses).
bBolded model is the best-fitting model in the most sensitive sex (females), which is used in the RfC derivation.
Source: Nitschke et al. (1988a).
F-6
142
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Log Probit Model, Female Rats (Nitschke et al., 1988a), CYP Metabolism (Rate of
Production) Metric
LogProbit Model with 0.95 Confidence Level
LogProbit
0.85
0.8
0.75
0.7
0.65
0.6
0.55
0.5
0.45
BMDL
BMD
0
100
200
300
400
500
600
700
800
dose
16:55 04/28 2011
Figure F-2. Predicted (log-probit model) and observed incidence of
noncancer liver lesions in female Sprague-Dawley rats inhaling
dichloromethane for 2 years (Nitschke et al., 1988a).
Probit Model. (Version: 3.1; Date: 05/16/2008)
Input Data File: C:\Usepa\BMDS2l\Data\lnpNitschke_new_CYPSetting.(d)
Gnuplot Plotting File: C:\Usepa\BMDS21\Data\lnpNitschke_new_CYPSetting.plt
Thu Apr 28 16:55:00 2011
BMDS Model Run
The form of the probability function is:
P[response] = Background
+ (1-Background) * CumNorm(Intercept+Slope*Log(Dose)),
where CumNormf .) is the cumulative normal distribution function
Dependent variable = Effect
Independent variable = Dose
Slope parameter is restricted as slope >= 1
F-7
143
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Total number of observations = 4
Total number of records with missing values = 0
Maximum number of iterations = 250
Relative Function Convergence has been set to: le-008
Parameter Convergence has been set to: le-008
User has chosen the log transformed model
Default Initial (and Specified) Parameter Values
background = 0.585714
intercept = -7.71354
slope = 1
Asymptotic Correlation Matrix of Parameter Estimates
( *** The model parameter(s) -slope
have been estimated at a boundary point, or have been specified by
the user,
background
intercept
and do not appear in the correlation matrix )
background
1
-0.37
intercept
-0.37
Limit
Variable
background
intercept
slope
Estimate
0.590372
-120.151
18
Parameter Estimates
95.0% Wald Confidence Interval
Std. Err. Lower Conf. Limit Upper Conf.
0.0339907
0.346802
NA
0.523751
-120.831
0.656992
-119.471
NA - Indicates that this parameter has hit a bound implied by some ineguality
constraint and thus has no standard error.
Model
Full model
Fitted model
Reduced model
Analysis of Deviance Table
Log(likelihood) # Param's Deviance Test d.f. P-value
-180.889 4
-180.909 2 0.0403892 2 0.98
-184.186 1 6.5937 3 0.08604
AIC:
365.818
Goodness of Fit
Scaled
Dose
Est. Prob.
Expected
Observed
Size
Residual
0.0000
0.5904
41.326
41.000
70
-0.079
285 .3000
0.5904
41.326
42.000
70
0.164
665.3000
0.5907
41.350
41.000
70
-0.085
782.1000
0.7571
52.998
53.000
70
0. 001
ChiA2 =0.04 d.f. = 2
Benchmark Dose Computation
P-value
0.9800
Specified effect =
Risk Type =
Confidence level =
HMD =
BMDL =
0.1
Extra risk
0. 95
737.929
531.817
F-8
144
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