United States hi Environmental Protection Agency Office of Chemical Safety and Pollution Prevention Final Risk Evaluation for 1,4-Dioxane Systematic Review Supplemental File: Data Quality Evaluation of Epidemiological Studies CASRN: 123-91-1 December 2020 ------- Table Listing 1 Young 1977: Evaluation of ADME/PBPK Outcomes 2 2 Young 1977: Evaluation of Irritation Outcomes 5 3 Union Carbide 1989: Evaluation of Cancer Outcomes 8 4 Garcia et al. 2015: Evaluation of Cancer Outcomes 12 This document presents data quality evaluation results for epidemiological studies evaluated for the Risk Evaluation for 1,4-Dioxane. EPA's Office of Pollution Prevention and Toxics (OPPT) developed data quality criteria for epidemiological studies. The first version of the criteria was documented in the Application of Systematic Review in TSCA Risk Evaluations document (EPA Document #740-Pl-8001). The initial criteria were updated as described in the supplemental file Final Risk Evaluation for 1,4-Dioxane Systematic Review Supplemental File: Updates to the Data Quality Criteria for Epidemiological Studies. 1 ------- Table 1: Young 1977: Evaluation of ADME/PBPK Outcomes Study Citation: Young, JD; Braun, WH; Rampy, LW; Chenoweth, MB; Blau, GE (1977). Toxicology and Environmental Health, 3(3,3), 507-520 Data Type: Dow_volunteers_14D_TK_Half-life_Urine- ADME/PBPK HERO ID: 62956 Pharmacokinetics of 1,4-dioxane in humans Journal of Domain Metric Rating^ MWF* Score Comments^ Domain 1: Study Participation Metric 1: Participant selection Medium x 0.5 Metric 2: Attrition Metric 3: Comparison Group Medium x 0.5 Not Rated NA NA Some key elements of the study design were not present and a limited number of subjects were se- lected for the study raises the potential for selec- tion 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 un- clear whether the study population is likely to be representative of the exposure-outcome distribution of the population of persons eligible for inclusion. No attrition. Metabolite used for TK model (HEAA) was not determined in the plasma of 2-3 participants due to poor ability to separate from an- other chemical. Comparison group not relevant for TK model. Subjects provided history and underwent exten- sive physical examination, chest x-ray, electrocardio- gram, blood chemistry panel, and urine analysis. All tests were repeated 24 hrs and 2 weeks after expo- sure. Results were not presented, but qualitatively stated to be healthy. Domain 2: Exposure Characterization Metric 4: Measurement of Exposure High x 0.4 Metric 5: Exposure levels Medium x 0.2 0.4 Controlled dosage study. Subjects exposed in a con- trolled airflow chamber with 1,4-dioxane concentra- tion of 48-52 ppm. Concentration in 3 breathing zones confirmed using a Wilks Miram I 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. 0.4 Blood plasma reached a plateau concentration dur- ing the study (~4hrs into exposure). Plasma con- centrations indicated a dosage of 5.4 +/- 1.1 mg/kg. Multiple levels of exposure not relevant for this study, but exposure sufficiently high to determine TK parameters. Continued on next page . .. 2 ------- . continued from previous page Study Citation: Young, JD; Braun, WH; Rampy, LW; Chenoweth, MB; Blau, GE (1977). Toxicology and Environmental Health, 3(3,3), 507-520 Data Type: Dow_volunteers_14D_TK_Half-life_Urine- ADME/PBPK HERO ID: 62956 Pharmacokinetics of 1,4-dioxane in humans Journal of Domain Metric Rating^ MWF* Score Comments^ Metric 6: Temporality High X 0.4 0.4 Plasma collection started 30 minutes after exposure began and continued for another 6 hrs. Urine collec- tion throughout exposure and for the following. Eye irritation and smell sensitization evaluated through- out exposure. Domain 3: Outcome Assessment Metric 7: Outcome measurement or characterization High Metric 8: Reporting Bias High X 0.667 0.67 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. X 0.333 0.33 Plasma 14D presented as means/standard devia- tions, 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. Domain 4: Potential Counfounding/Variable Control Metric 9: Covariate Adjustment Metric 10: Covariate Characterization Metric 11: Co-exposure Confounding Not Rated NA Not Rated Medium NA x 1 NA No covariates were adjusted for in the TK mod- els, which is appropriate when trying to represent a larger population. Minimal variation in SES ex- pected (based on job titles). All Caucasian males ages 40-49. NA Covariates determined from interviews and physi- cals. 2 No co-exposures expected. Participants experienced identical exposure scenario, but previous history not detailed. As some participants were scientists work- ing at DOW, previous co-exposures are likely. How- ever, not relevant to the current TK analysis. Domain 5: Analysis Metric 12: Study Design and Methods Metric 13: Statistical power Medium X 0.4 0.8 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 X 0.2 0.4 Only 4 participants. Statistical power not stated, but able to establish TK parameters with moderate standard deviations. Continued on next page 3 ------- . continued from previous page Study Citation: Young, JD; Braun, WH; Rampy, LW; Chenoweth, MB; Blau, GE (1977). Pharmacokinetics of 1,4-dioxane in humans Journal of Toxicology and Environmental Health, 3(3,3), 507-520 Data Type: Dow_volunteers_14D_TK_Half-life_Urine- ADME/PBPK HERO ID: 62956 Domain Metric Rating^ MWF* Score Comments^ Metric 14: Reproducibility of analyses Medium X 0.2 0.4 Calculations used for the models are clear and fully presented in tables/figures. All data needed to re- created provided. Metric 15: Statistical models Medium X 0.2 0.4 One-compartment toxicokinetic model developed for 14D using nonlinear parameter estimates. Model pa- rameters obtained per subject, such that standard deviations of individuals would reflect wider popu- lation.. Domain 6: Other Considerations for Biomarker Selection and Measurement Metric 16: Use of Biomarker of Exposure Low X 0.167 0.5 14D and primary metabolite b-hydroxyethoxyacetic acid (HEAA) were determined. HEAA was only de- termined in 3/4 of the participants (due to inter- ference - 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. Metric 17: Effect biomarker Not Rated NA NA Metric 18: Method Sensitivity Medium X 0.167 0.33 14D detected in all samples. HEAA had some inter- ferences 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. Metric 19: Biomarker stability Low X 0.167 0.5 Storage history and stability not stated. Metric 20: Sample contamination Low X 0.167 0.5 Contamination not discussed, but not anticipated. Metric 21: Method requirements High X 0.167 0.17 Instrumentation that provides unambiguous identi- fication and quantitation of the biomarker at the re- quired sensitivity (GC-MS). Metric 22: Matrix adjustment Low X 0.167 0.5 Creatinine levels determined in blood plasma and urine, but not clear if adjustments were made. Study only provides results using one method. Overall Quality Determination1 Medium 1.8 Extracted Yes MWF = Metric Weighting Factor High = 1; Medium = 2; Low = 3; Unacceptable = 4; N/A has no value. The overall rating is calculated as necessary. EPA may not always provide a comment for a metric that has been categorized as High. Overall rating = ]T\ (Metric Score; X MWF;) / J] . MWFj if any metric is Unacceptable (round to the nearest tenth) otherwise where High => 1 to < 1.7; Medium => 1.7 to < 2.3; Low => 2.3 to < 3.0. If the reviewer determines that the overall rating needs adjustment, the original rating is crossed out and an arrow points to the new rating. ^ This metric met the criteria for high confidence as expected for this type of study^ ------- Table 2: Young 1977: Evaluation of Irritation Outcomes Study Citation: Young, JD; Braun, WH; Rampy, LW; Chenoweth, MB; Blau, GE (1977). Pharmacokinetics of 1,4-dioxane in humans Journal of Toxicology and Environmental Health, 3(3,3), 507-520 Data Type: Dow volunteers 14D Eyelrritation SmellSensitization-Irritation HERO ID: 62956 Domain Metric Rating^ MWF* Score Comments^ Domain 1: Study Participation Metric 1: Participant selection Medium X 0.4 0.8 Some key elements of the study design were not present and a limited number of subjects were se- lected for the study raises the potential for selec- tion 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 un- clear whether the study population is likely to be representative of the exposure-outcome distribution of the population of persons eligible for inclusion. Metric 2: Attrition High X 0.4 0.4 No attrition. Metric 3: Comparison Group High X 0.2 0.2 Table 1 indicates characteristics of the 4 subjects were generally similar, although there were varia- tions in urine flow rate (range: 1.14 - 2.74 ml/min) and weight (range: 74.5 - 100.75 kg) Domain 2: Exposure Characterization Metric 4: Measurement of Exposure High X 0.4 0.4 Controlled dosage study. Subjects exposed in a con- trolled airflow chamber with 1,4-dioxane concentra- tion of 48-52 ppm. Concentration in 3 breathing zones confirmed using a Wilks Miram I 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. Metric 5: Exposure levels Low X 0.2 0.6 Same individuals served as unexposed and exposed group (physical before/after exposure). Metric 6: Temporality High X 0.4 0.4 Plasma collection started 30 minutes after exposure began and continued for another 6 hrs. Urine collec- tion throughout exposure and for the following. Eye irritation and smell sensitization evaluated through- out exposure. Domain 3: Outcome Assessment Metric 7: Outcome measurement or characterization Low X 0.667 2 The outcome assessment method is an insensitive measure: eye irritation and the loss of sensitivity to the smell of dioxane were self-reported. Continued on next page .. 5 ------- .. . continued from previous page Study Citation: Young, JD; Braun, WH; Rampy, LW; Chenoweth, MB; Blau, GE (1977). Pharmacokinetics of 1,4-dioxane in humans Journal of Toxicology and Environmental Health, 3(3,3), 507-520 Data Type: Dow volunteers 14D Eyelrritation SmellSensitization-Irritation HERO ID: 62956 Domain Metric Rating^ MWF* Score Comments^ Metric 8: Reporting Bias Medium x 0.333 0.67 No specific result (e.g., frequency) presented on eye irritation other than the comment 'Eye irritation was a frequent complaint throughout exposure'. Domain 4: Potential Counfounding/Variable Control Metric 9: Covariate Adjustment Medium x 0.5 1 Participants served as own controls for the eye irri- tation. Minimal variation in SES expected (based on job titles). All Caucasian males ages 40-49. Metric 10: Covariate Characterization Medium x 0.25 0.5 Covariates determined from interviews and physicals with no method validation against well-established methods. Metric 11: Co-exposure Confounding Medium x 0.25 0.5 No co-exposures expected. Participants experienced identical exposure scenario, but previous history not detailed. As some participants were scientists work- ing at DOW, previous co-exposures are likely. How- ever, not relevant to the current TK analysis. Domain 5: Analysis Metric 12: Study Design and Methods Medium x 0.5 1 Study exposed 4 volunteers to 14D in an controlled experiment. Monitored irritations and smell sensiti- zation during the experiment. Conducted full phys- icals before and after. Smell sensitization results were descriptive. Metric 13: Statistical power Unacceptable x 0.25 0.06 Only 4 participants. Metric 14: Reproducibility of analyses Medium x 0.25 0.5 The study did not use a statistical model. Metric 15: Statistical models Not Rated NA NA No statistical models were used in the study. Domain 6: Other Considerations for Biomarker Selection and Measurement Metric 16: Use of Biomarker of Exposure Low x 0.167 0.5 14D and primary metabolite b-hydroxyethoxyacetic acid (HEAA) were determined. HEAA was only de- termined in 3/4 of the participants (due to inter- ference - 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. Metric 17: Effect biomarker Not Rated NA NA Metric 18: Method Sensitivity Medium x 0.167 0.33 14D detected in all samples. HEAA had some inter- ferences 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. Metric 19: Biomarker stability Low x 0.167 0.5 Storage history and stability not stated. Metric 20: Sample contamination Low x 0.167 0.5 Contamination not discussed, but not anticipated. Continued on next page .. . 6 ------- ... continued from previous page Study Citation: Young, JD; Braun, WH; Rampy, LW; Chenoweth, MB; Blau, GE (1977). Pharmacokinetics of 1,4-dioxane in humans Journal of Toxicology and Environmental Health, 3(3,3), 507-520 Data Type: Dow_volunteers_14D_EyeIrritation_SmellSensitization-Irritation HERO ID: 62956 Domain Metric Rating^ MWF* Score Comments^ Metric 21: Method requirements Metric 22: Matrix adjustment High Low x 0.167 x 0.167 0.17 0.5 Instrumentation that provides unambiguous identi- fication and quantitation of the biomarker at the re- quired sensitivity (GC-MS). Creatinine levels determined in blood plasma and urine, but not clear if adjustments were made. Study only provides results using one method. Overall Quality Determination1" Unacceptable** 1.9 Extracted No * Consistent with our Application of Systematic Review in TSCARisk 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 or more of the metrics were rated as unacceptable. As such, the study is considered unacceptable and the score is presented solely to increase transparency. MWF = Metric Weighting Factor High = 1; Medium = 2; Low = 3; Unacceptable = 4; N/A has no value. The overall rating is calculated as necessary. EPA may not always provide a comment for a metric that has been categorized as High. Overall rating = ]T\ (Metric Score; X MWF;) / J] . MWFj if any metric is Unacceptable (round to the nearest tenth) otherwise where High => 1 to < 1.7; Medium => 1.7 to < 2.3; Low => 2.3 to < 3.0. If the reviewer determines that the overall rating needs adjustment, the original rating is crossed out and an arrow points to the new rating. ^ This metric met the criteria for high confidence as expected for this type of study 7 ------- Table 3: Union Carbide 1989: Evaluation of Cancer Outcomes Study Citation: Union Carbide (1989). Lymphatic and hematopoietic tissue cancer in a chemical manufacturing environment with attached tables and cover letter dated 02/21/89 Data Type: occupational 1,4-D, lymphatic & hematopoietic cancer-Cancer HERO ID: 597727 Domain Metric Rating^ MWF* Score Comments^ Domain 1: Study Participation Metric 1: Participant selection High Metric 2: Attrition Low Metric 3: Comparison Group Low X 0.4 0.4 Subjects were part of a large cohort mortality study in two Union Carbide Corporation chemical manu- facturing facilities and a research and development center. This case-control study selected cases of four distinct subcategories of lymphatic and hematopoi- etic tissue cancers. Study was restricted to men be- cause only 4 cases were identified in women. Con- trols were selected from the total employee cohort. Participation rates are not a concern because all in- formation was obtained via records. Controls were randomly selected and all cases (follow-up was avail- able for 96%) were included indicating that selection into or out of the study was not likely to be biased. X 0.4 1.2 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 se- lected. 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 insuffi- cient information provided on the control numbers during important stages of the study to determine if there was any attrition. x 0.2 0.6 It is unclear that the controls were free of the out- comes. The study authors did not provide baseline characteristics for the subjects to determine if the cases and controls were similar. Analysis only ad- dressed 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 em- ployed in the same decade and survived to the same five year survival period as the case. Continued on next page 8 ------- . continued from previous page Study Citation: Union Carbide (1989). Lymphatic and hematopoietic tissue cancer in a chemical manufacturing environment with attached tables and cover letter dated 02/21/89 Data Type: occupational 1,4-D, lymphatic & hematopoietic cancer-Cancer HERO ID: 597727 Domain Metric Rating^ MWF* Score Comments^ Domain 2: Exposure Characterization Metric 4: Measurement of Exposure Metric 5: Metric 6: Exposure levels Temporality Medium X 0.4 0.8 Exposure was based on job assignment and poten- tial 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 avail- able 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 his- torical information regarding process dates and de- scriptions 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 de- partmental 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. Low X 0.2 0.6 Exposure was ever/never Medium X 0.4 0.8 Temporality is established, but it is unclear whether exposures fall within relevant exposure windows for the outcome of interest. In the event that exposures which occurred close to the time of death were unre- lated to outcome, the data were also analyzed with a lagged dose. Crude odds ratios were recalculated ex- cluding 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 specif- ically determined if exposure occurred prior to de- velopment 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. Domain 3: Outcome Assessment Continued on next page 9 ------- .. . continued from previous page Study Citation: Union Carbide (1989). Lymphatic and hematopoietic tissue cancer in a chemical manufacturing environment with attached tables and cover letter dated 02/21/89 Data Type: occupational 1,4-D, lymphatic & hematopoietic cancer-Cancer HERO ID: 597727 Domain Metric Rating^ MWF* Score Comments^ Metric 7: Outcome measurement or characterization Medium X 0.667 1.33 Cases were identified from a review of both under- lying and contributory causes of death among male decedents (1940-1978) from the cohort. Based in in- formation provided in HERO ID 1010430, this in- formation was obtained from death certificate di- agnosis. 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 certifi- cates and tumor registry diagnoses for these tumors. Metric 8: Reporting Bias Medium X 0.333 0.67 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. Domain 4: Potential Counfounding/Variable Control Metric 9: Covariate Adjustment Low X 0.5 1.5 Only age-adjusted stratified analyses were also con- ducted. No other confounder was considered. Metric 10: Covariate Characterization Medium X 0.25 0.5 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. Metric 11: Co-exposure Confounding Low X 0.25 0.75 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. Domain 5: Analysis Metric 12: Study Design and Methods Medium X 0.4 0.8 The case-control design and calculation of odds ra- tios were appropriate for determining the associa- tion between exposure to 1-4D and lymphatic and hematopoietic tissue cancers. Continued on next page .. . 10 ------- . continued from previous page Study Citation: Union Carbide (1989). Lymphatic and hematopoietic tissue cancer in a chemical manufacturing environment with attached tables and cover letter dated 02/21/89 Data Type: occupational 1,4-D, lymphatic & hematopoietic cancer-Cancer HERO ID: 597727 Domain Metric Rating^ MWF* Score Comments^ Metric 13 Statistical power Unacceptable x 0.2 0.04 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. Metric 14 Reproducibility of analyses Low x 0.2 0.6 The description of the analysis is insufficient to un- derstand precisely what has been done and to be reproducible. Metric 15 Statistical models Low x 0.2 0.6 No description of the model was provided. Domain 6: Other Considerations for Biomarker Selection and Measurement Metric 16 Use of Biomarker of Exposure NA NA Metric 17 Effect biomarker NA NA Metric 18 Method Sensitivity NA NA Metric 19 Biomarker stability NA NA Metric 20 Sample contamination NA NA Metric 21 Method requirements NA NA Metric 22 Matrix adjustment NA NA Overall Quality Determination"1' Unacceptable** 2.4 Extracted No * Consistent with our Application of Systematic Review in TSCARisk 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 or more of the metrics were rated as unacceptable. As such, the study is considered unacceptable and the score is presented solely to increase transparency. MWF = Metric Weighting Factor High = 1; Medium = 2; Low = 3; Unacceptable = 4; N/A has no value. The overall rating is calculated as necessary. EPA may not always provide a comment for a metric that has been categorized as High. Overall rating = ]T\ (Metric Score; X MWF;) / J] . MWFj if any metric is Unacceptable (round to the nearest tenth) otherwise where High => 1 to < 1.7; Medium => 1.7 to < 2.3; Low => 2.3 to < 3.0. If the reviewer determines that the overall rating needs adjustment, the original rating is crossed out and an arrow points to the new rating, ft This metric met the criteria for high confidence as expected for this type of study 11 ------- Table 4: Garcia et al. 2015: Evaluation of Cancer Outcomes Study Citation: Garcia, E; Hurley, S; Nelson, DO; 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 Data Type: Cohort 1,4-D CTS BreastCancer Ql-Cancer HERO ID: 3014082 Domain Metric Rating^ MWF* Score Comments^ Domain 1: Study Participation Metric 1: Participant selection High x 0.4 Metric 2: Attrition High x 0.4 Metric 3: Comparison Group High x 0.2 0.4 California Teachers Study including active and re- tired female teachers and administrators were en- rolled in the California State Teachers Retirement System and completed a questionnaire. Study pop- ulation was comprised on 5676 women. All partic- ipants were included using the same inclusion and exclusion criteria. 0.4 Large sample of study population excluded due to women who were not residing in California at base- line, had unknown history of prior cancer, had prior history of invasive or in situ breast cancer, asked to be removed from study after joining, or had an ad- dress that couldn't be geocoded. This represents ad- equate explanation of attrition and is not expected to bias the results. 0.2 Cases and controls were stated to be similar. Covari- ates that were different between groups were consid- ered and included as covariates in the final model., including a term for grouped personal risk factors. Domain 2: Exposure Characterization Metric 4: Measurement of Exposure Medium x 0.4 Metric 5: Exposure levels Medium x 0.2 0.8 NATA identified and prioritized the air toxicants with respect to their potential population health risks. The first NATA was conducted based on 1996 emissions. EPA models annual ambient HAP con- centrations using the Assessment System for Pop- ulation Exposure Nationwide (ASPEN). This is a well-established method of determining exposure., but may lead to some non-differential exposure mis- classification. 0.4 By examining each compound individually, they cat- egorized them into four quantiles of concentration without including exposure from any other com- pound in the model. Level of exposure adequate. Included four quantiles of exposure, Q1 being no ex- posure. Continued on next page . .. 12 ------- . continued from previous page Study Citation: Garcia, E; Hurley, S; Nelson, DO; 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 Data Type: Cohort 1,4-D CTS BreastCancer Ql-Cancer HERO ID: 3014082 Domain Metric Rating^ MWF* Score Comments^ Metric 6: Temporality Medium x 0.4 0.8 Chose to use the 2002 ambient air concentration es- timates for this study because that year was approx- imately the mid-point for the follow up period. De- cided against combining multiple years of estimate due to inconsistent methodical approaches and tem- poral variations in the level of agreement between years of the assessments which could introduce ex- posure misclassification. Domain 3: Outcome Assessment Metric 7: Outcome measurement or characterization Metric 8: Reporting Bias High X 0.667 0.67 CTS cohort is followed annually for cancer diagno- sis, 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 his- tology codes for 9050-9055, 9140, and 9590-9992) af- ter the date they completed their baseline question- naire through Dec 31, 2011. High X 0.333 0.33 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. Domain 4: Potential Counfounding/Variable Control Metric 9: Covariate Adjustment Metric 10: Covariate Characterization High x 0.5 Metric 11: Co-exposure Confounding Medium x 0.25 Medium x 0.25 0.5 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. 0.5 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. 0.5 No indication of unbalanced co exposures. Domain 5: Analysis Metric 12: Study Design and Methods Metric 13: Statistical power Medium x 0.4 0.8 Medium x 0.2 0.4 Cohort was appropriate study design. Examined the relationship between risk of breast cancer and nu- merous compounds of interest. Used two different methods of parameterizing exposure in the models. Number of subjects for estimated exposure was 5676 women. There were enough subjects to detect effects for some chemicals and for some trends. Continued on next page . .. 13 ------- . continued from previous page Study Citation: Garcia, E; Hurley, S; Nelson, DO; 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 Data Type: Cohort_l,4-D_CTS_BreastCancer_Ql-Cancer HERO ID: 3014082 Domain Metric Rating^ MWF* Score Comments^ Metric 14 Reproducibility of analyses Medium x 0.2 0.4 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. Metric 15 Statistical models Medium x 0.2 0.4 Used COX proportional hazard models to estimate hazard rate ratios. Parameterized exposures into quantiles, modeled exposure as a continuous vari- able, and tested for non-zero slope using a likelihood ratio test. Domain 6: Other Considerations for Biomarker Selection and Measurement Metric 16 Use of Biomarker of Exposure NA NA Metric 17 Effect biomarker NA NA Metric 18 Method Sensitivity NA NA Metric 19 Biomarker stability NA NA Metric 20 Sample contamination NA NA Metric 21 Method requirements NA NA Metric 22 Matrix adjustment NA NA Overall Quality Determination1" High 1.5 Extracted Yes MWF = Metric Weighting Factor High = 1; Medium = 2; Low = 3; Unacceptable = 4; N/A has no value. The overall rating is calculated as necessary. EPA may not always provide a comment for a metric that has been categorized as High. Overall rating = ]T\ (Metric Score; x MWF;) / J] . MWFj if any metric is Unacceptable (round to the nearest tenth) otherwise where High => 1 to < 1.7; Medium => 1.7 to < 2.3; Low => 2.3 to < 3.0. If the reviewer determines that the overall rating needs adjustment, the original rating is crossed out and an arrow points to the new rating. ^ This metric met the criteria for high confidence as expected for this type of study 14 ------- |