Does Fiber Counting Count?

Transcription

1 Does Fiber Counting Count? David Egilman MD, MPH Expert in Externalities Clinical Associate Professor Department of Community Health Brown University Editor-in-Chief International Journal of Occupational and Environmental Medicine 1

2 Harold St. John 2

3 The Construct Brake exposures do not cause mesothelioma because lung fiber counts in brake workers are comparable to those in unexposed controls. Srebro, Roggli & Samsa 1995 Malignant mesothelioma associated with low pulmonary tissue asbestos burdens 3

4 Study design in theory Call lung fibers counts in unexposed hospital pts who did not have asbestos related disease or exposure Control levels and assume these levels are safe background exposures. Pts who have mesothelioma whose levels are above control levels asbestos caused 4

5 Problem* If controls worked side by side with meso cases this is a meaningless comparison. If you do not know where the controls worked You cannot assume they were unexposed 5

6 Problem* The listed occupation for three of the 19 controls was NA (not available) No information on smoking for 10 of the controls This indicates that Srebro failed to access or record from information sources that almost always contain this information, such as complete medical records or interviews with family members, to determine what jobs or environmental exposures the controls had. 6

7 Did controls have occupational or environmental exposures?* No interviews conducted on deceased controls Three of 19 controls had no employment history available (Originally 20 controls) Ten of 19 controls had no smoking history available, indicating full medical records and interviews were not accessed CONTROLS 7

8 Did controls have environmental exposures? Did not check controls for possible environmental exposures. Roggli believes household exposures can cause mesothelioma Roggli believes living near an asbestos mine or manufacturing plant can cause mesothelioma 8

9 Did controls have occupational exposures? Control cases included: 3 manual laborers 2 Air Force enlistees 2 hospital workers 1 electrical engineer 1 spinning mill worker 1 truck driver 1 garage owner CONTROLS 9

10 Did controls have occupational exposures? Among the top 10 most frequent occupations recorded in workers with mesothelioma: Truck drivers Hospital workers (22 AB in Roggli s control) Electricians These are in the control group. Work-Related Lung Disease Surveillance Report, Cincinnati, OH: National Institute for Occupational Safety and Health; Report No.:

11 Did controls have occupational exposures?* Spinning mill worker had fibers and may have had exposure to asbestos through work. In control group. CONTROLS 11

12 Did controls have occupational exposures? Roggli reports in 1992 that manual laborers had occupational exposures and had median asbestos body counts of 830, nearly three times higher than levels in shipyard workers. Henderson DW. Malignant mesothelioma. New York: Hemisphere Pub. Corp.; 1992:295. Srebro, Roggli and Samsa put them in their control group. CONTROLS 12

13 Did controls have occupational or environmental exposures? Controls only statistically distinguishable from exposed cases after throwing out one control with amosite level that seemed too high. No effort made to investigate possible exposures of other controls Control 24, unknown occupation, had highest fiber count among controls more than 3X the next highest control and the fifth highest level for all cases reported. 13

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15 What Happens when Roggli applied this method? Conclusion: He deemed mesotheliomas in workers with these work histories of Uncertain etiology = Idiopathic Shipyard worker Ship engine room Brake worker 15

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17 Method applied Brake workers are these caused cases? 17

18 Case 5 Roggli discounts brake exposure as a cause for mesothelioma based on two of the single fiber tremolite control cases 20 (manual laborer with 19.6 Abs) and 24 the control with alzheimer s. Otherwise, case 5 has higher tremolite levels than all but one of his controls (and no amphiboles). This would meet his original criteria of > 95% of controls 18

19 Additional Flight problems 1. Lung fiber counts are not indicative of what actually gets into the pleura and causes cancer 2. Unexposed controls were probably exposed or exposure was unknown 3. Fiber counting is not reliable (Not reproducible) or accurate (not actual value) 19

20 Why is this bad? 1. If lung fiber burdens are not reflective of pleura fiber burdens, the results are at best useless and at worse misleading. 2. If controls had occupational exposures, the premise on which Roggli s conclusions are based is invalid. 3. If methods are inaccurate or inconsistent, results are invalid or misleading. 20

21 Is fiber counting reliable? Roggli writes: Non-standard technique The wide variety of preparative techniques and analytical methodologies that have been employed by various investigators make it difficult to extrapolate results from ne laboratory to another. The actual analytical result obtained on any one sample can be profoundly influenced by the steps employed in the analytical procedure. Interlaboratory comparison trials demonstrate that striking differences can occur among laboratories even when the same sample is analyzed. Roggli VL, Oury TD, Sporn TA. Pathology of asbestos-associated diseases. 2nd ed. New York: Springer; DOES FIBER COUNTING COUNT? 21

22 Is fiber counting reliable? Roggli writes: large intra- and inter-laboratory variation In addition to inter-laboratory variation, intra-laboratory variation can occur, which may be due either to changes in a laboratory s procedures over time, or to variation in fiber content from one site to another within the lung. Morgan and Holmes have reported a five to tenfold site-to-site variation based on analyses of multiple samples from a single lung using phase contrast light microscopy. Roggli VL, Oury TD, Sporn TA. Pathology of asbestos-associated diseases. 2nd ed. New York: Springer; DOES FIBER COUNTING COUNT? 22

23 Is fiber counting reliable? Sampling variability: Roggli has agreed that the numbers of fibers can vary from site to site within the lung by a factor of anywhere from two to five. Roggli has agreed that there are as many as ten short chrysotile fibers for every one he can count >5μm. Roggli VL. Deposition Testimony. Jones, v. Dana Corporation, Circuit Court for the City of Newport News Virginia, Law No T-01.; 2006 Jan 13. This 15,000% variability would appear to violate the Daubert standard for reliability. DOES FIBER COUNTING COUNT? 23

24 Do fibers in the lung predict what fibers will be in the pleura? Fibers in the pleura NOT THE LUNG are responsible for pleural mesothelioma. Chrysotile fibers are biopersistent in the pleura, but not in the lung. Churg warns that lung fiber counting suffers from unknown patters of fiber clearance over time. Churg A. Chrysotile, tremolite, and malignant mesothelioma in man. Ches. 1988;93: DOES FIBER COUNTING COUNT? 24

25 Do fibers in the lung predict what fibers will be in the pleura? Using a one year half-life for chrysotile and a 20 year half-life for amphiboles, the amount of chrysotile remaining in the lung 30 years after exposure would be 1 billionth of what was inhaled, while almost 30 percent of the amosite would still be present in the lung. DOES FIBER COUNTING COUNT? 25

26 Mean weight of dust in lungs of rats in relation to dose and time Amphiboles biopersists in the lung Chrysotile biopersists in the pleura Wagner JC, Berry G, Skidmore JW, Timbrell V. The effects of the inhalation of asbestos in rats. Br J Cancer 1974;29: DOES FIBER COUNTING COUNT? 26

27 Lung fiber counts systematically underestimate chrysotile pathogenicity Predominant fibers in lung Predominant fibers in pleura Based on data from Suzuki Y, Yuen SR. Asbestos tissue burden study on human malignant mesothelioma. Ind Health 2001; 39: DOES FIBER COUNTING COUNT? 27

28 Relative Proportion of Short and Long Fibers in Lung Tissue. uncounted Reproduced from: LeBouffant L. Investigation and analysis of asbestos fibers and accompanying minerals in biological materials. Environ Health Perspect 1974;9: DOES FIBER COUNTING COUNT? 28

29 Amphiboles uber allis Roggli discounts chrysotile if any amphibole is present due to Relative Potency But there are synergy issues and animal testing issues. Human data has not accounted for short fibers or pleural content 29

30 Relative mesothelioma potency by fiber type in rats DOES FIBER COUNTING COUNT? 30

31 Relative lung tumor potency by fiber type in rats DOES FIBER COUNTING COUNT? 31

32 Can fiber counting determine how long a fiber has been in the lung? Q. Now, the asbestos fibers that you would find on a lung tissue digestion on autopsy, you have no way of knowing when any particular fiber that you see entered the lung, do you? A. That's correct. Roggli VL. Testimony. St. John v. Affina Group, Superior Court of New Jersey, Law Division: Middlesex County Docket No. Mid-L ; 2009 Mar 10. DOES FIBER COUNTING COUNT? 32

33 Looking where the light is better Roggli and coauthors reject the use of pleural fiber counts because of the alledged difficulties in obtaining samples. Roggli VL. Deposition testimony. Paz v AW Chesterton et al., Circuit Court, Third Judicial Circuit, Madison County, Illinois Jan 27. DOES FIBER COUNTING COUNT? 33

34 Did the counting method count short fibers? Short fibers are the most common and often the only type found in the pleura Roggli s method fails to count fibers shorter than 5 µm Blinded cross-laboratory comparison: Dodson found 84 chrysotile fibers Roggli found 1 METHODS 34

35 Did the counting method reflect actual fiber levels? SEM (scanning electron microscope) set at 1000X misses chrysotile fibers <0.15 µm in diameter Most chrysotile fibers are between µm Misleading conclusion: chrysotile is not an important cause of mesothelioma METHODS 35

36 Was a standard procedure used for all cases and controls? Srebro, Roggli & Samsa used two different techniques They claimed these techniques were comparable HOWEVER, the range of counts for their subjects showed that values differed by 10 fold ( ) between the techniques METHODS 36

37 Was a standard method used to compare cases to controls? Different standards for cases and controls One-fiber Cases: DISCOUNTED One-fiber Controls: INCLUDED Discounted fivers found when the result was positive but below the highest detection limit in any of the controls Discounted chrysotile as a cause even if levels were greater than 95% of all controls METHODS 38

38 DOES FIBER COUNTING COUNT? Counting fibers in the lung does not tell us what caused cancer in the pleura. Controls with potential exposures above background levels negates the conclusion that exposure from brake work does not significantly contribute to mesothelioma. Inaccuracies in measuring techniques lead to systematic underestimation of chrysotile burden and systematic overemphasis on importance of amphiboles. 39

39 DOES FIBER COUNTING COUNT? Roggli said it himself in a 2000 paper: Fiber burden studies do not accurately reflect past exposures to chrysotile. These studies afford limited information regarding the role of chrysotile asbestos-related lung cancer since chrysotile is broken down in and removed from the lung. And long, thin, greater than 5 micron chrysotile fibers are not readily detectable by our technique. 40