Risk Evaluation for 1,4-dioxane Systematic Review Supplemental File: Data Quality Evaluation of Epidemiological Studies Casrn: 123-91-1


PEER REVIEW DRAFT, DO NOT CITE OR QUOTE
jjnited States	Office of Chemical Safety and
IhI	Environmental Protection Agency	Pollution Prevention
Risk Evaluation for
1,4-Dioxane
Systematic Review Supplemental File:
Data Quality Evaluation of Epidemiological Studies
CASRN: 123-91-1
June 2019
1

-------
PEER REVIEW DRAFT, DO NOT CITE OR QUOTE
Table of Contents
1. Epidemiological Studies	3
1.1.	Epidemiological evaluation results of the Garcia et al 2015 study for cancer
outcomes in general	3
1.2.	Epidemiological evaluation results of the Union et al 1989 study for cancer
outcomes in general	7
1.3.	Epidemiological evaluation results of the Young et al 1977 study for irritation
outcomes for DOW volunteers eye irritation	12
1.4.	Epidemiological evaluation results of the Young et al 1977 study for
ADME/PBPK outcomes for DOW volunteers TK half-life plasma	16
1.5.	Epidemiological evaluation results of the Young et al 1977 study for
ADME/PBPK outcomes for DOW volunteers TK half-life urine	20
2

-------
PEER REVIEW DRAFT, DO NOT CITE OR QUOTE
1. Epidemiological Studies
1.1. Epidemiological evaluation results of the Garcia et al 2015 study for cancer
	outcomes in general	

Garcia, E.,Hurley, S.,Nelson, D. 0.,Hertz, A.,Reynolds, P. (2015). Hazardous air pollutants and breast cancer risk in California teachers: a cohort
Study
study Environmental Health: A Global Access Science Source, 14(1), 14




reference:







HERO ID: 3014082




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


California Teachers Study including active and





c
retired female teachers and administrators were





03 C
.9- o
enrolled in the California State Teachers Retirement





'u '+->
t_ 
(N
had an address that couldn't be geocoded. This




3
4-*

represents adequate explanation of attrition and is





categorized them into four quantiles of




X
LU
OJ
3
CO
O
Q.
X
LU
LO
concentration without including exposure from any
other compound in the model. Level of exposure
adequate. Included four quantiles of exposure, Q1
being no exposure.
Medium
2
0.200
0.400
3

-------
PEER REVIEW DRAFT, DO NOT CITE OR QUOTE
Study
reference:
Garcia, E.,Hurley, S.,Nelson, D. O.,Hertz, A.,Reynolds, P. (2015). Hazardous air pollutants and breast cancer risk in California teachers: a cohort
study Environmental Health: A Global Access Science Source, 14(1), 14
HERO ID: 3014082
Domain
Metric
Comments
Qualitative
Determination
Metric Score
Metric
Weighting
Factor
Weighted
Score

6. Temporality
Chose to use the 2002 ambient air concentration
estimates for this study because that year was
approximately the mid-point for the follow up
period. Decided against combining multiple years
of estimate due to inconsistent methodical
approaches and temporal variations in the level of
agreement between years of the assessments
which could introduce exposure misclassification.
Medium
2
0.400
0.800
Outcome Assessment
7. Outcome measurement
or characterization
CTS cohort is followed annually for cancer
diagnosis, death, and change of address. Annual
linkage between CCR and cohort membership was
used to identify incident cancer rates. Defined a
case as any woman diagnosed with invasive breast
cancer (ICD-03 site codes C500-C509, excluding
those with histology codes for 9050-9055, 9140,
and 9590-9992) after the date they completed their
baseline questionnaire through Dec 31, 2011.
High
1
0.670
0.667
8. Reporting
Bias
CCR maintains high standards for data quality and
completeness and is estimated to be 99%
complete. Ascertained date and cause of death
from mortality files as well as reports from
relatives.
High
1
0.330
0.333
Potential Counfounding/Variable Control
9. Covariate
Adjustment
All models were stratified by age and adjusted
either for race alone or for race and personal risk
factors of interest. For each compound, p-values no
each non-degenerative quantile HR were adjusted
for multiple testing across the ten subsets using
False Discovery Rates.
High
1
0.500
0.500
10. Covariate
Characterization
Covariates were obtained from the CTS baseline
questionnaire. This was self-reported information,
but there is no evidence to suggest that it is not a
valid method of obtaining covariate information.
Medium
2
0.250
0.500
11. Co-exposure
Confounding
No indication of unbalanced co exposures.
Medium
2
0.250
0.500
Analysis
12. Study
Design and
Methods
Cohort was appropriate study design. Examined the
relationship between risk of breast cancer and
numerous compounds of interest. Used two
different methods of parameterizing exposure in
the models.
Medium
2
0.400
0.800
4

-------
PEER REVIEW DRAFT, DO NOT CITE OR QUOTE
Study
reference:
Garcia, E.,Hurley, S.,Nelson, D. O.,Hertz, A.,Reynolds, P. (2015). Hazardous air pollutants and breast cancer risk in California teachers: a cohort
study Environmental Health: A Global Access Science Source, 14(1), 14
HERO ID: 3014082
Domain
Metric
Comments
Qualitative
Determination
Metric Score
Metric
Weighting
Factor
Weighted
Score

13. Statistical
power
Number of subjects for estimated exposure was
5676 women. There were enough subjects to
detect effects for some chemicals and for some
trends.
Medium
2
0.200
0.400
14.
Reproducibility of
analyses
Study design and methods can be reproducible
with information provided. Provided reasoning on
how categories were created for exposure
quantiles, why covariates were used. Covariates
included in the models are reported explicitly.
Medium
2
0.200
0.400
15. Statistical
models
Used COX proportional hazard models to estimate
hazard rate ratios. Parameterized exposures into
quantiles, modeled exposure as a continuous
variable, and tested for non-zero slope using a
likelihood ratio test.
Medium
2
0.200
0.400
Other
16. Use of
Biomarker of
Exposure
This metric was not applicable.
NA
NA
NA
NA
17. Effect
biomarker
This metric was not applicable.
NA
NA
NA
NA
18. Method
Sensitivity
This metric was not applicable.
NA
NA
NA
NA
19. Biomarker
stability
This metric was not applicable.
NA
NA
NA
NA
20. Sample
contamination
This metric was not applicable.
NA
NA
NA
NA
5

-------
PEER REVIEW DRAFT, DO NOT CITE OR QUOTE
Study
reference:
Garcia, E.,Hurley, S.,Nelson, D. O.,Hertz, A.,Reynolds, P. (2015). Hazardous air pollutants and breast cancer risk in California teachers: a cohort
study Environmental Health: A Global Access Science Source, 14(1), 14
HERO ID: 3014082
Domain
Metric
Comments
Qualitative
Determination
Metric Score
Metric
Weighting
Factor
Weighted
Score

21. Method
requirements
This metric was not applicable.
NA
NA
NA
NA
22. Matrix
adjustment
This metric was not applicable.
NA
NA
NA
NA
High: >=1 and <1.7
Medium: >=1.7 and <2.3
Low: >=2.3 and <=3
Sum of scores:

5
7.5
Overall Score = Sum of Weighted Scores/Sum of Metric Weighting
Factors:
1.5
Overall
Score:
1.5
Overall Quality Level:
High
6

-------
PEER REVIEW DRAFT, DO NOT CITE OR QUOTE
1.2. Epidemiological evaluation results of the Union et al 1989 study for cancer
outcomes in general
Study
reference:
Union, Carbide (1989). Lymphatic and hematopoietic tissue cancer in a chemical manufacturing environment with attached tables and cover letter
dated 02/21/89
HERO ID: 597727
Domain
Metric
Comments
Qualitative
Determination
Metric Score
Metric
Weighting
Factor
Weighted
Score

1. Participant selection
Subjects were part of a large cohort mortality study
in two Union Carbide Corporation chemical
manufacturing facilities and a research and
development center. This case-control study
selected cases of four distinct subcategories of
lymphatic and hematopoietic tissue cancers. Study
was restricted to men because only 4 cases were
identified in women. Controls were selected from
the total employee cohort. Participation rates are
not a concern because all information was obtained
via records. Controls were randomly selected and
all cases (follow-up was available for 96%) were
included indicating that selection into or out of the
study was not likely to be biased.
High
1
0.400
0.400
Study Participation
2. Attrition
Vital status at follow-up was complete for 96% of
the 29,139 men in the cohort. It was noted that 5
controls were selected per case. Based on the 129
cases identified this would suggest 645 controls
selected. However, the study report does not
indicate how many controls were included in the
study nor does it report the numbers of controls in
the different work areas or chemical exposures.
There is insufficient information provided on the
control numbers during important stages of the
study to determine if there was any attrition.
Low
3
0.400
1.200

3. Comparison Group
It is unclear that the controls were free of the
outcomes. The study authors did not provide
baseline characteristics for the subjects to
determine if the cases and controls were similar.
Analysis only addressed age (and only males were
used), but no other potential differences were
addressed. Controls were selected from the total
employee cohort according to an unmatched
incidence density sampling design. It was noted
that there were 5 controls selected per case, but
other than that the number of controls was not
mentioned. Time of hire to death for cases was
categorized into five year increments of survival.
Controls were selected such that they were first
employed in the same decade and survived to the
same five year survival period as the case.
Low
3
0.200
0.600
7

-------
PEER REVIEW DRAFT, DO NOT CITE OR QUOTE
Study
reference:
Union, Carbide (1989). Lymphatic and hematopoietic tissue cancer in a chemical manufacturing environment with attached tables and cover letter
dated 02/21/89
HERO ID: 597727
Domain
Metric
Comments
Qualitative
Determination
Metric Score
Metric
Weighting
Factor
Weighted
Score
Exposure Characterization
4. Measurement of Exposure
Exposure was based on job assignment and
potential exposure, and classified on an ever/never
basis. Ever exposure was based on working 1 or
more days with the chemical. Details were stated
to be available in Ott et al., 1989 (HERO ID 104202),
which provides more details on the definition of
work areas and environmental agents. All
workplace exposures were subdivided into six
major categories. Using departmental and job
assignment records and historical information
regarding process dates and descriptions from
1925-1978, all work activities were further
subdivided into 111 distinct and mutually exclusive
work areas. Exposure to each work area or activity
was based on the work history information for each
subject. 1,020 substances were identified as having
been used or produce in one or more of the
production units over the 54 years. Potential
employee contact was based on assignment to a
departmental unit, which implied potential
exposure to any chemical in use during the time
period of the employee's assignment to that unit.
21 substances were selected for analysis. Because
1,4-dioxane did not have more than 4 cases, it was
not evaluated by duration of exposure.
Medium
2
0.400
0.800
5. Exposure
levels
Exposure was ever/never
Low
3
0.200
0.600
6. Temporality
Temporality is established, but it is unclear whether
exposures fall within relevant exposure windows
for the outcome of interest. If exposures which
occurred close to the time of death were unrelated
to outcome, the data were also analyzed with a
lagged dose. Crude odds ratios were recalculated
excluding exposures that occurred 5 years or less
from the beginning of the case survival interval. The
lag period was an average of 7 years. Because
mortality was evaluated and not incidence it cannot
be specifically determined if exposure occurred
prior to development of the disease, just that it
occurred prior to death. Nor can it be determined if
7 years is a sufficient window to be considered a
critical window for the mortality from these
cancers.
Medium
2
0.400
0.800
8

-------
PEER REVIEW DRAFT, DO NOT CITE OR QUOTE
Study
reference:
Union, Carbide (1989). Lymphatic and hematopoietic tissue cancer in a chemical manufacturing environment with attached tables and cover letter
dated 02/21/89
HERO ID: 597727
Domain
Metric
Comments
Qualitative
Determination
Metric Score
Metric
Weighting
Factor
Weighted
Score
Outcome Assessment
7. Outcome measurement or
characterization
Cases were identified from a review of both
underlying and contributory causes of death among
male decedents (1940-1978) from the cohort.
Based in information provided in HERO ID 1010430,
this information was obtained from death
certificate diagnosis. This misses cases that survived
and cases where there may have been another
cause of death. The study authors acknowledge
that there may be some misclassification of disease
status, they also note that there was agreement
between death certificates and tumor registry
diagnoses for these tumors.
Medium
2
0.670
1.333
8.
Reporting
Bias
All outcomes were reported. Confidence intervals
for risk estimates are provided in the text, but not
in tables. Number of cases were reported, but
number of controls was not.
Medium
2
0.330
0.667
Potential Confounding/Variable Control
9. Covariate
Adjustment
Only age-adjusted stratified analyses were also
conducted. No other confounder was considered.
Low
3
0.500
1.500
10. Covariate
Characterization
Work records were presumably the source of the
information, but it was not specifically identified.
Age and gender were the only covariates
considered and work records are likely a reliable
source. For cases, this information was also likely
available on the death records.
Medium
2
0.250
0.500
11. Co-exposure
Confounding
Co-exposures were considered when discussing the
cases and their exposures. However, for dioxane
this information was not available nor was
indicated if this exposure occurred in a single work
area or over several areas where co-exposures
would have varied. Controls might have been
subject to different co-exposures than cases.
Low
3
0.250
0.750
Analysis
12. Study
Design and
Methods
The case-control design and calculation of odds
ratios were appropriate for determining the
association between exposure to 1-4D and
lymphatic and hematopoietic tissue cancers.
Medium
2
0.400
0.800
13. Statistical power
The number of cases exposed to dioxane was too
low to detect an effect of exposure. The number of
controls was not reported. There were only 4 cases
total exposed to dioxane and the 4 outcomes were
evaluated separately so there was 1 case with non-
Hodgkins lymphoma and 3 cases of non-lymphatic
leukemia. This was likely insufficient to determine
the effects of exposure.
Unacceptable
4
0.2
0.800
9

14.
Reproducibility of
analyses
The description of the analysis is insufficient to
understand precisely what has been done and to be
reproducible.
Low
3
0.2
0.600

15. Statistical
models
No description of the model was provided.
Low
3
0.2
0.600

16. Use of
Biomarker of
Exposure
This metric was not applicable.
NA
NA
NA
NA

17. Effect
biomarker
This metric was not applicable.
NA
NA
NA
NA

18. Method
Sensitivity
This metric was not applicable.
NA
NA
NA
NA
<2J

4-*
O
19. Biomarker
stability
This metric was not applicable.
NA
NA
NA
NA

20. Sample
contamination
This metric was not applicable.
NA
NA
NA
NA

CO
II
si
This metric was not applicable.
NA
NA
NA
NA

. 3
T-\ CT
fN
-------
PEER REVIEW DRAFT, DO NOT CITE OR QUOTE
Study
reference:
Union, Carbide (1989). Lymphatic and hematopoietic tissue cancer in a chemical manufacturing environment with attached tables and cover letter
dated 02/21/89
HERO ID: 597727
Domain
Metric
Comments
Qualitative
Determination
Metric Score
Metric
Weighting
Factor
Weighted
Score

22. Matrix
adjustment
This metric was not applicable.
NA
NA
NA
NA
High: >=1 and <1.7
Medium: >=1.7 and <2.3
Low: >=2.3 and <=3
Sum of scores:

5
11.95
Overall Score = Sum of Weighted Scores/Sum of Metric Weighting
Factors:
2.390
Overall
Score:
2.41
Overall Quality Level:
Unacceptable1
Footnote:
1 Consistent with our Application of 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, one of the metrics were rated as
unacceptable. As such, the study is considered unacceptable and the score is presented solely to increase transparency.
11
-------
PEER REVIEW DRAFT, DO NOT CITE OR QUOTE
1.3. Epidemiological evaluation results of the Young et al 1977 study for
irritation outcomes for DOW volunteers eye irritation
Study
reference:
J. D. Young, W. H. Braun, L. W. Rampy, M. B. Chenoweth, G. E. Blau (1977). Pharmacokinetics of 1,4-dioxane in humans Journal of Toxicology and
Environmental Health, 3(3,3), 507-520
HERO ID: 62956
Domain
Metric
Comments
Qualitative
Determination
Metric Score
Metric
Weighting
Factor
Weighted
Score
Study Participation
1. Participant selection
Some key elements of the study design were not
present, and a limited number of subjects were
selected for the study raises the potential for
selection bias. Specifically, the study was
conducted on 4 Caucasian male volunteers
comprised of healthy scientists and business men
ranging in age from 40-49. Due to the low number
of participants it is unclear whether the study
population is likely to be representative of the
exposure-outcome distribution of the population of
persons eligible for
Medium
2
0.400
0.800
2. Attrition
No attrition.
High
1
0.400
0.400
3. Comparison Group
Table 1 indicates characteristics of the 4 subjects
were generally similar, although there were
variations in urine flow rate (range: 1.14 - 2.74
ml/min) and weight (range: 74.5 - 100.75 kg)
High
1
0.200
0.200
Exposure Characterization
4. Measurement of
Exposure
Controlled dosage study. Subjects exposed in a
controlled airflow chamber with 1,4-dioxane
concentration of 48-52 ppm. Concentration in 3
breathing zones confirmed using a Wilks Miram 1 IR
analyzer (8.75 um wavelength, standard curve).
Exposure lasted for 6 hrs. Plasma concentrations
indicated a dosage of 5.4 +/-1.1 mg/kg.
High
1
0.400
0.400
5. Exposure
levels
Same individuals served as unexposed and exposed
group (physical before/after exposure).
Low
3
0.200
0.600
6. Temporality
Plasma collection started 30 minutes after
exposure began and continued for another 6 hrs.
Urine collection throughout exposure and for the
following. Eye irritation and smell sensitization
evaluated throughout exposure.
High
1
0.400
0.400
12
-------
PEER REVIEW DRAFT, DO NOT CITE OR QUOTE
Study
reference:
J. D. Young, W. H. Braun, L. W. Rampy, M. B. Chenoweth, G. E. Blau (1977). Pharmacokinetics of 1,4-dioxane in humans Journal of Toxicology and
Environmental Health, 3(3,3), 507-520
HERO ID: 62956
Domain
Metric
Comments
Qualitative
Determination
Metric Score
Metric
Weighting
Factor
Weighted
Score
Outcome Assessment
7. Outcome
measurement or
characterization
The outcome assessment method is an insensitive
measure: eye irritation and the loss of sensitivity to
the smell of dioxane were self-reported.
Low
3
0.670
2.000
8.
Reporting
Bias
No specific result (e.g., frequency) presented on
eye irritation other than the comment 'Eye
irritation was a frequent complaint throughout
exposure'.
Medium
2
0.330
0.667
Potential Counfounding/Variable Control
9. Covariate
Adjustment
Participants served as own controls for the eye
irritation. Minimal variation in SES expected (based
on job titles). All Caucasian males ages 40-49.
Medium
2
0.500
1.000
10. Covariate
Characterization
Covariates determined from interviews and
physicals with no method validation against well-
established methods.
Medium
2
0.250
0.500
11. Co-exposure
Confounding
No co-exposures expected. Participants
experienced identical exposure scenario, but
previous history not detailed. As some participants
were scientists working at DOW, previous co-
exposures are likely. However, not relevant to the
current TK analysis.
Medium
2
0.250
0.500
Analysis
12. Study
Design and
Methods
Study exposed 4 volunteers to 14D in a controlled
experiment. Monitored irritations and smell
sensitization during the experiment. Conducted full
physicals before and after. Smell sensitization
results were descriptive.
Medium
2
0.500
1
13. Statistical
power
Only 4 participants.
Unacceptable
4
0.250
1
14.
Reproducibility of
analyses
The study did not use a statistical model.
Medium
2
0.200
0.400
13
-------
PEER REVIEW DRAFT, DO NOT CITE OR QUOTE
Study
reference:
J. D. Young, W. H. Braun, L. W. Rampy, M. B. Chenoweth, G. E. Blau (1977). Pharmacokinetics of 1,4-dioxane in humans Journal of Toxicology and
Environmental Health, 3(3,3), 507-520
HERO ID: 62956
Domain
Metric
Comments
Qualitative
Determination
Metric Score
Metric
Weighting
Factor
Weighted
Score

15. Statistical
models
No statistical models were used in the study.
Not Rated
NA
NA
NA

16. Use of Biomarker of
Exposure
14D and primary metabolite b-hydroxyethoxyacetic
acid (HEAA) were determined. HEAA was only
determined in 3/4 of the participants (due to
interference - not further explained). Study served
as a means of determining a quantitative
relationship between 14D dose and plasma/urine
concentrations. Precision and accuracy of
measurement technique not reported.
Low
3
0.167
0.500

17. Effect
biomarker

Not Rated
NA
NA
NA

20. Sample
contamination
Contamination not discussed, but not anticipated.
Low
3
0.167
0.500

21. Method
requirements
Instrumentation that provides unambiguous
identification and quantitation of the biomarker at
the required sensitivity (GC-MS).
High
1
0.167
0.167

22. Matrix
adjustment
Creatinine levels determined in blood plasma and
urine, but not clear if adjustments were made.
Study only provides results using one method.
Low
3
0.167
0.500
14
-------
PEER REVIEW DRAFT, DO NOT CITE OR QUOTE
Study
reference:
J. D. Young, W. H. Braun, L. W. Rampy, M. B. Chenoweth, G. E. Blau (1977). Pharmacokinetics of 1,4-dioxane in humans Journal of Toxicology and
Environmental Health, 3(3,3), 507-520
HERO ID: 62956
Domain
Metric
Comments
Qualitative
Determination
Metric Score
Metric
Weighting
Factor
Weighted
Score
High: >=1 and <1.7
Medium: >=1.7 and <2.3
Low: >=2.3 and <=3
Sum of scores:

5.952
12.367
Overall Score = Sum of Weighted Scores/Sum of Metric Weighting
Factors:
2.077
Overall
Score:
2.11
Overall Quality Level:
Unacceptable1
Footnote:
1 Consistent with our Application of 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, one of the metrics were rated as
unacceptable. As such, the study is considered unacceptable and the score is presented solely to increase transparency.
15
-------
PEER REVIEW DRAFT, DO NOT CITE OR QUOTE
1.4. Epidemiological evaluation results of the Young et al 1977 study for
ADME/PBPK outcomes for DOW volunteers TK half-life plasma
Study
reference:
J. D. Young, W. H. Braun, L. W. Rampy, M. B. Chenoweth, G. E. Blau (1977). Pharmacokinetics of 1,4-dioxane in humans Journal of Toxicology and
Environmental Health, 3(3,3), 507-520
HERO ID: 62956
Domain
Metric
Comments
Qualitative
Determination
Metric Score
Metric
Weighting
Factor
Weighted
Score
£
o
+¦»
03
Q.
1. Participant selection
Some key elements of the study design were not
present and a limited number of subjects were
selected for the study raises the potential for
selection bias. Specifically, the study was
conducted on 4 Caucasian male volunteers
comprised of healthy scientists and business men
ranging in age from 40-49. Due to the low number
of participants it is unclear whether the study
population is likely to be representative of the
exposure-outcome distribution of the population of
persons eligible for
Medium
2
0.500
1.000
+¦»
03
Q_
>
72
3
+¦»
-------
PEER REVIEW DRAFT, DO NOT CITE OR QUOTE
1,4-Dioxane
Study
reference:
J. D. Young, W. H. Braun, L. W. Rampy, M. B. Chenoweth, G. E. Blau (1977). Pharmacokinetics of 1,4-dioxane in humans Journal of Toxicology and
Environmental Health, 3(3,3), 507-520
HERO ID: 62956
Domain
Metric
Comments
Qualitative
Determination
Metric Score
Metric
Weighting
Factor
Weighted
Score
Outcome Assessment
7. Outcome
measurement or
characterization
Venous blood was drawn every hour beginning 30
minutes after initial exposure. Blood samples were
collected for 12.5 hrs after initial exposure, yielding
13 time points. Urine was collected for the 6 hrs
(during exposure), in 2 hr intervals for the next 10
hrs, then from 16-24, 24-36, and 36-48 hrs. 14D
levels in each were determined using GC/MS.
High
1
0.667
0.667
8. Reporting Bias
Plasma 14D presented as means/standard
deviations, and plasma presented as means alone
for HEAA metabolite. Urine concentrations of 14D
and HEAA presented for each individual and with
mean/standard deviation. All parameters in the TK
model and half-lives fully presented.
High
1
0.333
0.333
Potential Counfounding/Variable Control
9. Covariate
Adjustment
No covariates were adjusted for in the TK models,
which is appropriate when trying to represent a
larger population. Minimal variation in SES
expected (based on job titles). All Caucasian males
ages 40-49.
Not Rated
NA
NA
NA
10. Covariate
Characterization
Covariates determined from interviews and
physicals.
Not Rated
NA
NA
NA
11. Co-exposure
Confounding
No co-exposures expected. Participants
experienced identical exposure scenario, but
previous history not detailed. As some participants
were scientists working at DOW, previous co-
exposures are likely. However, not relevant to the
current TK analysis.
Medium
2
1.000
2.000
Analysis
12. Study Design
and Methods
Study exposed 4 volunteers to 14D and monitored
concentrations of 14D and its primary metabolite in
blood plasma and urine over the course of 2 days
to create a one-compartment toxicokinetic model
for 14D . Study design appropriate for TK models,
but not for health outcomes (eye irritation).
Medium
2
0.400
0.800
13. Statistical
power
Only 4 participants. Statistical power not stated,
but able to establish TK parameters with moderate
standard deviations.
Medium
2
0.200
0.400
17
-------
1,4-Dioxane
PEER REVIEW DRAFT, DO NOT CITE OR QUOTE

J. D. Young, W. H. Braun, L. W. Rampy, M. B. Chenoweth, G. E. Blau (1977). Pharmacokinetics of 1,4-dioxane in humans Journal of Toxicology and
Study
Environmental Health, 3(3,3), 507-520

reference:

HERO ID: 62956

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

M—
o

>•

— CO
O OJ
Calculations used for the models are clear and fully

^ u >•
T-l 3 03
presented in tables/figures. All data needed to re-
Medium
2
0.200
0.400

~a c
O 03
Q.
OJ
created provided.

75
One-compartment toxicokinetic model developed

CO
.2 "aj
3 o
for 14D using nonlinear parameter estimates.

Model parameters obtained per subject, such that
Medium
2
0.200
0.400

on E
standard deviations of individuals would reflect

T—1
wider population..

M—
o
14D and primary metabolite b-hydroxyethoxyacetic

cu
acid (HEAA) were determined. HEAA was only

2 aj
determined in 3/4 of the participants (due to

1 s
CO O
m_ a.
interference - not further explained). Study served
as a means of determining a quantitative
Low
3
0.167
0.500

LU
OJ
relationship between 14D dose and plasma/urine

=)
concentrations. Precision and accuracy of

VD
T—1
measurement technique not reported.

17. Effect
biomarker
This metric was not applicable.
Not Rated
NA
NA
NA
<2J
-C
o &
14D detected in all samples. HEAA had some

o
>
QJ
Sh 1/1
interferences for plasma. LOD 0.1-0.2 ug/ml for 14D
in plasma and urine. LOD for HEAA 1 ug/ml in urine
and 2-10 ug/ml in plasma.
Medium
2
0.167
0.333

19. Biomarker
stability
Storage history and stability not stated.
Low
3
0.167
0.500

C
QJ .2
Q. "re
E .£
03 C
CO ^
Contamination not discussed, but not anticipated.
Low
3
0.167
0.500

. ro
o
^ o
U

18
-------
PEER REVIEW DRAFT, DO NOT CITE OR QUOTE
1,4-Dioxane
Study
reference:
J. D. Young, W. H. Braun, L. W. Rampy, M. B. Chenoweth, G. E. Blau (1977). Pharmacokinetics of 1,4-dioxane in humans Journal of Toxicology and
Environmental Health, 3(3,3), 507-520
HERO ID: 62956
Domain
Metric
Comments
Qualitative
Determination
Metric Score
Metric
Weighting
Factor
Weighted
Score

21. Method
requirements
Instrumentation that provides unambiguous
identification and quantitation of the biomarker at
the required sensitivity (GC-MS).
High
1
0.167
0.167
22. Matrix
adjustment
Creatinine levels determined in blood plasma and
urine, but not clear if adjustments were made.
Study only provides results using one method.
Low
3
0.167
0.500
High: >=1 and <1.7
Medium: >=1.7 and <2.3
Low: >=2.3 and <=3
Sum of scores:

6
10.7
Overall Score = Sum of Weighted Scores/Sum of Metric Weighting
Factors:
1.777
Overall
Score:
1.8
Overall Quality Level:
Medium
19
-------
1,4-Dioxane
PEER REVIEW DRAFT, DO NOT CITE OR QUOTE
1.5. Epidemiological evaluation results of the Young et al 1977 study for
ADME/PBPK outcomes for DOW volunteers TK half-life urine
Study
reference:
J. D. Young, W. H. Braun, L. W. Rampy, M. B. Chenoweth, G. E. Blau (1977). Pharmacokinetics of 1,4-dioxane in humans Journal of Toxicology and
Environmental Health, 3(3,3), 507-520
HERO ID: 62956
Domain
Metric
Comments
Qualitative
Determination
Metric Score
Metric
Weighting
Factor
Weighted
Score
£
o
+¦»
03
Q.
1. Participant selection
Some key elements of the study design were not
present and a limited number of subjects were
selected for the study raises the potential for
selection bias. Specifically, the study was
conducted on 4 Caucasian male volunteers
comprised of healthy scientists and business men
ranging in age from 40-49. Due to the low number
of participants it is unclear whether the study
population is likely to be representative of the
exposure-outcome distribution of the population of
persons eligible for inclusion.
Medium
2
0.500
1.000
+¦»
03
Q_
>
72
3
+¦»
-------
PEER REVIEW DRAFT, DO NOT CITE OR QUOTE
1,4-Dioxane
Study
reference:
J. D. Young, W. H. Braun, L. W. Rampy, M. B. Chenoweth, G. E. Blau (1977). Pharmacokinetics of 1,4-dioxane in humans Journal of Toxicology and
Environmental Health, 3(3,3), 507-520
HERO ID: 62956
Domain
Metric
Comments
Qualitative
Determination
Metric Score
Metric
Weighting
Factor
Weighted
Score
Outcome Assessment
7. Outcome
measurement or
characterization
Venous blood was drawn every hour beginning 30
minutes after initial exposure. Blood samples were
collected for 12.5 hrs after initial exposure, yielding
13 time points. Urine was collected for the 6 hrs
(during exposure), in 2 hr intervals for the next 10
hrs, then from 16-24, 24-36, and 36-48 hrs. 14D
levels in each were determined using GC/MS.
High
1
0.667
0.667
8. Reporting Bias
Plasma 14D presented as means/standard
deviations, and plasma presented as means alone
for HEAA metabolite. Urine concentrations of 14D
and HEAA presented for each individual and with
mean/standard deviation. All parameters in the TK
model and half-lives fully presented.
High
1
0.333
0.333
Potential Counfounding/Variable Control
9. Covariate
Adjustment
No covariates were adjusted for in the TK models,
which is appropriate when trying to represent a
larger population. Minimal variation in SES
expected (based on job titles). All Caucasian males
ages 40-49.
Not Rated
NA
NA
NA
10. Covariate
Characterization
Covariates determined from interviews and
physicals.
Not Rated
NA
NA
NA
11. Co-exposure
Confounding
No co-exposures expected. Participants
experienced identical exposure scenario, but
previous history not detailed. As some participants
were scientists working at DOW, previous co-
exposures are likely. However, not relevant to the
current TK analysis.
Medium
2
1.000
2.000
Analysis
12. Study Design
and Methods
Study exposed 4 volunteers to 14D and monitored
concentrations of 14D and its primary metabolite in
blood plasma and urine over the course of 2 days
to create a one-compartment toxicokinetic model
for 14D . Study design appropriate for TK models,
but not for health outcomes (eye irritation).
Medium
2
0.400
0.800
13. Statistical
power
Only 4 participants. Statistical power not stated,
but able to establish TK parameters with moderate
standard deviations.
Medium
2
0.200
0.400
21
-------
1,4-Dioxane
PEER REVIEW DRAFT, DO NOT CITE OR QUOTE
Study
reference:
J. D. Young, W. H. Braun, L. W. Rampy, M. B. Chenoweth, G. E. Blau (1977). Pharmacokinetics of 1,4-dioxane in humans Journal of Toxicology and
Environmental Health, 3(3,3), 507-520
HERO ID: 62956
Domain
Metric
Comments
Qualitative
Determination
Metric Score
Metric
Weighting
Factor
Weighted
Score

14.
Reproducibility of
analyses
Calculations used for the models are clear and fully
presented in tables/figures. All data needed to re-
created provided.
Medium
2
0.200
0.400

15. Statistical
models
One-compartment toxicokinetic model developed
for 14D using nonlinear parameter estimates.
Model parameters obtained per subject, such that
standard deviations of individuals would reflect
wider population..
Medium
2
0.200
0.400

Not Rated
NA
NA
NA

18. Method
Sensitivity
14D detected in all samples. HEAA had some
interferences for plasma. LOD 0.1-0.2 ug/ml for 14D
in plasma and urine. LOD for HEAA 1 ug/ml in urine
and 2-10 ug/ml in plasma.
Medium
2
0.167
0.333
o
4-*
£
o
u
.a
.1S
'u
03
19. Biomarker
stability
Storage history and stability not stated.
Low
3
0.167
0.500
CUD
C
'-a
c
3
£
c
o
u
20. Sample
contamination
Contamination not discussed, but not anticipated.
Low
3
0.167
0.500
22
-------
PEER REVIEW DRAFT, DO NOT CITE OR QUOTE
1,4-Dioxane
Study
reference:
J. D. Young, W. H. Braun, L. W. Rampy, M. B. Chenoweth, G. E. Blau (1977). Pharmacokinetics of 1,4-dioxane in humans Journal of Toxicology and
Environmental Health, 3(3,3), 507-520
HERO ID: 62956
Domain
Metric
Comments
Qualitative
Determination
Metric Score
Metric
Weighting
Factor
Weighted
Score
Data Presentation and Analysis
21. Method
requirements
Instrumentation that provides unambiguous
identification and quantitation of the biomarkerat
the required sensitivity (GC-MS).
High
1
0.167
0.167
22. Matrix
adjustment
Creatinine levels determined in blood plasma and
urine, but not clear if adjustments were made.
Study only provides results using one method.
Low
3
0.167
0.500
High: >=1 and <1.7
Medium: >=1.7 and <2.3
Low: >=2.3 and <=3
Sum of scores:

6
10.7
Overall Score = Sum of Weighted Scores/Sum of Metric Weighting
Factors:
1.7833
Overall
Score:
1.8
Overall Quality Level:
Medium
23
-------