Use of Biomarker Data and Relative Potencies of Mutagenic Metabolites to Support Derivation of Cancer Unit Risk Values for 1,3-Butadiene from Rodent Tumor Data
Abstract
:1. Introduction
2. Background
2.1. Previous Rodent-Based Cancer Risk Assessments for BD
2.2. Metabolism Overview
2.3. Mode of Action Summary
3. Methods
3.1. Exposure Concentration and Duration (CxT) in Tumor Response
3.2. Unit Risk Derivation
3.2.1. Human Equivalent Concentration Calculation
3.2.2. Endpoint/Dataset Selection
3.2.3. Benchmark Dose Modeling
4. Results
4.1. Exposure Concentration and Duration (CxT)
4.2. Human Equivalent Concentrations
4.3. Unit Risk Values and Species Concordance
4.4. Consideration of Sensitive Subpopulations and Additional Adjustments
5. Discussion and Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Assessor (Year) | Endpoint | Dataset | DR Model | POD Type | POD Value | Species Extrapolation Assumption | Low-Dose Extrapolation Assumption | Unit Risk (ppm−1) |
---|---|---|---|---|---|---|---|---|
USEPA [6] | Leydig cell, pancreatic exocrine cell, Zymbal gland, mammary gland, thyroid follicular cell | Male and Female Rats [7] | Multistage | LEC10 | NS | Air concentration equivalence | Linear | 0.0042–0.056 |
Lymphocytic lymphomas, histiocytic sarcomas, heart hemangiosarcomas, lung, forestomach, Harderian gland, liver, preputial gland, ovary, mammary gland | Male and Female Mice [3] | Multistage-Weibull time-to-tumor | LEC10 | 0.7–13.3 ppm | Air concentration equivalence | Linear | 0.0064–0.29 | |
Health Canada [8] | Multiple | Male and Female Rats [7] | Multistage | TC05 | 4.7–905 mg/m3 | Air concentration equivalence | NA | 0.00012–0.024 * |
Multiple | Male & Female Mice [3] | Multistage | TC05 | 1.4–23 mg/m3 | Air concentration equivalence | NA | 0.0048–0.079 * | |
OEHHA [9] | Multiple | Female MouseMale and Female Mice [3]; Male and Female Rats [7] | Multistage | NS | NS | Surface area scaling | Linear | 0.077 0.002–0.16 |
Gender | Duration (Reference) | Exposure | Concentration (ppm) | Lymphoma | Histiocytic Sarcoma | Heart | Alveolar–Bronchiolar | Forestomach | Mammary Gland | Liver | Harderian | Preputial, Ovary |
---|---|---|---|---|---|---|---|---|---|---|---|---|
Male | Acute [14] | 2 h (1×) | 0 | 7/59 | NR | NR | 8/59 | 0/59 | 0/59 | 17/59 | NR | NR |
1000 | 8/58 | NR | NR | 9/58 | 1/58 | 0/58 | 21/58 | NR | NR | |||
5000 | 8/58 | NR | NR | 12/57 | 1/58 | 0/58 | 21/58 | NR | NR | |||
10,000 | 10/58 | NR | NR | 8/58 | 3/58 | 1/58 | 18/58 | NR | NR | |||
Long-term [3] | 6 h/d, 5 d/wk, 40 wk | 200 | 8/50 | 5/50 | 15/50 | 36/50 | 3/50 | NR | 33/49 | 27/50 | 1/50 | |
6 h/d, 5 d/wk, 52 wk | 312 | 8/50 | 7/50 | 33/50 | 32/50 | 9/50 | NR | 25/50 | 30/50 | 4/50 | ||
6 h/d, 5 d/wk, 13 wk | 625 | 22/50 | 2/50 | 7/50 | 28/50 | 7/50 | NR | 24/49 | 23/50 | 5/50 | ||
6 h/d, 5 d/wk, 26 wk | 625 | 33/50 | 2/50 | 13/50 | 17/50 | 10/50 | NR | 13/50 | 13/50 | 3/50 | ||
Lifetime [3] | 6 h/d, 5 d/wk, 103 wk | 0 | 4/50 | 0/50 | 0/50 | 21/50 | 1/50 | NR | 21/50 | 6/50 | 0/50 | |
6.25 | 2/50 | 0/50 | 0/49 | 23/50 | 0/50 | NR | 23/50 | 7/50 | 0/50 | |||
20 | 4/50 | 4/50 | 1/50 | 19/50 | 0/50 | NR | 30/50 | 9/50 | 0/50 | |||
62.5 | 6/50 | 5/50 | 5/48 | 31/49 | 1/50 | NR | 25/48 | 20/50 | 0/50 | |||
200 | 2/50 | 7/50 | 20/48 | 35/50 | 8/50 | NR | 33/48 | 31/50 | 5/50 | |||
625 | 51/73 | 4/73 + | 4/73 + | 3/73 + | 4/73 + | NR | 5/72 + | 6/73 + | 0/73 + | |||
Female | Acute [14] | 2 h (1×) | 0 | 13/57 | NR | NR | 3/56 | 0/57 | 2/57 | 5/56 | NR | 0/53 |
1000 | 19/56 | NR | NR | 4/56 | 1/56 | 1/56 | 6/55 | NR | 0/52 | |||
5000 | 18/57 | NR | NR | 0/57 | 0/57 | 3/57 | 8/57 | NR | 1/53 | |||
10,000 | 13/58 | NR | NR | 3/58 | 0/58 | 4/58 | 3/58 | NR | 0/56 | |||
Lifetime [3] | 6 h/d, 5 d/wk, 103 wk | 0 | 6/50 | 3/50 | 0/50 | 4/50 | 0/50 | 0/50 | 15/49 | 8/50 | 1/49 | |
6.25 | 12/50 | 2/50 | 0/50 | 15/50 | 0/50 | 2/50 | 14/49 | 10/50 | 0/49 | |||
20 | 11/50 | 7/50 | 0/50 | 19/50 | 3/50 | 4/50 | 15/50 | 7/50 | 1/48 | |||
62.5 | 7/50 | 4/50 | 1/49 | 24/50 | 2/50 | 12/50 | 19/50 | 15/50 | 9/50 | |||
200 | 9/50 | 7/50 | 21/50 | 25/50 | 4/50 | 15/50 | 16/50 | 20/50 | 8/50 | |||
625 | 32/80 | 4/80 + | 23/80 + | 22/78 + | 22/80 + | 16/80 + | 2/80 + | 9/80 + | 6/79 + |
Target Tissues | |||||||||
---|---|---|---|---|---|---|---|---|---|
Gender | Duration | Exposure | Concentration (ppm) | Pancreas | Zymbal | Mammary | Thyroid | Glial Cell | Testis, Uterus |
Male | Lifetime | 6 h/d, 5 d/wk, 103 wk | 0 | 3/100 | 1/100 | 1/100 | 3/100 | 1/100 | 0/100 |
1000 | 1/100 | 1/100 | 2/100 | 5/100 | 4/100 | 3/100 | |||
8000 | 11/100 | 2/100 | 0/100 | 1/100 | 5/100 | 8/100 | |||
Female | Lifetime | 6 h/d, 5 d/wk, 103 wk | 0 | 2/100 | 0/100 | 50/100 | 0/100 | NR | 1/100 |
1000 | 0/100 | 0/100 | 79/100 | 4/100 | NR | 4/100 | |||
8000 | 0/100 | 4/100 | 81/100 | 11/100 | NR | 5/100 |
Metabolite-Specific Unit Internal Dose (nM*h per ppm*h BD) 1 | |||||
---|---|---|---|---|---|
Mouse | Rat | Human 1 | |||
Metabolite | Female | Male | Female | Male | Male |
EB | 13 ± 2 | 15 ± 2 | 0.77 ± 0.1 | 0.72 ± 0.1 | 0.11 ± 0.076 |
DEB | 27 ± 7 | 38 ± 8 | 1.45 ± 0.2 | 1.37 ± 0.3 | 0.024 ± 0.020 |
EBD | 266 ± 71 | 210 ± 30 | 19 ± 0.9 | 19 ± 2 | 52 ± 36 |
Metabolite | |||||
---|---|---|---|---|---|
Endpoint | EB | DEB | EDB | In Vitro Cell System | Reference |
DNA Damage | 1.00 | 11.21 | 0.961 | Human hepatocytes, pH 11.9 | [43,44] |
1.00 | 4.22 | 0.955 | Human hepatocytes, pH 9 | ||
DNA Damage Mean ± SD | 1.00 | 7.72 ± 4.94 | 0.96 ± 0.004 | ||
Mutations | 1.00 | 81.66 | 2.10 | Human TK6 (HPRT) | [45] |
1.00 | 277.12 | 4.46 | Human TK6 (TK) | ||
1.00 | 58.10 | 0.45 | Human TK6 (HPRT) | [46] | |
1.00 | 114.83 | 0.71 | Human TK6 (TK) | ||
1.00 | 49.08 | 0.35 | BB Mouse Fibroblasts | [47] | |
— 2 | — 2 | — 2 | BB Rat Fibroblasts | ||
1.00 | 4.20 | 3.87 | SA T100 | [48] | |
Mutations Mean ± SD | 1.00 | 97.5 ± 95.3 | 1.99 ± 1.81 | ||
Micronuclei | 1.00 | 128.28 | 0.58 | BB Mouse Fibroblasts | [47] |
1.00 | 124.08 | 0.74 | BB Rat Fibroblasts | ||
— 2 | — 2 | — 2 | Rat spermatids | [49] | |
Micronuclei Mean ± SD | 1.00 | 126.18 ± 2.97 | 0.66 ± 0.12 | ||
Overall Mean ± SD 3 | 1.00 | 85.28 ± 82.81 | 1.52 ± 1.48 |
Individual Metabolites | |||||
---|---|---|---|---|---|
Parameter (units) | Species/Extrapolation | EB | DEB | EBD | Metabolites Combined 3 |
Genotoxicity Index (nM*h per ppm*h BD) 1 | Female Mouse | 13.0 | 2303 | 404 | 2719 |
Male Mouse | 15.0 | 3241 | 319 | 3574 | |
Female Rat | 0.77 | 124 | 28.8 | 153 | |
Male Rat | 0.72 | 117 | 28.5 | 146 | |
Human | 0.109 | 2.04 | 79.2 | 81.4 | |
EFAK (Unitless) 2 | Human: Female Mouse | 0.00842 | 0.000886 | 0.196 | 0.0300 4 |
Human: Male Mouse | 0.00730 | 0.000630 | 0.249 | 0.0228 4 | |
Human: Female Rat | 0.142 | 0.0165 | 2.75 | 0.531 4 | |
Human: Male Rat | 0.152 | 0.0175 | 2.75 | 0.556 4 |
Dataset | Range of Model Fit Statistics for Individual Tumor Types | Unit Risk for Combined Tumor Types (ppm−1 HEC) * | |||
---|---|---|---|---|---|
Dataset | N | Range of Observation, (HEC, ppm Continuous) | p-Values | AICs | |
Female Mouse (Table 2) | 558 | 52–27,800 | 0.103–0.867 | 81.6–349.1 | 8.8 × 10−4 (5.7 × 10−4–1.2 × 10−3) |
Male Mouse (Table 2) | 756 | 49–36,550 | 0.052–0.966 | 35.6–337.3 | 3.5 × 10−4 (2.8 × 10−4–4.3 × 10−4) |
Female Rat (Table 3) | 300 | 336–2690 | 0.00016–0.969 | 35.7–357 | 6.7 × 10−5 (4.2 × 10−5–9.6 × 10−5) |
Male Rat (Table 3) | 300 | 321–2570 | 0.131–0.163 | 88.7–109 | 1.4 × 10−5 (7.5 × 10−6–2.1 × 10−5) |
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Kirman, C.R.; Hays, S.M. Use of Biomarker Data and Relative Potencies of Mutagenic Metabolites to Support Derivation of Cancer Unit Risk Values for 1,3-Butadiene from Rodent Tumor Data. Toxics 2022, 10, 394. https://doi.org/10.3390/toxics10070394
Kirman CR, Hays SM. Use of Biomarker Data and Relative Potencies of Mutagenic Metabolites to Support Derivation of Cancer Unit Risk Values for 1,3-Butadiene from Rodent Tumor Data. Toxics. 2022; 10(7):394. https://doi.org/10.3390/toxics10070394
Chicago/Turabian StyleKirman, Christopher R., and Sean M. Hays. 2022. "Use of Biomarker Data and Relative Potencies of Mutagenic Metabolites to Support Derivation of Cancer Unit Risk Values for 1,3-Butadiene from Rodent Tumor Data" Toxics 10, no. 7: 394. https://doi.org/10.3390/toxics10070394