Document e73N3gDQbBv4MreRkGNxE9kgm
DRAFT PRESENTATION
QUEST
Kenneth A. Mundt, PhD, FACE P. Robinan Gentry, PhD, DABT Sonja Sax, ScD
Sierra Club v. EPA 18cv3472 NDCA
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EPA published the IRIS Toxicological Review of Chloroprene in 2010, with an inhalation unit risk (IUR) of 5 x 10-4perjig/m3.
This is the 5th highest IUR derived by IRIS for any chemical classified by IARC as carcinogenic (Group 1) or probably carcinogenic (Group 2a).
IARC classified chloroprene as possibly carcinogenic (Group 2b).
Ramboll Environ was requested to conduct a detailed review of the 2010 IRIS, and to derive an IUR for Chloroprene.
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Key Findings: All lines of evidence indicate that the IUR should be corrected:
The highest quality epidemiological studies demonstrated no excess lung or liver cancer risk.
Toxicological data do not support a mutagenic mode of action.
Multiple lines of evidence indicate large differences between across species.
Using NRC best practices recommendations, EPA methods and pharmacokinetic data, the Ramboll Environ IUR is 156 times lower than the 2010 IRIS IUR.
Cancer risk estimates based on the Ramboll Environ IUR are consistent with the epidemiological data.
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EPA published the IRIS Toxicological Review of Chloroprene* in 2010, with an inhalation unit risk (IUR) of 5 x 10"4per xg/m3.
Denka Performance Elastomer (DPE) acquired the Neoprene production facility in LaPlace, Louisiana from DuPont on November 1, 2015.
On December 17, 2015, EPA published the 2011 National Air Toxics Assessment (NATA), including a risk assessment based on facility's emissions and the 2010 IRIS IUR.
The NATA study identified DPE's facility as associated with one of the highest offsite cancer risks of any chemical facility in the US.
DPE retained Ramboll Environ to evaluate the scientific validity of the 2010 IRIS IUR.
Using EPA standard methods and publicly available data, Ramboll Environ determined that the 2010 IRIS IUR is overestimated by a factor of 156.
* U.S. Environmental Protection Agency, Washington, DC, EPA/635/R-09/010F, 2010. LNViRON
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Evaluate the 2010 IRIS Review of Chloroprene, especially the IUR, in light of NRC (2011, 2014) guidance on improving IRIS assessments:
How studies are evaluated: quality assessment and weighting
Better integration of data across all lines of evidence
Critically review and integrate the published epidemiological, toxicological, and mode of action evidence on chloroprene carcinogenicity.
Apply a standard pharmacokinetic correction to the chloroprene IUR. Provide a "reality check"for the IUR.
RON
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US and Europe
Armenia
Key Criteria ( M a r s h e t a / . 2 0 0 7 ) (Bulbulyanet ai. 1999)
Sample Size
12,430
2,314
Follow -up
1949--2000
Exposure
Exposure modeling -
Assessment
7 categories
1979--1993
Index (none, low, high)before/after 1980
Baseline rates
National, local plant area counties 1960-1994
Confounding
Used local rate comparisons; Low prevalence of other liver cancer risk
factors
Armenian rates 1980-1989
Alcohol use (high cirrhosis rates) and smoking prevalent
i.
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Russia
China
(Bulbulyanef al. 1998) (Li e t a L 1 9 8 9 )
5,185
1,258
1979-1993
Index (none, med, high)IH (inadequate) + job
Moscow rates 1979-1993 or 1992-1993 (liver)
1969" 1983
High vs. low based on recall
From "local area" 1973-1975
expected lung cancers: 0.4
Alcohol use (high cirrhosis rates) and smoking; Co-exposure to VC
Hepatitis B and aflatoxin;
Co-exposures to VC
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US ERA Criteria Clear objectives
Marsh et al. (2007 a,b) Study
Kentucky1 North
Louisiana1 France-
Ireland
Mortality1
Armenia2
Ht
H
H
H
H
Comparison groups
H
H-M
H-M
M
M
Exposure
H
H
H
H
M
Follow-up
H
H-M
H
H-M
M-L
Case ascertainment
H
H-M
H-M
H-M
M
Control of bias
H-M
H-M
H-M
M
M-L
Sample size
H
H
M
L
M-L
Data collection and p\/a li ip tin n Adequate response
H
H
H
H
M
H
H
H
H
M
Documentation of results
H
H
H
H
M-L
Overall rank (l=best)
1
2
3
4
5
Other Studies
France-
Russia4
Incidence3
China5
H-M
H
M
M
M-L
L
M
L
L
M-L
M-L
M-L
M
M
H-M
M
M
M-L
L
H-M
M-L
M
M-L
M-L
M
M
H-M
M
M
L
5
5
6
Source: Bukowski 2009 t Subjective estimate of study quality for each specific criterion H=high, M=medium, L=low; 1 - Marsh et al. 2007; 2 - Bulbulyan et al. 1999; 3 - Colonna and Laydevant 2001; 4 - Bulbulyan et al. 1998; 5 - Li et al. 1989
I N VIRON
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Respiratory cancers RRs and SMRs by cumulative chloroprene exposure, Louisville plant
p-trend =0.71
Liver cancers RRs and SMRs by cumulative chloroprene exposure, Louisville plant
p-trend =0.09
ENVIRON
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Source; Marsh 2007b
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Cumulative (ppm-yrs) Source; Marsh 2007b
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Cancer incidence data from the Louisiana Tumor Registry for St. John the Baptist Parish (where DPE plant is located) and for the state of Louisiana
Five most recent years
Cancer site
All cancers Respiratory cancers Liver cancers
Parish Rate State Rate
463.2
60.1
< 3 cases (too few to report)
478.7 70.5
Ranking ( l =lowest cancer rate)
15/64
7/64
Unknown *
`Unknown as as there were 28 parishes with too few liver cancer cases
Source: https://statecancerprofiles.cancer.gov/incidencerates/index.php?stateFIPS=22&cancer= 001&race=00&sex=0&age=001&type=incd&sortVariableName=rate&sortC)rder=default#results
ENVIRON
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Marsh et al. (2007a) results for 1,357 workers at the Pontchartrain facility in LA (US and local reference rates)
Cancer site All cancers Respiratory cancers Liver cancers
US-based SMR 0,74 (0.51-1.04) 0.72 (0.37-1.26) None reported
Local-based SMR 0.68 (0.47-0.95) 0.62 (0.32-1.09) None reported
INVIKON Sierra Club v. EPA 18cv3472 NDCA
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Marsh et al. (2007) should be given greater weight than studies from Asia, Russia and Armenia:
" We conclude that persons exposed to ch/oroprene or vinyl chloride at the levels encountered in the four study sites did not have elevated risks of mortality from any of the causes o f death examined, including all cancers combined and lung and liver cancer, the cancer sites of a priori interest."
"This conclusion is corroborated by our detailed analyses of mortality in relation to qualitative and quantitative exposures to CD and VC at each of the four study sites."
Source: G.M. Marsh et ai. / Chemico-Biological Interactions 166 (2007) 285-300
ENVIRON
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Studies conducted in B6C3F1 mice and Fischer rats (NTP, 1998), and in Wistar rats and Syrian hamsters (Trochimowicz et al., 1998) at chloroprene concentrations ranging from 10 to 80 ppm.
A significant incidence of tumors seen across many organ sites, primarily in mice and at the highest exposure levels.
The most sensitive species/tumorsite is the female mouse and the lung.
Fewer tumors in Wistar rats and Syrian hamsters; little consistency across species both in the number of tumors and in tumor location.
Differences in tumor incidence can be explained by using PBPK modeling and the calculated internal dose of metabolized chloroprene.
ENVIRON!
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K^^M Exposure concentration (ppm)
Syrian Hamster
0
(Trochimowicz et
10
al., 1998)
50
Wistar rat
0
(Trochimowicz et
10
al., 1998)
50
0
Fischer rat (NTP, 1998)
12.8 32
80
O
B6C3F1 mouse (NTP, 1998)
12.8 32
80
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PBPK internal dose (mg/g)
0 0.18 0.88
0 0.18 0.89
0 0.22 0.55 1.37
O
3.46 5.3 7.18
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Lung tumor incidence
0 0 0 0 0 0 3 3 6 9 15 32 40 46
Number of animals
100
97
97
97
13
100
50
50
49
50
50
50
50
15
50
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In vitro mutagenicity results are inconsistent
Study Bartsch et al., 1979 Westphal et al., 1994 NTP, 1998 Willems, 1980
Method Desiccator Pre-incubation Pre-incubation Desiccator
Exposure 4 hours 2 hours 20 min.
24-48 hours
Response
+
In vivo results are mostly negative, and mutagenicity profile is different from 1,3-butadiene
Chemical
In Vivo (B6C3F1 mouse)
CA
SCE
MN
Chloroprene
-
1,3 - Butadiene
+
+
+
CA - chrom osom e aberrations; SCE - sister chromatid exchange; MN - micro nucleus test; Source: Tice 1988
Weight of evidence is not consistent with a mutagenic MOA. An alternative MOA should be considered in accordance with EPA and NRC guidelines.
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HLOROPRENEIUR
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Compound (Year of Review)
IUR per ug/m3
Basis
PBPK adjustment
Classification
Chloroprene (2010)
Multiple tumors in 5 x 10"4 mice, mutagenic MOA
No
Possibly Carcinogenic
1,3 Butadiene (2002a)
Benzene(2002b)
5 Human occupational
j X 1U
st, ud,.ies
2 x 10'6- Human occupational 7.8 x 10"6 studies
Vinyl Chloride (2000) 4.4 x 10"6 Liver tumors in rats
No
Known Carcinogen
No
Known Carcinogen
Yes
Known Carcinogen
Ratio 1
-20 250 --100
Adjusted IUR of chloroprene is more in line with other known carcinogens; e.g., VC IUR is based on animal data, but with PBPK model adjustments.
ENVIRON
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Step Most sensitive endpoint/species (portal-of-entry DAF=1.7)
Most sensitive endpoint/species (systemic lesion DAF=1)
Multiple tumor adjustment Rounding
Application of ADAF
IUR per ug/m3
1.06 x IO 4
1.81 x IO 4 2.7 x IO"4
3 x 10"4 5 x IQ'4
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Basis Lung tumors in female mice as a porta I-of-entry effect
Lung tumors in female mice as a systemic effect
Multiple tumors Rounding
Adjustment
US EPA (2010)
IUR per ug/m3
5 x IO"4
Allen et al. (2014)
1,86 x IO'6
Ramboll Environ (2017)
3,2 x IO"6
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Basis
Resulting decrease in IUR
Fully adjusted composite value in female mice with ADAF correction
Referent
PBPK dosimetric adjustment of lung tumors in female mice in target organ; includes animal and
human data
PBPK dosimetric adjustment of lung tumors in female mice in the
target organ; based on animal data only
-250 fold decrease
156 fold decrease
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PBPK model was published by Himmelstein et al. (2004).
Data were provided to EPA at the time of the review to check the validity of the model; however, EPA did not incorporate these data into the final IUR estimate.
Data provided to EPA have been published (Yang et al., 2012; Thomas et al., 2013).
Allen et al. (2014) reported that an IUR that incorporates pharmacokinetic differences 250 times lower than the 2010 IRIS IUR.
Using the internal dose estimates from PBPK modeling from Yang et al. (2012) Ramboll Environ derived an IUR of 3.2 x 10-6 per ug/m3which is 156 times lower than the 2010 IRIS IUR.
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Source US ERA (2010)
lung tumor
multi tumor
w/ADAF Allen et al. (2014)
lung tumor Ramboll Environ
lung tumor
Unit Risk (per ppm)
0.65
1.08
1.80 0.0067
0.012
*Mean exposure reported by Marsh et al. 2007a
Mean Exposure*
(ppm) 8.42
8.42
8.42
8.42
8.42
Excess Cancers
(Risk Estimate)
5.5
9.1
15.2
0.06
0.1
Excess Cancers (Observed-Expected)
Local referent
-84 (lung) -1.9 (liver)
IUR corrected for pharmacokinetic differences results in a cancer risk estimate consistent with epidemiological results (i.e., no observable excess risk).
L N VI R O N
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:ancer classification
ENVIRON
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EPA classified chloroprene as "likely to be a human carcinogen" based on :
National Toxicology Program (NTP, 1998) chronic inhalation bioassay; Associations between chloroprene exposure and liver cancer in four of nine epidemiological
studies; Limited evidence of lung cancer; Proposed mutagenic mode of action; and Analogies with 1,3-butadiene and vinyl chloride
Critical review of the evidence indicated that four of these five cannot be substantiated. The classification should be revisited and a dearer narrative provided.
ENVIRON
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The highest quality epidemiological studies do not demonstrate a causal relationship between occupational exposures to chloropreneand cancer.
Many lines of evidence point to pharmacokinetic differences across species. PBPK modeling is the best approach for correcting the IUR because of large
pharmacokinetic differences between the mouse and humans. Using PBPK model output and standard EPA methods, Ramboll Environ calculated an IUR
that is 156 times lower than the 2010 IRIS IUR.
Integration of the full body of evidence indicates that the pharmacokinetic differences between the mouse and humans require that the IUR be corrected using PBPK model results.
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Ken Mundt kmundt@ramboll.com Robinan Gentry raentrv @ ramboll.com Sonja Sax ssax@ramboll.com
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