Source: http://www2.bloomberglaw.com/public/desktop/document/Milward_v_Acuity_Specialty_Products_Group_Inc_639_F3d_11_1st_Cir_
Timestamp: 2013-06-19 00:47:07
Document Index: 707983291

Matched Legal Cases: ['§ 28', '§ 28', '§ 28', '§ 28', '§ 28', '§ 28', '§ 28']

Milward v. Acuity Specialty Products Group, Inc., 639 F.3d 11, 31 IER Cases 1812 (1st Cir. 2011), Court Opinion
Milward v. Acuity Specialty Products Group, Inc., 639 F.3d 11, 31 IER Cases 1812 (1st Cir. 2011) [2011 BL 74218]
Brian K. MILWARD and Linda J. Milward, Plaintiffs, Appellants, v.
ACUITY SPECIALTY PRODUCTS GROUP, INC., et al., Defendants, Appellees.
No. 09-2270.
Heard December 7, 2010.
Decided March 22, 2011.
NEGLIGENCE [1] General causation — Expert witness — Scientific reliability ►220.13 ►400.07 ►515.25 [Show Topic Path]
Exclusion, in refrigeration technician's negligence action, of testimony of recognized leukemia expert that benzene exposure can cause Acute Promyelocytic Leukemia was error, where scientific reliability is demonstrated by expert's use of “weight of the evidence” methodology, requiring integration of evidence using professional judgment to conclude best explanation, fact that judgment plays more apparent role than in other methodologies does not mean approach is less scientific, and question is whether expert applied methodology with “same level of intellectual rigor” that he uses in his scientific practice.
[2] Expert witness — Scientific reliability —
Application of method ►220.13 ►400.07 ►515.25 [Show Topic Path]
Testimony that benzene exposure can cause Acute Promyelocytic Leukemia is admissible in employee's negligence action, where expert reached opinion after considering five bodies of evidence from peer-reviewed scientific literature on benzene and leukemia that:
(1) benzene causes main category of leukemia, of which APL is rare subtype, (2) all subtypes likely have common etiology, (3) benzene is known to cause chromosomal damage characteristic of APL, (4) benzene is known to inhibit enzyme whose inhibition is known to cause APL, and (5) APL was reported in benzene-exposed workers in epidemiological studies.
[3] Expert witness — Evidence — Weight of evidence ►220.13 ►400.07 ►515.25 ►515.4205 [Show Topic Path]
District court erred when it found inadmissible expert testimony that benzene exposure can cause Acute Promyelocytic Leukemia, where court improperly evaluated weight of evidence when it concluded expert's opinion was not scientifically reliable because other plausible hypotheses might also be true, took sides on questions that are focus of extensive scientific research and debate and on which reasonable scientists can disagree, and misunderstood nature of expert's analysis. [4] Expert witness — Epidemiological evidence ►220.13 ►400.07 ►515.25 [Show Topic Path]
Exclusion of expert's opinion that benzene exposure can cause Acute Promyelocytic Leukemia based on lack of statistically significant epidemiological evidence was error, where peer-reviewed epidemiological studies are not required as condition of admissibility, and this is not situation in which available studies found no causal link or no cases of APL among benzene-exposed workers but rather one in which few available studies do not offer conclusive evidence either way, partly because rarity of APL makes it nearly impossible to perform large enough study.
[5] Expert witness — ‘Biological plausibility' ►220.13 ►400.07 ►515.25 ►515.4205 [Show Topic Path]
District court erred when it misconstrued concept of “biological plausibility” in analysis by expert whose opinion that benzene exposure can cause Acute Promyelocytic Leukemia was excluded, where concept of biological plausibility asks whether hypothesized causal link is credible in light of what is known from science and medicine about human body and potentially offending agent, and, according to guidelines for “weight of the evidence”
methodology, is one factor used in concluding whether observed association between disease and feature of environment is causal. Appeal from the District of Massachusetts, George A.
O'Toole, Jr., J.
[*12] [EDITORS' NOTE: THIS PAGE CONTAINS HEADNOTES. HEADNOTES ARE NOT AN
[*13] Steve Baughman Jensen, with whom Allen Stewart, P.C., James
Gotz, and Kreindler & Kreindler were on brief, for
Raphael Metzger, Gregory Coolidge, and Metzger Law Group on
brief for the Council for Education and Research on Toxins, et
Joseph J. Leghorn, with whom Nixon Peabody LLP was on brief,
Before LYNCH, Chief Judge, LIPEZ and HOWARD, Circuit
Brian and Linda Milward brought negligence claims against
defendant chemical companies alleging that the rare type of
leukemia that Brian Milward suffers, Acute Promyelocytic
Leukemia (APL), was caused by his routine workplace exposure to
benzene-containing products that had been manufactured or
supplied by defendants. Milward worked as a refrigeration
technician and asserted that he was exposed to benzene from
1973 until the time he filed this complaint and jury demand in
October 2007. He had been diagnosed with APL in October 2004.
At defendants' request, the district court bifurcated the suit
into two phases. The first phase concerned whether the expert
opinion offered by plaintiffs on "general causation" was
admissible under Federal Rule of Evidence 702. "`General
causation' exists when a substance is capable of causing a
disease." Restatement (Third) of Torts: Liability for
Physical and Emotional Harm § 28 cmt. c(3) (2010)
("Restatement"). If plaintiffs' expert evidence had
been ruled admissible, the second phase would have considered
all other issues, including negligence, exposure, and the
"specific causation" of Milward's leukemia. "`Specific
causation' exists when exposure to an agent caused a particular
plaintiffs disease." Id. § 28 cmt. c(4).
This case never reached the second phase. The district court
ruled that the testimony of plaintiffs' expert on general
causation, Dr. Martyn Smith, was inadmissible under Federal
Rule of Evidence 702. The court so ruled after reviewing
written statements and materials and conducting a four-day
evidentiary hearing in which it heard testimony from
plaintiffs' experts Dr. Smith, a toxicologist, and Dr. Carl
Cranor, an expert on scientific methodology; and from
defendants' experts Dr. David Garabrant, an epidemiologist, Dr.
David Pyatt, a toxicologist, and Dr. John Bennett, a
pathologist. The district court, in a detailed opinion, ruled
that "Dr. Smith's proffered testimony that exposure to benzene
can cause APL lacks sufficient demonstrated scientific
reliability to warrant its admission under Rule 702."
Milward v. Acuity Specialty Prods. Grp., Inc.,
664 F.Supp.2d 137, 140 (D.Mass. 2009). The court entered final
judgment for defendants and plaintiffs [**2] timely appealed.
The appellate standard of review for Rule 702 rulings is abuse
of discretion. Gen. Elec. Co. v. Joiner, 522 U.S. 136,
146, 118 S.Ct. 512, 139 L.Ed.2d 508 (1997). "This standard is
not monolithic: within it,
[*14] embedded findings of fact are reviewed for clear error,
questions of law are reviewed de novo, and judgment calls are
subjected to classic abuse-of-discretion review." Ungar v.
Palestine Liberation Org., 599 F.3d 79, 83 (1st Cir. 2010);
see also Baker v. Dalkon Shield Claimants Trust,
156 F.3d 248, 251-52 (1st Cir. 1998) (noting these three dimensions
of the abuse of discretion standard in reviewing exclusion of
expert testimony).
We reverse the district court's exclusion of Dr. Smith's
general causation testimony. Cf. Ruiz-Troche v. Pepsi Cola
of P.R. Bottling Co., 161 F.3d 77 (1st Cir. 1998) (reversing
exclusion of expert testimony); Dalkon Shield,
156 F.3d 248 (same). Dr. Smith's testimony is admissible. We stress
that it is up to the jury to decide whether to accept his
opinion that exposure to benzene can cause APL — a
proposition that plaintiffs must prove by a preponderance of
The Supreme Court in Daubert v. Merrell Dow
Pharmaceuticals, Inc., 509 U.S. 579, 113 S.Ct. 2786,
125 L.Ed.2d 469 (1993), vested in trial judges a gatekeeper
function, requiring that they assess proffered expert
scientific testimony for reliability before admitting it.[fn1]
The Court held that Rule 702 displaced the "general acceptance"
test of Frye v. United States, 293 F. 1013
(D.C. Cir. 1923), under which "the admissibility of an expert
opinion or technique turned on its `general acceptance' vel
non within the scientific community."
Ruiz-Troche, 161 F.3d at 80. Under Rule 702:
If scientific, technical, or other specialized
knowledge will assist the trier of fact to understand
the evidence or to determine a fact in issue, a
witness qualified as an expert by knowledge, skill,
experience, training, or education, may testify
thereto in the form of an opinion or otherwise, if (1)
the testimony is based upon sufficient facts or data,
(2) the testimony is the product of reliable
principles and methods, and (3) the witness has
applied the principles and methods reliably to the
The Daubert Court identified four factors that might
assist a trial court in determining the admissibility of an
expert's testimony: "(1) whether the theory or technique can be
and has been tested; (2) whether the technique has been subject
to peer review and publication; (3) the technique's known or
potential rate of error; and (4) the level of the theory or
technique's acceptance within the relevant discipline."
United States v. Mooney, 315 F.3d 54, 62 (1st
Cir. 2002) (citing Daubert, 509 U.S. at 593-94,
113 S.Ct. 2786). These factors "do not constitute a `definitive
checklist or test.'" Kumho Tire Co. v. Carmichael,
526 U.S. 137, 150, 119 S.Ct. 1167, 143 L.Ed.2d 238 (1999) (emphasis
omitted) (quoting Daubert, 509 U.S. at 593,
113 S.Ct. 2786). Given that "there are many different kinds of experts,
and many different kinds of expertise," these factors "may or
may not be pertinent in assessing reliability, depending on the
nature of the issue, the expert's particular expertise, and the
subject of his testimony." Id.
Exactly what is involved in "reliability" was not and could not
have been filled out by Daubert. Rather, the answers
must come from developing case law in adjudicating individual
controversies. "[T]he question [**3] of admissibility `must be
[*15] tied to the facts of a particular case.'" Beaudette v.
Louisville Ladder, Inc., 462 F.3d 22, 25-26 (1st Cir. 2006)
(quoting Kumho Tire, 526 U.S. at 150, 119 S.Ct. 1167).
Although Daubert stated that trial courts should focus
"on principles and methodology, not on the conclusions that
they generate," Daubert, 509 U.S. at 595,
113 S.Ct. 2786, the Court subsequently clarified that this focus "need
not completely pretermit judicial consideration of an expert's
conclusions," Ruiz-Troche, 161 F.3d at 81 (citing
Joiner, 522 U.S. at 146, 118 S.Ct. 512). In
Joiner, the Court explained that "conclusions and
methodology are not entirely distinct from one another" and
"nothing in either Daubert or the Federal Rules of
Evidence requires a district court to admit opinion evidence
that is connected to existing data only by the ipse
dixit of the expert." Joiner, 522 U.S. at 146,
118 S.Ct. 512. Expert testimony may be excluded if there is
"too great an analytical gap between the data and the opinion
proffered." Id. "[T]rial judges may evaluate the data
offered to support an expert's bottom-line opinions to
determine if that data provides adequate support to mark the
expert's testimony as reliable." Ruiz-Troche,
161 F.3d at 81.
This does not mean that trial courts are empowered "to
determine which of several competing scientific theories has
the best provenance." Id. at 85. "Daubert
does not require that a party who proffers expert testimony
carry the burden of proving to the judge that the expert's
assessment of the situation is correct." Id. The
proponent of the evidence must show only that "the expert's
conclusion has been arrived at in a scientifically sound and
methodologically reliable fashion." Id.; see also United
States v. Vargas, 471 F.3d 255, 265 (1st Cir. 2006). The
object of Daubert is "to make certain that an expert,
whether basing testimony on professional studies or personal
experience, employs in the courtroom the same level of
intellectual rigor that characterizes the practice of an expert
in the relevant field." Kumho Tire, 526 U.S. at 152,
119 S.Ct. 1167.
So long as an expert's scientific testimony rests upon "`good
grounds,' based on what is known,"Daubert,
509 U.S. at 590, 113 S.Ct. 2786, it should be tested by the adversarial
process, rather than excluded for fear that jurors will not be
able to handle the scientific complexities, id.
at 596, 113 S.Ct. 2786. "Vigorous cross-examination, presentation
of contrary evidence, and careful instruction on the burden of
proof are the traditional and appropriate means of attacking
shaky but admissible evidence." Id.; see also Currier v.
United Techs. Corp., 393 F.3d 246, 252 (1st Cir. 2004).
It is uncontested that Dr. Smith's opinion about the causal
link between benzene and APL satisfies certain requirements of
Rule 702. His opinion would "assist the trier of fact to
understand the evidence or to determine a fact in issue."
Fed.R.Evid. 702. And Dr. Smith is "a witness qualified as an
expert by knowledge, skill, experience, training, or
education." Id. He is acknowledged as a leading expert
on the study of the toxic effects of chemicals and drugs on the
human body, with particular emphasis on the mechanisms by which
benzene and its metabolites cause damage to both cells and the
human organism as a whole. The research in Dr. Smith's
laboratory, which is funded by the National Institutes of
[**4] Health, focuses on the causes of leukemia and lymphoma, and he
has authored or co-authored over 215 articles in peer-reviewed
journals in the field of toxicology.
[*16] The question before us is whether the district court abused its
discretion in concluding that the other requirements of
Rule 702, concerning the reliability of Dr. Smith's opinion, were
not met. We will first discuss some basic facts about leukemia,
the weight of the evidence methodology, and Dr. Smith's use of
that methodology, and we will then turn to an evaluation of the
district court's ruling.
Leukemia is a cancer of the blood cells. There are different
types of leukemia, which are generally classified in two ways.
The first classification is between leukemia's acute and
chronic forms: acute leukemia is characterized by a rapid
increase in the number of immature blood cells, while chronic
leukemia is characterized by the excessive buildup of
relatively mature but abnormal white blood cells. The second
classification is between the types of stem cells affected:
leukemia can be either "myeloid" or "lymphoid." Combining these
two classifications provides a total of four main categories of
leukemia: acute myeloid leukemia (AML); chronic myeloid
leukemia (CML); acute lymphoid leukemia (ALL); and chronic
lymphoid leukemia (CLL).[fn2] Within each of these categories,
there are typically several sub-categories.
The general category of AML can be subdivided in more than one
way. Under the common French-American-British classification
system used by the parties, subtypes are classified
morphologically according to the degree of differentiation
along different cell lines and the extent of cell maturation.
This classification system identifies subtypes by convention as
MO through M7.[fn3]
Brian Milward's leukemia, APL, is sub-type M3 and is an
extremely rare disease. APL accounts for only five to ten
percent of all cases of AML, which is itself rare, with an
annual incidence of 3.5 cases per 100,000 people. APL is
characterized by a deficiency of mature blood cells in the
myeloid cell line and an excess of immature cells called
promyelocytes.
APL is in part caused by the chromosomal translocation of a
gene known as the retinoic acid receptor-alpha gene (RARa) on
chromosome 17.[fn4] Although APL and the other subtypes of AML have
been the subject of extensive research, there is not yet a
scientific consensus as to the causes of the genetic
translocation that induces APL.
Dr. Smith's opinion is that what is known about both AML and
APL supports the inference that exposure to benzene can cause
APL. He reached this opinion using a "weight of the evidence"
methodology in which he considered five lines of evidence drawn
from the peer-reviewed scientific literature on leukemia and
benzene. We first discuss the reliability of this methodology
in general, and then turn to Dr. Smith's application of it.
[*17] A. The Reliability of the Weight of the Evidence
Dr. Smith's opinion was based on a "weight of the evidence"
methodology in which he followed the guidelines articulated by
world-[**5] renowned epidemiologist Sir Arthur Bradford Hill in his
seminal methodological article on inferences of causality.
See Arthur Bradford Hill, The Environment and
Disease: Association or Causation?,
58 Proc. Royal Soc'y Med. 295 (1965).
Hill's article explains that one should not conclude that an
observed association between a disease and a feature of the
environment (e.g., a chemical) is causal without first
considering a variety of "viewpoints" on the issue. These
viewpoints include: the strength or frequency of the
association; the consistency of the association in varied
circumstances; the specificity of the association; the temporal
relationship between the disease and the posited cause; the
dose response curve between them; the biological plausibility
of the causal explanation given existing scientific knowledge;
the coherence of the explanation with generally known facts
about the disease; the experimental data that relates to it;
and the existence of analogous causal relationships. See
id. at 295-99.[fn5]
Although Hill identified nine viewpoints, it is generally
agreed that this list is not exhaustive and that no one type of
evidence must be present before causality may be inferred. For
example, when a group from the National Cancer Institute was
asked to rank the different types of evidence, it concluded
that "[t]here should be no such hierarchy."[fn6] Michele Carbon
et al., Modern Criteria to Establish Human Cancer
Etiology, 64 Cancer Res. 5518, 5522 (2004); see
also Sheldon Krimsky, The Weight of Scientific
Evidence in Policy and Law, 95 Am. J. Pub. Health S129,
S130 (2005).
This "weight of the evidence" approach to making causal
determinations involves a mode of logical reasoning often
described as "inference to the best explanation," in which the
conclusion is not guaranteed by the premises.[fn7] See
Bitler v. A.O. Smith Corp., 391 F.3d 1114, 1124 n. 5 (10th
Cir. 2004). As explained by plaintiffs' expert on methodology
Dr. Cranor, Distinguished Professor of Philosophy at the
University of California, Riverside, inference to the best
explanation can be thought of as involving six general steps,
[*18] may be implicit. The scientist must (1) identify an
association between an exposure and a disease, (2) consider a
range of plausible explanations for the association, (3) rank
the rival explanations according to their plausibility, (4)
seek additional evidence to separate the more plausible from
the less plausible explanations, (5) consider all of the
relevant available evidence, and (6) integrate the evidence
using professional judgment to come to a conclusion about the
In this mode of reasoning, the use of scientific judgment is
necessary. "No algorithm exists for applying the Hill
guidelines to determine whether an association truly reflects
a causal relationship or is spurious." Restatement
§ 28 cmt. c(3). Because "[n]o scientific methodology exists
for this process . . . reasonable scientists may come to
different judgments about whether such an inference is
appropriate." Id. § 28 reporters' note cmt. c(4).
The fact that the role of judgment in [**6] the weight of the
evidence approach is more readily apparent than it is in other
methodologies does not mean that the approach is any less
scientific. No matter what methodology is used, "an evaluation
of data and scientific evidence to determine whether an
inference of causation is appropriate requires judgment and
interpretation." Id. § 28 cmt. c(l).[fn8] The use
of judgment in the weight of the evidence methodology is
similar to that in differential diagnosis, see Cruz v.
Bridge-stone/Firestone N. Am. Tire, LLC,
388 Fed.Appx. 803, 806-07 (10th Cir. 2010) (explaining that differential
analysis in general is best characterized as a process of
reasoning to the best explanation), which we have repeatedly
found to be a reliable method of medical diagnosis, see
Granfield v. CSX Transp., Inc., 597 F.3d 474, 486 (1st
Cir. 2010); Dalkon Shield, 156 F.3d at 253.
Defendants argue that "regardless of its level of acceptance in
the scientific community, a pure `weight of the evidence'
approach like that utilized by Dr. Smith . . . is hardly the
type of reliable scientific evidence contemplated by
Daubert."[fn9] No serious argument can be made that
[*19] weight of the evidence approach is inherently unreliable.
Rather, admissibility must turn on the particular facts of the
case. See, e.g., Cruz, 388 Fed.Appx. at 807
(explaining that expert testimony based on "inference to the
best explanation" may be admissible, but that there was no
error in the district court's finding that the expert's
specific theory did not have sufficient scientific support).
Here, the question is whether Dr. Smith, in reaching his
opinion, applied the methodology with "the same level of
intellectual rigor" that he uses in his scientific practice.
Kumho Tire, 526 U.S. at 152, 119 S.Ct. 1167.
B. Dr. Smith's Application of the Methodology
[2] In concluding that the weight of the evidence supported the
conclusion that benzene can cause APL, Dr. Smith relied on his
knowledge and experience in the field of toxicology and
molecular epidemiology and considered five bodies of evidence
drawn from the peer-reviewed scientific literature on benzene
First, Dr. Smith considered the near-consensus among
governmental agencies, experts, and active researchers in the
field that benzene can cause AML as a class. The existence of
this causal connection has been established since the late
1970s. See Bernard D. Goldstein & Gisela Witz,
Benzene, in Environmental Toxicants: Human Exposures and
Their Health Effects 459, 478 (Morton Lippmann ed.,
3rd ed. 2009). Dr. Smith noted that epidemiological studies have
found a statistically significant increased incidence of AML in
benzene-exposed workers and have identified a dose-response
Second, Dr. Smith considered evidence concerning the etiology,
or origins, of leukemia indicating that all types of AML derive
from a genetically damaged pluripotent stem cell. Dr. Smith
referred to a recent peer-reviewed article that provided a
review of the current literature and reported numerous studies
demonstrating that both AML and CML are stem cell diseases. He
cited peer-reviewed studies finding that in the APL and Core
Binding Factor (CBF) subtypes of AML, as well [**7] as in CML, the
stem cell mutation is often in part caused by a chromosomal
translocation. He also cited evidence that APL and CBF share
common genetic susceptibility factors, common risk factors, and
the same incidence pattern occurring at a constant incidence
with age after age 20. Dr. Smith concluded that the best
explanation for this evidence is that all AMLs, including APL,
have a common etiology.[fn10]
Third, Dr. Smith considered toxicology studies establishing
that metabolites of benzene cause significant chromosomal
damage at the stem cell level in the bone marrow — the
type of damage that is known to cause APL and other types of
AML.[fn11] He also cited peer-reviewed work published by his
lab showing that leukemia cases associated with benzene
exposure are more likely to contain clonal chromosome
aberrations than leukemias arising in the general population.
[*20] Fourth, Dr. Smith considered two sets of studies concerning the
inhibition of a cellular enzyme known as topoisomerase II (or
"topo II") that is essential for the maintenance of proper
chromosome structure and segregation. One set of studies
— including both test tube and animal studies — has
established that two benzene metabolites are catalytic
inhibitors of topo 11. A second set of studies has established
that a variety of chemotherapeutic agents that are catalytic
inhibitors of topo II cause APL.[fn12] Dr. Smith explained that
taken together, these studies provided evidence of a known
biological mechanism by which exposure to benzene could cause
Fifth, Dr. Smith considered the small set of epidemiological
studies that provide data on the relationship between benzene
exposure and subtypes of AML.[fn13] He concluded that the
evidence showed an increased risk factor for APL, which
although not statistically significant was consistent with
causality, and provided no grounds for concluding otherwise.
Dr. Smith explained that taking into account all of the
evidence described above — the fact that benzene causes
AML as a class, that all subtypes of AML likely have a common
etiology, that benzene is known to cause the general types of
cellular damage that are known to cause APL, that benzene is
known to inhibit an enzyme whose inhibition is known to cause
APL, and that APL has been reported in benzene-exposed workers
in a number of epidemiological studies — he reached the
opinion that the weight of the evidence supports the conclusion
that benzene exposure is capable of causing APL. Dr. Smith's
opinion rests on a scientifically sound and methodologically
reliable foundation, as is required by Daubert.
In finding Dr. Smith's opinion inadmissible under Rule 702, the
district court relied on (a) its evaluation of the mechanistic
and epidemiological evidence on which Dr. Smith based his
opinion, and (b) its understanding of the scientific concept
of "biological plausibility" as used by Dr. Smith when he
explained his conclusions. As we explain below, on both of
these points, the district court erred. In the end, the court's
exclusion of the testimony was based on [**8] its evaluation of the
weight of the evidence, which is an issue that is the province
of the jury, and on its misperception of the methodology and
analysis that provided the basis for Dr. Smith's opinion.
A. The Evidentiary Basis of Dr. Smith's Opinion
1. Mechanistic Evidence
[3] The district court's exclusion of Dr. Smith's testimony was
based to a significant
[*21] extent on its rejection of what it took to be his three key
subsidiary conclusions regarding the weight of the mechanistic
evidence. We briefly summarize the court's analysis on these
points before turning to our discussion of the ways in which
the court erred in its analysis.
First, the court held that there was insufficient evidence to
support Dr. Smith's opinion that all subtypes of AML likely
have a common etiology. The court reasoned that the "clear
differences" among AML subtypes — in particular, APL's
unique response to certain types of therapy, and the subtypes'
different chromosomal abnormalities — made "a broad
extrapolation from AML generally to APL specifically"
inappropriate.[fn14] Milward, 664 F.Supp.2d at 144.
The court also noted that a series of recent studies had "led
investigators to think that the `leukemic stem cell' may exist
in more mature, differentiated cell lines," such that "the
`leukemic stem cell' may not be a stem cell in the usual sense,
but rather a differentiated cell that has somehow acquired the
ability to reproduce itself, as a stem cell can." Id.
at 145. If the various AML subtypes did not arise from the same
progenitor or stem cell, the court reasoned, they might well
not share a common etiology.[fn15] Finally, the court
emphasized that there was "no scientific consensus" on this
issue, and that the question of when the key chromosomal
translocation occurs was considered by researchers to be "a
question that remains unanswered in the APL field." Id.
(quoting S. Wojiski et al., PML-RARa Initiates Leukemia by
Conferring Properties of Self-Renewal to Committed Promyelocytic
Progenitors, 23 Leukemia 1462, 1469 (2009) (emphasis
added)) (internal quotation marks omitted).
Second, the court held that what was known about the types of
chromosomal translocations caused by benzene did not offer
sufficient support for Dr. Smith's opinion that it is
biologically plausible that benzene causes the characteristic
t(15;17)(q22;q12) translocation seen with APL. The court
explained that this opinion would be warranted if benzene's
impact on chromosomes were randomly experienced, but it noted
that a paper coauthored by Dr. Smith concluded that "benzene
can initiate or promote leukemia induction by a
nonrandom selective effect" on specific chromosomes.
Id. at 147 (emphasis added). This defeated "the
generalization that because . . . benzene causes damage to some
chromosomes, it is `biologically plausible' that it causes
damage to other chromosomes." Id.
Third, the court held that there was insufficient evidence to
support the inference that benzene metabolites inhibit topo II
in such a way as to cause the chromosomal translocation seen in
cases of APL. The court's conclusion was in part based on
evidence [**9] that "[t]here are different classes of topo II
inhibitors and the different
[*22] classes have been associated with different AML subtypes."
Id. Highlighting one article's finding that leukemias
induced by benzene do not appear to exhibit the defining
characteristics associated with four other classes of topo II
inhibitors, id. at 148, the court held that to "the
extent that Dr. Smith's opinion rests on the proposition that
all topo II inhibitors act similarly to cause a similar effect,
then, it does not appear to be based on reliable scientific
knowledge," id. at 147.
In reaching these three conclusions about some of the evidence
on which Dr. Smith based his opinion, the court both placed
undue weight on the lack of general acceptance of Dr. Smith's
conclusions and crossed the boundary between gatekeeper and
Although general acceptance is still a relevant consideration
under Daubert, the court's demands went too far.
Cf. Smith v. Ford Motor Co., 215 F.3d 713, 721 (7th
Cir. 2000) (reversing district court that had treated lack of
peer review as dispositive grounds for excluding expert
opinion). On the question of the origins of APL, for example,
the court explained that in the absence of consensus about the
target cell for the leukemic mutation, Dr. Smith's opinion that
all forms of AML likely share a common origin was "at best a
plausible hypothesis." Milward, 664 F.Supp.2d at 146.
The court explained that the fact that "other plausible
hypotheses . . . might be true as well, including the
hypothesis that the genetic mutation that leads to APL occurs
in relatively mature cells," meant that Dr. Smith's opinion was
not "based on sufficient facts and data to be accepted as a
reliable scientific conclusion." Id; see also id.
at 148 (focusing on lack of consensus as to the topo II question).
But the fact that another explanation might be right is not a
sufficient basis for excluding Dr. Smith's testimony. "Lack of
certainty is not, for a qualified expert, the same thing as
guesswork." Primiano v. Cook, 598 F.3d 558, 565 (9th
In addition, the alleged flaws identified by the court go to
the weight of Dr. Smith's opinion, not its admissibility. There
is an important difference between what is unreliable
support and what a trier of fact may conclude is
insufficient support for an expert's conclusion.
The court's analysis repeatedly challenged the factual
underpinnings of Dr. Smith's opinion, and took sides on
questions that are currently the focus of extensive scientific
research and debate — and on which reasonable scientists
can clearly disagree. In this, the court over-stepped the
authorized bounds of its role as gatekeeper. "The soundness of
the factual underpinnings of the expert's analysis and the
correctness of the expert's conclusions based on that analysis
are factual matters to be determined by the trier of fact."
Smith, 215 F.3d at 718. "When the factual underpinning
of an expert's opinion is weak, it is a matter affecting the
weight and credibility of the testimony — a question to
be resolved by the jury." Vargas, 471 F.3d at 264
(quoting Int'l Adhesive Coating Co. v. Bolton Emerson
Int'l, 851 F.2d 540, 545 (1st Cir. 1988)) (internal
quotation marks omitted); [**10] see also Quiet Tech. DC-8, Inc.
v. Hurel-Dubois UK Ltd., 326 F.3d 1333, 1345 (11th
Cir. 2003); Amorgianos v. Nat'l R.R. Passenger Corp.,
303 F.3d 256, 267 (2d Cir. 2002).
Of course, following Joiner, a "district court
properly may exclude expert testimony if the court concludes
too great an analytical gap exists between the existing data
and the expert's conclusion." Kennedy v. Collagen
Corp., 161 F.3d 1226, 1230 (9th Cir. 1998). Here, however,
"the gap was of the district court's making." Id. Dr.
Smith's opinion was based on a reliable
[*23] methodology and substantial evidence that he carefully
explained. The questions that the court posed were sensible
ones, but ones for the jury to resolve.
At times, the court's error in excluding Dr. Smith's testimony
derived from a mistake in its understanding of the weight of
the evidence methodology employed by Dr. Smith. The court
treated the separate evidentiary components of Dr. Smith's
analysis atomistically, as though his ultimate opinion was
independently supported by each. For example, the
court referred to "Dr. Smith's opinion that because
benzene metabolites inhibit topo II and because some classes of
topo II inhibitors appear to have a causal relationship to APL,
therefore benzene has a causal relationship to APL."
Milward, 664 F.Supp.2d at 148 (emphasis added). This
overstates Dr. Smith's conclusion as to the topo II evidence,
and is indicative of an error in the court's understanding of
the nature of Dr. Smith's analysis.
In Dr. Smith's weight of the evidence approach, no body of
evidence was itself treated as justifying an inference of
causation. Rather, each body of evidence was treated as grounds
for the subsidiary conclusion that it would, if combined with
other evidence, support a causal inference. The district court
erred in reasoning that because no one line of evidence
supported a reliable inference of causation, an inference of
causation based on the totality of the evidence was unreliable.
Cf. Nutra-Sweet Co. v. X-L Eng'g Co., 227 F.3d 776,
789 (7th Cir. 2000) (holding that an expert's reliance on
individual pieces of evidence, insufficient in themselves to
prove a point, "did not render his opinion speculative").[fn16]
The hallmark of the weight of the evidence approach is
reasoning to the best explanation for all of the available
evidence. Cf. Dalkon Shield, 156 F.3d at 253
(reversing district court's exclusion of expert testimony as
"guesswork" or without "basis" when testimony was based on
differential diagnosis and there was no showing that any one of
the expert's premises was "so faulty that it could not even be
tendered to the jury for its consideration"); see also
Hardyman v. Norfolk & W. Ry. Co., 243 F.3d 255, 261
(6th Or.2001).
[4] As to the epidemiological evidence on which Dr. Smith based his
opinion in part, the court held that the published articles on
which Dr. Smith relied did not support his opinion, and that in
any event, the evidence was not statistically significant. On
these grounds, the court rejected Dr. Smith's conclusion that
the available epidemiological evidence offered some support for
an inference of causation.
In concluding that the papers cited by Dr. Smith did not
support his opinion, the court reasoned that "[**11] Dr. Garabrant
convincingly demonstrated, especially with respect to the
Golomb and Travis papers, that Dr. Smith's conclusions that
there was a positive association between exposure to benzene
and APL were based on faulty calculations of odds ratios."
Milward, 664 F.Supp.2d at 149. An odds ratio
represents the difference in the incidence of a disease between
a population that has been exposed to benzene and one that has
not. In Dr. Garabrant's opinion, Dr. Smith should have used the
incidence rate of APL for the general population as a
base-line, rather than the rate for non-benzene-exposed
workers. In the Daubert hearing
[*24] and in his supplemental report, however, Dr. Smith
explained that he disagreed with Dr. Garabrant on this point,
but that in any event, the odds ratio was still elevated,
consistent with an inference of causation. Where, as here, both
experts' opinions are supported by evidence and sound
scientific reasoning, the question of who is right is a
question for the jury.[fn17]
The court explained, however, that even if "some of the data
reported in the various studies could be properly understood to
suggest a positive association, the findings are not
statistically significant," id., and that although
"epidemiological evidence is not always essential," the
defendants were "correct that sound epidemiological studies are
ordinarily needed to confirm, by consistent observation, an
hypothesis of causation," id. at 148.
In context, the district court read too much into the paucity
of statistically significant epidemiological studies. The
absence of peer-reviewed epidemiological studies does not, as
defendants contend, make it "almost impossible" for Dr. Smith's
opinion to be admissible. Epidemiological studies are not per
se required as a condition of admissibility regardless of
context. See Rider v. Sandoz Pharm. Corp.,
295 F.3d 1194, 1198 (11th Cir. 2002) ("It is well-settled that while
epidemiological studies may be powerful evidence of causation,
the lack thereof is not fatal to a plaintiffs case.");
Restatement § 28 reporters' note cmt. c(3)
(listing federal circuit cases holding that epidemiological
data is not necessary). Nor are such studies treated as always
essential in the relevant scientific communities.
To be clear, this is not a situation in which the available
epidemiological studies found that there is no causal link, or
even one in which no cases of APL were found among
benzene-exposed workers. Cf. Norris v. Baxter Healthcare
Corp., 397 F.3d 878, 882 (10th Cir. 2005) (holding that
epidemiological studies are not required to prove causation,
but that a substantial body of epidemiological evidence
challenging causation cannot be ignored); Allen v. Pa.
Eng'g Corp., 102 F.3d 194, 197 (5th Cir. 1996) (finding it
significant that "numerous reputable epidemiological studies
covering in total thousands of workers" indicated that there
was no causation).
Rather, this is a case in which there is a lack of
statistically significant epidemiological evidence, and in
which the rarity of APL and difficulties of data collection in
the United States make it very difficult to perform an
epidemiological study [**12] of the causes of APL that would yield
statistically significant results.[fn18] Dr. Smith estimated that
in order to obtain statistically significant results, one
would need hundreds of thousands of highly exposed workers, the
same number of controls, and millions of dollars in funding.
The court erred in treating the lack of statistical
significance as a crucial flaw. See Collagen Corp.,
161 F.3d at 1229 (finding that the district court
[*25] placed too much emphasis on lack of epidemiological studies
where such studies "would be almost impossible to perform");
see also Primiano, 598 F.3d at 566-67 (noting that
peer-reviewed studies are not necessary, especially when there
are good reasons why such studies have not been performed).
Under these circumstances, the court erred in holding that "Dr.
Smith's attempt to support his conclusion with data that
concededly lacks statistical significance" was "a deviation
from sound practice of the scientific method" that provided
grounds for exclusion. Milward, 664 F.Supp.2d at 149.
The court's evaluation of the epidemiological evidence is also
in tension with the weight of the evidence methodology. Dr.
Smith explained that his citation to epidemiological data was
meant to challenge the theory that benzene exposure could not
cause APL, and to highlight that the limited data available was
consistent with the conclusions that he had reached on the
basis of other bodies of evidence. He stated that "[i]f
epidemiologic studies of benzene-exposed workers were devoid of
workers who developed APL, one could hypothesize that benzene
does not cause this particular subtype of AML." The fact that,
on the contrary, "APL is seen in studies of workers exposed to
benzene where the subtypes of AML have been separately analyzed
and has been found at higher levels than expected" suggested to
him that the limited epidemiological evidence was at the very
least consistent with, and suggestive of, the conclusion that
benzene can cause APL.
The court rejected Dr. Smith's reasoning, stating that a
"`suggestion' may give rise to a plausible hypothesis, but not
a reliable inference." Milward, 664 F.Supp.2d at 149.
But as noted above, this is inconsistent with the
scientifically accepted methodology employed by Dr. Smith. Dr.
Smith did not infer causality from this suggestion alone, but
rather from the accumulation of multiple scientifically
acceptable inferences from different bodies of evidence.
B. The Concept of "Biological Plausibility"
[5] The district court also erred in its apprehension of the
scientific concept of biological plausibility and its place in
Dr. Smith's analysis. The concept of biological plausibility,
which numbers among the nine Hill viewpoints, asks whether the
hypothesized causal link is credible in light of what is known
from science and medicine about the human body and the
potentially offending agent. At two places in the court's
analysis, it conflated the scientific question of biological
plausibility with the legal question of probability.
In the court's discussion of the epidemiological evidence, it
stated that even if the evidence "`suggests' a [**13] causal
relationship," providing support for Dr. Smith's opinion
regarding biological plausibility, a "plausible hypothesis" is
not a "reliable inference" and is therefore inadmissible.
Id. Here, the court not only misconstrued the concept
of biological plausibility by equating it with a merely
plausible or possible hypothesis, but also misconstrued the
concept's role in Dr. Smith's analysis by assuming that Dr.
Smith treated the criteria as sufficient grounds for inferring
causality (rather than as one consideration that entered into
his weighing of the evidence).
The court made a similar error in its conclusion, where it
While Dr. Smith's hypotheses are, to use his term,
"plausible," they remain hypotheses, the validity of
which has not been reliably established. . . . [T]he
sum of Dr. Smith's testimony, fairly understood, is
that benzene might be a cause of APL.
[*26] Id., Again, the district court misunderstood Dr. Smith
to be saying that causation is possible rather than probable.
The sum of Dr. Smith's testimony was not merely that it is
possible, or even biologically plausible, that benzene causes
APL. Rather, the sum of his testimony was that a weighing of
the Hill factors, including biological plausibility, supported
the inference that the association between benzene exposure and
APL is genuine and causal.
The record clearly demonstrates that Dr. Smith's opinion was
based on an analysis in which he employed the "same level of
intellectual rigor" that he employs in his academic work.
Kumho Tire, 526 U.S. at 152, 119 S.Ct. 1167. In
excluding Dr. Smith's testimony, the district court did not
properly apply Daubert and exceeded the scope of its
discretion. We reverse the district court's judgment for the
defendants and its exclusion of Dr. Smith's testimony, and we
remand for proceedings consistent with this opinion.[fn19]
[fn1] Kumho Tire Co. v. Carmichael, 526 U.S. 137,
119 S.Ct. 1167, 143 L.Ed.2d 238 (1999), clarified that courts have
this function with respect to all expert testimony, not just
[fn2] There are also some types of leukemia that are considered
to be outside of this four-part classification scheme.
[fn3] The World Health Organization has adopted a different
classification system that utilizes not only morphological
characteristics, but also genetic, immunophenotypic, biologic,
and clinical characteristics to define specific disease
entities that have clinical and biological relevance. See
generally James W. Vardiman et al., The World Health
Organization (WHO) Classification of the Myeloid
Neoplasms, 100 Blood 2292 (2002).
[fn4] In approximately 95% of cases of APL, RARa is involved in
a reciprocal translocation with the promyelocytic leukemia gene
(PML) on chromosome 15 — a translocation denoted as
t(15;17)(q22;q12) — which creates a fusion gene known as
PML-RARa. In the remaining cases of APL, RARa translocates and
fuses with one of four other genes.
[fn5] See also Sheldon Krimsky, The Weight of
Scientific Evidence in Policy and Law, 95 Am. J. Pub.
Health S129, S129 (2005) (explaining that the term "weight of
the evidence" is used "to characterize a process or method in
which all scientific evidence that is relevant to the status of
a causal hypothesis is taken into account").
[fn6] This point was also emphasized by Hill, who cautioned in
None of my nine viewpoints can bring indisputable
evidence for or against the cause-and-effect
hypothesis and none can be required as a sine qua non.
What they can do, with greater or less strength, is to
help us to make up our minds on the fundamental
question — is there any other way of explaining
the set of facts before us, is there any other answer
equally, or more, likely than cause and effect?
Austin Bradford Hill, The Environment and Disease:
Association or Causation?, 58 Proc. Royal Soc'y Med. 295,
299 (1965).
[fn7] "Unlike a logical inference made by deduction where one
proposition can be logically inferred from other known
propositions, and unlike induction where a generalized
conclusion can be inferred from a range of known particulars,
inference to the best explanation — or `abductive
inferences' — are drawn about a particular proposition or
event by a process of eliminating all other possible
conclusions to arrive at the most likely one, the one that best
explains the available data." Bitler v. A.O. Smith
Corp., 391 F.3d 1114, 1124 n. 5 (10th Cir. 2004).
[fn8] The fact that epidemiology relies on statistical methods
does not avoid the use of judgment, as "[e]ven sampling error,
which is analyzed using quantitative statistical methods, only
provides a range of outcomes (associations) that might have
been produced by sampling error even if there is no association
between the agent and disease. Thus, interpreting the results
of epidemiologic studies requires informed judgment and is
subject to uncertainty." Restatement (Third) of Torts:
Liability for Physical and Emotional Harm § 28
reporters' note cmt. c(3) (2010).
[fn9] Defendants draw our attention to a Fifth Circuit case,
excluding testimony based on a weight of the evidence
methodology, in which the court explained:
We are also unpersuaded that the `weight of the
evidence' methodology these experts use is
scientifically acceptable for demonstrating a medical
link between Allen's EtO exposure and brain cancer.
Regulatory and advisory bodies such as IARC, OSHA and
EPA utilize a `weight of the evidence' method to
assess the carcinogenicity of various substances in
human beings and suggest or make prophylactic
rules governing human exposure. This methodology results
from the preventive perspective that the agencies
adopt in order to reduce public exposure to harmful
substances. The agencies' threshold of proof is
reasonably lower than that appropriate in tort law. .
Allen v. Pa. Eng'g Corp., 102 F.3d 194, 198 (5th
Cir. 1996). However, the Fifth Circuit did not, as defendants
contend, hold "that the `weight-of-the evidence' approach is
per se unreliable." Rather, the court rejected its use in that
case — a case in which it found that the experts'
conclusion was "at best weakly supported, if not contradicted,
by the evidence on which they rely," and in which the experts
"all declined to say that they would subject their findings to
the test of peer review for publication." Id.
[fn10] Defendants' experts questioned Dr. Smith's conclusion
that all of the subtypes of AML have a common etiology.
However, on cross examination in the district court
Daubert hearing, defendants' expert Dr. Pyatt agreed
with the statement that "there are a group of reasonable
scientists who reasonably believe that all forms of AML arise
from the same progenitor cell" and stated that Dr. Smith's
opinion was "consistent with most of the evidence." Defendants'
expert Dr. Bennett likewise agreed that "reasonable scientists
can and do" agree with Dr. Smith.
[fn11] Defendants' expert Dr. Bennett agreed that "there have
been innumerable studies that demonstrate that benzene actually
works at multiple levels to create damage to the DNA structure
of this hematopoietic stem cell."
[fn12] Dr. Smith cited a long list of peer-reviewed
publications and quoted a recent authoritative paper in a
prominent journal stating that "[t]herapy-related acute
promyelocytic leukemia (t-APL) with the t(15; 17) translocation
is a well recognized complication of cancer treatment with
agents targeting topoisomerase II." Syed Khizer Hasan et
al. Molecular Analysis of t(15;17) Genomic Breakpoints in
Secondary Acute Promyelocytic Leukemia Arising After Treatment
of Multiple Sclerosis, 112 Blood 3383, 3383 (2008).
Defendants' hematopathologist, Dr. Bennett, acknowledged that
chemotherapeutic compounds that inhibit topo II can cause
[fn13] He considered a multi-center Chinese case-control study
of 1257 cases of leukemia in which there was a 40% increased
risk of APL in benzene-exposed workers; a cohort study of 74,
828 workers exposed to benzene in China in which APL was the
most common form of AML diagnosed; a multi-center Italian
case-control study of 38 cases of APL that showed a strong
association between APL and shoe-making, an industry that had
for many years used benzene as an adhesive; and several case
reports of APL in benzene-exposed workers.
[fn14] Dr. Smith's supplemental report makes it clear that this
is something on which reasonable scientific disagreement is
possible. He explained that in his view, defendants' experts
erred in concluding that the fact that APL is therapeutically
unique means that it is also etiologically unique. Identifying
the biological mechanism that made APL therapeutically unique
— the sensitivity of the PML-RARa fusion gene to retinoic
acid and arsenic — he explained that this was
"irrelevant" to APL's etiology.
[fn15] In the Daubert hearing, Dr. Smith made it clear
that he had considered the key paper cited by the district
court on this point. He noted that it was based on studies in
"mice using a highly artificial system," and he explained that
even if the mutation could occur at a later point in
differentiation as indicated by this paper, "it doesn't mean
that it has to occur only in that compartment."
[fn16] As a general evidentiary matter, "individual pieces of
evidence, insufficient in themselves to prove a point, may in
cumulation prove it," and "a piece of evidence, unreliable in
isolation, may become quite probative when corroborated by
other evidence." Bourjaily v. United States,
483 U.S. 171, 179-80, 107 S.Ct. 2775, 97 L.Ed.2d 144 (1987).
[fn17] The court also rejected Dr. Smith's analysis of the
epidemiological evidence on the grounds that "none of the
studies purports to give direct support to the proposition that
benzene causes APL." Milward v. Acuity Specialty Prods.
Grp., Inc., 664 F.Supp.2d 137, 148 (D.Mass. 2009). Yet Dr.
Smith did not claim that the studies provided direct support.
Rather, his characterization of his methodology makes clear
that he was using them as indirect support.
[fn18] The difficulty of performing such a study has even been
expressly affirmed in the scientific literature. See
Dan Douer, The Epidemiology of Acute Promyelocytic
16 Best Prac. & Res. Clinical Haematology
357, 358 (2003) ("It is difficult to perform
epidemiological studies in AML subtypes classified according to
cytogenetic abnormalities owing to the small number of patients
within each subgroup.").
[fn19] We wish to acknowledge the able briefing of the issues
by the parties and amici.