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Perspectives Correspondence


									  Perspectives Correspondence
Radiographic Abnormalities                          false positive bias due to subpleural fat,                 The results presented by Peipins et al.
and Asbestos Exposure:                              which would be expected to be greater in               (2003) and results from other studies of
Libby, Montana                                      the environmental exposure group than in               asbestos in Libby indicate that occupational
                                                    the mine worker group (Price B. In press).             exposure—not low-level environmental
Peipins et al. (2003) described the study               Peipins et al. (2003) implied that                 exposure—is the most significant risk factor
conducted by the Agency for Toxic                   asbestos exposure was high in Libby:                   for asbestos-related disease. Peipins et al.
Substances and Disease Registry (ATSDR               Air sampling in downtown Libby in 1975 and at         should have stated that conclusion explicitly,
2001, 2002a) to analyze the association              several points in the 1980s detected levels well      taking the first step toward correcting mis-
between the prevalence of radiographic               above the Occupational Safety and Health              perceptions about asbestos disease in Libby
abnormalities and asbestos exposure path-            Administration’s [OSHA] occupational limit of         and, more generally, the risk of disease asso-
ways for residents of Libby, Montana.                0.1 fiber/cm3 over 8 hr of exposure (Atkinson et      ciated with low-level exposures to amphibole
                                                     al. 1982; Dixon et al. 1985; U.S. Department of
Although Peipins et al. presented many               Labor 1994).                                          asbestos.
detailed results, they failed to explicitly state                                                            The author declares he has no competing
the obvious conclusion of their analysis:           However, the cited references do not con-              financial interests.
excess risk of asbestos-related disease for         tain data for samples collected in 1975.
Libby residents is a consequence of occupa-         Dixon et al. (1985) reported that a total of                                         Bertram Price
tional exposure, and risk associated with           four stationary samples were collected, each                                  Price Associates, Inc.
low-level exposure is negligible. This find-        for 2 hr (Atkinson et al. 1982). These sam-                                 White Plains, New York
ing is extremely important for guiding              ples, analyzed by two laboratories, produced                  E-mail:
future public health assessments of exposure        the following measurements, respectively:
to vermiculite from the Libby mine and              0.08 and 0.50 fiber/cm 3 , 0.10 and                                           REFERENCES
exposure to amphibole asbestos in general.          0.02 fiber/cm3, 0.03 fiber/cm3 and none
    Peipins et al. (2003) made a clear case for     detected, and 0.03 and 0.02 fiber/cm 3 .               Amandus HE, Wheeler R. 1987. The morbidity and mortality of
                                                                                                                vermiculite miners and millers exposed to tremolite-acti-
the importance of occupational exposure.            Comparison of these 2-hr sampling results                   nolite: Part II. Mortality. Am J Ind Med 11(1):15–26.
They reported the following statistically sig-      to OSHA’s 8-hr limit is not meaningful.                Atkinson GR, Rose D, Thomas K, Chatfield EJ, Going JE.
nificant factors for predicting pleural abnor-      Also, because the measurements vary con-                    1982. Collection, Analysis and Characterization of
                                                                                                                Vermiculite Samples for Fiber Content and Asbestos
malities: being a former mine worker; being         siderably between laboratories, the largest                 Contamination. EPA Contract 68-01-5915. Washington,
older; having been a household contact of a         measurement is not a reliable estimate of                   DC:U.S. Environmental Protection Agency.
mine worker; and being male. These results          exposure in Libby.                                     ATSDR. 2000. Health Consultation, Mortality from Asbestosis
                                                                                                                in Libby, Montana. Atlanta, GA:Agency for Toxic
associate pleural abnormalities with high               Recently, the U.S. Environmental                        Substances and Disease Registry. Available: http://
occupational exposure groups—mine                   Protection Agency (U.S. EPA 2001, 2002)           
workers and household contacts of mine              measured airborne asbestos levels in Libby                  [accessed 7 January 2004].
                                                                                                           ———. 2001. Year 2000 Medical Testing of Individuals
workers. Only one environmental exposure            and estimated exposure for Libby residents                  Potentially Exposed to Asbestiform Minerals Associated
pathway was statistically significant—              engaged in activities that disturbed house-                 with Vermiculite in Libby, Montana: A Report to the
played in vermiculite pile, which may               hold dust, vermiculite attic insulation, and                Community. Atlanta, GA:Agency for Toxic Substances and
                                                                                                                Disease Registry.
involve exposures as high as occupational           soil. The results, stated as lifetime average          ———. 2002a. Preliminary Findings of Libby, Montana
exposures.                                          daily exposure, ranged from 0.00007 to                      Asbestos Medical Testing (Combined Testing, 2000 and
    The ATSDR data (ATSDR 2001,                     0.005 fiber/cm3. Risk levels calculated by                  2001). Atlanta, GA:Agency for Toxic Substances and
2002a) indicate that 17.8% of the 6,668             the U.S. EPA for these exposures were                       Disease Registry.
                                                                                                           ———. 2002b. Mortality in Libby, Montana, 1979-1998.
subjects with X-ray films had pleural abnor-        between 1 × 10–6 and 1 × 10–4, the accept-                  Atlanta, GA:Agency for Toxic Substances and Disease
malities. This percentage appears large in          able range defined by the U.S. EPA (1989)                   Registry.
comparison to 6.7% of subjects with                 for regulatory decisions.                              Dixon GH, Doria J, Freed JR, Wood P, May I, Chambers T, et al.
                                                                                                                1985. Exposure Assessment for Asbestos-Contaminated
pleural abnormalities in the internal control           The study described by Peipins et al.                   Vermiculite. EPA-560/5-85- 013. Washington, DC:U.S.
group (no exposure). However, occupa-               (2003) is one of a number of studies                        Environmental Protection Agency.
tional exposures inflate the difference.            addressing asbestos exposure and risk in               McDonald C. 2001. Carcinogenicity of fibrous tremolite in
                                                                                                                workplace and general environments. Presented at the
I reanalyzed the data by forming three              Libby (Amandus and Wheeler 1987;                            Asbestos Health Effects Conference, 24 May 2001,
exposure groups: mine workers, residents            ATSDR 2000, 2001, 2002a, 2002b;                             Oakland, CA. Available:
with other occupational or domestic expo-           McDonald 2001; McDonald et al. 1986;                        ahec/summary.htm [accessed 12 January 2004].
                                                                                                           McDonald JC, McDonald AD, Armstrong B, Sebastien P.
sure, and residents with no occupational or         McDonald JC. Unpublished data; U.S. EPA                     1986. Cohort study of mortality of vermiculite miners
domestic exposure (the “environmental               2001, 2002). The perception that mine                       exposed to tremolite. Br J Ind Med 43(7):436–444.
exposure only” group) (Price B. In press).          workers’ disease rates apply to all Libby resi-        Peipins LA, Lewin M, Campolucci S, Lybarger JA, Miller A,
                                                                                                                Middleton D, et al. 2003. Radiographic abnormalities and
Pleural abnormalities were recorded for 51%         dents gained credibility through the                        exposure to asbestos-contaminated vermiculite in the
of mine workers, 19.9% of residents with            ATSDR (2000) asbestosis mortality study:                    community of Libby, Montana, USA. Environ Health
other occupational or domestic exposure,            “… mortality in Libby resulting from                        Perspect 111:1753–1759; doi:10.1289/ehp.6346 [Online
and 9.1% of residents with no occupational          asbestosis was approximately 40–60 times                    2 July 2003]
                                                                                                           Price B. In press. Asbestos Exposure and Health Risks: Libby
or domestic exposure.                               higher than expected.” Later, the ATSDR                     Montana. J Regul Toxicol Pharmacol.
    These results again demonstrate the             (2002b) explained that the excess mortality            U.S. Department of Labor. 1994. Occupational Exposure to
importance of occupational exposure for             was a consequence of occupational exposure.                 Asbestos. 29CFR Parts 1910, 1915, 1926. Final Rule. Fed
                                                                                                                Reg 59:40964–41162.
pleural abnormalities. The percentage for           As noted by Peipins et al. (2003), the                 U.S. EPA. 1989. Risk Assessment Guidance for Superfund,
the “environmental exposure only” group is          ATSDR observed a total of 12 asbestosis                     Part B. EPA/540/1-89/002. Washington, DC:U.S.
close to the percentage for the internal con-       deaths: 11 males who were previously                        Environmental Protection Agency. Available: http://
trols. Other confounding factors mentioned          employed at the Libby mine and 1 female                     [accessed 12 January 2004].
by Peipins et al. (2003) could further reduce       who was a household contact of a mine                  U.S. EPA. 2001. Memorandum from Chris Weis, U.S. EPA, to
the difference. One of those factors is the         worker.                                                     Paul Peronard, U.S. EPA. Amphibole Mineral Fibers in

A 82                                                                           VOLUME   112 | NUMBER 2 | February 2004 • Environmental Health Perspectives

     Source Materials in Residential and Commercial Area of   WRG workers. We controlled for subpleural           The authors declare they have no competing
     Libby Pose an Imminent and Substantial Endangerment to   fat by including BMI in both our multivari-       financial interests.
     Public Health. Washington, DC:U.S. Environmental
     Protection Agency, 20 December 2001.                     ate analyses and our pathways analyses.
U.S. EPA. 2002. Memorandum from Chris Weis, U.S. EPA, to      Therefore, the associations between environ-                                Lucy A. Peipins
     Paul Peronard, U.S. EPA. Revised Screening Risk          mental exposures, as well as occupational         Centers for Disease Control and Prevention
     Estimates. Washington, DC:US Environmental Protection
     Agency, 22 November 2002.
                                                              and domestic exposure, and pleural abnor-                                   Atlanta, Georgia
                                                              malities remained when controlled for BMI.
                                                                   In regard to Price’s comments on past                                          Michael Lewin
Radiographic Abnormalities:                                   exposures in Libby, sampling performed by                                     Sharon Campolucci
Response from Peipins et al.                                  WRG in 1975 showed markedly elevated                                           Jeffrey A. Lybarger
                                                              ambient air asbestos concentrations in                                                 Vikas Kapil
We appreciate Price’s interest in our article                 downtown Libby [U.S. Environmental                                                 Dan Middleton
(Peipins et al. 2003). We stated clearly that                 Protection Agency (EPA 2002)]. These                                   Agency for Toxic Substances
being a former W.R. Grace (WRG) worker                        findings are consistent with the limited                                      and Disease Registry
was a significant risk factor for both pleural                ambient air samples collected by the U.S.                                          Atlanta, Georgia
and interstitial abnormalities. We also noted                 EPA (Dixon et al. 1985; Atkinson et al.                                   E-mail:
that only age was more strongly associated                    1982). Although Price points out that the
with these outcomes in multivariate analyses                  variation in detectable laboratory results                                    Aubrey Miller
and that these results were not unexpected.                   ranged from 0.02 to 0.5 fiber/cm3, depend-                                Christopher Weis
     However, we disagree with Price’s state-                 ing on the laboratory, it is clear that the             U.S. Environmental Protection Agency
ment that the obvious conclusion of our                       ambient air concentrations in Libby easily                                 Denver, Colorado
analysis is that risk associated with low-level               approached, if not exceeded, occupational
environmental exposure is negligible. Such a                  8-hr limits. In a cross-sectional study of                                    Michael Spence
conclusion ignores key results. For example,                  workers at an Ohio fertilizer plant that                         Montana Department of Health
we found that playing in the vermiculite                      processed vermiculite from Libby, Montana,                                and Human Services
piles and longer duration of residence in                     Lockey et al. (1984) found that workers with                                Helena, Montana
Libby, Montana, were associated with                          daily time-weighted-average exposures of
pleural abnormalities, even after controlling                 0.031–0.415 fiber/cm3, similar to the ambi-                                          Brad Black
for occupational and domestic exposures                       ent air concentrations reported in Libby, had                      Lincoln County Department of
(Peipins et al. 2003). We also found that the                 significantly elevated radiographic pleural                                Environmental Health
prevalence of pleural abnormalities increased                 changes and pleuritic chest pain.                                                Libby, Montana
with increasing number of exposure path-                           Price asserts that Agency for Toxic
ways, even after we removed WRG workers                       Substances and Disease Registry (ATSDR)                                  REFERENCES
from the analysis. This suggests a cumulative                 mortality studies conducted for the Libby
effect from multiple exposures that exclude                   area have created a false perception of the       Anderson H, Lilis R, Daum S, Selikoff IJ. 1979. Asbestosis
                                                                                                                     among household contacts of asbestos factory workers.
working in the mine.                                          community’s asbestos-related mortality expe-           Ann NY Acad Sci 330:387–399.
     Price incorrectly labels our “no-apparent-               rience. Results from ATSDR’s mortality            Atkinson GR, Rose D, Thomas K, Chatfield EJ, Going JE. 1982.
exposure” group as an “internal control                       study (ATSDR 2002) revealed significantly              Collection, Analysis and Characterization of Vermiculite
                                                                                                                     Samples for Fiber Content and Asbestos Contamination.
group.” We did not have an internal no-                       elevated rates of mesothelioma, asbestosis,            EPA Contract 68-01-5915. Washington, DC:U.S.
exposure group (Peipins et al. 2003). Our                     and lung cancer when compared with the                 Environmental Protection Agency.
no-apparent-exposure group consisted of                       Montana and U.S. populations. Workers             ATSDR. 2000. Health Consultation, Mortality from Asbestosis
                                                                                                                     in Libby, Montana. Atlanta, GA:Agency for Toxic
participants who responded “no” to the                        were included in the determination of                  Substances and Disease Registry. Available: http://
exposure pathways listed in the questionnaire                 asbestos-related mortality in Libby, as is done
and who were likely exposed via ambient air                   as a matter of practice throughout the nation          [accessed 7 January 2004].
                                                                                                                ATSDR. 2002. Mortality in Libby, Montana, 1979-1998. Atlanta,
and other pathways not assessed by our                        to determine comparative standardized mor-             GA:Agency for Toxic Substances and Disease Registry
screening questionnaire. The rate of 6.7%                     tality rates. Nevertheless, there were several    Castellan RM, Sanderson WT, Petersen MR. 1985. Prevalence
for the no-apparent-exposure group in our                     deaths found that did not appear to be occu-           of radiographic appearance of pneumoconiosis in an
                                                                                                                     unexposed blue collar population. Am Rev Respir Dis
analysis and the rate of 9.1% given by Price                  pationally related. Notably, one of the three          131:684–686.
in his letter are considerably higher than the                mesothelioma cases identified for inclusion in    Dixon GH, Doria J, Freed JR, Wood P, May I, Chambers T, et al.
prevalence rates of pleural abnormalities                     our study (Peipins et al. 2003) did not occur          1985. Exposure Assessment for Asbestos-Contaminated
found in published studies of other nonoccu-                  among former mine workers (ATSDR 2002).                Vermiculite. EPA-560/5-85-013. Washington, DC:U.S.
                                                                                                                     Environmental Protection Agency.
pationally exposed populations in the United                  Additionally, Lincoln County, Montana, had        Lockey JE, Brooks SM, Jarabek AM, Khoury PR, McKay RT,
States, which range from 0.2% among blue-                     the highest age-adjusted asbestosis mortality          Carson A, et al. 1984. Pulmonary changes after exposure
collar workers in North Carolina (Castellan                   rate in the United States for 1988–1997,               to vermiculite contaminated with fibrous tremolite. Am
                                                                                                                     Rev Respir Dis 129:952–958.
et al. 1985) to 2.3% among patients at                        even when compared to other counties that         Miller JA, Zurlo JV. Asbestos plaques in a typical Veteran’s
Veterans Affairs hospitals in New Jersey                      contain large asbestos exposed workforces              hospital population. 1996. Am J Ind Med 6:726–729.
(Miller and Zurlo 1996). Of note, these                       (Castellan R. Unpublished data).                  Peipins LA, Lewin M, Campolucci S, Lybarger JA, Miller A,
                                                                                                                     Middleton D, et al. 2003. Radiographic abnormalities and
studies did not exclude family contacts of                         On the basis of our results, we conclude          exposure to asbestos-contaminated vermiculite in the
workers or domestic exposures (Castellan                      that both occupational and environmental               community of Libby, Montana, USA. Environ Health
et al. 1985; Anderson et al. 1979).                           risk factors are important predictors of               Perspect 111:1753–1759; doi:10.1289/ehp.6346 [Online
                                                                                                                     2 July 2003].
     When assessing subpleural fat as a con-                  asbestos-related radiographic abnormalities       U.S. EPA. 2002. Libby Site Administrative Record. Denver,
founding factor, we found former WRG                          in this community. We thank Price for his              CO:EPA Record Center, Superfund Reference Desk.
workers to have higher body mass indexes                      comments and hope that this letter provides            Available:
                                                                                                                     libby/qdocs020610.html [accessed 9 January 2004].
(BMIs) than those who were not former                         additional insights to these issues.

Environmental Health Perspectives            • VOLUME 112 | NUMBER 2 | February 2004                                                                                 A 83

Overstating the Consequences                         B-readers 1 and 2 prior to making his                                                J. Jay Flynn
of Radiographic Abnormalities                        interpretation. Although control films or a                                      Stephen Kardos
“Radiographic Abnormalities and Exposure             control group would have been useful in                                                   Lin Yan
to Asbestos-Contaminated Vermiculite in              resolving these issues, they were not used.                          Health Network America, Inc.
the Community of Libby, Montana, USA”                    Peipins et al. (2003) bolstered their                             West Eatontown, New Jersey
by Peipins et al. (2003) is the first journal        findings with the assertion that “if two out            E-mail:
publication by the Agency for Toxic                  of three B-readers indicated…,” implying
Substances and Disease Registry (ATSDR)              agreement between these readers. The                                          REFERENCES
of the results of their multiyear medical            HNA’s review (HNA. Unpublished data)
testing program of Libby residents. Peipins          reveals that in many instances this was not            ATSDR. 2001. Year 2000 Medical Testing of Individuals
                                                                                                                Potentially Exposed To Asbestoform Minerals Associated
et al.’s (2003) conclusion that 18% of study         the case. For example, if one reader found a               with Vermiculite in Libby, Montana A Report to the
participants had pleural abnormalities has           potential pleural plaque on the right chest                Community. Atlanta, GA:Agency for Toxic Substances and
received wide attention and has lead to              wall and the second reader recorded a possi-               Disease Registry. Available:
                                                                                                                asbestos/doc_phl_testreport.html [accessed 12 January
understandable concern among Libby resi-             ble pleural plaque on the left chest wall or               2004].
dents and health professionals. We, as prin-         diaphragm, this was apparently recorded as             Peipins LA, Lewin M, Campolucci S, Lybarger JA, Miller A,
cipals of Health Network America (HNA)               a positive finding of an abnormality by two                Middleton D, et al. 2003. Radiographic abnormalities and
                                                                                                                exposure to asbestos-contaminated vermiculite in the
and administrators of the Libby Medical              B-readers. These discrepancies were not                    community of Libby, Montana, USA. Environ Health
Plan (LMP), are in the unique position of            reported by the ATSDR to study partici-                    Perspect 111:1753–1759; doi:10.1289/ehp.6346 [Online
having participated in the peer review of            pants or by Peipins et al. (2003).                         2 July 2003].
applicants and members of the LMP. The                   Perhaps the most troubling issue in the
LMP is a health benefit program for the peo-         study by Peipins et al. (2003) is the misread-
ple who lived in and around Libby and                ing of plaques or thickening when only
developed an asbestos-related condition. The         pleural fat was present. While acknowledging           Overstating the Consequences:
peer reviewers include two board-certified           the confounding influence of obesity and               Peipins et al.’s Response
radiologists who specialize in chest radiogra-       pleural fat in determining pleural disease,            Flynn et al. raise concerns about differences
phy and/or pneumoconiosis and are certi-             Peipins et al. (2003) failed to scientifically         in chest radiograph interpretation and bias
fied B-readers, and a third board-certified          account for this. The ATSDR (2001)                     among B-readers in our study (Peipins et al.
radiologist who specializes in interpretation        reported that the body mass indexes (BMIs)             2003). Furthermore, they suggest that an
of pleural disease on chest computed tomog-          of 67% of the 7,307 participants were ≥ 25,            internal review by Health Network America
raphy (CT) scans. Although the review                indicating overweight, and 32% of these                (HNA) found misdiagnosis in many cases,
process is ongoing, some of our preliminary          were obese (BMI of ≥ 30). We indepen-                  with subpleural fat being miscoded as
observations are relevant because they               dently verified the true incidence of over-            asbestos-related pleural changes.
include many cases reported as “abnormal”            weight and obesity by calculating BMIs of                   In the Libby, Montana, screening pro-
by the ATSDR. In this letter we seek to              the LMP participants: 89% were overweight              gram, all films were reviewed by at least two
communicate the more serious issues raised           and 54% were obese (Table 1).                          experienced B-readers, with a third B-reader
by this review process.                                  Peipins et al. (2003) conceded that                functioning as a “tiebreaker” to settle dis-
     The basic ATSDR study design included            a heavier BMI can make it more difficult to dis-      agreements. Participants were categorized as
a three-view chest X ray (posterior–anterior,         tinguish between pleural abnormalities and sub-       “positive” if two B-readers reported any
left and right, and obliques) on all partici-         pleural or extraplural fat ...                        pleural abnormality, and as “indeterminate”
pants over 18 years of age, with the X rays to                                                              if only one B-reader reported an abnormal-
be interpreted by three B-readers. If two of         This difficulty was clearly present in their           ity. For clinical purposes, participants in
the B-readers identified a pleural or interstitial   study. As part of the HNA review, X rays               both the “positive” and the “indeterminate”
abnormality, this would be regarded as a pos-        and CT scans of study participants were sent           categories were notified and encouraged to
itive response by the ATSDR. If only one of          for peer review as described above. Although           follow up with their personal physician.
the initial two B-readers identified an abnor-       this review is continuing, it is clear that in         The three B-readers are respected experts in
mality, the third B-reader also performed an         many cases, participants coded as positive             the field and are distinguished members of
interpretation.                                      for pleural changes either had no visible              academic institutions. Furthermore, the
     Several problems are raised by this             asbestos-related changes on their X rays or            design of the screening program employed
design. First, all B-readers were aware that         they had subpleural fat that was misdiag-              is similar to that used in previous studies of
the X rays were of Libby residents, opening          nosed as pleural thickening or plaques.                asbestos-related radiographic abnormalities
the door to reader bias. Second, the B-read-             As a result of the study bias, non-                (Rogan et al. 1987, 2000).
ers knew the sequence in which they                  conformity of the B-reader reports, and not                 Although the B-readers in the screening
reviewed the films. B-readers 1 and 2 knew           accounting for high BMIs and pleural fat,              program were aware that the X rays were
they were always the first or second reader.         the study by Peipins et al. (2003) markedly            from the Libby area, they had no other
B-reader 3, then, not only knew the X rays           overstated the consequences of asbestos                information about occupational or environ-
were from Libby but also had the reports of          exposure in Libby, Montana.                            mental exposure pathways and were blinded
                                                       The authors are employees of Health Network          to the identities of individuals who were
Table 1. BMIs from LMP applicant and member          America, which is the plan administrator for the       screened. This is important because a clear
data (n = 341).
                                                     Libby Medical Plan. Medical evidence in support        exposure–response relationship was docu-
BMI                                      No. (%)     of applications is peer-reviewed by independent        mented between the presence of pleural
≥ 40                                      23 (7)     medical professionals to determine eligibility.        abnormalities and the number of exposure
30–39.9                                  160 (47)    Health Network America is paid a fee for its ser-      pathways reported by participants. Only
25–29.9                                  120 (35)    vices that is independent of admission or nonad-       6.7% of the group with “no apparent expo-
< 25                                      38 (11)    mission of applicants to the plan.                     sure” had pleural abnormalities, compared

A 84                                                                            VOLUME   112 | NUMBER 2 | February 2004 • Environmental Health Perspectives

to 10.8% of the group reporting one to                                     REFERENCES                               expert’s practice and avoid liability problems.
three exposure pathways, 14.4% of the                                                                               Also, all communications should be carefully
group reporting four to five exposure path-         Peipins LA, Lewin M, Campolucci S, Lybarger JA, Miller A,       edited before they are sent.
                                                        Middleton D, et al. 2003. Radiographic abnormalities and
ways, and 23.7% of the group reporting six              exposure to asbestos-contaminated vermiculite in the             Scientists who serve as expert witnesses
or more pathways. This trend remained sig-              community of Libby, Montana, USA. Environ Health            in federal lawsuits should be prepared to jus-
nificant even after controlling for body mass           Perspect 111:1753–1759; doi:10.1289/ehp.6346 [Online        tify their theories and methods used in each
                                                        2 July 2003].
index in the multivariate analysis.                 Rogan WJ, Ragan NB, Dinse GE. 2000. X-ray evidence of           case in a Daubert hearing. This is a layman’s
    We recently evaluated preliminary data              increased asbestos exposure in the US population from       shorthand reference to the 1993 U.S.
from high resolution chest computed                     NHANES I and NHANES II, 1973-1978. National Health          Supreme Court decision in Daubert v.
                                                        Examination Survey. Cancer Causes Control 11:441–449.
tomography (CT) scans conducted on                  Rogan WJ, Gladen BC, Ragan NB, Anderson HA. 1987. US
                                                                                                                    Merrell Dow Pharmaceuticals, Inc. (1993).
353 Libby medical screening participants                prevalence of occupational pleural thickening. A look at    The Daubert case radically altered the rules
with “indeterminate” chest radiographs.                 chest X-rays from the first National Health and Nutrition   for expert witnesses in federal court. For
                                                        Examination Survey. Am J Epidemiol 126:893–900.
Pleural abnormalities were identified in                                                                            most of the twentieth century, federal courts
98 persons (28% of all tested) whose chest                                                                          were supposed to permit expert witnesses to
radiographs were classified as “indetermi-                                                                          offer scientific evidence at trial only if the
                                                    Expert Witnesses Need to
nate” (i.e., only one out of three B-readers                                                                        scientific principles involved were generally
noted an abnormality). This suggests that           Know About the New Risks                                        accepted within their field. In the Daubert
the results of the Libby screening program          Professionals should not enter into provid-                     case, the Supreme Court held that the gen-
may have actually underestimated the                ing witness or consulting services without                      eral acceptance test was too restrictive and
number of abnormal findings.                        considering their personal liabilities. I                       was not compatible with modern rules of
    In summary, we disagree with Flynn              would like to provide some recent changes                       evidence.
et al.’s assertion that these findings can be       and liability issues for the consideration of                        On one hand, the Daubert case (Daubert
explained by study bias issues related to           expert witnesses and consultants.                               v. Merrell Dow Pharmaceuticals, Inc. 1993)
chest radiograph B-readings or by misinter-              Times change, as does the law. Under                       opened the courthouse door to novel scien-
pretation of pleural fat. Rather, more recent       recent court decisions, an expert witness                       tific evidence. On the other hand, this case
high-resolution CT scanning results suggest         whose work fails to meet professional stan-                     vested trial judges with a gatekeeping role to
that our estimates of pleural abnormalities         dards may find himself/herself being hauled                     weed out “irrational pseudoscientific asser-
in this population may be conservative and          back into court as a defendant in a malprac-                    tions,” or to separate cutting-edge principles
may actually underestimate the true preva-          tice claim. If the expert knows of possible per-                from “junk science” (Daubert v. Merrell
lence of these abnormalities seen on chest          sonal weaknesses, hiring additional experts to                  Dow Pharmaceuticals, Inc. 1993). As part
radiographs.                                        cover these weak areas is a feasible solution.                  of their gatekeeping function, judges are
  The authors declare they have no competing             Historically, witnesses could not be sued                  required to make a preliminary assessment
financial interests.                                for defamation on the basis of their testimony                  to determine whether the expert’s theory or
                                                    in court. The law granted this immunity to                      technique has been and can be tested,
                          Lucy A. Peipins           encourage candid testimony, or as one court                     whether it has been subject to peer review
Centers for Disease Control and Prevention          put it, “to ensure that the path to truth is left               and publication, and whether the theory or
                          Atlanta, Georgia          as free and unobstructed as possible.”                          technique has a known or potential rate of
                                                         In 1999, however, the Supreme Court                        error.
                            Michael Lewin           of Pennsylvania carved a large exception out                         Courts have not established hard and
                      Sharon Campolucci             of the immunity doctrine for expert wit-                        fast rules on the manner in which they will
                       Jeffrey A. Lybarger          nesses. In the case of LLMD of Michigan,                        decide Daubert objections. The process
                               Vikas Kapil          Inc. v. Jackson-Cross Co. (1999), the court                     could be as simple as the lawyers submitting
                           Dan Middleton            held that a client could sue his expert wit-                    documents to the judge, or it could involve
               Agency for Toxic Substances          ness for negligence if the expert fails to exer-                a form of mini-trial in which the court
                      and Disease Registry          cise the care and skill common to his                           hears testimony from the expert and other
                           Atlanta, Georgia         profession in forming his opinions on the                       experts who attempt to validate or discredit
                  E-mail:            client’s case.                                                  the expert’s theories and practices at issue.
                                                         In 2002, the Supreme Court of Appeals                           What should scientists do, knowing that
                          Aubrey Miller             in West Virginia took the issue further in                      their work as expert witnesses may be
                      Christopher Weis              Davis v. Wallace (2002) when it suggested                       rejected by a judge and knowing that their
    U.S. Environmental Protection Agency            that an expert witness could be sued for neg-                   own clients may sue them if the case turns
                       Denver, Colorado             ligence not only by his own client but also by                  out badly? Some experts may decide that it
                                                    the opposing party against whom the expert                      is not worth the liability exposure and may
                        Michael Spence              testifies. Experts need to keep up with their                   decline invitations to serve as an expert wit-
           Montana Department of Health             fields of interest in the era of rapid new                      ness. But doing good, reliable, legally defen-
                    and Human Services              information. This can be done by reading,                       sible work is the best way a scientist can
                      Helena, Montana               attending meetings, and talking with other                      survive a Daubert challenge.
                                                    experts. Publishing articles in peer-reviewed                     The author declares he has no competing
                              Brad Black            journals can help document and prove exper-                     financial interests.
            Lincoln County Department of            tise to the judge. Keeping good records,
                    Environmental Health            which display knowledge through good writ-                                           Henry G. Nowicki
                          Libby, Montana            ing skills, is critical; many decisions are based                 PACS Testing, Consulting, and Training
                                                    on written documents. Continuing educa-                                         Pittsburgh, Pennsylvania
                                                    tion courses are available to improve the                                       E-mail:

Environmental Health Perspectives   • VOLUME 112 | NUMBER 2 | February 2004                                                                                 A 85

                           REFERENCES                                In most cases, a model user cannot ascertain                       Jaworska JS, Comber M, Auer C, Van Leeuwen CJ. 2003.
                                                                                                                                            Summary of a workshop on regulatory acceptance of
                                                                     whether a particular model may or may not                              (Q)SARs for human health and environmental endpoints.
    Daubert v. Merrell Dow Pharmaceuticals, Inc. 1993. Case No.      be used for a particular compound and end
        92-102. U.S. Supreme Court, Washington, DC.                                                                                         Environ Health Perspect 111:1358–1360.
    Davis v. Wallace. 2002. Case No. 29966. Civil Action 99-C-146.   point to be estimated. Without tests of com-                       Kaiser KLE, Niculescu SP. 1999. Using probabilistic neural
        West Virginia Supreme Court of Appeals, Charleston,          parative performance, this conundrum exists                            networks to model the toxicity of chemicals to the fat-
        WV.                                                                                                                                 head minnow (Pimephales promelas): a study based on
                                                                     for users of most models. Even for quite                               865 compounds. Chemosphere 38:3237–3245.
    LLMD of Michigan, Inc. v. Jackson-Cross Co. 1999. Case No.
        559, Pa.297, 740 A.2d 186. Pennsylvania Supreme Court of     similar compounds, model outputs can vary                          ———. 2001a. Modeling the acute toxicity of chemicals to
s       Appeals, Harrisburg, PA.                                     by several orders of magnitude between both                            Daphnia magna: a probabilistic neural network approach.
                                                                                                                                            Environ Toxicol Chem 20:420–431.
                                                                     models and measured values. For example,                           ———. 2001b. On the PNN modelling of estrogen receptor
                                                                     predictions of octanol/water partition coeffi-                         binding data for carboxylic acid esters and organochlo-
    Validation of (Q)SARs Models                                     cients (a physical property) for a small set of                        rine compounds. Water Qual Res J Canada 36:619–630.
                                                                                                                                        ———. In press. Neural network modeling of Vibrio fischeri
    From a practitioner’s point of view (but                         quite similar compounds by commonly used                               toxicity data with structural physico-chemical parame-
    not having been part of the workshop), I                         models show a large divergence of values                               ters and molecular indicator variables. In: QSARs for
    feel compelled to comment on “Summary                            (Vrakas et al. 2003). Therefore, the (only)                            Predicting Ecological Effects of Chemicals (Walker JD,
                                                                                                                                            ed). Pensacola, FL:SETAC Press.
    of a Workshop on Regulatory Acceptance                           proof of model accuracy is in the testing of                       Moore DRJ, Breton RL, MacDonald DB. 2003. A comparison
    of (Q)SARs for Human Health and                                  each model’s performance against a broad                               of model performance for six quantitative structure-
    Environmental Endpoints” by Jaworska                             spectrum of measured data, which are not                               activity relationship packages that predict acute toxicity
                                                                                                                                            to fish. Environ Technol Chem 22:1799–1809.
    et al. (2003).                                                   part of the training set of each model. In                         Niculescu SP, Kaiser KLE, Schultz TW. 2000. Modeling the
         There are a variety of quantitative struc-                  practice, this means that performance of a                             toxicity of chemicals to Tetrahymena pyriformis using
    ture–activity relationships [(Q)SARs] models                     model should be the driving force for its                              molecular fragment descriptors and probabilistic neural
    available for a variety of purposes, and, as                     acceptability in the regulatory world, not its                         networks. Arch Environ Toxicol Chem 39:289–298.
                                                                                                                                        TerraBase, Inc. 2002. TerraQSAR – FHM. Fish Toxicity
    stated by Jaworska et al. (2003), predictive                     statistics.                                                            Computation              Program.           Available:
    power is a critical issue in evaluating any                          Regular scrutiny of performance has                       [accessed
    model. Regrettably, the accompanying arti-                       been commonplace in other areas. For exam-                             7 January 2004].
                                                                                                                                        ———. 2003a. TerraQSAR – RMIV. Rat / Mouse intravenous
    cles by Eriksson et al. (2003) and Cronin et                     ple, the performance of Canadian environ-                              LD50 Computation Program. Available: http://www.
    al. (2003a, 2003b) fail to mention any of the                    mental analytical laboratories is regularly                   [accessed 7 January
    recent publications on the application of                        checked with round robin testing. The pre-                             2004].
                                                                                                                                        ———. 2003b. TerraQSAR – E2-RBA. Estrogen Receptor
    probabilistic neural networks (PNNs) for the                     dictive power of carcinogenicity and muta-                             Binding Affinity Computation Program. Available: http://
    modeling of toxicity endpoints. Highly effec-                    genicity models has been evaluated in several                 [accessed
    tive PNN models have been demonstrated                           rounds of testing, with the biological testing                         7 January 2004.
                                                                                                                                        Vrakas D, Tsantili-Kakoulidou A, Hadjipavlou-Litina D. 2003.
    for the fathead minnow (Kaiser and                               subsequent to the models’ predictions. There                           Exploring the consistency of logP estimation for substi-
    Niculescu 1999), the waterflea Daphnia                           is a great need for such comparative testing                           tuted coumarins. QSAR Combin Sci 22:622–629.
    magna (Kaiser and Niculescu 2001a), the cil-                     of the usefulness of various existing (Q)SAR
    iate Tetrahymena pyriformis (Niculescu et al.                    models. The valiant performance testing of
    2000), the Microtox bacterium Vibrio fis-                        several toxicity-prediction (Q)SARs models                         Validation of (Q)SARs Models:
    cheri (Kaiser and Niculescu. In press), and                      by Moore et al. (2003) shows some surpris-                         Jaworska et al.’s Response
    estrogen receptor binding affinity (Kaiser                       ing results and further gives credence to this
    and Niculescu 2001b). Indeed, Moore et al.                       thought. Indeed, Jaworska et al. (2003) also                       We warmly welcome and agree with the
    (2003) have shown that fathead minnow                            stress the need for an independent organiza-                       comments from Kaiser. In writing the
    PNN has superior performance in essentially                      tion to validate data and models irrespective                      reports that comprised the Mini-Monograph
    all aspects when compared to the other                           of any model’s claims.                                             on “Regulatory Acceptance of (Q)SARS”
    methods. Other types of neural networks                            The author is the director of research and a                     published in EHP and also during the work-
    have similarly been shown to be robust and                       principal of TerraBase, Inc.                                       shop sponsored by the International Council
    to provide optimal predictions (e.g., Burden                                                                                        of Chemical Associations and the European
    and Winkler 1999). Furthermore, commer-                                                       Klaus L.E. Kaiser                     Chemical Industry Council and held in
    cially available programs using PNN                                                              TerraBase, Inc.                    Setubal, Portugal, in March 2002 (Jaworska
    methodology have recently become available                                          Hamilton, Ontario, Canada                       et al. 2003), it was never our stated or under-
    for the estimation of several toxicologic end-                                   E-mail:                     lying intention to make a thorough review of
    points, such as fathead minnow 96-hr                                                                                                (Q)SARs for toxicologic endpoints and fate.
    median lethal concentrations (LC 50 )                                                    REFERENCES                                 This has been more than adequately
    (TerraBase, Inc. 2002), rat and mouse intra-                                                                                        achieved in recent editions of Environmental
    venous LD50 (TerraBase, Inc. 2003a), and                         Burden FR, Winkler DA. 1999. Robust QSAR models using              Toxicology and Chemistry (2003) and the
                                                                          Bayesian regularized neural networks. J Med Chem
    estrogen receptor binding affinity                                    42:3183–3187.                                                 Journal of Molecular Structure-THEOCHEM
    (TerraBase, Inc. 2003b).                                         Cronin MT, Jaworska JS, Walker JD, Comber MH, Watts CD,            (THEOCHEM 2003). This is firmly stated
         Although representativity or domain of                           Worth AP. 2003a. Use of QSARs in international decision-      in the papers themselves (Cronin et al.
                                                                          making frameworks to predict health effects of chemical
    a model are good concepts in theory, they                             substances. Environ Health Perspect 111:1391–1401.            2003a, 2003b; Eriksson et al. 2003). Instead,
    are difficult to define or use in practice.                      Cronin MTD, Walker JD, Jaworska JS, Comber MH, Watts CD,           the purpose of these articles was to review the
    Moreover, the statistical descriptors of a                            Worth AP. 2003b. Use of QSARs in international decision-      use of (Q)SARs to predict toxicity and fate
                                                                          making frameworks to predict ecologic effects and envi-
    model’s performance—such as goodness of                               ronmental fate of chemical substances. Environ Health
                                                                                                                                        by regulatory bodies. However, it should be
    fit, specificity, sensitivity, transparency, and                      Perspect 111:1376–1390.                                       understood, that such reviews will be needed,
    similarity—are often misleading because the                      Eriksson L, Jaworska J, Worth AP, Cronin MTD, McDowell RM,         and are ongoing, in order for (Q)SARs to
                                                                          Gramatica P. 2003. Methods for reliability and uncertainty
    applied data set(s) for many (Q)SARs are                              assessment and for applicability evaluations of classifica-
                                                                                                                                        find a more extensive and transparent use in
    narrow, skewed, or otherwise nonrepresenta-                           tion- and regression-based QSARs. Environ Health              regulatory schemes and thus achieve their
    tive of the chemical world existing in reality.                       Perspect 111:1361–1375.                                       stated goal of reducing animal testing. In

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general, only predictive techniques used by          even if it means losing some statistical fit. We                            REFERENCES
regulatory bodies are mentioned, although            understand that problems could arise in some
some other work to illustrate various other          PNN approaches that have used large num-           ETC. 2003. Environ Toxicol Chem 22(8):1651–1936.
                                                                                                        Cronin M, Schultz TW. 2001. Development of quantitative
techniques was cited to provide examples.            bers of descriptors, some with no relevance to          structure-activity relationships for the toxicity of aromatic
We did state that the probabilistic neural           the mechanism of action (Cronin and Schultz             compounds to Tetrahymena pyriformis: comparative
network (PNN) provided the best predic-              2001). A further issue with PNNs is the fact            assessment of the methodologies. Chem Res Toxicol
tions for fish toxicity on the basis of an           that they do not provide the same numerical        Cronin MTD, Walker JD, Jaworska JS, Comber MHI,
external test set (Cronin et al. 2003a), but         solution to a problem when repeated.                    Watts CD, Worth AP. 2003a. Use of QSARs in interna-
like the vast majority of examples of                    The goal of the Setubal workshop was to             tional decision-making frameworks to predict ecological
                                                                                                             effects and environmental fate of chemical substances.
(Q)SARs in the literature, the other end-            encourage further development of the                    Environ Health Perspect 111:1376–1390.
points were not included. With regard to             (Q)SAR sciences toward practical use and           Cronin MTD, Jaworska JS, Walker JD, Comber MHI, Watts CD,
the article by Eriksson et al. (2003), the           application. It is important, that as these             Worth AP. 2003b. Use of QSARs in international decision-
                                                                                                             making frameworks to predict human health effects.
scope was clearly defined in the title; that is,     models develop into more efficient tools for            Environ Health Perspect 111:1391–1401.
it provided an assessment of regression- and         society to understand the fate and effect of       Jaworska JS, Comber M, Auer C, Van Leeuwen CJ. 2003.
projection-based methods. There are also             chemicals, without extensive use of animals             Summary of the workshop on regulatory acceptance of
                                                                                                             (Q)SARs. Environ Health Perspect 111:1358–1360.
other approaches to (Q)SAR, such as sup-             and other resources, they be seen to be valid      JRC. 2003. QSARS. Ispra, Italy:European Commission, Joint
port vectors machines; however, these were           and suitable for the purpose. To achieve this           Research Centre. Available:
not included because they are not used               goal, there are a number of ongoing attempts            [accessed 2 Dec 2003].
broadly in all (Q)SAR disciplines. Further,          to validate (Q)SARs (e.g., at the European         Erriksson L, Jaworska J, Worth AP, Cronin MTD, McDowell
                                                                                                             RM, Gramatica P. 2002. Methods for reliability and
these techniques are not in frequent use by          Union and the Organisation for Economic                 uncertainty assessment and for applicability evaluations
regulatory bodies.                                   Co-operation and Development level). These              of classification and regression-based QSARs. Environ
    We agree with Kaiser that the perfor-            will attempt to weigh all the evidence and              Health Perspect 111:1361–1375.
                                                                                                        THEOCHEM. 2003. J Mol Structure 622(1–2):1–184.
mance of a model should be a driving force           produce scientifically sound and usable vali-
and is more important than statistics.               dation techniques. Interested parties are
Appropriate measures of predictivity or per-         encouraged to join in these efforts. More
formance are enshrined in the cornerstones of        information is available on the European
current attempts at validation. As part of the       Commission Joint Research Centre website
validation process, the domain of applicabil-        (JRC 2003).
ity should also be defined. This will allow a          The authors declare they have no competing
user to know whether a prediction is likely to       financial interests.
be valid. It should also be noted that Eriksson
et al. (2003) explain that representativity and                                Joanna S. Jaworska                             Correction
homogeneity are basic requirements for                                  Procter & Gamble Eurocor
(Q)SAR modeling, regardless of the statistical                          Strombeek-Bever, Belgium          In the January Forum article “Tidal
method used to develop the model. Eriksson                              E-mail:         Turbines: Wave of the Future?” [EHP
et al. (2003) also noted that these concepts                                                              112:A26 (2004)], Bjørn Bekken was
were easy to check and accomplish. Provided                                        Mark Cronin
                                                                                                          incorrectly quoted as saying, “Once we
the basic conditions of representativity and                    Liverpool John Moores University
homogeneity are not violated, statistical                             Liverpool, United Kingdom           pass peak production of fossil fuels, the
descriptors of a model’s performance are not                                                              difference between supply and demand
misleading. Indeed, failure to comply with                                      Lennart Eriksson          decreases day by day and energy prices
representativity and homogeneity will result                                            Umetrics          will go up.” What Bekken in fact said
in the statistical assessment of model perfor-                                         ˚
                                                                                  Umea, Sweden
                                                                                                          was that the difference between supply
mance becoming inappropriate.
    The reality is that simple and transparent                                     Mike Comber            and demand increases day by day. EHP
models are (on the whole) favored by regula-                                          ExxonMobil          regrets the error.
tory bodies over more opaque approaches,                                         Brussels, Belgium

Environmental Health Perspectives    • VOLUME 112 | NUMBER 2 | February 2004                                                                                     A 87

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