Draft Risk Evaluation for N-Methylpyrrolidone Systematic Review Supplemental File: Data Quality Evaluation of Epidemiologic Studies CASRN 872-50-4


PEER REVIEW DRAFT - DO NOT CITE OR QUOTE
v»EPA
United States	Office of Chemical Safety and
Environmental Protection Agency	Pollution Prevention
Draft Risk Evaluation for
N-Methylpyrrolidone
Systematic Review Supplemental File:
Data Quality Evaluation of Epidemiologic Studies
CASRN 872-50-4
October 2019
1

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PEER REVIEW DRAFT - DO NOT CITE OR QUOTE
Table of Contents
Epidemiological Studies	3
1.1.	Epidemiological evaluation results of the Bader et al 2006 study for irritation
outcomes in general	3
1.2.	Epidemiological evaluation results of the Haufroid et al 2014 study for renal
outcomes for cross-sectional occupational renal	7
1.3.	Epidemiological evaluation results of the Haufroid et al 2014 study for hepatic
outcomes for cross-sectional occupational liver	11
1.4.	Epidemiological evaluation results of the Haufroid et al 2014 study for respiratory
outcomes for cross-sectional occupational lung	15
1.5.	Epidemiological evaluation results of the Nishimura et al 2009 study for
musculoskeletal/motor function outcomes for cross-sectional occupational	19
1.6.	Epidemiological evaluation results of the Nishimura et al 2009 study for
neurological/behavior outcomes in general	23
2

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PEER REVIEW DRAFT - DO NOT CITE OR QUOTE
Epidemiological Studies
1.1. Epidemiological evaluation results of the Bader et al 2006 study for irritation
outcomes in general
Study
reference:
Bader. M..Rosenberger. W..Rebe. T..Keener. S. A..Brock. T. H..Hemmerling. H. J..Wrbitzkv. R. (2006). Ambient monitoring and
biomonitoring of workers exposed to N-methyl-2-pyrrolidone in an industrial facility International Archives of Occupational and
Environmental Health, 79(5), 357-364

HERO ID: 3539720

Domain
Metric
Comments
Qualitative
Determination
Metric Score
Metric
Weighting
Factor
Weighted
Score

1. Participant
selection
Participant selection not clear. 7 workers and 3 on-
site examiners running the study in adhesive
bonding facility in Germany volunteered to physical
exams, interviews and urine samples before/after
shifts. Number of eligible workers not stated.
Low
3
0.400
1.200
a
#o
"s
o.
'3
2. Attrition
Participation rates at study stages and
inclusion/exclusion criteria not stated.
Low
3
0.400
1.200
t:
es
a.
¦a
5
Tfl
3. Comparison Group
Workers served as own controls (pre/post shift) for
acute outcomes following a day of work after an
exposure-free weekend. Personal exposures 0.9-15.5
mg/m3 across workers, with duties including
foreman, maintenance, and production worker.
Additionally, the 3 examiners conducting the study
(physician, study coordinator, and technician) were
exposed only to air contamination and included in
analysis. Note that for at least 1 worker, the "pre-
shift" sample/interview occurred 2 hours after their
shift began. Characteristics not reported.
Medium
2
0.200
0.400
a
"s
4. Measurement of
Exposure
Well established and detailed methods of direct
exposure measurements. Ambient air monitoring of
average workplace concentrations and short-term
peaks monitored by stationary and personal air
monitoring. NMP and metabolites (5-HNMP, 2-
HMSI) measured in spot urine tests. Dermal
exposure noted to occur (inconsistent PPE usage),
but should be accounted for in the biomonitoring
data.
High
1
0.400
0.400
~-
(J
si
~-
es
-fl
U
£
o
5. Exposure
levels
Exposure range in workers ranged from < LOD to
472 ug/g while exposure in examiners ranged from
< LOD to 123. The range and distribution are
limited.
Low
3
0.200
0.600
&
UJ
6. Temporality
Temporality established for post-shift
measurements, but not for the pre-shift
measurements. Two pre-shift urine sample
contained NMP and metabolites. For worker 7 (pre-
shift urine had NMP), the pre-shift sample was
taken 2 hours AFTER the shift began. When
considering these measurements served as controls,
it is problematic.
Medium
2
0.400
0.800
3

-------
N-Methyl-2-pyrrolidone
Study
reference:
Bader. M..Rosenberger. W..Rebe. T..Keener. S. A..Brock. T. H..Hemmerling. H. J..Wrbitzkv. R. (2006\ Ambient monitoring and
biomonitoring of workers exposed to N-methyl-2-pyrrolidone in an industrial facility International Archives of Occupational and
Environmental Health, 79(5), 357-364

HERO ID: 3539720

Domain
Metric
Comments
Qualitative
Determination
Metric Score
Metric
Weighting
Factor
Weighted
Score
C
S
5«
5«
5«
«!
0>
S
7. Outcome
measurement or
characterization
Examined before and after shifts by occupational
physician for irritation of the eyes, mucus
membranes and skin. Interviewed for related health
effects. Bias is possible from both parties, due to
awareness of exposure, but no direct evidence of
misclassification. Presumably, the physician
interviewed/examined themselves, as a subject in
the study.
Medium
2
0.670
1.333
(J
5
O
8.
Reporting
Bias
Interview/examination results presented
qualitatively for selected participants. Outcomes
stated for "workers" and not directly linked to
participant exposure or biomonitoring data.
Low
3
0.330
1.000
"o
~-
c
9. Covariate
Adjustment
Workplace and tasks presented (vary across 7
workers and 3 examiners), but no other
characteristics (age, sex...). Comparison of pre-shift
and post-shift outcomes mediates the concern here
though.
Low
3
0.670
2.000
o
U
—
10. Covariate
Characterization

es
¦e
es
1
¦3
c
No covariates/confounders were assessed.
Not Rated
NA
NA
NA
s
£
c
5
O
U
!§
c
o
a.
11. Co-exposure
Confounding
Solvents used in cleaning process - aromatic
hydrocarbons, acetone, propylene glycol
monomethyl ether, and 3-methoxybutyl acetate.
Residues in production vessels - glutaric and
succinic acid dimethyl ester. Only low levels of
acetone and aromatic hydrocarbons detected in air
during cleaning procedures, thus co-exposures
deemed negligible. Due to lapses in PPE, the
glutaric and succinic acid dimethyl ester could still
be relevant and weren't accounted for.
Low
3
0.330
1.000
%
*5«
12. Study
Design and
Methods
Study design appropriate for monitoring acute
exposure outcomes. Descriptive outcome reporting
did not include any statistical methods (no means,
medians...).Workers with common colds were not
excluded.
Unacceptable
NA
NA
NA
13
c
<<
13. Statistical
power
Low statistical power (7 subjects, 3 controls, with
varied levels of exposure). Unable to determine if
effects related to exposure.
Unacceptable
NA
NA
NA
4

-------
N-Methyl-2-pyrrolidone
Study
reference:
Bader. M..Rosenberger. W..Rebe. T..Keener. S. A..Brock. T. H..Hemmerling. H. J..Wrbitzkv. R. (2006). Ambient monitoring and
biomonitoring of workers exposed to N-methyl-2-pyrrolidone in an industrial facility International Archives of Occupational and
Environmental Health, 79(5), 357-364
HERO ID: 3539720
Domain
Metric
Comments
Qualitative
Determination
Metric Score
Metric
Weighting
Factor
Weighted
Score

14.
Reproducibility of
analyses
Sufficient detail reported for only statistical method
applied (linear regression of air monitoring and
post-shift biomonitoring). No statistical method
applied to health outcomes.
Medium
2
0.070
0.143

15. Statistical
models
No models used to calculate risk estimates. Linear
regression personal air monitoring results and post-
shift biomonitoring data (metabolite 5-HNMP in
urine) appropriate and transparent.
Low
3
0.070
0.214

16. Use of
Biomarker of
Exposure
NMP and metabolites (5-HNMP, 2-HMSI)
measured in spot urine tests. Shown by linear
regression to correlate with ambient air exposure,
and suspected to also account for dermal exposure.
High
1
0.170
0.167
Other
17. Effect
biomarker
No biomarker of effect was measured.
Not Rated
NA
NA
NA

18. Method
Sensitivity
LOD reported and sufficiently low to detect parent
and metabolites in 100%-40% of samples.
Medium
2
0.170
0.333
Confounding / Variable Control
19. Biomarker
stability
Storage duration and stability not noted. Stored at
4C during study, and -27C in the laboratory.
Medium
2
0.170
0.333
20. Sample
contamination
Blanks used for NMP metabolites, but no
documentation of steps used to ensure
contamination free from collection to measurement.
Low
3
0.170
0.500
Data
Presentation
and Analysis
21. Method
requirements
Analyzed with GC-MS.
Medium
2
0.170
0.333
5

-------
N-Methyl-2-pyrrolidone
Study
reference:
Bader. M..Rosenberger. W..Rebe. T..Keener. S. A..Brock. T. H..Hemmerling. H. J..Wrbitzkv. R. (2006). Ambient monitoring and
biomonitoring of workers exposed to N-methyl-2-pyrrolidone in an industrial facility International Archives of Occupational and
Environmental Health, 79(5), 357-364
HERO ID: 3539720
Domain
Metric
Comments
Qualitative
Determination
Metric Score
Metric
Weighting
Factor
Weighted
Score

22. Matrix
adjustment
Only creatine-adjusted levels provided.
Medium
2
0.170
0.333
High: >=1 and <1.7
Medium: >=1.7 and <2.3
Low: >=2.3 and <=3
Sum of scores:

5.14
12.3
Overall Score = Sum of Weighted Scores/Sum of Metric
Weighting Factors:
2.945
Overall
Score:
Nearest *:
2.91
Overall Quality Level:
Unacceptable1
Study
Quality
Comment:
The reviewer agreed with this study's overall quality level. Footnote 1: Consistent with our Application of A
Systematic Review in TSCA Risk Evaluations document, if a metric for a data source receives a score of
Unacceptable (score = 4), EPA will determine the study to be unacceptable. In this case, two of the metrics were
rated as unacceptable. As such, the study is considered unacceptable and the score is presented solely to increase
transparency.
6

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N-Methyl-2-pyrrolidone
1.2. Epidemiological evaluation results of the Haufroid et al 2014 study for renal
outcomes for cross-sectional occupational renal
Study
reference:
Haufroid. V..Jaeger. V. K..Jeggli. S..Eisenegger. R..Bernard. A..Friedli. D.Xison. D..Hotz. P. (20\4\ Biological monitoring and health effects of
low-level exposure to N-methyl-2-pyrrolidone: a cross-sectional study International Archives of Occupational and Environmental Health, 87(6),
663-674

HERO ID: 2654929

Domain
Metric
Comments
Qualitative
Determination
Metric Score
Metric
Weighting
Factor
Weighted
Score
a
1. Participant
selection
Occupational NMP study in Switzerland from 2006-
2011. From an initial list of 61 potential companies,
21 were included in the final study. Exposures were
related to graffiti removal or by solvent exposure
(production or synthesis); not always daily
exposures. Analysis conducted on 91 exposed
workers and 114 unexposed workers (all males)
High
i
0.400
0.400
"s
.5-
"3
es
&
2. Attrition
Of the 327 eligible workers, 207 (63%) participated.
Exclusion based on desire of participants (113),
organization reasons (7) and gender (1 woman). No
indication of bias from non-participation.
Medium
2
0.400
0.800
5
Tfl
3. Comparison Group
Unexposed and exposed workers has similar
distributions of age. Unexposed workers had a
slightly higher education levels, were less likely to
be smokers and had lower alcohol consumption.
However, these differences were not large.
High
1
0.200
0.200

4. Measurement
of Exposure
Personal air sampling for a full day with solid
sorbent tubes and pumps (150 ml/min); NMP
determined with NIOSH method. Exposure noted to
vary greatly by days, but samples only collected
from one day. Monthly exposures estimated by
occupational history.
Medium
2
0.400
0.800
a
#o
"s
N
¦e
cS
-fl
U
B
5
5. Exposure levels
Range of NMP: below LOD-25.8 mg/m3 (median
0.18 mg/m). Participants categorized into 5 groups
based on current and past exposures: never exposed,
former solvent exposure, current NMP exposure
only, current solvent exposure (no NMP), current
exposure to NMP and other solvents. Relatively low
NMP exposure and use of protect equipment result
in a limited ability to determine dose-response.
Low
3
0.200
0.600
o
O.
UJ
6. Temporality
Biomarkers for health outcomes measured directly
after shift with air monitoring and again before next
shift (16 hrs off of work). Clinical symptoms, such
as skin irritation/headaches, determined within a
week of air monitoring; only 37 workers (43% of
"exposed" group) worked with NMP the day before
clinical assessments. Biomarkers for liver, renal and
respiratory health also expected to fall within this
exposure window.
Medium
2
0.400
0.800
7

-------
N-Methyl-2-pyrrolidone
Study
reference:
Haufroid. V..Jaeger. V. K..Jeggli. S..Eisenegger. R..Bernard. A..Friedll. D.Xison. D..Hotz. P. (20141. Biological monitoring and health effects of
low-level exposure to N-methyl-2-pyrrolidone: a cross-sectional study International Archives of Occupational and Environmental Health, 87(6),
663-674
HERO ID: 2654929
Domain
Metric
Comments
Qualitative
Determination
Metric Score
Metric
Weighting
Factor
Weighted
Score
Outcome Assessment
7. Outcome
measurement or
characterization
Clinical outcomes (skin irritation, headaches,
neurotoxic outcomes) assessed with a semi-
structured clinical examination and questionnaires.
Spirometry results assessed by 2 physicians.
Biomarkers for haematological, renal, liver and
respiratory health also used (see metrics 16-22).
Medium
2
0.670
1.333
8.
Reporti
ng Bias
Clinical outcomes are briefly qualitatively
described, and thus cannot be extracted. The
outcome biomarkers are fully reported.
Medium
2
0.330
0.667
Potential Counfounding/Variable Control
9. Covariate Adjustment
Adjustment for age, smoking (pack years & number
of years since smoking cessation), skin disease,
glove usage, and genetic factors considered in
various analyses. Differences in nationality between
exposed and controls were not provided, but most
non-Swiss participants were German or Italian. Data
on education provided, but not adjustment for this
factor or SES. However, it is unclear if these
covariates were considered in the analysis between
NMP exposure and health outcomes.
Low
3
0.500
1.500
10. Covariate
Characterization
Smoking status/history determined with
questionnaire. Other covariates assumed to be
collected from employment records, but this is not
explicitly states.
Medium
2
0.250
0.500
11. Co-exposure
Confounding
Categorized based on exposure to additional organic
solvents. Hand washing with organic solvents also
noted on the day of biomonitoring data collection.
Medium
2
0.250
0.500
Analysis
12. Study Design and
Methods
The study design chosen was appropriate for the
research questions however the scarce
data on symptomatic effects limited the analysis.
Due to wide variation in daily NMP exposure for
individual participants, only 43% of "exposed"
workers worked with NMP the day before clinical
examination. So determination of acute health
effects in this population is somewhat compromised.
Medium
2
0.400
0.800
13. Statistical
power
Only 8 participants had exposure to only NMP,
while 38 had current exposure a mix of organic
solvents (including NMP), and 30 were never
exposed to NMP or organic solvents. Although
power calculations were done apriori, the number of
symptomatic cases was low making interpretation
difficult.
Medium
2
0.200
0.400
8

14.
Reproducibility of
analyses
Description of analysis sufficient to understand and
reproduce.
Medium
2
0.200
0.400
15. Statistical
models
Multiple linear regression models used for exposed
group and for the entire group for 2-HSMI/5-HNMP
and s-creatinine.
Medium
2
0.200
0.400
Other
16. Use of
Biomarker of
Exposure
2-HMSI (mg/1; before next shift) covered 70% of
variance. Metabolites measured in urine have long
half-lives (6-26 hrs) and are unique to NMP.
High
1
0.140
0.143
17. Effect
biomarker
Biomarkers for renal health (urinary RBP, urinary
albumin, and serum creatinine), hepatic health
(GGT expression), and respiratory health (serum
CC16) were used. Well established, but mechanisms
of action not described.
Medium
2
0.140
0.286
18. Method
Sensitivity
Metabolites measured with LC-MS/MS and a LOQ
of 0.2 mg/L.
Medium
2
0.140
0.286
Confounding / Variable Control
19. Biomarker
stability
Storage history not described, but do not have a
high likelihood of biomarker instability.
Medium
2
0.140
0.286
20. Sample
contamination
Blanks used for NMP metabolites, but no
documentation of steps used to ensure
contamination free from collection to measurement.
Low
3
0.140
0.429
Data
Presentation
and Analysis
21. Method
requirements
LC-MS/MS used for NMP metabolites
High
1
0.140
0.143
9

-------
N-Methyl-2-pyrrolidone
Study
reference:
Haufroid. V..Jaeger. V. K..Jeggli. S..Eisenegger. R..Bernard. A..Friedll. D.Xison. D..Hotz. P. (20141. Biological monitoring and health effects of
low-level exposure to N-methyl-2-pyrrolidone: a cross-sectional study International Archives of Occupational and Environmental Health, 87(6),
663-674
HERO ID: 2654929
Domain
Metric
Comments
Qualitative
Determination
Metric Score
Metric
Weighting
Factor
Weighted
Score

22. Matrix
adjustment
Creatinine adjusted and unadjusted values provided
(Table 2).
High
1
0.140
0.143
High: >=1 and <1.7
Medium: >=1.7 and <2.3
Low: >=2.3 and <=3
Sum of scores:

6
11.82
Overall Score = Sum of Weighted Scores/Sum of Metric
Weighting Factors:
NA
Overall
Score:
Nearest *:
NA
Overall Quality Level:
Low
Study
Quality
Comment:
The reviewer downgraded this study's overall quality rating. They did not provide an explanation. Note: The
original calculated score for this study was 2.0. This value is not presented above because the final rating was
changed based on professional judgement.
10

-------
N-Methyl-2-pyrrolidone
1.3. Epidemiological evaluation results of the Haufroid et al 2014 study for hepatic
outcomes for cross-sectional occupational liver
Study
reference:
Haufroid. V..Jaeger. V. K..Jeggli. S..Eisenegger. R..Bernard. A..Friedli. D.Xison. D..Hotz. P. (20\4\ Biological monitoring and health effects of
low-level exposure to N-methyl-2-pyrrolidone: a cross-sectional study International Archives of Occupational and Environmental Health, 87(6),
663-674

HERO ID: 2654929

-------
N-Methyl-2-pyrrolidone
Study
reference:
Haufroid. V..Jaeger. V. K..Jeggli. S..Eisenegger. R..Bernard. A..Friedll. D.Xison. D..Hotz. P. (20141. Biological monitoring and health effects of
low-level exposure to N-methyl-2-pyrrolidone: a cross-sectional study International Archives of Occupational and Environmental Health, 87(6),
663-674
HERO ID: 2654929
Domain
Metric
Comments
Qualitative
Determination
Metric Score
Metric
Weighting
Factor
Weighted
Score
Outcome Assessment
7. Outcome
measurement or
characterization
Clinical outcomes (skin irritation, headaches,
neurotoxic outcomes) assessed with a semi-
structured clinical examination and questionnaires.
Spirometry results assessed by 2 physicians.
Biomarkers for haematological, renal, liver and
respiratory health also used (see metrics 16-22).
Medium
2
0.670
1.333
8.
Reporti
ng Bias
Clinical outcomes are briefly qualitatively
described, and thus cannot be extracted. The
outcome biomarkers are fully reported.
Medium
2
0.330
0.667
Potential Confounding/Variable Control
9. Covariate Adjustment
Adjustment for age, smoking (pack years & number
of years since smoking cessation), skin disease,
glove usage, and genetic factors considered in
various analyses. Differences in nationality between
exposed and controls were not provided, but most
non-Swiss participants were German or Italian. Data
on education provided, but not adjustment for this
factor or SES. However, it is unclear if these
covariates were considered in the analysis between
NMP exposure and health outcomes.
Low
3
0.500
1.500
10. Covariate
Characterization
Smoking status/history determined with
questionnaire. Other covariates assumed to be
collected from employment records, but this is not
explicitly states.
Medium
2
0.250
0.500
11. Co-exposure
Confounding
Categorized based on exposure to additional organic
solvents. Hand washing with organic solvents also
noted on the day of biomonitoring data collection.
Medium
2
0.250
0.500
Analysis
12. Study Design and
Methods
The study design chosen was appropriate for the
research questions however the scarce data on
symptomatic effects limited the analysis. Due to
wide variation in daily NMP exposure for individual
participants, only 43% of "exposed" workers
worked with NMP the day before clinical
examination, so determination of acute health
effects in this population is somewhat compromised.
Medium
2
0.400
0.800
13. Statistical
power
Only 8 participants had exposure to only NMP,
while 38 had current exposure a mix of organic
solvents (including NMP). For reported outcomes,
and 30 were never exposed to NMP or organic
solvents. Although power calculations were done
apriori, the number of symptomatic cases was low
making interpretation difficult.
Medium
2
0.200
0.400
12

14.
Reproducibility of
analyses
Description of analysis sufficient to understand and
reproduce.
Medium
2
0.200
0.400
15. Statistical
models
Multiple linear regression models used for exposed
group and for the entire group for 2-HSMI/5-HNMP
and GGT.
Medium
2
0.200
0.400
Other
16. Use of
Biomarker of
Exposure
2-HMSI (mg/1; before next shift) covered 70% of
variance. Metabolites measured in urine have long
half-lives (6-26 hrs) and are unique to NMP.
High
1
0.140
0.143
17. Effect
biomarker
Biomarkers for renal health (urinary RBP, urinary
albumin, and serum creatinine), hepatic health
(GGT expression), and respiratory health (serum
CC16) were used. Well established, but mechanisms
of action not described.
Medium
2
0.140
0.286
18. Method
Sensitivity
Metabolites measured with LC-MS/MS and a LOQ
of 0.2 mg/L.
Medium
2
0.140
0.286
Confounding / Variable Control
19. Biomarker
stability
Storage history not described, but do not have a
high likelihood of biomarker instability.
Medium
2
0.140
0.286
20. Sample
contamination
Blanks used for NMP metabolites, but no
documentation of steps used to ensure
contamination free from collection to measurement.
Low
3
0.140
0.429
Data
Presentation
and Analysis
21. Method
requirements
LC-MS/MS used for NMP metabolites
High
1
0.140
0.143
13

-------
N-Methyl-2-pyrrolidone
Study
reference:
Haufroid. V..Jaeger. V. K..Jeggli. S..Eisenegger. R..Bernard. A..Friedll. D.Xison. D..Hotz. P. (20141. Biological monitoring and health effects of
low-level exposure to N-methyl-2-pyrrolidone: a cross-sectional study International Archives of Occupational and Environmental Health, 87(6),
663-674
HERO ID: 2654929
Domain
Metric
Comments
Qualitative
Determination
Metric Score
Metric
Weighting
Factor
Weighted
Score

22. Matrix
adjustment
Creatinine adjusted and unadjusted values provided
(Table 2).
High
1
0.140
0.143
High: >=1 and <1.7
Medium: >=1.7 and <2.3
Low: >=2.3 and <=3
Sum of scores:

6
11.82
Overall Score = Sum of Weighted Scores/Sum of Metric
Weighting Factors:
1.97
Overall
Score:
Nearest *:
2
Overall Quality Level:
Medium
Study
Quality
Comment:
The reviewer agreed with this study's overall quality level.
14

-------
N-Methyl-2-pyrrolidone
1.4. Epidemiological evaluation results of the Haufroid et al 2014 study for
respiratory outcomes for cross-sectional occupational lung
Study
reference:
Haufroid. V..Jaeger. V. K..Jeggli. S..Eisenegger. R..Bernard. A..Friedli. D.Xison. D..Hotz. P. (2014). Biological monitoring and health effects of
low-level exposure to N-methyl-2-pyrrolidone: a cross-sectional study International Archives of Occupational and Environmental Health, 87(6),
663-674

HERO ID: 2654929

4. Measurement
of Exposure
Personal air sampling for a full day with solid
sorbent tubes and pumps (150 ml/min); NMP
determined with NIOSH method. Exposure noted to
vary greatly by days, but samples only collected
from one day. Monthly exposures estimated by
occupational history.
Medium
2
0.400
0.800
a
#o
"s
N
¦e
es
-fl
U
B
5
5. Exposure levels
Range of NMP: below LOD-25.8 mg/m3 (median
0.18 mg/m). Participants categorized into 5 groups
based on current and past exposures: never exposed,
former solvent exposure, current NMP exposure
only, current solvent exposure (no NMP), current
exposure to NMP and other solvents. Relatively low
NMP exposure and use of protect equipment result
in a limited ability to determine dose-response.
Low
3
0.200
0.600
O
o.
UJ
6. Temporality
Biomarkers for health outcomes measured directly
after shift with air monitoring and again before next
shift (16 hrs off of work). Clinical symptoms, such
as skin irritation/headaches, determined within a
week of air monitoring; only 37 workers (43% of
"exposed" group) worked with NMP the day before
clinical assessments. Biomarkers for liver, renal and
respiratory health also expected to fall within this
exposure window.
Medium
2
0.400
0.800
15

-------
N-Methyl-2-pyrrolidone
Study
reference:
Haufroid. V..Jaeger. V. K..Jeggli. S..Eisenegger. R..Bernard. A..Friedll. D..Lison. D..Hotz. P. (2014). Biological monitoring and health effects of
low-level exposure to N-methyl-2-pyrrolidone: a cross-sectional study International Archives of Occupational and Environmental Health, 87(6),
663-674
HERO ID: 2654929
Domain
Metric
Comments
Qualitative
Determination
Metric Score
Metric
Weighting
Factor
Weighted
Score
Outcome Assessment
7. Outcome
measurement or
characterization
Clinical outcomes (skin irritation, headaches,
neurotoxic outcomes) assessed with a semi-
structured clinical examination and questionnaires.
Spirometry results assessed by 2 physicians.
Biomarkers for haematological, renal, liver and
respiratory health also used (see metrics 16-22).
Medium
2
0.670
1.333
8.
Reporti
ng Bias
Clinical outcomes are briefly qualitatively
described, and thus cannot be extracted. The
outcome biomarkers are fully reported.
Medium
2
0.330
0.667
Potential Counfounding/Variable Control
9. Covariate Adjustment
Adjustment for age, smoking (pack years & number
of years since smoking cessation), skin disease,
glove usage, and genetic factors considered in
various analyses. Differences in nationality between
exposed and controls were not provided, but most
non-Swiss participants were German or Italian. Data
on education provided, but not adjustment for this
factor or SES. However, it is unclear if these
covariates were considered in the analysis between
NMP exposure and health outcomes.
Low
3
0.500
1.500
10. Covariate
Characterization
Smoking status/history determined with
questionnaire. Other covariates assumed to be
collected from employment records, but this is not
explicitly states.
Medium
2
0.250
0.500
11. Co-exposure
Confounding
Categorized based on exposure to additional organic
solvents. Hand washing with organic solvents also
noted on the day of biomonitoring data collection.
Medium
2
0.250
0.500
Analysis
12. Study Design and
Methods
The study design chosen was appropriate for the
research questions however the scarce data on
symptomatic effects limited the analysis. Due to
wide variation in daily NMP exposure for individual
participants, only 43% of "exposed" workers
worked with NMP the day before clinical
examination, so determination of acute health
effects in this population is somewhat compromised.
Medium
2
0.400
0.800
13. Statistical
power
Only 8 participants had exposure to only NMP,
while 38 had current exposure a mix of organic
solvents (including NMP). For reported outcomes,
and 30 were never exposed to NMP or organic
solvents. Although power calculations were done
apriori, the number of symptomatic cases was low
making interpretation difficult.
Medium
2
0.200
0.400
16

-------
N-Methyl-2-pyrrolidone
Study
reference:
Haufroid. V..Jaeger. V. K..Jeggli. S..Eisenegger. R..Bernard. A..Friedli. D..Lison. D..Hotz. P. (2014). Biological monitoring and health effects of
low-level exposure to N-methyl-2-pyrrolidone: a cross-sectional study International Archives of Occupational and Environmental Health, 87(6),
663-674
HERO ID: 2654929
Domain
Metric
Comments
Qualitative
Determination
Metric Score
Metric
Weighting
Factor
Weighted
Score

14.
Reproducibility of
analyses
Description of analysis sufficient to understand and
reproduce.
Medium
2
0.200
0.400
15. Statistical
models
Multiple linear regression models used for exposed
group and for the entire group for some outcome but
notFEVl.
Low
3
0.200
0.600
Other
16. Use of
Biomarker of
Exposure
2-HMSI (mg/1; before next shift) covered 70% of
variance. Metabolites measured in urine have long
half-lives (6-26 hrs) and are unique to NMP.
High
1
0.140
0.143
17. Effect
biomarker
Biomarkers for renal health (urinary RBP, urinary
albumin, and serum creatinine), hepatic health
(GGT expression), and respiratory health (serum
CC16) were used. Well established, but mechanisms
of action not described.
Medium
2
0.140
0.286
18. Method
Sensitivity
Metabolites measured with LC-MS/MS and a LOQ
of 0.2 mg/L.
Medium
2
0.140
0.286
Confounding / Variable Control
19. Biomarker
stability
Storage history not described, but do not have a
high likelihood of biomarker instability.
Medium
2
0.140
0.286
20. Sample
contamination
Blanks used for NMP metabolites, but no
documentation of steps used to ensure
contamination free from collection to measurement.
Low
3
0.140
0.429
Data
Presentation
and Analysis
21. Method
requirements
LC-MS/MS used for NMP metabolites
High
1
0.140
0.143
17

-------
N-Methyl-2-pyrrolidone
Study
reference:
Haufroid. V..Jaeger. V. K..Jeggli. S..Eisenegger. R..Bernard. A..Friedll. D..Lison. D..Hotz. P. (2014). Biological monitoring and health effects of
low-level exposure to N-methyl-2-pyrrolidone: a cross-sectional study International Archives of Occupational and Environmental Health, 87(6),
663-674
HERO ID: 2654929
Domain
Metric
Comments
Qualitative
Determination
Metric Score
Metric
Weighting
Factor
Weighted
Score

22. Matrix
adjustment
Creatinine adjusted and unadjusted values provided
(Table 2).
High
1
0.140
0.143
High: >=1 and <1.7
Medium: >=1.7 and <2.3
Low: >=2.3 and <=3
Sum of scores:

6
12.02
Overall Score = Sum of Weighted Scores/Sum of Metric
Weighting Factors:
NA
Overall
Score:
Nearest *:
NA
Overall Quality Level:
Low
Study
Quality
Comment:
The reviewer downgraded this study's overall quality rating. They did not provide an explanation. Note: The
original calculated score for this study was 2.0. This value is not presented above because the final rating was
changed based on professional judgement.
18

-------
N-Methyl-2-pyrrolidone
1.5. Epidemiological evaluation results of the Nishimura et al 2009 study for
musculoskeletal/motor function outcomes for cross-sectional occupational
Study
reference:
Nishimura. S..Yasui. H..Mivauchi. H..Kikuchi. Y..Kondo. N..Takebavashi. T..Tanaka. S..Mikoshiba. Y..Omae. K..Nomivama. T. C2009^. A
cross-sectional observation of effect of exposure to N-methyl-2-pyrrolidone (NMP) on workers' health Industrial Health, 47(4), 355-362
HERO ID: 735269
Domain
Metric
Comments
Qualitative
Determination
Metric Score
Metric
Weighting
Factor
Weighted
Score
a
©
1. Participant selection
Participants include 15 male workers in a factory
using NMP for cleaning instruments without
protective respiratory devices or clothing (wore
polyethylene gloves). Not stated if these 15
encompassed the entire exposed workforce or a
select subset. No information provided on
participation rate, inclusion or exclusion criteria, or
methods of participation selection.
Low
3
0.400
1.200
"S
o.
'3
"H
es
&
¦o
2. Attrition
One exposed worked excluded from study, because
he missed work on the day of health effects exam.
High
1
0.400
0.400
Tfl
3. Comparison Group
Controls selected from workers at the same factory
with no occupational NMP exposure, matched by
age, education and work load. No significant
differences in age, physical status, education,
drinking levels or smoking habits. Controls were
only sampled on the last day of the 5 day study,
compared to daily sampling in exposed group.
High
1
0.200
0.200
a
©
4.
Measurement
of Exposure
Sampling tube of 400 mg activated charcoal and air
sampling pump (flow rate 0.1 L/min) worn for 8
hr/day for 1 week (exposed) or 1 day (controls).
Analyzed with GC-MS. See reference (Xiaofei et
al.. 2000) for details.
High
1
0.400
0.400
"es
N
¦e
t5
es
~-
es
-fl
U
5. Exposure
levels
Exposure maximum (0.80 ppm) and daily means
(0.14-0.26 ppm) were below the OEL of 1 ppm
recommended by the Japan Society for
Occupational Health (JSOH). Likely to result in a
bias towards the null.
Low
3
0.200
0.600
5
O
o.
UJ
6. Temporality
Outcomes measured directly after a 1-5 days of
exposure, but history of exposure not stated.
Outcomes of skin irritation/headaches expected to
fall within this window, but some neurobehavioral
outcomes (depression, response time, and nerve
conductivity) may fall outside of this exposure
window.
Low
3
0.400
1.200
19

-------
N-Methyl-2-pyrrolidone
Study
reference:
Nishimura. S..Yasui. H..Mivauchi. H..Klkuchi. Y..Kondo. N..Takebavashi. T..Tanaka. S..Mikoshiba. Y..Omae. K..Nomivama. T. (2009). A
cross-sectional observation of effect of exposure to N-methyl-2-pyrrolidone (NMP) on workers' health Industrial Health, 47(4), 355-362
HERO ID: 735269
Domain
Metric
Comments
Qualitative
Determination
Metric Score
Metric
Weighting
Factor
Weighted
Score
Outcome Assessment
7. Outcome measurement or
characterization
Motor and sensory nerve conduction velocities of
median nerve of dominant arm (Neuropack).
Neurobehavioral tests (finger tapping, response
time, reaction time, digit span, and Benton visual
retention test) carried out on a personal computer.
These objective metrics would be ranked high.
Subjective symptoms (>50 subjective symptoms,
depression, and anxiety) were determined from self-
administered questionnaires, which would be ranked
as low. Therefore, the full study was ranked as
medium.
Medium
2
0.670
1.333
8.
Reporting
Bias
States that no significant differences were reported
in symptoms related to irritation, but no data
provided. All other outcomes fully reported and
extractable.
Medium
2
0.330
0.667
Potential Counfounding/Variable Control
9. Covariate
Adjustment
Multiple regression, multiple logistic regression and
stratification were used to adjust for potential
confounders including age, education, BMI and
smoking/drinking habits. These results were not
quantitatively reported, however, the exposed and
control groups do not have significant differences
with regards to these covariates.
Medium
2
0.500
1.000
10. Covariate
Characterization
Smoking and medical histories collected from self-
administered questionnaires. Source of age, body
weight information not stated.
Medium
2
0.250
0.500
11. Co-exposure
Confounding
Identified co-exposure to xylene (10% of cleaning
solution), which was measured by a NIOSH
method. Primary xylene metabolite (methylhippuric
acid) was measured in urine. Both measurements
fell below the limits of detection (0.1 ppm in air and
0.01 mg/dL in urine).
Medium
2
0.250
0.500
Analysis
12. Study
Design and
Methods
Study design is appropriate for the outcomes
measured. Means, standard deviations and number
of participants reported for outcomes. Linear
regression conducted, but quantitative results not
presented.
Medium
2
0.400
0.800
13. Statistical
power
Number of participants (14 exposed, 15 controls) is
small and no information on the derivation of
statistical power is provided. The number of
participants is assumed to be adequate.
Medium
2
0.200
0.400
20

-------
N-Methyl-2-pyrrolidone
Study
reference:
Nishimura. S..Yasui. H..Mivauchi. H..Kikuchi. Y..Kondo. N..Takebavashi. T..Tanaka. S..Mikoshiba. Y..Omae. K..Nomivama. T. (2009). A
cross-sectional observation of effect of exposure to N-methyl-2-pyrrolidone (NMP) on workers' health Industrial Health, 47(4), 355-362
HERO ID: 735269
Domain
Metric
Comments
Qualitative
Determination
Metric Score
Metric
Weighting
Factor
Weighted
Score

14.
Reproducibility of
analyses
Simple analysis is reproducible.
Medium
2
0.200
0.400
15. Statistical
models
Means with standard deviations presented for
outcomes. Regression models not discussed in
detail, but not reported either. The presented
analysis is sufficient.
Medium
2
0.200
0.400
Other
16. Use of
Biomarker of
Exposure
NMP was used as a biomarker, not its metabolites.
Previous study showed that it can be reflective of
exposure CBader et al.. 20071 but it was not a
quantitative association in this study. All workers
with inhalation exposure had NMP in urine, while
all controls had NMP below the limit of detection.
Medium
2
0.170
0.333
17. Effect
biomarker
Biomarker not used for effects.
Not Rated
NA
NA
NA
18. Method
Sensitivity
LOD stated and sufficiently low to detect biomarker
in all exposed samples.
Medium
2
0.170
0.333
Confounding / Variable Control
19. Biomarker
stability
Urine samples stored at 4C, which differs from the
80C stated in the method reference (Xiaofci et al..
2000). Stability and time between collection and
analysis not stated in either study.
Medium
2
0.170
0.333
20. Sample
contamination
Aside from requesting that participants washed their
hands before providing samples, no information is
provided regarding contamination.
Medium
2
0.170
0.333
Data
Presentation
and Analysis
21. Method
requirements
GC-MS used for high degree of confidence in
chemical identification.
Medium
2
0.170
0.333
21

-------
N-Methyl-2-pyrrolidone
Study
reference:
Nishimura. S..Yasui. H..Mivauchi. H..Kikuchi. Y..Kondo. N..Takebavashi. T..Tanaka. S..Mikoshiba. Y..Omae. K..Nomivama. T. (2009). A
cross-sectional observation of effect of exposure to N-methyl-2-pyrrolidone (NMP) on workers' health Industrial Health, 47(4), 355-362
HERO ID: 735269
Domain
Metric
Comments
Qualitative
Determination
Metric Score
Metric
Weighting
Factor
Weighted
Score

22. Matrix
adjustment
Creatinine adjusted and unadjusted values provided
(Table 2).
High
1
0.170
0.167
High: >=1 and <1.7
Medium: >=1.7 and <2.3
Low: >=2.3 and <=3
Sum of scores:

6
11.82
Overall Score = Sum of Weighted Scores/Sum of Metric
Weighting Factors:
1.97
Overall
Score:
Nearest *:
2
Overall Quality Level:
Medium
Study
Quality
Comment:
The reviewer agreed with this study's overall quality level.
22

-------
N-Methyl-2-pyrrolidone
1.6. Epidemiological evaluation results of the Nishimura et al 2009 study for
neurological/behavior outcomes in general
Study
reference:
Nishimura. S..Yasui. H..Mivauchi. H..Kikuchi. Y..Kondo. N..Takebavashi. T..Tanaka. S..Mikoshiba. Y..Omae. K..Nomivama. T. C2009X A
cross-sectional observation of effect of exposure to N-methyl-2-pyrrolidone (NMP) on workers' health Industrial Health, 47(4), 355-362
HERO ID: 735269
Domain
Metric
Comments
Qualitative
Determination
Metric Score
Metric
Weighting
Factor
Weighted
Score
a
©
1. Participant selection
Participants include 15 male workers in a factory
using NMP for cleaning instruments without
protective respiratory devices or clothing (wore
polyethylene gloves). Not stated if these 15
encompassed the entire exposed workforce or a
select subset. No information provided on
participation rate, inclusion or exclusion criteria, or
methods of participation selection.
Low
3
0.400
1.200
"S
o.
'3
"H
es
&
¦o
2. Attrition
One exposed worked excluded from study, because
he missed work on the day of health effects exam.
High
1
0.400
0.400
Tfl
3. Comparison Group
Controls selected from workers at the same factory
with no occupational NMP exposure, matched by
age, education and work load. No significant
differences in age, physical status, education,
drinking levels or smoking habits. Controls were
only sampled on the last day of the 5 day study,
compared to daily sampling in exposed group.
High
1
0.200
0.200
a
©
4.
Measurement
of Exposure
Sampling tube of 400 mg activated charcoal and air
sampling pump (flow rate 0.1 L/min) worn for 8
hr/day for 1 week (exposed) or 1 day (controls).
Analyzed with GC-MS. See reference (Xiaofei et
al.. 2000) for details.
High
1
0.400
0.400
"3
N
¦e
t5
es
~-
es
£
U
5. Exposure
levels
Exposure maximum (0.80 ppm) and daily means
(0.14-0.26 ppm) were below the OEL of 1 ppm
recommended by the Japan Society for
Occupational Health (JSOH). Likely to result in a
bias towards the null.
Low
3
0.200
0.600
5
O
o.
UJ
6. Temporality
Outcomes measured directly after a 1-5 days of
exposure, but history of exposure not stated.
Outcomes of skin irritation/headaches expected to
fall within this window, but some neurobehavioral
outcomes (depression, response time, and nerve
conductivity) may fall outside of this exposure
window.
Low
3
0.400
1.200
23

-------
N-Methyl-2-pyrrolidone
Study
reference:
Nishimura. S..Yasui. H..Mivauchl. H..Klkuchi. Y..Kondo. N..Takebavashl. T..Tanaka. S..Mikoshiba. Y..Omae. K..Nomivama. T. (2009). A
cross-sectional observation of effect of exposure to N-methyl-2-pyrrolidone (NMP) on workers' health Industrial Health, 47(4), 355-362
HERO ID: 735269
Domain
Metric
Comments
Qualitative
Determination
Metric Score
Metric
Weighting
Factor
Weighted
Score
Outcome Assessment
7. Outcome measurement or
characterization
Motor and sensory nerve conduction velocities of
median nerve of dominant arm (Neuropack).
Neurobehavioral tests (finger tapping, response
time, reaction time, digit span, and Benton visual
retention test) carried out on a personal computer.
These objective metrics would be ranked high.
Subjective symptoms (>50 subjective symptoms,
depression, and anxiety) were determined from self-
administered questionnaires, which would be ranked
as low. Therefore, the full study was ranked as
medium.
Medium
2
0.670
1.333
8.
Reporting
Bias
States that no significant differences were reported
in symptoms related to irritation, but no data
provided. All other outcomes fully reported and
extractable.
Medium
2
0.330
0.667
Potential Counfounding/Variable Control
9. Covariate
Adjustment
Multiple regression, multiple logistic regression and
stratification were used to adjust for potential
confounders including age, education, BMI and
smoking/drinking habits. These results were not
quantitatively reported, however, the exposed and
control groups do not have significant differences
with regards to these covariates.
Medium
2
0.500
1.000
10. Covariate
Characterization
Smoking and medical histories collected from self-
administered questionnaires. Source of age, body
weight information not stated.
Medium
2
0.250
0.500
11. Co-exposure
Confounding
Identified co-exposure to xylene (10% of cleaning
solution), which was measured by a NIOSH
method. Primary xylene metabolite (methylhippuric
acid) was measured in urine. Both measurements
fell below the limits of detection (0.1 ppm in air and
0.01 mg/dL in urine).
Medium
2
0.250
0.500
Analysis
12. Study
Design and
Methods
Study design is appropriate for the outcomes
measured. Means, standard deviations and number
of participants reported for outcomes. Linear
regression conducted, but quantitative results not
presented.
Medium
2
0.400
0.800
13. Statistical
power
Number of participants (14 exposed, 15 controls) is
small and no information on the derivation of
statistical power is provided. The number of
participants is assumed to be adequate.
Medium
2
0.200
0.400
24

O
£•
^ C/3
•-H W

'o
8 a
Qh
&
Simple analysis is reproducible.
Medium
2
0.200
0.400

15. Statistical
models
Means with standard deviations presented for
outcomes. Regression models not discussed in
detail, but not reported either. The presented
analysis is sufficient.
Medium
2
0.200
0.400

16. Use of
Biomarker of
Exposure
NMP was used as a biomarker, not its metabolites.
Previous study showed that it can be reflective of
exposure (Bader et al.. 20071 but it was not a
quantitative association in this study. All workers
with inhalation exposure had NMP in urine, while
all controls had NMP below the limit of detection.
Medium
2
0.170
0.333
Other
17. Effect
biomarker
Biomarker not used for effects.
Not Rated
NA
NA
NA

18. Method
Sensitivity
LOD stated and sufficiently low to detect biomarker
in all exposed samples.
Medium
2
0.170
0.333
Confounding / Variable Control
19. Biomarker
stability
Urine samples stored at 4C, which differs from the
80C stated in the method reference CXiaofei et al..
2000). Stability and time between collection and
analysis not stated in either study.
Medium
2
0.170
0.333
20. Sample
contamination
Aside from requesting that participants washed their
hands before providing samples, no information is
provided regarding contamination.
Medium
2
0.170
0.333
Data
Presentation
and Analysis
21. Method
requirements
GC-MS used for high degree of confidence in
chemical identification.
Medium
2
0.170
0.333
25

-------
N-Methyl-2-pyrrolidone
Study
reference:
Nishimura. S..Yasui. H..Mivauchi. H..Kikuchi. Y..Kondo. N..Takebavashi. T..Tanaka. S..Mikoshiba. Y..Omae. K..Nomlvama. T. (2009). A
cross-sectional observation of effect of exposure to N-methyl-2-pyrrolidone (NMP) on workers' health Industrial Health, 47(4), 355-362
HERO ID: 735269
Domain
Metric
Comments
Qualitative
Determination
Metric Score
Metric
Weighting
Factor
Weighted
Score

22. Matrix
adjustment
Creatinine adjusted and unadjusted values provided
(Table 2).
High
1
0.170
0.167
High: >=1 and <1.7
Medium: >=1.7 and <2.3
Low: >=2.3 and <=3
Sum of scores:

6
11.82
Overall Score = Sum of Weighted Scores/Sum of Metric
Weighting Factors:
1.97
Overall
Score:
Nearest *:
2
Overall Quality Level:
Medium
Study
Quality
Comment:
The reviewer agreed with this study's overall quality level.
26

-------
N-Methyl-2-pyrrolidone
References
Bader. M: Rosenberger. W: Rebe. T: Keener. SA: Brock. TH: Hemmerling. HJ: Wrbitzkv. R. (2006).
Ambient monitoring and biomonitoring of workers exposed to N-methyl-2-pyrrolidone in an
industrial facility. Int Arch Occup Environ Health 79: 357-364. http://dx.doi.org/10.1007/sQ0420-
005-0065-4
Bader. M: Wrbitzkv. R: Blaszkewicz. M: van Thriel. C. (2007). Human experimental exposure study on
the uptake and urinary elimination of N-methyl-2-pyrrolidone (NMP) during simulated workplace
conditions. Arch Toxicol 81: 335-346. http://dx.doi.org/10.1007/s00204-006-Q161-6
Haufroid. V: Jaeger. VK: Jeggli. S: Eisenegger. R: Bernard. A: Friedli. D: Lison. D: Hotz. P. (2014).
Biological monitoring and health effects of low-level exposure to N-methyl-2-pyrrolidone: a
cross-sectional study. Int Arch Occup Environ Health 87: 663-674.
http://dx.doi.org/10.1007/s00420-013-09Q6-5
Nishimura. S: Yasui. H: Mivauchi. H: Kikuchi. Y: Kondo. N: Takebavashi. T: Tanaka. S: Mikoshiba. Y:
Omae. K: Nomivama. T. (2009). A cross-sectional observation of effect of exposure to N-methyl-
2-pyrrolidone (NMP) on workers' health. Ind Health 47: 355-362.
Xiaofei. E: Wada. Y: Nozaki. J: Mivauchi. H: Tanaka. S: Seki. Y: Koizumi. A. (2000). A linear
pharmacokinetic model predicts usefulness of N-methyl-2-pyrrolidone (NMP) in plasma or urine
as a biomarker for biological monitoring for NMP exposure. J Occup Health 42: 321-327.
27

-------