1 Asbestos & Cancer: An Update Suresh H. Moolgavkar, M.D., Ph.D.
2 Fiber Type and Cancer Epidemiological data clearly indicate that not all fiber types have the same potency as carcinogens. With respect to potency: Crocidolite>>Amosite>>Chrysotile
3 Outline of Talk Review of epidemiological evidence. Role of biopersistence in determining carcinogenic potency. Experimental evidence relating biological halflife to potency. Quantitative relationship between half-life and carcinogenic potency. Implications for asbestos risk.
4 Review of Epidemiological Evidence Hodson & Darnton, Berman & Crump, McDonald et al, 2001.
5 Hodgson & Darnton, Careful quantitative analyses based on 17 cohorts occupationally exposed to asbestos. Conclusions: Mesothelioma: Croc:Amosite:Chrysotile::500:100:1 Lung Cancer: Amphiboles:Chrysotile::10-50:1
6 Berman & Crump, 2005 Careful quantitative analyses of 20 cohorts occupationally exposed to asbestos (14 of 17 in H&D included). Conclusions: Mesothelioma: Amphiboles:Chrysotile::660:1 Lung Cancer: Amphiboles:Chrysotile::3.5:1
7 McDonald et al, 2001 Case-control study of mesothelioma and lung burden of asbestos. Clear association with amphiboles. Much weaker association with chrysotile. Caveat: Appropriate controls were difficult to obtain.
8 Central Issues Biopersistence Fiber Dimensions
9 Risk Assessment Paradigm Time dependent Exposure Dose Response Deposition, Clearance (Biopersistence) Dose-response model
10 Figure 1 Fiber Burden as Function of Age Exposure: 100 fibers/ml from day 70 for 728 days Fiber burden Amosite e-glass RCF 1a 0 X Age
11 Model for analyses Need model that takes explicit account of time-dependent pattern of lung dose, i.e., fiber burden. Not sufficient to consider cumulative or average dose. Empirical statistical models do not have desirable properties. Models based on ideas of multistage carcinogenesis are preferable.
12 General Multistage Model Three main phases in cancer development: 1. Accumulation of genetic changes leading to partial abrogation of growth control: Initiation. 2. Clonal expansion of initiated cells: Promotion. 3. Acquisition of further genetic changes during clonal expansion leading to one (or more) malignant cells: Malignant Conversion. Consider action of environmental agents (e.g., smoking, exposure to fibers) on each of the phases of the process.
13 Risk Assessment for Fibers Objective of Analyses: Develop rationale for regulation based on relatively short-term deposition and clearance experiments so that long-term oncogenicity experiments need not be performed. Strategy: Demonstrate that a fiber is a fiber independent of chemistry, i.e., oncogenic potential depends only on temporal pattern of fiber burden and not on fiber type.
14 Have experimental data on the following types of fibers: RCF1 (controls, 3, 9, 16 and 30 mg./m 3 exposure groups); RCF2, RCF3, RCF4 (each at 30mg./ m 3 exposure); MMVFs 10, 11, 21, 22 (controls, and for each MMVF 3, 16, 30 mg./ m 3 exposures); X607 (30 mg./ m 3 exposure group); Chrysotile (10 mg./ m 3 exposure group). Serial sacrifices performed - information on fiber count in the lungs and on tumor pathology.
15 RESULTS Data consistent with the hypothesis that a fiber is a fiber.
16 Range of unit risks is about 2.0 x x X607 alone 4.5 x 10-5 NS RCF1 alone 8.8 x 10-5 NS X607 + RCF1 7.0 x 10-5 NS MMVF x 10-5 NS MMVF x 10-5 NS MMVF x 10-5 NS MMVF X 10-5 NS All MMVF 4.4 x 10-5 S!! All Fibers 6.1 x 10-5 S!!
17 Extend analyses to other fibers Extend analyses to 12 fibers considered by Bernstein et al (1996). Use their estimated weighted half lives for the long fibers to generate lung burdens under the EU protocol. Use estimated consensus parameter from analyses of RCF and MMVF to generate Unit Risks and tumor probabilities.
18 Figure 1 Fiber Burden as Function of Age Exposure: 100 fibers/ml from day 70 for 728 days Fiber burden Amosite e-glass RCF 1a 0 X Age in days
19 Figure 2 Tumor Probability as a Function of Age 0.20 Exposure: 100 fibers/ml from day 70 for 728 days Amosite 0.15 e-glass Tumor Probability X 607 RCF 1a 0.00 Control Age in days
20 Figure 3 Unit Risk for various fibers Amosite Unit Risk Fiber L 45.0 e-glass 68.4 RCF1a MMVF Fiber H 13.0 X607 Fiber F Fiber A Fiber B Fiber C Fiber G Fiber
21 Figure 4 Unit Risk as a function of WHL III III II II Unit Risk I Unit Risk I WHL WHL
22 Figure 2 Excess Risk as a function of exposure 0.3 Amosite 0.2 Excess Risk e-glass RCF1a 0.1 X Exposure (fibers/ml)
23 Conclusions 1. Good evidence from limited experimental data that carcinogenic potential of long fibers is determined principally by biopersistence (half-life). 2. The ratio of amphibole/chrysotile half-lives in rodent lungs is consistent with the amphibole/chrysotile ratio in human lung cancer risks as reported in Hodgson & Darnton, but not Berman & Crump. 3. The ratio of amphibole/chrysotile half-lives in rodent lungs under-estimates the amphibole/chrysotile ratio in human mesothelioma risks.
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