NAS RAIAS DA LEI

2. Information bias
Information bias refers to the bias resulting from inaccurate information about
the study participants regarding either their disease or exposure status. In a casecontrol
study, potential information bias is an important consideration because
the researcher depends on information from the past to determine exposure and
disease and their temporal relationship. In some situations the researcher is required
to interview the subjects about past exposures, thus relying on the subjects’
memories. Research has shown that individuals with disease (cases) may
more readily recall past exposures than individuals with no disease (controls);88
this creates a potential for bias called recall bias.
For example, consider a case-control study conducted to examine the cause
of congenital malformations. The epidemiologist is interested in whether the
malformations were caused by an infection during the mother’s pregnancy.89 A
group of mothers of malformed infants (cases) and a group of mothers of infants
with no malformation (controls) are interviewed regarding infections during
pregnancy. Mothers of children with malformations may recall an inconsequential
fever or runny nose during pregnancy that readily would be forgotten by a
mother who had a normal infant. Even if in reality the infection rate in mothers
of malformed children is no different from the rate in mothers of normal children,
the result in this study would be an apparently higher rate of infection in
the mothers of the children with the malformations solely on the basis of recall
differences between the two groups. The issue of recall bias can sometimes be
evaluated by finding a second source of data to validate the subject’s response
88. Steven S. Coughlin, Recall Bias in Epidemiologic Studies, 43 J. Clinical Epidemiology 87 (1990).
89. See Brock v. Merrell Dow Pharms., Inc., 874 F.2d 307, 311–12 (5th Cir. 1989) (discussion of
recall bias among women who bear children with birth defects), cert. denied, 494 U.S. 1046 (1990). We
note that the court was mistaken in its assertion that a confidence interval could correct for recall bias,
or for any bias for that matter. Confidence intervals are a statistical device for analyzing error that may
result from random sampling. Systematic errors (bias) in the design or data collection are not addressed
by statistical methods, such as confidence intervals or statistical significance. See Green, supra note 39, at
667–68; Vincent M. Brannigan et al., Risk, Statistical Inference, and the Law of Evidence: The Use of
Epidemiological Data in Toxic Tort Cases, 12 Risk Analysis 343, 344–45 (1992).
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(e.g., blood test results from prenatal visits or medical records that document
symptoms of infection).90 Alternatively, the mothers’ responses to questions about
other exposures may shed light on the presence of a bias affecting the recall of
the relevant exposures. Thus, if mothers of cases do not recall greater exposure
than controls’ mothers to pesticides, children with German measles, and so forth,
then one can have greater confidence in their recall of illnesses.
Bias may also result from reliance on interviews with surrogates, individuals
other than the study subjects. This is often necessary when, for example, a subject
(in a case-control study) has died of the disease under investigation.
There are many sources of information bias that affect the measure of exposure,
including its intensity and duration. Exposure to the agent can be measured
directly or indirectly.91 Sometimes researchers use a biological marker as a
direct measure of exposure to an agent—an alteration in tissue or body fluids
that occurs as a result of an exposure and that can be detected in the laboratory.
Biological markers are only available for a small number of toxins and only
reveal whether a person was exposed. Biological markers rarely help determine
the intensity or duration of exposure.92
Monitoring devices also can be used to measure exposure directly but often
are not available for exposures that occurred in the past. For past exposures,
epidemiologists often use indirect means of measuring exposure, such as interviewing
workers and reviewing employment records. Thus, all those employed
to install asbestos insulation may be treated as having been exposed to asbestos
during the period that they were employed. However, there may be a wide
variation of exposure within any job, and these measures may have limited applicability
to a given individual. If the agent of interest is a drug, medical or
hospital records can be used to determine past exposure. Thus, retrospective
90. Two researchers who used a case-control study to examine the association between congenital
heart disease and the mother’s use of drugs during pregnancy corroborated interview data with the
mother’s medical records. See Sally Zierler & Kenneth J. Rothman, Congenital Heart Disease in Relation
to Maternal Use of Bendectin and Other Drugs in Early Pregnancy, 313 New Eng. J. Med. 347, 347–48
(1985).
91. See In re Paoli R.R. Yard PCB Litig., No. 86-2229, 1992 U.S. Dist LEXIS 18430, at *9–*11
(E.D. Pa. Oct. 21, 1992) (discussing valid methods of determining exposure to chemicals).
92. Dose generally refers to the intensity or magnitude of exposure multiplied by the time exposed.
See Sparks v. Owens-Illinois, Inc., 38 Cal. Rptr. 2d 739, 742 (Ct. App. 1995). For a discussion of the
difficulties of determining dose from atomic fallout, see Allen v. United States, 588 F. Supp. 247, 425–26
(D. Utah 1984), rev’d on other grounds, 816 F.2d 1417 (10th Cir. 1987), cert. denied, 484 U.S. 1004
(1988). The timing of exposure may also be critical, especially if the disease of interest is a birth defect.
In Smith v. Ortho Pharmaceutical Corp., 770 F. Supp. 1561, 1577 (N.D. Ga. 1991), the court criticized a
study for its inadequate measure of exposure to spermicides. The researchers had defined exposure as
receipt of a prescription for spermicide within 600 days of delivery, but this definition of exposure is too
broad because environmental agents are only likely to cause birth defects during a narrow band of time.
A different, but related, problem often arises in court. Determining the plaintiff’s exposure to the
alleged toxic substance always involves a retrospective determination and may involve difficulties simiReference
Guide on Epidemiology
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occupational or environmental measurements of exposure are usually less accurate
than prospective studies or follow-up studies, especially ones in which a
drug or medical intervention is the independent variable being measured.
The route (e.g., inhalation or absorption), duration, and intensity of exposure
are important factors in assessing disease causation. Even with environmental
monitoring, the dose measured in the environment generally is not the same
as the dose that reaches internal target organs. If the researcher has calculated the
internal dose of exposure, the scientific basis for this calculation should be examined
for soundness.93
In assessing whether the data may reflect inaccurate information, one must
assess whether the data were collected from objective and reliable sources. Medical
records, government documents, employment records, death certificates, and
interviews are examples of data sources that are used by epidemiologists to measure
both exposure and disease status.94 The accuracy of a particular source may
affect the validity of a research finding. If different data sources are used to
collect information about a study group, differences in the accuracy of those
sources may affect the validity of the findings. For example, using employment
records to gather information about exposure to narcotics probably would lead
to inaccurate results, since employees tend to keep such information private. If
the researcher uses an unreliable source of data, the study may not be useful to
the court.
The kinds of quality-control procedures used may affect the accuracy of the
data. For data collected by interview, quality-control procedures should probe
the reliability of the individual and whether the information is verified by other
sources. For data collected and analyzed in the laboratory, quality-control procedures
should probe the validity and reliability of the laboratory test.
Information bias may also result from inaccurate measurement of disease status.
The quality and sophistication of the diagnostic methods used to detect a
lar to those faced by an epidemiologist planning a study. Thus, in Christophersen v. Allied-Signal Corp.,
939 F.2d 1106, 1113 (5th Cir. 1991), cert. denied, 503 U.S. 912 (1992), the court criticized the plaintiff’s
expert, who relied on an affidavit of a co-worker to determine the dose of nickel and cadmium to
which the decedent had been exposed.
In asbestos litigation, a number of courts have adopted a requirement that the plaintiff demonstrate
(1) regular use by an employer of the defendant’s asbestos-containing product; (2) the plaintiff’s proximity
to that product; and (3) exposure over an extended period of time. See, e.g., Lohrmann v. Pittsburgh
Corning Corp., 782 F.2d 1156, 1162–64 (4th Cir. 1986).
93. See also Bernard D. Goldstein & Mary Sue Henifin, Reference Guide on Toxicology § I.D, in
this manual.
94. Even these sources may produce unanticipated error. Identifying the causal connection between
asbestos and mesothelioma, a rare form of cancer, was complicated and delayed because doctors
who were unfamiliar with mesothelioma erroneously identified other causes of death in death certificates.
See David E. Lilienfeld & Paul D. Gunderson, The “Missing Cases” of Pleural Malignant Mesothelioma
in Minnesota, 1979–81: Preliminary Report, 101 Pub. Health Rep. 395, 397–98 (1986).
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disease should be assessed. The proportion of subjects who were examined also
should be questioned. If, for example, many of the subjects refused to be tested,
the fact that the test used was of high quality would be of relatively little value.
The scientific validity of the research findings is influenced by the reliability
of the diagnosis of disease or health status.95 For example, a researcher interested
in studying spontaneous abortion in the first trimester needs to test women for
pregnancy. Diagnostic criteria that are accepted by the medical community should
be used to make the diagnosis. If a diagnosis is made using an unreliable home
pregnancy kit known to have a high rate of false positive results (indicating
pregnancy when the woman is not pregnant), the study will overestimate the
number of spontaneous abortions.
Misclassification bias is a form of information bias in which, because of problems
with the information available, individuals in the study may be misclassified
with regard to exposure status or disease status. Misclassification bias has been
subdivided into differential misclassification and nondifferential misclassification.
Nondifferential misclassification occurs when inaccuracies in determining exposure
are independent of disease status or when inaccuracies in diagnoses are
independent of exposure status. This is a common problem resulting from the
limitations of data collection. Generally, nondifferential misclassification bias
leads to a shift in the odds ratio toward one, or, in other words, toward a finding
of no effect. Thus, if the errors are nondifferential, it is generally misguided to
criticize an apparent association between an exposure and disease on the grounds
that data were inaccurately classified. Instead, nondifferential misclassification
generally serves to reduce the observed association below its true magnitude.
Differential misclassification refers to the differential error in determining
exposure in cases as compared with controls, or disease status in unexposed
cohorts relative to exposed cohorts. In a case-control study this would occur,
for example, if, in the process of anguishing over the possible causes of the
disease, parents of ill children recalled more exposures to a particular agent than
actually occurred, or if parents of the controls, for whom the issue was less
emotionally charged, recalled fewer. This can also occur in a cohort study in
which, for example, birth control users, the exposed cohort, are monitored
more closely for potential side effects, leading to a higher rate of disease
identification in that cohort than in the unexposed cohort. Depending on how
the misclassification occurs, a differential bias can produce an error in either
direction—the exaggeration or understatement of an association.
95. In In re Swine Flu Immunization Products Liability Litigation, 508 F. Supp. 897, 903 (D. Colo.
1981), aff’d sub nom. Lima v. United States, 708 F.2d 502 (10th Cir. 1983), the court critically evaluated
a study relied on by an expert whose testimony was stricken. In that study, determination of whether a
patient had Guillain-Barré syndrome was made by medical clerks, not physicians who were familiar
with diagnostic criteria.
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3. Other conceptual problems
Sometimes studies are flawed because of flawed definitions or premises that do
not fall under the rubric of selection bias or information bias. For example, if the
researcher defines the disease of interest as all birth defects, rather than a specific
birth defect, he or she must have a scientific basis to hypothesize that the effects
of the agent being investigated could be so varied. If the effect is in fact more
limited, the result of this conceptualization error could be to dilute or mask any
real effect that the agent might have on a specific type of birth defect.96
Examining a study for potential sources of bias is an important task that helps
determine the accuracy of a study’s conclusions. In addition, when a source of
bias is identified, it may be possible to determine whether the error tended to
exaggerate or understate the true association. Thus, bias may exist in a study that
nevertheless has probative value.
Even if one concludes that the findings of a study are statistically stable and
that biases have not created significant error, additional considerations remain.
As repeatedly noted, an association does not necessarily mean a causal relationship
exists. To make a judgment about causation, a knowledgeable expert must
consider the possibility of confounding factors. The expert must also evaluate
several criteria to determine whether an inference of causation is appropriate.
These matters are discussed below.
C. Could a Confounding Factor Be Responsible for the Study
Result? 97
Even when an association exists, researchers must determine whether the exposure
causes the disease or whether the exposure and disease are caused by some
other confounding factor. A confounding factor is both a risk factor for the
disease and a factor associated with the exposure of interest. For example, researchers
may conduct a study that finds individuals with gray hair have a higher
rate of death than those with hair of another color. Instead of hair color having
an impact on death, the results might be explained by the confounding factor of
age. If old age is associated differentially with the gray-haired group (those with
gray hair tend to be older), old age may be responsible for the association found
between hair color and death.98 Researchers must separate the relationship be-
96. In Brock v. Merrell Dow Pharmaceuticals, Inc., 874 F.2d 307, 312 (5th Cir. 1989), cert. denied, 494
U.S. 1046 (1990), the court discussed a reanalysis of a study in which the effect was narrowed from all
congenital malformations to limb reduction defects. The magnitude of the association changed by 50%
when the effect was defined in this narrower fashion. See Rothman & Greenland, supra note 49, at 132
(“Unwarranted assurances of a lack of any effect can easily emerge from studies in which a wide range
of etiologically unrelated outcomes are grouped.”).
97. See Grassis v. Johns-Manville Corp., 591 A.2d 671, 675 (N.J. Super. Ct. App. Div. 1991)
(discussing the possibility that confounders may lead to an erroneous inference of a causal relationship).
98. This example is drawn from Kahn & Sempos, supra note 25, at 63.
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370
tween gray hair and risk of death from that of old age and risk of death. When
researchers find an association between an agent and a disease, it is critical to
determine whether the association is causal or the result of confounding.99 Some
epidemiologists classify confounding as a form of bias. However, confounding is
a reality—that is, the observed association of a factor and a disease is actually the
result of an association with a third, confounding factor. Failure to recognize
confounding can introduce a bias—error—into the findings of the study.
In 1981, Dr. Brian MacMahon, Professor and Chairman of the Department
of Epidemiology at the Harvard School of Public Health, reported an association
between coffee drinking and cancer of the pancreas in the New England
Journal of Medicine.100 This observation caused a great stir, and in fact, one coffee
distributor ran a large advertisement in the New York Times refuting the findings
of the study. What could MacMahon’s findings mean? One possibility is that
the association is causal and that drinking coffee causes an increased risk of cancer
of the pancreas. However, there is also another possibility. We know that
smoking is an important risk factor for cancer of the pancreas. We also know
that it is difficult to find a smoker who does not drink coffee. Thus, drinking
coffee and smoking are associated. An observed association between coffee consumption
and an increased risk of cancer of the pancreas could reflect the fact
that smoking causes cancer of the pancreas and that smoking also is associated
closely with coffee consumption. The association MacMahon found between
drinking coffee and pancreatic cancer could be due to the confounding factor of
smoking. To be fair to MacMahon, we must note that he was aware of the
possibility of confounding and took it into account in his study design by gathering
and analyzing data separately for smokers and nonsmokers. The association
between coffee and pancreatic cancer remained even when smoking was
taken into account.
The main problem in many observational studies such as MacMahon’s is that
the individuals are not assigned randomly to the groups being compared.101 As
discussed above, randomization maximizes the possibility that exposures other
99. Confounding can bias a study result by either exaggerating or diluting any true association. One
example of a confounding factor that may result in a study’s outcome understating an association is
vaccination. Thus, if a group exposed to an agent has a higher rate of vaccination for the disease under
study than the unexposed group, the vaccination may reduce the rate of disease in the exposed group,
thereby producing an association that is less than the true association without the confounding of
vaccination.
100. Brian MacMahon et al., Coffee and Cancer of the Pancreas, 304 New Eng. J. Med. 630 (1981).
101. Randomization attempts to ensure that the presence of a characteristic, such as coffee drinking,
is governed by chance, as opposed to being determined by the presence of an underlying medical
condition. For additional comments on randomization and confounding, see the Glossary of Terms.
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371
than the one under study are evenly distributed between the exposed and the
control cohorts.102 In observational studies, by contrast, other forces, including
self-selection, determine who is exposed to other (possibly causal) factors. The
lack of randomization leads to the potential problem of confounding. Thus, for
example, the exposed cohort might consist of those who are exposed at work to
an agent suspected of being an industrial toxin. The members of this cohort
may, however, differ from controls by residence, socioeconomic status, age, or
other extraneous factors.103 These other factors may be causing the disease, but
because of potential confounding, an apparent (yet false) association of the disease
with exposure to the agent may appear. Confounders, like smoking in the
MacMahon study, do not reflect an error made by the investigators; rather, they
reflect the inherently “uncontrolled” nature of observational studies. When they
can be identified, confounders should be taken into account. Confounding factors
that are suspected or known in advance can be controlled during the study
design through study-group selection. Unanticipated confounding factors that
are suspected after data collection can sometimes be controlled during data analysis,
if data have been gathered about them.
MacMahon’s study found that coffee drinkers had a higher rate of pancreatic
cancer than those who did not drink coffee. To evaluate whether smoking is a
confounding factor, the researcher would divide each of the exposed and control
groups into smoking and nonsmoking subgroups to examine whether subjects’
smoking status affects the study results. If the outcome in the smoking
subgroups is the same as that in the nonsmoking subgroups, smoking is not a
confounding factor. If the subjects’ smoking status affects the outcome, then
smoking is a confounder, for which adjustment is required. If the association
between coffee drinking and pancreatic cancer completely disappears when the
subjects’ smoking status is considered, then smoking is a confounder that fully
accounts for the association with coffee observed. Table 4 reveals a hypothetical
study’s results, with smoking being a weak confounding factor, which, when
accounted for, does not eliminate the association between coffee drinking and
cancer.
102. See Rothman & Greenland, supra note 49, at 124; see also supra § II.A.
103. See, e.g., In re “Agent Orange” Prod. Liab. Litig., 597 F. Supp. 740, 783 (E.D.N.Y. 1984)
(discussing the problem of confounding that might result in a study of the effect of exposure to Agent
Orange on Vietnam servicemen), aff’d, 818 F.2d 145 (2d Cir. 1987), cert. denied, 484 U.S. 1004 (1988).
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Table 4. Pancreatic Cancer Study Data
Smokers
Pancreatic All Subjects >1 Pack per Day Nonsmokers
Cancer Coffee Coffee Coffee
Status Controls Drinkers Controls Drinkers Controls Drinkers
Cancer 14 17 8 11 6 6
No Cancer 1,393 476 733 263 660 213
RR 1.1 3.9 1.2 4.6 1.0 3.1
Note: RR = relative risk.
There is always a real risk that an undiscovered or unrecognized confounding
factor may contribute to a study’s findings, by either magnifying or reducing the
observed association.104 It is, however, necessary to keep that risk in perspective.
Often the mere possibility of uncontrolled confounding is used to call into question
the results of a study. This was certainly the strategy of those seeking, or
unwittingly helping, to undermine the implications of the studies persuasively
linking cigarette smoking to lung cancer. The critical question is whether it is
plausible that the findings of a given study could indeed be due to unrecognized
confounders.
1. What techniques can be used to prevent or limit confounding?
Choices in the design of a research project (e.g., methods for selecting the subjects)
can prevent or limit confounding. When a factor or factors, such as age,
sex, or even smoking status, are considered potential confounders in a study,
investigators can limit the differential distribution of these factors in the study
groups by selecting controls to “match” cases (or the exposed group) in terms of
these variables. If the two groups are matched, for example, by age, then any
association observed in the study cannot be due to age, the matched variable.105
Restricting the persons who are permitted as subjects in a study is another
method to control for confounders. If age or sex is suspected as a confounder,
then the subjects enrolled in a study can be limited to those of one sex and those
who are within a specified age range. When there is no variance among subjects
in a study with regard to a potential confounder, confounding as a result of that
variable is eliminated.
104. Rothman & Greenland, supra note 49, at 120; see also supra § II.A.
105. Selecting a control population based on matched variables necessarily affects the representativeness
of the selected controls and may affect how generalizable the study results are to the population
at large. However, for a study to have merit, it must first be internally valid, that is, it must not be
subject to unreasonable sources of bias or confounding. Only after a study has been shown to meet this
standard does its universal applicability or generalizability to the population at large become an issue.
When a study population is not representative of the general or target population, existing scientific
knowledge may permit reasonable inferences about the study’s broader applicability, or additional confirmatory
studies of other populations may be necessary.
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373
2. What techniques can be used to identify confounding factors?
Once the study data are ready to be analyzed, the researcher must assess a range
of factors that could influence risk. In the case of MacMahon’s study, the researcher
would evaluate whether smoking is a confounding factor by comparing
the risk of pancreatic cancer in all coffee drinkers (including smokers) with the
risk in nonsmoking coffee drinkers. If the risk is substantially the same, smoking
is not a confounding factor (e.g., smoking does not distort the relationship between
coffee drinking and the development of pancreatic cancer), which is what
MacMahon found. If the risk is substantially different, but still exists in the
nonsmoking group, then smoking is a confounder, but doesn’t wholly account
for the association with coffee. If the association disappears, then smoking is a
confounder that fully accounts for the association with coffee observed.
3. What techniques can be used to control for confounding factors?
To control for confounding factors during data analysis, researchers can use one
of two techniques: stratification or multivariate analysis.
Stratification reduces or eliminates confounding by evaluating the effect of an
exposure at different levels (strata) of exposure to the confounding variable.
Statistical methods then can be applied to combine the results of exposure at
each stratum into an overall single estimate of risk. For example, in MacMahon’s
study of smoking and pancreatic cancer, if smoking had been a confounding
factor, the researchers could have stratified the data by creating subgroups based
on how many cigarettes each subject smoked a day (e.g., a nonsmoking group,
a light smoking group, a medium smoking group, and a heavy smoking group).
When different rates of pancreatic cancer for people in each group who drink
the same amount of coffee are compared, the effect of smoking on pancreatic
cancer is revealed. The effect of the confounding factor can then be removed
from the study results.
Multivariate analysis controls for the confounding factor through mathematical
modeling. Models are developed to describe the simultaneous effect of exposure
and confounding factors on the increase in risk.106
Both of these methods allow for “adjustment” of the effect of confounders.
They both modify an observed association to take into account the effect of risk
factors that are not the subject of the study and that may distort the association
between the exposure being studied and the disease outcomes.
If the association between exposure and disease remains after the researcher
completes the assessment and adjustment for confounding factors, the researcher
then applies the guidelines described in section V to determine whether an
inference of causation is warranted.
106. For a more complete discussion, of multivariate analysis, see Daniel L. Rubinfeld, Reference
Guide on Multiple Regression, in this manual.
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V. General Causation: Is an Exposure a Cause of
the Disease?
Once an association has been found between exposure to an agent and development
of a disease, researchers consider whether the association reflects a true
cause–effect relationship. When epidemiologists evaluate whether a cause–effect
relationship exists between an agent and disease, they are using the term
causation in a way similar to, but not identical with, the way the familiar “but
for,” or sine qua non, test is used in law for cause in fact. “An act or an omission
is not regarded as a cause of an event if the particular event would have occurred
without it.”107 This is equivalent to describing the act or occurrence as a necessary
link in a chain of events that results in the particular event.108 Epidemiologists
use causation to mean that an increase in the incidence of disease among
the exposed subjects would not have occurred had they not been exposed to the
agent. Thus, exposure is a necessary condition for the increase in the incidence
of disease among those exposed.109 The relationship between the epidemiologic
concept of cause and the legal question of whether exposure to an agent caused
an individual’s disease is addressed in section VII.
As mentioned in section I, epidemiology cannot objectively prove causation;
rather, causation is a judgment for epidemiologists and others interpreting the
epidemiologic data. Moreover, scientific determinations of causation are inherently
tentative. The scientific enterprise must always remain open to reassessing
the validity of past judgments as new evidence develops.
In assessing causation, researchers first look for alternative explanations for
the association, such as bias or confounding factors, which were discussed in
section IV. Once this process is completed, researchers consider how guidelines
107. W. Page Keeton et al., Prosser and Keeton on the Law of Torts 265 (5th ed. 1984); see also
Restatement (Second) of Torts § 432(1) (1965).
When multiple causes are each operating and capable of causing an event, the but-for, or necessarycondition,
concept for causation is problematic. This is the familiar “two-fires” scenario in which two
independent fires simultaneously burn down a house and is sometimes referred to as overdetermined
cause. Neither fire is a but-for, or necessary condition, for the destruction of the house, because either
fire would have destroyed the house. See id. § 432(2). This two-fires situation is analogous to an individual
being exposed to two agents, each of which is capable of causing the disease contracted by the
individual. A difference between the disease scenario and the fire scenario is that, in the former, one will
have no more than a probabilistic assessment of whether each of the exposures would have caused the
disease in the individual.
108. See supra note 8.
109. See Rothman & Greenland, supra note 49, at 8 (“We can define a cause of a specific disease
event as an antecedent event, condition, or characteristic that was necessary for the occurrence of the
disease at the moment it occurred, given that other conditions are fixed.”); Allen v. United States, 588
F. Supp. 247, 405 (D. Utah 1984) (quoting a physician on the meaning of the statement that radiation
causes cancer), rev’d on other grounds, 816 F.2d 1417 (10th Cir. 1987), cert. denied, 484 U.S. 1004 (1988).
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for inferring causation from an association apply to the available evidence. These
guidelines consist of several key inquiries that assist researchers in making a
judgment about causation.110 Most researchers are conservative when it comes
to assessing causal relationships, often calling for stronger evidence and more
research before a conclusion of causation is drawn.111
The factors that guide epidemiologists in making judgments about causation
are
1. temporal relationship;
2. strength of the association;
3. dose–response relationship;
4. replication of the findings;
5. biological plausibility (coherence with existing knowledge);
6. consideration of alternative explanations;
7. cessation of exposure;
8. specificity of the association; and
9. consistency with other knowledge.
There is no formula or algorithm that can be used to assess whether a causal
inference is appropriate based on these guidelines. One or more factors may be
absent even when a true causal relationship exists. Similarly, the existence of
some factors does not ensure that a causal relationship exists. Drawing causal
inferences after finding an association and considering these factors requires judgment
and searching analysis, based on biology, of why a factor or factors may be
absent despite a causal relationship, and vice-versa. While the drawing of causal
inferences is informed by scientific expertise, it is not a determination that is
made by using scientific methodology.
110. See Mervyn Susser, Causal Thinking in the Health Sciences: Concepts and Strategies in Epidemiology
(1973); In re Joint E. & S. Dist. Asbestos Litig., 52 F.3d 1124, 1128–30 (2d Cir. 1995)
(discussing lower courts’ use of factors to decide whether an inference of causation is justified when an
association exists).
111. Berry v. CSX Transp., Inc., 709 So. 2d 552, 568 n.12 (Fla. Dist. Ct. App. 1998) (“Almost all
genres of research articles in the medical and behavioral sciences conclude their discussion with qualifying
statements such as ‘there is still much to be learned.’ This is not, as might be assumed, an expression
of ignorance, but rather an expression that all scientific fields are open-ended and can progress from
their present state . . . .”); Hall v. Baxter Healthcare Corp., 947 F. Supp. 1387 App. B. at 1446–51 (D.
Or. 1996) (report of Merwyn R. Greenlick, court-appointed epidemiologist). In Cadarian v. Merrell
Dow Pharmaceuticals, Inc., 745 F. Supp. 409 (E.D. Mich. 1989), the court refused to permit an expert to
rely on a study that the authors had concluded should not be used to support an inference of causation
in the absence of independent confirmatory studies. The court did not address the question whether the
degree of certainty used by epidemiologists before making a conclusion of cause was consistent with the
legal standard. See DeLuca v. Merrell Dow Pharms., Inc., 911 F.2d 941, 957 (3d Cir. 1990) (standard of
proof for scientific community is not necessarily appropriate standard for expert opinion in civil litigation);
Wells v. Ortho Pharm. Corp., 788 F.2d 741, 745 (11th Cir.), cert. denied, 479 U.S. 950 (1986).
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These guidelines reflect criteria proposed by the U.S. Surgeon General in
1964112 in assessing the relationship between smoking and lung cancer and expanded
upon by A. Bradford Hill in 1965.113
A. Is There a Temporal Relationship?
A temporal, or chronological, relationship must exist for causation. If an exposure
causes disease, the exposure must occur before the disease develops.114 If
the exposure occurs after the disease develops, it cannot cause the disease. Although
temporal relationship is often listed as one of many factors in assessing
whether an inference of causation is justified, it is a necessary factor: Without
exposure before disease, causation cannot exist.
B. How Strong Is the Association Between the Exposure and
Disease? 115
The relative risk is one of the cornerstones for causal inferences.116 Relative risk
measures the strength of the association. The higher the relative risk, the greater
the likelihood that the relationship is causal.117 For cigarette smoking, for example,
the estimated relative risk for lung cancer is very high, about 10.118 That
is, the risk of lung cancer in smokers is approximately ten times the risk in
nonsmokers.
A relative risk of 10, as seen with smoking and lung cancer, is so high that it
is extremely difficult to imagine any bias or confounding factor that might account
for it. The higher the relative risk, the stronger the association and the
lower the chance that the effect is spurious. Although lower relative risks can
112. U.S. Dep’t of Health, Educ., and Welfare, Public Health Serv., Smoking and Health: Report
of the Advisory Committee to the Surgeon General (1964).
113. A. Bradford Hill, The Environment and Disease: Association or Causation?, 58 Proc. Royal Soc’y
Med. 295 (1965) (Hill acknowledged that his factors could only serve to assist in the inferential process:
“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.”).
114. See Carroll v. Litton Sys., Inc., No. B-C-88-253, 1990 U.S. Dist. LEXIS 16833, at *29
(W.D.N.C. Oct. 29, 1990) (“[I]t is essential for . . . [the plaintiffs’ medical experts opining on causation]
to know that exposure preceded plaintiffs’ alleged symptoms in order for the exposure to be
considered as a possible cause of those symptoms . . . .”).
115. Assuming that an association is determined to be causal, the strength of the association plays an
important role legally in determining the specific causation question—whether the agent caused an
individual plaintiff’s injury. See infra § VII.
116. See supra § III.A.
117. See Cook v. United States, 545 F. Supp. 306, 316 n.4 (N.D. Cal. 1982); Landrigan v. Celotex
Corp., 605 A.2d 1079, 1085 (N.J. 1992). The use of the strength of the association as a factor does not
reflect a belief that weaker effects occur less frequently than stronger effects. See Green, supra note 39, at
652–53 n.39. Indeed, the apparent strength of a given agent is dependent on the prevalence of the other
necessary elements that must occur with the agent to produce the disease, rather than on some inherent
characteristic of the agent itself. See Rothman & Greenland, supra note 49, at 9–11.
118. See Doll & Hill, supra note 7.
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reflect causality, the epidemiologist will scrutinize such associations more closely
because there is a greater chance that they are the result of uncontrolled confounding
or biases.
C. Is There a Dose–Response Relationship?
A dose–response relationship means that the more intense the exposure, the
greater the risk of disease. Generally, higher exposures should increase the incidence
(or severity) of disease. However, some causal agents do not exhibit a
dose–response relationship when, for example, there is a threshold phenomenon
(i.e., an exposure may not cause disease until the exposure exceeds a certain
dose).119 Thus, a dose–response relationship is strong, but not essential,
evidence that the relationship between an agent and disease is causal.
D. Have the Results Been Replicated?
Rarely, if ever, does a single study conclusively demonstrate a cause–effect relationship.
120 It is important that a study be replicated in different populations and
by different investigators before a causal relationship is accepted by epidemiologists
and other scientists.
The need to replicate research findings permeates most fields of science. In
epidemiology, research findings often are replicated in different populations.121
Consistency in these findings is an important factor in making a judgment about
causation. Different studies that examine the same exposure–disease relationship
119. The question whether there is a no-effect threshold dose is a controversial one in a variety of
toxic substances areas. See, e.g., Irving J. Selikoff, Disability Compensation for Asbestos-Associated
Disease in the United States: Report to the U.S. Department of Labor 181–220 (1981); Paul Kotin,
Dose–Response Relationships and Threshold Concepts, 271 Annals N.Y. Acad. Sci. 22 (1976); K. Robock,
Based on Available Data, Can We Project an Acceptable Standard for Industrial Use of Asbestos? Absolutely, 330
Annals N.Y. Acad. Sci. 205 (1979); Ferebee v. Chevron Chem. Co., 736 F.2d 1529, 1536 (D.C. Cir.)
(dose–response relationship for low doses is “one of the most sharply contested questions currently
being debated in the medical community”), cert. denied, 469 U.S. 1062 (1984); In re TMI Litig. Consol.
Proc., 927 F. Supp. 834, 844–45 (M.D. Pa. 1996) (discussing low-dose extrapolation and no-dose
effects for radiation exposure).
Moreover, good evidence to support or refute the threshold-dose hypothesis is exceedingly unlikely
because of the inability of epidemiology or animal toxicology to ascertain very small effects. Cf. Arnold
L. Brown, The Meaning of Risk Assessment, 37 Oncology 302, 303 (1980). Even the shape of the dose–
response curve—whether linear or curvilinear, and if the latter, the shape of the curve—is a matter of
hypothesis and speculation. See Allen v. United States, 588 F. Supp. 247, 419–24 (D. Utah 1984), rev’d
on other grounds, 816 F.2d 1417 (10th Cir. 1987), cert. denied, 484 U.S. 1004 (1988); Troyen A. Brennan
& Robert F. Carter, Legal and Scientific Probability of Causation for Cancer and Other Environmental Disease
in Individuals, 10 J. Health Pol’y & L. 33, 43–44 (1985).
120. In Kehm v. Procter & Gamble Co., 580 F. Supp. 890, 901 (N.D. Iowa 1982), aff’d sub nom.
Kehm v. Procter & Gamble Mfg. Co., 724 F.2d 613 (8th Cir. 1983), the court remarked on the
persuasive power of multiple independent studies, each of which reached the same finding of an association
between toxic shock syndrome and tampon use.
121. See Cadarian v. Merrell Dow Pharms., Inc., 745 F. Supp. 409, 412 (E.D. Mich. 1989) (holdReference
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ing a study on Bendectin insufficient to support an expert’s opinion, because “the study’s authors
themselves concluded that the results could not be interpreted without independent confirmatory evidence”).
122. A number of courts have adverted to this criterion in the course of their discussions of causation
in toxic substances cases. E.g., Cook v. United States, 545 F. Supp. 306, 314–15 (N.D. Cal. 1982)
(discussing biological implausibility of a two-peak increase of disease when plotted against time); Landrigan
v. Celotex Corp., 605 A.2d 1079, 1085–86 (N.J. 1992) (discussing the existence vel non of biological
plausibility). See also Bernard D. Goldstein & Mary Sue Henifin, Reference Guide on Toxicology,
§ III.E, in this manual.
123. See supra § IV.B–C.
generally should yield similar results. While inconsistent results do not rule out
a causal nexus, any inconsistencies signal a need to explore whether different
results can be reconciled with causality.
E. Is the Association Biologically Plausible (Consistent with
Existing Knowledge)?122
Biological plausibility is not an easy criterion to use and depends upon existing
knowledge about the mechanisms by which the disease develops. When biological
plausibility exists, it lends credence to an inference of causality. For example,
the conclusion that high cholesterol is a cause of coronary heart disease is
plausible because cholesterol is found in atherosclerotic plaques. However, observations
have been made in epidemiologic studies that were not biologically
plausible at the time but subsequently were shown to be correct. When an
observation is inconsistent with current biological knowledge, it should not be
discarded, but the observation should be confirmed before significance is attached
to it. The saliency of this factor varies depending on the extent of scientific
knowledge about the cellular and subcellular mechanisms through which the
disease process works. The mechanisms of some diseases are understood better
than the mechanisms of others.
F. Have Alternative Explanations Been Considered?
The importance of considering the possibility of bias and confounding and ruling
out the possibilities was discussed above.123
G. What Is the Effect of Ceasing Exposure?
If an agent is a cause of a disease one would expect that cessation of exposure to
that agent ordinarily would reduce the risk of the disease. This has been the case,
for example, with cigarette smoking and lung cancer. In many situations, however,
relevant data are simply not available regarding the possible effects of ending
the exposure. But when such data are available and eliminating exposure
reduces the incidence of disease, this factor strongly supports a causal relationship.
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H. Does the Association Exhibit Specificity?
An association exhibits specificity if the exposure is associated only with a single
disease or type of disease.124 The vast majority of agents do not cause a wide
variety of effects. For example, asbestos causes mesothelioma and lung cancer
and may cause one or two other cancers, but there is no evidence that it causes
any other types of cancers. Thus, a study that finds that an agent is associated
with many different diseases should be examined skeptically. Nevertheless, there
may be causal relationships in which this guideline is not satisfied. Cigarette
manufacturers have long claimed that because cigarettes have been linked to
lung cancer, emphysema, bladder cancer, heart disease, pancreatic cancer, and
other conditions, there is no specificity and the relationships are not causal.
There is, however, at least one good reason why inferences about the health
consequences of tobacco do not require specificity: because tobacco and cigarette
smoke are not in fact single agents but consist of numerous harmful agents,
smoking represents exposure to multiple agents, with multiple possible effects.
Thus, while evidence of specificity may strengthen the case for causation, lack
of specificity does not necessarily undermine it where there is a plausible biological
explanation for its absence.
I. Are the Findings Consistent with Other Relevant Knowledge?
In addressing the causal relationship of lung cancer to cigarette smoking, researchers
examined trends over time for lung cancer and for cigarette sales in the
United States. A marked increase in lung cancer death rates in men was observed,
which appeared to follow the increase in sales of cigarettes. Had the
increase in lung cancer deaths followed a decrease in cigarette sales, it might
have given researchers pause. It would not have precluded a causal inference,
but the inconsistency of the trends in cigarette sales and lung cancer mortality
would have had to be explained.
124. This criterion reflects the fact that although an agent causes one disease, it does not necessarily
cause other diseases. See, e.g., Nelson v. American Sterilizer Co., 566 N.W.2d 671, 676–77 (Mich. Ct.
App. 1997) (affirming dismissal of plaintiff’s claims that chemical exposure caused her liver disorder, but
recognizing that evidence supported claims for neuropathy and other illnesses); Sanderson v. International
Flavors & Fragrances, Inc., 950 F. Supp. 981, 996–98 (C.D. Cal. 1996).
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VI. What Methods Exist for Combining the
Results of Multiple Studies?
Not infrequently, the court may be faced with a number of epidemiologic studies
whose findings differ. These may be studies in which one shows an association
and the other does not, or studies which report associations, but of different
magnitude. In view of the fact that epidemiologic studies may disagree and that
often many of the studies are small and lack the statistical power needed for
definitive conclusions, the technique of meta-analysis was developed.125 Metaanalysis
is a method of pooling study results to arrive at a single figure to represent
the totality of the studies reviewed. It is a way of systematizing the timehonored
approach of reviewing the literature, which is characteristic of science,
and placing it in a standardized framework with quantitative methods for estimating
risk. In a meta-analysis, studies are given different weights in proportion
to the sizes of their study populations and other characteristics.126
Meta-analysis is most appropriate when used in pooling randomized experimental
trials, because the studies included in the meta-analysis share the most
significant methodological characteristics, in particular, use of randomized assignment
of subjects to different exposure groups. However, often one is confronted
with non-randomized observational studies of the effects of possible
toxic substances or agents. A method for summarizing such studies is greatly
needed, but when meta-analysis is applied to observational studies—either casecontrol
or cohort—it becomes more problematic. The reason for this is that
often methodological differences among studies are much more pronounced
than they are in randomized trials. Hence, the justification for pooling the results
and deriving a single estimate of risk, for example, is not always apparent.
A number of problems and issues arise in meta-analysis. Should only published
papers be included in the meta-analysis, or should any available studies be
used, even if they have not been peer reviewed? How can the problem of differences
in the quality of the studies reviewed be taken into account? Can the
results of the meta-analysis itself be reproduced by other analysts? When there
125. See In re Paoli R.R. Yard PCB Litig., 916 F.2d 829, 856 (3d Cir. 1990), cert. denied, 499 U.S.
961 (1991); Hines v. Consolidated Rail Corp., 926 F.2d 262, 273 (3d Cir. 1991); Allen v. International
Bus. Mach. Corp., No. 94-264-LON, 1997 U.S. Dist. LEXIS 8016, at *71–*74 (meta-analysis of
observational studies is a controversial subject among epidemiologists). Thus, contrary to the suggestion
by at least one court, multiple studies with small numbers of subjects may be pooled to reduce the
possibility that sampling error is biasing the outcome. See In re Joint E. & S. Dist. Asbestos Litig., 827 F.
Supp. 1014, 1042 (S.D.N.Y. 1993) (“[N]o matter how many studies yield a positive but statistically
insignificant SMR for colorectal cancer, the results remain statistically insignificant. Just as adding a
series of zeros together yields yet another zero as the product, adding a series of positive but statistically
insignificant SMRs together does not produce a statistically significant pattern.”), rev’d, 52 F.3d 1124
(2d Cir. 1995); see also supra note 76.
126. Petitti, supra note 76.
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are several meta-analyses of a given relationship, why do the results of different
meta-analyses often disagree? Another consideration is that often the differences
among the individual studies included in a meta-analysis and the reasons for the
differences are important in themselves and need to be understood; however,
they may be masked in a meta-analysis. A final problem with meta-analyses is
that they generate a single estimate of risk and may lead to a false sense of
security regarding the certainty of the estimate. People often tend to have an
inordinate belief in the validity of the findings when a single number is attached
to them, and many of the difficulties that may arise in conducting a meta-analysis,
especially of observational studies like epidemiologic ones, may consequently
be overlooked.127
VII. What Role Does Epidemiology Play in
Proving Specific Causation?
Epidemiology is concerned with the incidence of disease in populations and
does not address the question of the cause of an individual’s disease.128 This
question, sometimes referred to as specific causation, is beyond the domain of
the science of epidemiology. Epidemiology has its limits at the point where an
127. Much has been written about meta-analysis recently, and some experts consider the problems
of meta-analysis to outweigh the benefits at the present time. For example, Bailar has written the
following:
[P]roblems have been so frequent and so deep, and overstatements of the strength of conclusions so
extreme, that one might well conclude there is something seriously and fundamentally wrong with the
method. For the present . . . I still prefer the thoughtful, old-fashioned review of the literature by a
knowledgeable expert who explains and defends the judgments that are presented. We have not yet
reached a stage where these judgments can be passed on, even in part, to a formalized process such as
meta-analysis.
John C. Bailar III, Assessing Assessments, 277 Science 528, 529 (1997) (reviewing Morton Hunt, How
Science Takes Stock (1997)); see also Point/Counterpoint: Meta-analysis of Observational Studies, 140 Am.
J. Epidemiology 770 (1994).
128. See DeLuca v. Merrell Dow Pharms., Inc., 911 F.2d 941, 945 & n.6 (3d Cir. 1990) (“Epidemiological
studies do not provide direct evidence that a particular plaintiff was injured by exposure to a
substance.”); Smith v. Ortho Pharm. Corp., 770 F. Supp. 1561, 1577 (N.D. Ga. 1991); Grassis v.
Johns-Manville Corp., 591 A.2d 671, 675 (N.J. Super. Ct. App. Div. 1991); Michael Dore, A Commentary
on the Use of Epidemiological Evidence in Demonstrating Cause-in-Fact, 7 Harv. Envtl. L. Rev. 429, 436
(1983).
There are some diseases that do not occur without exposure to a given toxic agent. This is the same
as saying that the toxic agent is a necessary cause for the disease, and the disease is sometimes referred to
as a signature disease (also, the agent is pathognomonic), because the existence of the disease necessarily
implies the causal role of the agent. See Kenneth S. Abraham & Richard A. Merrill, Scientific Uncertainty
in the Courts, Issues Sci. & Tech., Winter 1986, at 93, 101. Asbestosis is a signature disease for asbestos,
and adenocarcinoma (in young adult women) is a signature disease for in utero DES exposure. See In re
“Agent Orange” Prod. Liab. Litig., 597 F. Supp. 740, 834 (E.D.N.Y. 1984) (Agent Orange allegedly
caused a wide variety of diseases in Vietnam veterans and their offspring), aff’d, 818 F.2d 145 (2d Cir.
1987), cert. denied, 484 U.S. 1004 (1988).
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inference is made that the relationship between an agent and a disease is causal
(general causation) and where the magnitude of excess risk attributed to the
agent has been determined; that is, epidemiology addresses whether an agent
can cause a disease, not whether an agent did cause a specific plaintiff’s disease.
129
Nevertheless, the specific causation issue is a necessary legal element in a
toxic substance case. The plaintiff must establish not only that the defendant’s
agent is capable of causing disease but also that it did cause the plaintiff’s disease.
Thus, a number of courts have confronted the legal question of what is acceptable
proof of specific causation and the role that epidemiologic evidence plays in
answering that question.130 This question is not a question that is addressed by
epidemiology.131 Rather, it is a legal question a number of courts have grappled
with. An explanation of how these courts have resolved this question follows.
The remainder of this section should be understood as an explanation of judicial
opinions, not as epidemiology.
Before proceeding, one last caveat is in order. This section assumes that epidemiologic
evidence has been used as proof of causation for a given plaintiff.
The discussion does not address whether a plaintiff must use epidemiologic evidence
to prove causation.132
Two legal issues arise with regard to the role of epidemiology in proving
individual causation: admissibility and sufficiency of evidence to meet the burden
of production. The first issue tends to receive less attention by the courts
but nevertheless deserves mention. An epidemiologic study that is sufficiently
rigorous to justify a conclusion that it is scientifically valid should be admissible,
133 as it tends to make an issue in dispute more or less likely.134
129. Cf. “Agent Orange,” 597 F. Supp. at 780.
130. In many instances causation can be established without epidemiologic evidence. When the
mechanism of causation is well understood, the causal relationship is well established, or the timing
between cause and effect is close, scientific evidence of causation may not be required. This is frequently
the situation when the plaintiff suffers traumatic injury rather than disease. This section addresses
only those situations in which causation is not evident and scientific evidence is required.
131. Nevertheless, an epidemiologist may be helpful to the fact finder in answering this question.
Some courts have permitted epidemiologists (or those who use epidemiologic methods) to testify about
specific causation. See Ambrosini v. Labarraque, 101 F.3d 129, 137–41 (D.C. Cir. 1996), cert. dismissed,
520 U.S. 1205 (1997); Zuchowicz v. United States, 870 F. Supp. 15 (D. Conn. 1994); Landrigan v.
Celotex Corp., 605 A.2d 1079, 1088–89 (N.J. 1992). In general, courts seem more concerned with the
basis of an expert’s opinion than with whether the expert is an epidemiologist or clinical physician. See
Porter v. Whitehall, 9 F.3d 607, 614 (7th Cir. 1992) (“curb side” opinion from clinician not admissible);
Wade-Greaux v. Whitehall Labs., 874 F. Supp. 1441, 1469–72 (D.V.I.) (clinician’s multiple
bases for opinion inadequate to support causation opinion), aff’d, 46 F.3d 1120 (3d Cir. 1994); Landrigan,
605 A.2d at 1083–89 (permitting both clinicians and epidemiologists to testify to specific causation
provided the methodology used is sound).
132. See Green, supra note 39, at 672–73; 2 Modern Scientific Evidence, supra note 2, § 28-1.3.2 to
-1.3.3, at 306–11.
133. See DeLuca, 911 F.2d at 958; cf. Kehm v. Procter & Gamble Co., 580 F. Supp. 890, 902 (N.D.
Iowa 1982) (“These [epidemiologic] studies were highly probative on the issue of causation—they all
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383
Far more courts have confronted the role that epidemiology plays with regard
to the sufficiency of the evidence and the burden of production. The civil
burden of proof is described most often as requiring the fact finder to “believe
that what is sought to be proved . . . is more likely true than not true.”135 The
relative risk from epidemiologic studies can be adapted to this 50% plus standard
to yield a probability or likelihood that an agent caused an individual’s disease.
136 An important caveat is necessary, however. The discussion below speaks
in terms of the magnitude of the relative risk or association found in a study.
However, before an association or relative risk is used to make a statement
about the probability of individual causation, the inferential judgment, described
in section V, that the association is truly causal rather than spurious is required:
“[A]n agent cannot be considered to cause the illness of a specific person unless
concluded that an association between tampon use and menstrually related TSS [toxic shock syndrome]
cases exists.”), aff’d sub nom. Kehm v. Procter & Gamble Mfg. Co., 724 F.2d 613 (8th Cir. 1984).
Hearsay concerns may limit the independent admissibility of the study (see supra note 3), but the
study could be relied on by an expert in forming an opinion and may be admissible pursuant to Fed. R.
Evid. 703 as part of the underlying facts or data relied on by the expert.
In Ellis v. International Playtex, Inc., 745 F.2d 292, 303 (4th Cir. 1984), the court concluded that
certain epidemiologic studies were admissible despite criticism of the methodology used in the studies.
The court held that the claims of bias went to the studies’ weight rather than their admissibility. Cf.
Christophersen v. Allied-Signal Corp., 939 F.2d 1106, 1109 (5th Cir. 1991) (“As a general rule, questions
relating to the bases and sources of an expert’s opinion affect the weight to be assigned that
opinion rather than its admissibility . . . . ”), cert. denied, 503 U.S. 912 (1992).
134. Even if evidence is relevant, it may be excluded if its probative value is substantially outweighed
by prejudice, confusion, or inefficiency. Fed. R. Evid. 403. However, exclusion of an otherwise
relevant epidemiologic study on Rule 403 grounds is unlikely.
In Daubert v. Merrell Dow Pharmaceuticals, Inc., 509 U.S. 579, 591 (1993), the Court invoked the
concept of “fit,” which addresses the relationship of an expert’s scientific opinion to the facts of the case
and the issues in dispute. In a toxic substance case in which cause in fact is disputed, an epidemiologic
study of the same agent to which the plaintiff was exposed that examined the association with the same
disease from which the plaintiff suffers would undoubtedly have sufficient “fit” to be a part of the basis
of an expert’s opinion. The Court’s concept of “fit,” borrowed from United States v. Downing, 753 F.2d
1224, 1242 (3d Cir. 1985), appears equivalent to the more familiar evidentiary concept of probative
value, albeit one requiring assessment of the scientific reasoning the expert used in drawing inferences
from methodology or data to opinion.
135. 2 Edward J. Devitt & Charles B. Blackmar, Federal Jury Practice and Instruction § 71.13 (3d
ed. 1977); see also United States v. Fatico, 458 F. Supp. 388, 403 (E.D.N.Y. 1978) (“Quantified, the
preponderance standard would be 50%+ probable.”), aff’d, 603 F.2d 1053 (2d Cir. 1979), cert. denied,
444 U.S. 1073 (1980).
136. An adherent of the frequentist school of statistics would resist this adaptation, which may
explain why so many epidemiologists and toxicologists also resist it. To take the step identified in the
text of using an epidemiologic study outcome to determine the probability of specific causation requires
a shift from a frequentist approach, which involves sampling or frequency data from an empirical test, to
a subjective probability about a discrete event. Thus, a frequentist might assert, after conducting a
sampling test, that 60% of the balls in an opaque container are blue. The same frequentist would resist
the statement, “The probability that a single ball removed from the box and hidden behind a screen is
blue is 60%.” The ball is either blue or not, and no frequentist data would permit the latter statement.
“[T]here is no logically rigorous definition of what a statement of probability means with reference to
an individual instance . . . .” Lee Loevinger, On Logic and Sociology, 32 Jurimetrics J. 527, 530 (1992); see
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384
it is recognized as a cause of that disease in general.”137 The following discussion
should be read with this caveat in mind.138
The threshold for concluding that an agent was more likely than not the
cause of an individual’s disease is a relative risk greater than 2.0. Recall that a
relative risk of 1.0 means that the agent has no effect on the incidence of disease.
When the relative risk reaches 2.0, the agent is responsible for an equal number
of cases of disease as all other background causes. Thus, a relative risk of 2.0
(with certain qualifications noted below) implies a 50% likelihood that an exposed
individual’s disease was caused by the agent. A relative risk greater than
2.0 would permit an inference that an individual plaintiff’s disease was more
likely than not caused by the implicated agent.139 A substantial number of courts
in a variety of toxic substances cases have accepted this reasoning.140
also Steve Gold, Note, Causation in Toxic Torts: Burdens of Proof, Standards of Persuasion and Statistical
Evidence, 96 Yale L.J. 376, 382–92 (1986). Subjective probabilities about discrete events are the product
of adherents to Bayes Theorem. See Kaye, supra note 67, at 54–62; David H. Kaye & David A. Freedman,
Reference Guide on Statistics § IV.D, in this manual.
137. Cole, supra note 53, at 10284.
138. We emphasize this caveat, both because it is not intuitive and because some courts have failed
to appreciate the difference between an association and a causal relationship. See, e.g., Forsyth v. Eli
Lilly & Co., Civ. No. 95-00185 ACK, 1998 U.S. Dist. LEXIS 541, at *26–*31 (D. Haw. Jan. 5, 1998).
But see Berry v. CSX Transp., Inc., 709 So. 2d 552, 568 (Fla. Dist. Ct. App. 1998) (“From epidemiological
studies demonstrating an association, an epidemiologist may or may not infer that a causal relationship
exists.”).
139. See Davies v. Datapoint Corp., No. 94-56-P-DMC, 1995 U.S. Dist. LEXIS 21739, at *32–
*35 (D. Me. Oct. 31, 1995) (holding that epidemiologist could testify about specific causation, basing
such testimony on the probabilities derived from epidemiologic evidence).
140. See DeLuca v. Merrell Dow Pharms., Inc., 911 F.2d 941, 958–59 (3d Cir. 1990) (Bendectin
allegedly caused limb reduction birth defects); In re Joint E. & S. Dist. Asbestos Litig., 964 F.2d 92 (2d
Cir. 1992) (relative risk less than 2.0 may still be sufficient to prove causation); Daubert v. Merrell Dow
Pharms., Inc., 43 F.3d 1311, 1320 (9th Cir.) (requiring that plaintiff demonstrate a relative risk of 2),
cert. denied, 516 U.S. 869 (1995); Pick v. American Med. Sys., Inc., 958 F. Supp. 1151, 1160 (E.D. La.
1997) (recognizing that a relative risk of 2 implies a 50% probability of specific causation, but recognizing
that a study with a lower relative risk is admissible, although ultimately it may be insufficient to
support a verdict on causation); Sanderson v. International Flavors & Fragrances, Inc., 950 F. Supp.
981, 1000 (C.D. Cal. 1996) (acknowledging a relative risk of 2 as a threshold for plaintiff to prove
specific causation); Manko v. United States, 636 F. Supp. 1419, 1434 (W.D. Mo. 1986) (swine flu
vaccine allegedly caused Guillain-Barré syndrome), aff’d in part, 830 F.2d 831 (8th Cir. 1987); Marder
v. G.D. Searle & Co., 630 F. Supp. 1087, 1092 (D. Md. 1986) (pelvic inflammatory disease allegedly
caused by Copper 7 IUD), aff’d without op. sub nom. Wheelahan v. G.D. Searle & Co., 814 F.2d 655 (4th
Cir. 1987); In re “Agent Orange” Prod. Liab. Litig., 597 F. Supp. 740, 835–37 (E.D.N.Y. 1984) (Agent
Orange allegedly caused a wide variety of diseases in Vietnam veterans and their offspring), aff’d, 818
F.2d 145 (2d Cir. 1987), cert. denied, 484 U.S. 1004 (1988); Cook v. United States, 545 F. Supp. 306,
308 (N.D. Cal. 1982) (swine flu vaccine allegedly caused Guillain-Barré syndrome); Landrigan v. Celotex
Corp., 605 A.2d 1079, 1087 (N.J. 1992) (relative risk greater than 2.0 “support[s] an inference that the
exposure was the probable cause of the disease in a specific member of the exposed population”);
Merrell Dow Pharms., Inc. v. Havner, 953 S.W.2d 706, 718 (Tex. 1997) (“The use of scientifically
reliable epidemiological studies and the requirement of more than a doubling of the risk strikes a
balance between the needs of our legal system and the limits of science.”). But cf. In re Fibreboard Corp.,
893 F.2d 706, 711–12 (5th Cir. 1990) (The court disapproved a trial in which several representative
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385
An alternative, yet similar, means to address probabilities in individual cases is
use of the attributable risk parameter.141 The attributable risk is a measurement
of the excess risk that can be attributed to an agent, above and beyond the
background risk that is due to other causes.142 When the attributable risk exceeds
50% (equivalent to a relative risk greater than 2.0), this logically might
lead one to believe that the agent was more likely than not the cause of the
plaintiff’s disease.
The discussion above contains a number of assumptions: that the study was
unbiased, sampling error and confounding were judged unlikely or minimal,
the causal factors discussed in section V point toward causation, and the relative
risk found in the study is a reasonably accurate measure of the extent of disease
caused by the agent. It also assumes that the plaintiff in a given case is comparable
to the subjects who made up the exposed cohort in the epidemiologic
study and that there are no interactions with other causal agents.143
Evidence in a given case may challenge one or more of those assumptions.
Bias in a study may suggest that the outcome found is inaccurate and should be
estimated to be higher or lower than the actual result. A plaintiff may have been
exposed to a dose of the agent in question that is greater or lower than that to
which those in the study were exposed.144 A plaintiff may have individual factors,
such as higher age than those in the study, that make it less likely that
cases would be tried and the results extrapolated to a class of some 3,000 asbestos victims, without
consideration of any evidence about the individual victims. The court remarked that under Texas law,
general causation, which ignores any proof particularistic to the individual plaintiff, could not be substituted
for cause in fact.).
141. See supra § III.C.
142. Because cohort epidemiologic studies compare the incidences (rates) of disease, measures like
the relative risk and attributable risk are dependent on the time period during which disease is measured
in the study groups. Exposure to the agent may either accelerate the onset of the disease in a subject
who would have contracted the disease at some later time—all wrongful death cases entail acceleration
of death—or be the cause of disease that otherwise would never have occurred in the subject. This
creates some uncertainty (when pathological information does not permit determining which of the
foregoing alternatives is the case) and ambiguity about the proper calculation of the attributable risk,
that is, whether both alternatives should be included in the excess risk or just the latter. See Sander
Greenland & James M. Robins, Conceptual Problems in the Definition and Interpretation of Attributable
Fractions, 128 Am. J. Epidemiology 1185 (1988). If information were available, the legal issue with
regard to acceleration would be the characterization of the harm and the appropriate amount of damages
when a defendant’s tortious conduct accelerates development of the disease. See Restatement
(Second) of Torts § 924 cmt. e (1977); Keeton et al., supra note 107, § 52, at 353–54; Robert J. Peaslee,
Multiple Causation and Damages, 47 Harv. L. Rev. 1127 (1934).
143. See Greenland & Robins, supra note 142, at 1193.
144. See supra § V.C; see also Ferebee v. Chevron Chem. Co., 736 F.2d 1529, 1536 (D.C. Cir.)
(“The dose–response relationship at low levels of exposure for admittedly toxic chemicals like paraquat
is one of the most sharply contested questions currently being debated in the medical community.”),
cert. denied, 469 U.S. 1062 (1984); In re Joint E. & S. Dist. Asbestos Litig., 774 F. Supp. 113, 115
(S.D.N.Y. 1991) (discussing different relative risks associated with different doses), rev’d on other grounds,
964 F.2d 92 (2d Cir. 1992).
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exposure to the agent caused the plaintiff’s disease. Similarly, an individual plaintiff
may be able to rule out other known (background) causes of the disease, such as
genetics, that increase the likelihood that the agent was responsible for that
plaintiff’s disease. Pathological-mechanism evidence may be available for the
plaintiff that is relevant to the cause of the plaintiff’s disease.145 Before any causal
relative risk from an epidemiologic study can be used to estimate the probability
that the agent in question caused an individual plaintiff’s disease, consideration
of these (and similar) factors is required.146
Having additional evidence that bears on individual causation has led a few
courts to conclude that a plaintiff may satisfy his or her burden of production
even if a relative risk less than 2.0 emerges from the epidemiologic evidence.147
For example, genetics might be known to be responsible for 50% of the incidence
of a disease independent of exposure to the agent.148 If genetics can be
ruled out in an individual’s case, then a relative risk greater than 1.5 might be
sufficient to support an inference that the agent was more likely than not responsible
for the plaintiff’s disease.149
145. See Tobin v. Astra Pharm. Prods., Inc., 993 F.2d 528 (6th Cir.) (plaintiff’s expert relied predominantly
on pathogenic evidence), cert. denied, 510 U.S. 914 (1993).
146. See Merrell Dow Pharms., Inc. v. Havner, 953 S.W.2d 706, 720 (Tex. 1997); Mary Carter
Andrues, Note, Proof of Cancer Causation in Toxic Waste Litigation, 61 S. Cal. L. Rev. 2075, 2100–04
(1988). An example of a judge sitting as fact finder and considering individual factors for a number of
plaintiffs in deciding cause in fact is contained in Allen v. United States, 588 F. Supp. 247, 429–43 (D.
Utah 1984), rev’d on other grounds, 816 F.2d 1417 (10th Cir. 1987), cert. denied, 484 U.S. 1004 (1988); see
also Manko v. United States, 636 F. Supp. 1419, 1437 (W.D. Mo. 1986), aff’d, 830 F.2d 831 (8th Cir.
1987).
147. See, e.g., Grassis v. Johns-Manville Corp., 591 A.2d 671, 675 (N.J. Super. Ct. App. Div.
1991): “The physician or other qualified expert may view the epidemiological studies and factor out
other known risk factors such as family history, diet, alcohol consumption, smoking . . . or other factors
which might enhance the remaining risks, even though the risk in the study fell short of the 2.0
correlation.” See also In re Joint E. & S. Dist. Asbestos Litig., 52 F.3d 1124 (2d Cir. 1995) (holding that
plaintiff could provide sufficient evidence of causation without proving a relative risk greater than 2); In
re Joint E. & S. Dist. Asbestos Litig., 964 F.2d 92, 97 (2d Cir. 1992), rev’g 758 F. Supp. 199, 202–03
(S.D.N.Y. 1991) (requiring relative risk in excess of 2.0 for plaintiff to meet burden of production);
Jones v. Owens-Corning Fiberglas Corp., 672 A.2d 230 (N.J. Super. Ct. App. Div. 1996).
148. See In re Paoli R.R. Yard PCB Litig., 35 F.3d 717, 758–59 (3d Cir. 1994) (discussing the
technique of differential diagnosis to rule out other known causes of a disease for a specific individual).
149. The use of probabilities in excess of .50 to support a verdict results in an all-or-nothing
approach to damages that some commentators have criticized. The criticism reflects the fact that defendants
responsible for toxic agents with a relative risk just above 2.0 may be required to pay damages not
only for the disease that their agents caused, but also for all instances of the disease. Similarly, those
defendants whose agents increase the risk of disease by less than a doubling may not be required to pay
damages for any of the disease that their agents caused. See, e.g., 2 American Law Inst., Reporter’s Study
on Enterprise Responsibility for Personal Injury: Approaches to Legal and Institutional Change 369–75
(1991). To date, courts have not adopted a rule that would apportion damages based on the probability
of cause in fact in toxic substances cases.
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387
Glossary of Terms
The following terms and definitions were adapted from a variety of sources,
including A Dictionary of Epidemiology (John M. Last et al. eds. 3d ed. 1995);
1 Joseph L. Gastwirth, Statistical Reasoning in Law and Public Policy (1988);
James K. Brewer, Everything You Always Wanted To Know About Statistics,
But Didn’t Know How To Ask (1978); and R.A. Fisher, Statistical Methods for
Research Workers (1973).
adjustment. Methods of modifying an observed association to take into account
the effect of risk factors that are not the focus of the study and that
distort the observed association between the exposure being studied and the
disease outcome. See also direct age adjustment, indirect age adjustment.
agent. Also, risk factor. A factor, such as a drug, microorganism, chemical
substance, or form of radiation, whose presence or absence can result in the
occurrence of a disease. A disease may be caused by a single agent or a number
of independent alternative agents, or the combined presence of a complex
of two or more factors may be necessary for the development of the
disease.
alpha. The level of statistical significance chosen by a researcher to determine if
any association found in a study is sufficiently unlikely to have occurred by
chance (as a result of random sampling error) if the null hypothesis (no association)
is true. Researchers commonly adopt an alpha of .05, but the choice
is arbitrary and other values can be justified.
alpha error. Also called type I error and false positive error, alpha error occurs
when a researcher rejects a null hypothesis when it is actually true (i.e., when
there is no association). This can occur when an apparent difference is observed
between the control group and the exposed group, but the difference
is not real (i.e., it occurred by chance). A common error made by lawyers,
judges, and academics is to equate the level of alpha with the legal burden of
proof.
association. The degree of statistical relationship between two or more events
or variables. Events are said to be associated when they occur more or less
frequently together than one would expect by chance. Association does not
necessarily imply a causal relationship. Events are said not to have an association
when the agent (or independent variable) has no apparent effect on the
incidence of a disease (the dependent variable). This corresponds to a relative
risk of 1.0. A negative association means that the events occur less frequently
together than one would expect by chance, thereby implying a preventive or
protective role for the agent (e.g., a vaccine).
attributable proportion of risk (PAR). This term has been used to denote
the fraction of risk that is attributable to exposure to a substance (e.g., X% of
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388
lung cancer is attributable to cigarettes). Synonymous terms include attributable
fraction, attributable risk, and etiologic fraction. See attributable risk.
attributable risk. The proportion of disease in exposed individuals that can be
attributed to exposure to an agent, as distinguished from the proportion of
disease attributed to all other causes.
background risk of disease. Background risk of disease (or background rate
of disease) is the rate of disease in a population that has no known exposures
to an alleged risk factor for the disease. For example, the background risk for
all birth defects is 3%–5% of live births.
beta error. Also called type II error and false negative error, beta error occurs
when a researcher fails to reject a null hypothesis when it is incorrect (i.e.,
when there is an association). This can occur when no statistically significant
difference is detected between the control group and the exposed group, but
a difference does exist.
bias. Any effect at any stage of investigation or inference tending to produce
results that depart systematically from the true values. In epidemiology, the
term bias does not necessarily carry an imputation of prejudice or other subjective
factor, such as the experimenter’s desire for a particular outcome. This
differs from conventional usage, in which bias refers to a partisan point of
view.
biological marker. A physiological change in tissue or body fluids that occurs
as a result of an exposure to an agent and that can be detected in the laboratory.
Biological markers are only available for a small number of chemicals.
biological plausibility. Consideration of existing knowledge about human
biology and disease pathology to provide a judgment about the plausibility
that an agent causes a disease.
case-comparison study. See case-control study.
case-control study. Also, case-comparison study, case history study, case referent
study, retrospective study. A study that starts with the identification of
persons with a disease (or other outcome variable) and a suitable control
(comparison, reference) group of persons without the disease. Such a study is
often referred to as retrospective because it starts after the onset of disease and
looks back to the postulated causal factors.
case group. A group of individuals who have been exposed to the disease,
intervention, procedure, or other variable whose influence is being studied.
causation. Causation, as we use the term, denotes an event, condition, characteristic,
or agent’s being a necessary element of a set of other events that can
produce an outcome, such as a disease. Other sets of events may also cause
the disease. For example, smoking is a necessary element of a set of events
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389
that result in lung cancer, yet there are other sets of events (without smoking)
that cause lung cancer. Thus, a cause may be thought of as a necessary link in
at least one causal chain that results in an outcome of interest. Epidemiologists
generally speak of causation in a group context; hence, they will inquire
whether an increased incidence of a disease in a cohort was “caused” by
exposure to an agent.
clinical trial. An experimental study that is performed to assess the efficacy and
safety of a drug or other beneficial treatment. Unlike observational studies,
clinical trials can be conducted as experiments and use randomization, because
the agent being studied is thought to be beneficial.
cohort. Any designated group of persons followed or traced over a period of
time to examine health or mortality experience.
cohort study. The method of epidemiologic study in which groups of individuals
can be identified who are, have been, or in the future may be differentially
exposed to an agent or agents hypothesized to influence the probability
of occurrence of a disease or other outcome. The groups are observed to
find out if the exposed group is more likely to develop disease. The alternative
terms for a cohort study (concurrent study, follow-up study, incidence
study, longitudinal study, prospective study) describe an essential feature of
the method, which is observation of the population for a sufficient number of
person-years to generate reliable incidence or mortality rates in the population
subsets. This generally implies study of a large population, study for a
prolonged period (years), or both.
confidence interval. A range of values calculated from the results of a study
within which the true value is likely to fall; the width of the interval reflects
random error. Thus, if a confidence level of .95 is selected for a study, 95% of
similar studies would result in the true relative risk falling within the confidence
interval. The width of the confidence interval provides an indication
of the precision of the point estimate or relative risk found in the study; the
narrower the confidence interval, the greater the confidence in the relative
risk estimate found in the study. Where the confidence interval contains a
relative risk of 1.0, the results of the study are not statistically significant.
confounding factor. Also, confounder. A factor that is both a risk factor for
the disease and a factor associated with the exposure of interest. Confounding
refers to a situation in which the effects of two processes are not separated.
The distortion can lead to an erroneous result.
control group. A comparison group comprising individuals who have not
been exposed to the disease, intervention, procedure, or other variable whose
influence is being studied.
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cross-sectional study. A study that examines the relationship between disease
and variables of interest as they exist in a population at a given time. A crosssectional
study measures the presence or absence of disease and other variables
in each member of the study population. The data are analyzed to determine
if there is a relationship between the existence of the variables and
disease. Because cross-sectional studies examine only a particular moment in
time, they reflect the prevalence (existence) rather than the incidence (rate)
of disease and can offer only a limited view of the causal association between
the variables and disease. Because exposures to toxic agents often change
over time, cross-sectional studies are rarely used to assess the toxicity of exogenous
agents.
data dredging. Jargon that refers to results identified by researchers who, after
completing a study, pore through their data seeking to find any associations
that may exist. In general, good research practice is to identify the hypotheses
to be investigated in advance of the study; hence, data dredging is generally
frowned on. In some cases, however, researchers conduct exploratory studies
designed to generate hypotheses for further study.
demographic study. See ecological study.
dependent variable. The outcome that is being assessed in a study based on
the effect of another characteristic—the independent variable. Epidemiologic
studies attempt to determine whether there is an association between the
independent variable (exposure) and the dependent variable (incidence of
disease).
differential misclassification. A form of bias that is due to the misclassification
of individuals or a variable of interest when the misclassification varies among
study groups. This type of bias occurs when, for example, individuals in a
study are incorrectly determined to be unexposed to the agent being studied
when in fact they are exposed. See nondifferential misclassification.
direct adjustment. A technique used to eliminate any difference between two
study populations based on age, sex, or some other parameter that might
result in confounding. Direct adjustment entails comparison of the study group
with a large reference population to determine the expected rates based on
the characteristic, such as age, for which adjustment is being performed.
dose. Dose generally refers to the intensity or magnitude of exposure to an
agent multiplied by the duration of exposure. Dose may be used to refer only
to the intensity of exposure.
dose–response relationship. A relationship in which a change in amount,
intensity, or duration of exposure to an agent is associated with a change—
either an increase or a decrease—in risk of disease.
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double-blinding. A characteristic used in experimental studies in which neither
the individuals being studied nor the researchers know during the study
whether any individual has been assigned to the exposed or control group.
Double-blinding is designed to prevent knowledge of the group to which
the individual was assigned from biasing the outcome of the study.
ecological fallacy. An error that occurs when a correlation between an agent
and disease in a group (ecological) is not reproduced when individuals are
studied. For example, at the ecological (group) level, a correlation has been
found in several studies between the quality of drinking water and mortality
rates from heart disease; it would be an ecological fallacy to infer from this
alone that exposure to water of a particular level of hardness necessarily
influences the individual’s chances of contracting or dying of heart disease.
ecological study. Also, demographic study. A study of the occurrence of disease
based on data from populations, rather than from individuals. An ecological
study searches for associations between the incidence of disease and
suspected disease-causing agents in the studied populations. Researchers often
conduct ecological studies by examining easily available health statistics,
making these studies relatively inexpensive in comparison with studies that
measure disease and exposure to agents on an individual basis.
epidemiology. The study of the distribution and determinants of disease or
other health-related states and events in populations and the application of
this study to control of health problems.
error. Random error (sampling error) is the error that is due to chance when
the result obtained for a sample differs from the result that would be obtained
if the entire population (universe) were studied.
etiologic factor. An agent that plays a role in causing a disease.
etiology. The cause of disease or other outcome of interest.
experimental study. A study in which the researcher directly controls the
conditions. Experimental epidemiology studies (also clinical studies) entail
random assignment of participants to the exposed and control groups (or
some other method of assignment designed to minimize differences between
the groups).
exposed, exposure. In epidemiology, the exposed group (or the exposed) is
used to describe a group whose members have been exposed to an agent that
may be a cause of a disease or health effect of interest, or possess a characteristic
that is a determinant of a health outcome.
false negative error. See beta error.
false positive error. See alpha error.
follow-up study. See cohort study.
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general causation. General causation is concerned with whether an agent
increases the incidence of disease in a group and not whether the agent caused
any given individual’s disease. Because of individual variation, a toxic agent
generally will not cause disease in every exposed individual.
generalizable. A study is generalizable when the results are applicable to populations
other than the study population, such as the general population.
in vitro. Within an artificial environment, such as a test tube (e.g., the cultivation
of tissue in vitro).
in vivo. Within a living organism (e.g., the cultivation of tissue in vivo).
incidence rate. The number of people in a specified population falling ill from
a particular disease during a given period. More generally, the number of
new events (e.g., new cases of a disease in a defined population) within a
specified period of time.
incidence study. See cohort study.
independent variable. A characteristic that is measured in a study and that is
suspected to have an effect on the outcome of interest (the dependent variable).
Thus, exposure to an agent is measured in a cohort study to determine
whether that independent variable has an effect on the incidence of disease,
which is the dependent variable.
indirect adjustment. A technique employed to minimize error that might
result when comparing two populations because of differences in age, sex, or
another parameter that may affect the rate of disease in the populations. The
rate of disease in a large reference population, such as all residents of a country,
is calculated and adjusted for any differences in age between the reference
population and the study population. This adjusted rate is compared with the
rate of disease in the study population and provides a standardized mortality
(or morbidity) ratio, which is often referred to as SMR.
inference. The intellectual process of making generalizations from observations.
In statistics, the development of generalizations from sample data, usually
with calculated degrees of uncertainty.
information bias. Also, observational bias. Systematic error in measuring data
that results in differential accuracy of information (such as exposure status) for
comparison groups.
interaction. Risk factors interact, or there is interaction among risk factors,
when the magnitude or direction (positive or negative) of the effect of one
risk factor differs depending on the presence or level of the other. In interaction,
the effect of two risk factors together is different (greater or less) than
their individual effects.
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meta-analysis. A technique used to combine the results of several studies to
enhance the precision of the estimate of the effect size and reduce the plausibility
that the association found is due to random sampling error. Meta-analysis
is best suited to pooling results from randomly controlled experimental studies,
but if carefully performed, it also may be useful for observational studies.
misclassification bias. The erroneous classification of an individual in a study
as exposed to the agent when the individual was not, or incorrectly classifying
a study individual with regard to disease. Misclassification bias may exist
in all study groups (nondifferential misclassification) or may vary among groups
(differential misclassification).
morbidity rate. Morbidity is the state of illness or disease. Morbidity rate may
refer to the incidence rate or prevalence rate of disease.
mortality rate. Mortality refers to death. The mortality rate expresses the proportion
of a population that dies of a disease or of all causes. The numerator
is the number of individuals dying; the denominator is the total population in
which the deaths occurred. The unit of time is usually a calendar year.
model. A representation or simulation of an actual situation. This may be either
(1) a mathematical representation of characteristics of a situation that can
be manipulated to examine consequences of various actions; (2) a representation
of a country’s situation through an “average region” with characteristics
resembling those of the whole country; or (3) the use of animals as a substitute
for humans in an experimental system to ascertain an outcome of interest.
multivariate analysis. A set of techniques used when the variation in several
variables has to be studied simultaneously. In statistics, any analytic method
that allows the simultaneous study of two or more independent factors or
variables.
nondifferential misclassification. A form of bias that is due to misclassification
of individuals or a variable of interest into the wrong category when the
misclassification varies among study groups. This bias may result from limitations
in data collection and will often produce an underestimate of the true
association. See differential misclassification.
null hypothesis. A hypothesis that states that there is no true association between
a variable and an outcome. At the outset of any observational or experimental
study, the researcher must state a proposition that will be tested in
the study. In epidemiology, this proposition typically addresses the existence
of an association between an agent and a disease. Most often, the null hypothesis
is a statement that exposure to Agent A does not increase the occurrence
of Disease D. The results of the study may justify a conclusion that the
null hypothesis (no association) has been disproved (e.g., a study that finds a
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strong association between smoking and lung cancer). A study may fail to
disprove the null hypothesis, but that alone does not justify a conclusion that
the null hypothesis has been proved.
observational study. An epidemiologic study in situations in which nature is
allowed to take its course, without intervention from the investigator. For
example, in an observational study the subjects of the study are permitted to
determine their level of exposure to an agent.
odds ratio (OR). Also, cross-product ratio, relative odds. The ratio of the
odds that a case (one with the disease) was exposed to the odds that a control
(one without the disease) was exposed. For most purposes the odds ratio
from a case-control study is quite similar to a risk ratio from a cohort study.
pathognomonic. An agent is pathognomonic when it must be present for a
disease to occur. Thus, asbestos is a pathognomonic agent for asbestosis. See
signature disease.
placebo controlled. In an experimental study, providing an inert substance to
the control group, so as to keep the control and exposed groups ignorant of
their status.
p(probability), p-value. The p-value is the probability of getting a value of
the test outcome equal to or more extreme than the result observed, given
that the null hypothesis is true. The letter p, followed by the abbreviation
“n.s.” (not significant) means that p > .05 and that the association was not
statistically significant at the .05 level of significance. The statement “p < .05”
means that p is less than 5%, and, by convention, the result is deemed statistically
significant. Other significance levels can be adopted, such as .01 or .1.
The lower the p-value, the less likely that random error would have produced
the observed relative risk if the true relative risk is 1.
power. The probability that a difference of a specified amount will be detected
by the statistical hypothesis test, given that a difference exists. In less formal
terms, power is like the strength of a magnifying lens in its capability to
identify an association that truly exists. Power is equivalent to one minus type
II error. This is sometimes stated as Power = 1 - .
prevalence. The percentage of persons with a disease in a population at a
specific point in time.
prospective study. In a prospective study, two groups of individuals are
identified: (1) individuals who have been exposed to a risk factor and (2)
individuals who have not been exposed. Both groups are followed for a
specified length of time, and the proportion that develops disease in the first
group is compared with the proportion that develops disease in the second
group. See cohort study.
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random. The term implies that an event is governed by chance. See randomization.
randomization. Assignment of individuals to groups (e.g., for experimental
and control regimens) by chance. Within the limits of chance variation, randomization
should make the control group and experimental group similar at
the start of an investigation and ensure that personal judgment and prejudices
of the investigator do not influence assignment. Randomization should not
be confused with haphazard assignment. Random assignment follows a predetermined
plan that usually is devised with the aid of a table of random
numbers. Randomization cannot ethically be used where the exposure is
known to cause harm (e.g., cigarette smoking).
randomized trial. See clinical trial.
recall bias. Systematic error resulting from differences between two groups in
a study in accuracy of memory. For example, subjects who have a disease
may recall exposure to an agent more frequently than subjects who do not
have the disease.
relative risk (RR). The ratio of the risk of disease or death among people
exposed to an agent to the risk among the unexposed. For instance, if 10% of
all people exposed to a chemical develop a disease, compared with 5% of
people who are not exposed, the disease occurs twice as frequently among
the exposed people. The relative risk is 10%/5% = 2. A relative risk of 1
indicates no association between exposure and disease.
research design. The procedures and methods, predetermined by an investigator,
to be adhered to in conducting a research project.
risk. A probability that an event will occur (e.g., that an individual will become
ill or die within a stated period of time or by a certain age).
sample. A selected subset of a population. A sample may be random or nonrandom.
sample size. The number of subjects who participate in a study.
secular-trend study. Also, time-line study. A study that examines changes
over a period of time, generally years or decades. Examples include the decline
of tuberculosis mortality and the rise, followed by a decline, in coronary
heart disease mortality in the United States in the past fifty years.
selection bias. Systematic error that results from individuals being selected for
the different groups in an observational study who have differences other
than the ones that are being examined in the study.
sensitivity, specificity. Sensitivity measures the accuracy of a diagnostic or
screening test or device in identifying disease (or some other outcome) when
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it truly exists. For example, assume that we know that 20 women in a group
of 1,000 women have cervical cancer. If the entire group of 1,000 women is
tested for cervical cancer and the screening test only identifies 15 (of the
known 20) cases of cervical cancer, the screening test has a sensitivity of 15/
20, or 75%. Specificity measures the accuracy of a diagnostic or screening test
in identifying those who are disease free. Once again, assume that 980 women
out of a group of 1,000 women do not have cervical cancer. If the entire
group of 1,000 women is screened for cervical cancer and the screening test
only identifies 900 women as without cervical cancer, the screening test has a
specificity of 900/980, or 92%.
signature disease. A disease that is associated uniquely with exposure to an
agent (e.g., asbestosis and exposure to asbestos). See also pathognomonic.
significance level. A somewhat arbitrary level selected to minimize the risk
that an erroneous positive study outcome that is due to random error will be
accepted as a true association. The lower the significance level selected, the
less likely that false positive error will occur.
specific causation. Whether exposure to an agent was responsible for a given
individual’s disease.
standardized morbidity ratio (SMR). The ratio of the incidence of disease
observed in the study population to the incidence of disease that would be
expected if the study population had the same incidence of disease as some
selected standard or known population.
standardized mortality ratio (SMR). The ratio of the incidence of death
observed in the study population to the incidence of death that would be
expected if the study population had the same incidence of death as some
selected standard or known population.
statistical significance. A term used to describe a study result or difference
that exceeds the type I error rate (or p-value) that was selected by the researcher
at the outset of the study. In formal significance testing, a statistically
significant result is unlikely to be the result of random sampling error and
justifies rejection of the null hypothesis. Some epidemiologists believe that
formal significance testing is inferior to using a confidence interval to express
the results of a study. Statistical significance, which addresses the role of random
sampling error in producing the results found in the study, should not
be confused with the importance (for public health or public policy) of a
research finding.
stratification. The process of or result of separating a sample into several
subsamples according to specified criteria, such as age or socioeconomic status.
Researchers may control the effect of confounding variables by stratifyReference
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ing the analysis of results. For example, lung cancer is known to be associated
with smoking. To examine the possible association between urban atmospheric
pollution and lung cancer, the researcher may divide the population
into strata according to smoking status, thus controlling for smoking. The
association between air pollution and cancer then can be appraised separately
within each stratum.
study design. See research design.
systematic error. See bias.
teratogen. An agent that produces abnormalities in the embryo or fetus by
disturbing maternal health or by acting directly on the fetus in utero.
teratogenicity. The capacity for an agent to produce abnormalities in the embryo
or fetus.
threshold phenomenon. A certain level of exposure to an agent below which
disease does not occur and above which disease does occur.
time-line study. See secular-trend study.
toxicology. The science of the nature and effects of poisons. Toxicologists
study adverse health effects of agents on biological organisms.
toxic substance. A substance that is poisonous.
true association. Also, real association. The association that really exists between
exposure to an agent and a disease and that might be found by a perfect
(but nonetheless nonexistent) study.
Type I error. Rejecting the null hypothesis when it is true. See alpha error.
Type II error. Failing to reject the null hypothesis when it is false. See beta
error.
validity. The degree to which a measurement measures what it purports to
measure; the accuracy of a measurement.
variable. Any attribute, condition, or other item in a study that can have different
numerical characteristics. In a study of the causes of heart disease, blood
pressure and dietary fat intake are variables that might be measured.
Reference Manual on Scientific Evidence
398
References on Epidemiology
Causal Inferences (Kenneth J. Rothman ed., 1988).
William G. Cochran, Sampling Techniques (1977).
A Dictionary of Epidemiology (John M. Last et al. eds., 3d ed. 1995).
Anders Ahlbom & Steffan Norell, Introduction to Modern Epidemiology (2d
ed. 1990).
Joseph L. Fleiss, Statistical Methods for Rates and Proportions (1981).
Leon Gordis, Epidemiology (2d ed. 2000).
Morton Hunt, How Science Takes Stock: The Story of Meta-Analysis (1997).
Harold A. Kahn, An Introduction to Epidemiologic Methods (1983).
Harold A. Kahn & Christopher T. Sempos, Statistical Methods in Epidemiology
(1989).
David E. Lilienfeld, Overview of Epidemiology, 3 Shepard’s Expert & Sci. Evid.
Q. 25 (1995).
David E. Lilienfeld & Paul D. Stolley, Foundations of Epidemiology (3d ed.
1994).
Judith S. Mausner & Anita K. Bahn, Epidemiology: An Introductory Text (1974).
Marcello Pagano & Kimberlee Gauvreau, Principles of Biostatistics (1993).
Richard K. Riegelman & Robert A. Hirsch, Studying a Study and Testing a
Test: How to Read the Health Science Literature (3d ed. 1996).
Bernard Rosner, Fundamentals of Biostatistics (4th ed. 1995).
Kenneth J. Rothman & Sander Greenland, Modern Epidemiology (2d ed. 1998).
James J. Schlesselman, Case-Control Studies: Design, Conduct, Analysis (1982).
Mervyn Susser, Epidemiology, Health and Society: Selected Papers (1987).
References on Law and Epidemiology
2 American Law Institute, Reporters’ Study on Enterprise Responsibility for
Personal Injury (1991).
Bert Black & David H. Hollander, Jr., Unraveling Causation: Back to the Basics, 3
U. Balt. J. Envtl. L. 1 (1993).
Bert Black & David Lilienfeld, Epidemiologic Proof in Toxic Tort Litigation, 52
Fordham L. Rev. 732 (1984).
Gerald Boston, A Mass-Exposure Model of Toxic Causation: The Content of Scientific
Proof and the Regulatory Experience, 18 Colum. J. Envtl. L. 181 (1993).
Reference Guide on Epidemiology
399
Vincent M. Brannigan et al., Risk, Statistical Inference, and the Law of Evidence:
The Use of Epidemiological Data in Toxic Tort Cases, 12 Risk Analysis 343 (1992).
Troyen Brennan, Causal Chains and Statistical Links: The Role of Scientific Uncertainty
in Hazardous-Substance Litigation, 73 Cornell L. Rev. 469 (1988).
Troyen Brennan, Helping Courts with Toxic Torts: Some Proposals Regarding Alternative
Methods for Presenting and Assessing Scientific Evidence in Common Law
Courts, 51 U. Pitt. L. Rev. 1 (1989).
Philip Cole, Causality in Epidemiology, Health Policy, and Law, [1997] 27 Envtl.
L. Rep. (Envtl. L. Inst.) 10279 (June1997).
Comment, Epidemiologic Proof of Probability: Implementing the Proportional Recovery
Approach in Toxic Exposure Torts, 89 Dick. L. Rev. 233 (1984).
George W. Conk, Against the Odds: Proving Causation of Disease with Epidemiological
Evidence, 3 Shepard’s Expert & Sci. Evid. Q. 85 (1995).
Carl F. Cranor et al., Judicial Boundary Drawing and the Need for Context-Sensitive
Science in Toxic Torts After Daubert v. Merrell Dow Pharmaceuticals, Inc., 16
Va. Envtl. L.J. 1 (1996).
Richard Delgado, Beyond Sindell: Relaxation of Cause-in-Fact Rules for Indeterminate
Plaintiffs, 70 Cal. L. Rev. 881 (1982).
Michael Dore, A Commentary on the Use of Epidemiological Evidence in Demonstrating
Cause-in-Fact, 7 Harv. Envtl. L. Rev. 429 (1983).
Jean Macchiaroli Eggen, Toxic Torts, Causation, and Scientific Evidence After Daubert,
55 U. Pitt. L. Rev. 889 (1994).
Daniel A. Farber, Toxic Causation, 71 Minn. L. Rev. 1219 (1987).
Heidi Li Feldman, Science and Uncertainty in Mass Exposure Litigation, 74 Tex. L.
Rev. 1 (1995).
Stephen E. Fienberg et al., Understanding and Evaluating Statistical Evidence in
Litigation, 36 Jurimetrics J. 1 (1995).
Joseph L. Gastwirth, Statistical Reasoning in Law and Public Policy (1988).
Herman J. Gibb, Epidemiology and Cancer Risk Assessment, in Fundamentals of
Risk Analysis and Risk Management 23 (Vlasta Molak ed., 1997).
Steve Gold, Note, Causation in Toxic Torts: Burdens of Proof, Standards of Persuasion
and Statistical Evidence, 96 Yale L.J. 376 (1986).
Leon Gordis, Epidemiologic Approaches for Studying Human Disease in Relation to
Hazardous Waste Disposal Sites, 25 Hous. L. Rev. 837 (1988).
Michael D. Green, Expert Witnesses and Sufficiency of Evidence in Toxic Substances
Litigation: The Legacy of Agent Orange and Bendectin Litigation, 86 Nw. U. L.
Rev. 643 (1992).
Reference Manual on Scientific Evidence
400
Khristine L. Hall & Ellen Silbergeld, Reappraising Epidemiology: A Response to
Mr. Dore, 7 Harv. Envtl. L. Rev. 441 (1983).
Jay P. Kesan, Drug Development: Who Knows Where the Time Goes?: A Critical
Examination of the Post-Daubert Scientific Evidence Landscape, 52 Food Drug
Cosm. L.J. 225 (1997).
Constantine Kokkoris, Comment, DeLuca v. Merrell Dow Pharmaceuticals,
Inc.: Statistical Significance and the Novel Scientific Technique, 58 Brook. L. Rev.
219 (1992).
James P. Leape, Quantitative Risk Assessment in Regulation of Environmental Carcinogens,
4 Harv. Envtl. L. Rev. 86 (1980).
David E. Lilienfeld, Overview of Epidemiology, 3 Shepard’s Expert & Sci. Evid. Q.
23 (1995).
Junius McElveen, Jr., & Pamela Eddy, Cancer and Toxic Substances: The Problem
of Causation and the Use of Epidemiology, 33 Clev. St. L. Rev. 29 (1984).
2 Modern Scientific Evidence: The Law and Science of Expert Testimony (David
L. Faigman et al. eds.,1997).
Note, The Inapplicability of Traditional Tort Analysis to Environmental Risks: The
Example of Toxic Waste Pollution Victim Compensation, 35 Stan. L. Rev. 575
(1983).
Susan R. Poulter, Science and Toxic Torts: Is There a Rational Solution to the Problem
of Causation?, 7 High Tech. L.J. 189 (1992).
Jon Todd Powell, Comment, How to Tell the Truth with Statistics: A New Statistical
Approach to Analyzing the Data in the Aftermath of Daubert v. Merrell Dow
Pharmaceuticals, 31 Hous. L. Rev. 1241 (1994).
David Rosenberg, The Causal Connection in Mass Exposure Cases: A Public Law
Vision of the Tort System, 97 Harv. L. Rev. 849 (1984).
Joseph Sanders, The Bendectin Litigation: A Case Study in the Life-Cycle of Mass
Torts, 43 Hastings L.J. 301 (1992).
Joseph Sanders, Scientific Validity, Admissibility, and Mass Torts After Daubert, 78
Minn. L. Rev. 1387 (1994).
Richard W. Wright, Causation in Tort Law, 73 Cal. L. Rev. 1735 (1985).
Development in the Law—Confronting the New Challenges of Scientific Evidence, 108
Harv. L. Rev. 1481 (1995).
401
Reference Guide on Toxicology
bernard d. goldstein and mary sue henifin
Bernard D. Goldstein, M.D., is Director, Environmental & Occupational Health Sciences Institute, Piscataway,
New Jersey, and Chairman, Department of Environmental & Community Medicine, UMDNJ–Robert
Wood Johnson Medical School, Piscataway, New Jersey.
Mary Sue Henifin, J.D., M.P.H., is a partner with Buchanan Ingersoll, P.C., Princeton, New Jersey, and
Adjunct Professor of Public Health Law, Department of Environmental & Community Medicine, UMDNJ–
Robert Wood Johnson Medical School, Piscataway, New Jersey.
contents
I. Introduction, 403
A. Toxicology and the Law, 404
B. Purpose of the Reference Guide on Toxicology, 404
C. Toxicological Research Design, 405
1. In vivo research, 406
2. In vitro research, 410
D. Extrapolation from Animal and Cell Research to Humans, 410
E. Safety and Risk Assessment, 411
F. Toxicology and Epidemiology, 413
II. Expert Qualifications, 415
A. Does the Proposed Expert Have an Advanced Degree in Toxicology,
Pharmacology, or a Related Field? If the Expert Is a Physician, Is
He or She Board Certified in a Field Such As Occupational Medicine? 415
B. Has the Proposed Expert Been Certified by the American Board of
Toxicology, Inc., or Does He or She Belong to a Professional
Organization, Such As the Academy of Toxicological Sciences
or the Society of Toxicology? 417
C. What Other Criteria Does the Proposed Expert Meet? 418
III. Demonstrating an Association Between Exposure and Risk of Disease, 419
A. On What Species of Animals Was the Compound Tested? What Is Known
About the Biological Similarities and Differences Between the Test
Animals and Humans? How Do These Similarities and Differences Affect
the Extrapolation from Animal Data in Assessing the Risk to Humans? 419
B. Does Research Show That the Compound Affects a Specific
Target Organ? Will Humans Be Affected Similarly? 420
C. What Is Known About the Chemical Structure of the Compound and Its
Relationship to Toxicity? 421
D. Has the Compound Been the Subject of In Vitro Research, and
If So, Can the Findings Be Related to What Occurs In Vivo? 422
E. Is the Association Between Exposure and Disease
Biologically Plausible? 422
Reference Manual on Scientific Evidence
402
IV. Specific Causal Association Between an Individual’s Exposure and the Onset of
Disease, 422
A. Was the Plaintiff Exposed to the Substance, and If So, Did the Exposure
Occur in a Manner That Can Result in Absorption into the Body? 424
B. Were Other Factors Present That Can Affect the Distribution of the
Compound Within the Body? 425
C. What Is Known About How Metabolism in the Human Body Alters the
Toxic Effects of the Compound? 425
D. What Excretory Route Does the Compound Take, and How Does This
Affect Its Toxicity? 425
E. Does the Temporal Relationship Between Exposure and the Onset of
Disease Support or Contradict Causation? 425
F. If Exposure to the Substance Is Associated with the Disease, Is There a
No Observable Effect, or Threshold, Level, and If So, Was the Individual
Exposed Above the No Observable Effect Level? 426
V. Medical History, 427
A. Is the Medical History of the Individual Consistent with the Toxicologist’s
Expert Opinion Concerning the Injury? 427
B. Are the Complaints Specific or Nonspecific? 427
C. Do Laboratory Tests Indicate Exposure to the Compound? 428
D. What Other Causes Could Lead to the Given Complaint? 428
E. Is There Evidence of Interaction with Other Chemicals? 429
F. Do Humans Differ in the Extent of Susceptibility to the Particular
Compound in Question? Are These Differences Relevant in
This Case? 430
G. Has the Expert Considered Data That Contradict His or Her Opinion? 430
Glossary of Terms, 432
References on Toxicology, 437
Reference Guide on Toxicology
403
I. Introduction
Toxicology classically is known as the science of poisons. A modern definition
is “the study of the adverse effects of chemicals on living organisms.”1 Although
it is an age-old science, toxicology has only recently become a discipline distinct
from pharmacology, biochemistry, cell biology, and related fields.
There are three central tenets of toxicology. First, “the dose makes the poison”;
this implies that all chemical agents are intrinsically hazardous—whether
they cause harm is only a question of dose.2 Even water, if consumed in large
quantities, can be toxic. Second, each chemical agent tends to produce a specific
pattern of biological effects that can be used to establish disease causation.3 Third,
the toxic responses in laboratory animals are useful predictors of toxic responses
in humans. Each of these tenets, and their exceptions, are discussed in greater
detail in this reference guide.
The science of toxicology attempts to determine at what doses foreign agents
produce their effects. The foreign agents of interest to toxicologists are all chemicals
(including foods) and physical agents in the form of radiation, but not living
organisms that cause infectious diseases.4
The discipline of toxicology provides scientific information relevant to the
following questions:
1. What hazards does a chemical or physical agent present to human populations
or the environment?
2. What degree of risk is associated with chemical exposure at any given
dose?
Toxicological studies, by themselves, rarely offer direct evidence that a disease
in any one individual was caused by a chemical exposure. However, toxicology
can provide scientific information regarding the increased risk of contracting
a disease at any given dose and help rule out other risk factors for the
disease. Toxicological evidence also explains how a chemical causes a disease by
describing metabolic, cellular, and other physiological effects of exposure.
1. Casarett and Doull’s Toxicology: The Basic Science of Poisons 13 (Curtis D. Klaassen ed., 5th
ed. 1996).
2. A discussion of more modern formulations of this principle, which was articulated by Paracelsus
in the sixteenth century, can be found in Ellen K. Silbergeld, The Role of Toxicology in Causation: A
Scientific Perspective, 1 Cts. Health Sci. & L. 374, 378 (1991).
3. Some substances, such as central nervous system toxicants, can produce complex and nonspecific
symptoms, such as headaches, nausea, and fatigue.
4. Forensic toxicology, a subset of toxicology generally concerned with criminal matters, is not
addressed in this reference guide, since it is a highly specialized field with its own literature and methodologies
which do not relate directly to toxic tort or regulatory issues.
Reference Manual on Scientific Evidence
404
A. Toxicology and the Law
The growing concern about chemical causation of disease is reflected in the
public attention devoted to lawsuits alleging toxic torts, as well as in litigation
concerning the many federal and state regulations related to the release of potentially
toxic compounds into the environment. These lawsuits inevitably involve
toxicological evidence.
Toxicological evidence frequently is offered in two types of litigation: tort
and regulatory. In tort litigation, toxicologists offer evidence that either supports
or refutes plaintiffs’ claims that their diseases or injuries were caused by
chemical exposures.5 In regulatory litigation, toxicological evidence is used to
either support or challenge government regulations concerning a chemical or a
class of chemicals. In regulatory litigation, toxicological evidence addresses the
issue of how exposure affects populations rather than addressing specific causation,
and agency determinations are usually subject to the court’s deference.6
B. Purpose of the Reference Guide on Toxicology
This reference guide focuses on scientific issues that arise most frequently in
toxic tort cases. Where it is appropriate, the reference guide explores the use of
regulatory data and how the courts treat such data. The reference guide provides
an overview of the basic principles and methodologies of toxicology and
offers a scientific context for proffered expert opinion based on toxicological
data.7 The reference guide describes research methods in toxicology and the
relationship between toxicology and epidemiology, and it provides model questions
for evaluating the admissibility and strength of an expert’s opinion. Following
each question is an explanation of the type of toxicological data or information
that is offered in response to the question, as well as a discussion of its
significance.
5. See, e.g., General Elec. Co. v. Joiner, 522 U.S. 136 (1997); Daubert v. Merrell Dow Pharms.,
Inc., 509 U.S. 579 (1993).
6. See, e.g., Troy Corp. v. Browner, 129 F.3d 1290 (D.C. Cir. 1997) (EPA’s decision to list chemical
under Emergency Planning and Community Right to Know Act supported by substantial evidence
in that animal studies demonstrated significant increases in pathology); AFL-CIO v. OSHA, 965 F.2d
962, 969–70 (11th Cir. 1992) (determinations of the Secretary of Labor are conclusive if supported by
substantial evidence); Simpson v. Young, 854 F.2d 1429, 1435 (D.C. Cir. 1988) (toxicology research
methods approved by the Food and Drug Administration (FDA) given deference by the court).
7. The use of toxicological evidence in regulatory decision making is discussed in more detail in
Richard A. Merrill, Regulatory Toxicology, in Casarett and Doull’s Toxicology: The Basic Science of
Poisons, supra note 1, at 1011. For a more general discussion of issues that arise in considering expert
testimony, see Margaret A. Berger, The Supreme Court’s Trilogy on the Admissibility of Expert Testimony
§ IV, in this manual.
Reference Guide on Toxicology
405
C. Toxicological Research Design
Toxicological research usually involves exposing laboratory animals (in vivo
research) or cells or tissues (in vitro research) to chemicals, monitoring the outcomes
(such as cellular abnormalities, tissue damage, organ toxicity, or tumor
formation), and comparing the outcomes with those for unexposed control
groups. As explained below,8 the extent to which animal and cell experiments
accurately predict human responses to chemical exposures is subject to debate.9
However, because it is often unethical to experiment on humans by exposing
them to known doses of chemical agents, animal toxicological evidence often
provides the best scientific information about the risk of disease from a chemical
exposure.10
In contrast to their exposure to drugs, only rarely are humans exposed to
environmental chemicals in a manner that permits a quantitative determination
of adverse outcomes.11 This area of toxicological research, known as clinical
toxicology, may consist of individual or multiple case reports, or even experimental
studies in which individuals or groups of individuals have been exposed
to a chemical under circumstances that permit analysis of dose–response relationships,
mechanisms of action, or other aspects of toxicology. For example,
individuals occupationally or environmentally exposed to polychlorinated biphenyls
(PCBs) prior to prohibitions on their use have been studied to determine
the routes of absorption, distribution, metabolism, and excretion for this
chemical. Human exposure occurs most frequently in occupational settings where
workers are exposed to industrial chemicals like lead or asbestos; however, even
under these circumstances, it is usually difficult, if not impossible, to quantify
the amount of exposure. Moreover, human populations are exposed to many
other chemicals and risk factors, making it difficult to isolate the increased risk of
a disease that is due to any one chemical.12
Toxicologists use a wide range of experimental techniques, depending in part
on their area of specialization. Some of the more active areas of toxicological
research are classes of chemical compounds, such as solvents and metals; body
system effects, such as neurotoxicology, reproductive toxicology, and immunotoxicology;
and effects on physiological processes, including inhalation toxicology,
dermatotoxicology, and molecular toxicology (the study of how chemicals
8. See infra §§ I.D, III.A.
9. The controversy over the use of toxicological evidence in tort cases is described in Silbergeld,
supra note 2, at 378.
10. See, e.g., Office of Tech. Assessment, U.S. Congress, Reproductive Health Hazards in the
Workplace 8 (1985).
11. However, it is from drug studies in which multiple animal species are compared directly with
humans that many of the principles of toxicology have been developed.
12. See, e.g., Office of Tech. Assessment, U.S. Congress, supra note 10, at 8.
Reference Manual on Scientific Evidence
406
interact with cell molecules). Each of these areas of research includes both in
vivo and in vitro research.13
1. In vivo research
Animal research in toxicology generally falls under two headings: safety assessment
and classic laboratory science, with a continuum in between. As explained
in section I.E, safety assessment is a relatively formal approach in which a
chemical’s potential for toxicity is tested in vivo or in vitro using standardized
techniques often prescribed by regulatory agencies, such as the Environmental
Protection Agency (EPA) and the Food and Drug Administration (FDA).
The roots of toxicology in the science of pharmacology are reflected in an
emphasis on understanding the absorption, distribution, metabolism, and excretion
of chemicals. Basic toxicological laboratory research also focuses on the
mechanisms of action of external chemical and physical agents. It is based on the
standard elements of scientific studies, including appropriate experimental design
using control groups and statistical evaluation. In general, toxicological research
attempts to hold all variables constant except for that of the chemical
exposure.14 Any change in the experimental group not found in the control
group is assumed to be perturbation caused by the chemical. An important component
of toxicological research is dose–response relationships. Thus, most toxicological
studies generally test a range of doses of the chemical.15
a. Dose–response relationships
Animal experiments are conducted to determine the dose–response relationships
of a compound by measuring the extent of any observed effect at various
doses and diligently searching for a dose that has no measurable physiological
effect. This information is useful in understanding the mechanisms of toxicity
and extrapolating data from animals to humans.16
b. Acute toxicity testing—lethal dose 50 (LD50)
To determine the dose–response relationship for a compound, a short-term
lethal dose 50 (LD50) is derived experimentally. The LD50 is the dose at which
a compound kills 50% of laboratory animals within a period of days to weeks.
13. See infra §§ I.C.1, I.C.2.
14. See generally Alan Poole & George B. Leslie, A Practical Approach to Toxicological Investigations
(1989); Principles and Methods of Toxicology (A. Wallace Hayes ed., 2d ed. 1989); see also
discussion on acute, short-term, and long-term toxicity studies and acquisition of data in Frank C. Lu,
Basic Toxicology: Fundamentals, Target Organs, and Risk Assessment 77–92 (2d ed. 1991).
15. Rolf Hartung, Dose–Response Relationships, in Toxic Substances and Human Risk: Principles of
Data Interpretation 29 (Robert G. Tardiff & Joseph V. Rodricks eds., 1987).
16. See infra §§ I.D, III.A.
Reference Guide on Toxicology
407
The use of this easily measured end point for acute toxicity is being abandoned,
in part because recent advances in toxicology have provided other pertinent end
points, and in part because of pressure from animal rights activists to reduce or
replace the use of animals in laboratory research.
c. No observable effect level (NOEL)
A dose–response study also permits determination of another important characteristic
of the biological action of a chemical—the no observable effect level
(NOEL).17 The NOEL sometimes is called a threshold, since it is the level above
which observable effects in test animals are believed to occur and below which
no toxicity is observed.18 Of course, since the NOEL is dependent on the ability
to observe the effect, the level is sometimes lowered once more sophisticated
methods of detection are developed.
d. No threshold model and determination of cancer risk
Certain genetic mutations, such as those leading to cancer and some inherited
disorders, are believed to occur without any threshold. In theory, the cancercausing
mutation to the genetic material of the cell can be produced by any one
molecule of certain chemicals. The no threshold model led to the development
of the one hit theory of cancer risk, in which each molecule of a cancer-causing
chemical has some finite possibility of producing the mutation that leads to
cancer. This risk is very small, since it is unlikely that any one molecule of a
potentially cancer-causing agent will reach that one particular spot in a specific
cell and result in the change that then eludes the body’s defenses and leads to a
17. For example, undiluted acid on the skin can cause a horrible burn. As the acid is diluted to
lower and lower concentrations less and less of an effect occurs until there is a concentration sufficiently
low (e.g., one drop in a bathtub of water, or a sample with less than the acidity of vinegar) that no effect
occurs. This no observable effect concentration differs from person to person. For example, a baby’s
skin is more sensitive than that of an adult, and skin that is irritated or broken responds to the effects of
an acid at a lower concentration. However, the key point is that there is some concentration that is
completely harmless to the skin. See, e.g., Paul Kotin, Dose–Response Relationships and Threshold Concepts,
271 Annals N.Y. Acad. Sci. 22 (1976).
18. The significance of the NOEL was relied on by the court in Graham v. Canadian National
Railway Co., 749 F. Supp. 1300 (D. Vt. 1990), in granting judgment for the defendants. The court
found the defendant’s expert, a medical toxicologist, persuasive. The expert testified that the plaintiffs’
injuries could not have been caused by herbicides, since their exposure was well below the reference
dose, which he calculated by taking the NOEL and decreasing it by a safety factor to ensure no human
effect. Id. at 1311–12 & n.11. But see Louderback v. Orkin Exterminating Co., 26 F. Supp. 2d 1298 (D.
Kan. 1998) (failure to consider threshold levels of exposure does not necessarily render expert’s opinion
unreliable where temporal relationship, scientific literature establishing an association between exposure
and various symptoms, plaintiffs’ medical records and history of disease, and exposure to or the
presence of other disease-causing factors were all considered). For additional background on the concept
of NOEL, see Robert G. Tardiff & Joseph V. Rodricks, Comprehensive Risk Assessment, in Toxic
Substances and Human Risk: Principles of Data Interpretation, supra note 15, at 391.
Reference Manual on Scientific Evidence
408
clinical case of cancer. However, the risk is not zero. The same model also can
be used to predict the risk of inheritable mutational events.19
e. Maximum tolerated dose (MTD) and chronic toxicity tests
Another type of study uses different doses of a chemical agent to establish over a
90-day period what is known as the maximum tolerated dose (MTD) (the highest
dose that does not cause significant overt toxicity). The MTD is important
because it enables researchers to calculate the dose of a chemical that an animal
can be exposed to without reducing its life span, thus permitting evaluation of
the chronic effects of exposure.20 These studies are designed to last the lifetime
of the species.
Chronic toxicity tests evaluate carcinogenicity or other types of toxic effects.
Federal regulatory agencies frequently require carcinogenicity studies on both
sexes of two species, usually rats and mice. A pathological evaluation is done on
the tissues of animals that died during the study and those that are sacrificed at
the conclusion of the study.
19. For further discussion of the no threshold model of carcinogenesis, see Office of Tech. Assessment,
U.S. Congress, Assessment of Technologies for Determining the Cancer Risks from the Environment
(1981); Henry C. Pitot III & Yvonne P. Dragan, Chemical Carcinogenesis, in Casarett and
Doull’s Toxicology: The Basic Science of Poisons, supra note 1, at 201, 254–55. But see Marvin Goldman,
Cancer Risk of Low-Level Exposure, 271 Science 1821 (1996); V.P. Bond et al., Current Misinterpretations
of the Linear No-Threshold Hypothesis, 70 Health Physics 877 (1996).
The no threshold model, as adopted by the Occupational Safety and Health Administration (OSHA)
in its regulation of workplace carcinogens, has been upheld. Public Citizen Health Research Group v.
Tyson, 796 F.2d 1479, 1498 (D.C. Cir. 1986) (as set forth in 29 C.F.R. § 1990.143(h) (1985), “no
determination will be made that a ‘threshold’ or ‘no effect’ level of exposure can be established for a
human population exposed to carcinogens in general, or to any specific substance”), clarified sub nom.
Public Citizen Health Research Group v. Brock, 823 F.2d 626, 628 (D.C. Cir. 1987). But see Sutera v.
Perrier Group of Am., Inc., 986 F. Supp. 655, 666–67 (D. Mass. 1997) (no scientific evidence that
linear no-safe threshold analysis is an acceptable scientific technique as used by experts in this case to
determine causation).
While the one hit model explains the response to most carcinogens, there is accumulating evidence
that for certain cancers there is in fact a multistage process and that some cancer-causing agents act
through nonmutational processes, so-called epigenetic or nongenotoxic agents. Committee on Risk
Assessment Methodology, National Research Council, Issues in Risk Assessment 34–35, 187, 198–201
(1993). For example, the multistage cancer process may explain the carcinogenicity of benzo(a)pyrene
(produced by the combustion of hydrocarbons such as oil) and chlordane (a termite pesticide). However,
nonmutational responses to asbestos, dioxin, and estradiol cause their carcinogenic effects. What
the appropriate mathematical model is to depict the dose–response relationship for such carcinogens is
still a matter of debate. Id. at 197–201.
20. Even the determination of the MTD can be fraught with controversy. See, e.g., Simpson v.
Young, 854 F.2d 1429, 1431 (D.C. Cir. 1988) (petitioners unsuccessfully argued that the FDA improperly
certified color additive Blue No. 2 dye as safe because researchers failed to administer the MTD to
research animals, as required by FDA protocols). See generally David P. Rall, Laboratory and Animal
Toxicity and Carcinogenesis Testing: Underlying Concepts, Advantages and Constraints, 534 Annals N.Y.
Acad. Sci. 78 (1988); Frank B. Cross, Environmentally Induced Cancer and the Law: Risks, Regulation,
and Victim Compensation 54–57 (1989).
Reference Guide on Toxicology
409
The rationale for using the MTD in chronic toxicity tests, such as carcinogenicity
bioassays, often is misunderstood. It is preferable to use realistic doses of
carcinogens in all animal studies. However, this leads to a loss of statistical power,
thereby limiting the ability of the test to detect carcinogens or other toxic compounds.
Consider the situation in which a realistic dose of a chemical causes a
tumor in 1 in 100 laboratory animals. If the lifetime background incidence of
tumors in animals without exposure to the chemical is 6 in 100, a toxicological
test involving 100 control animals and 100 exposed animals who were fed the
realistic dose would be expected to reveal 6 control animals and 7 exposed
animals with the cancer. This difference is too small to be recognized as statistically
significant. However, if the study started with ten times the realistic dose,
the researcher would expect to get 16 cases in the exposed group and 6 cases in
the control group, a significant difference that is unlikely to be overlooked.
Unfortunately, even this example does not demonstrate the difficulties of
determining risk.21 Regulators are responding to public concern about cancer
by regulating risks often as low as 1 in a million—not 1 in 100, as in the example
given above. To test risks of 1 in a million, a researcher would have to either
increase the lifetime dose from 10 times to 100,000 times the realistic dose or
expand the numbers of animals under study into the millions. However, increases
of this magnitude are beyond the world’s animal-testing capabilities and
are also prohibitively expensive. Inevitably, then, animal studies must trade statistical
power for extrapolation from higher doses to lower doses.
Accordingly, proffered toxicological expert opinion on potentially
cancer-causing chemicals almost always is based on a review of research studies
that extrapolate from animal experiments involving doses significantly higher
than that to which humans are exposed.22 Such extrapolation is accepted in the
regulatory arena. However, in toxic tort cases, experts often use additional background
information23 to offer opinions about disease causation and risk.24
21. See, e.g., Committee on Risk Assessment Methodology, National Research Council, supra
note 19, at 43–51.
22. See, e.g., James Huff, Chemicals and Cancer in Humans: First Evidence in Experimental Animals, 100
Envtl. Health Persp. 201, 204 (1993); International Agency for Research on Cancer, World Health
Org., Preamble, in 63 IARC Monographs on the Evaluation of Carcinogenic Risks to Humans 9, 17
(1995).
23. Researchers have developed numerous biomathematical formulas to provide statistical bases for
extrapolation from animal data to human exposure. See generally Pitot & Dragen, supra note 19, at 255–
57; Animal Models in Toxicology (Shayne Cox Gad & Christopher P. Chengelis eds., 1992); V.A.
Filov et al., Quantitative Toxicology: Selected Topics (1979). See also infra §§ IV, V.
24. Policy arguments concerning extrapolation from low doses to high doses are explored in Troyen
A. Brennan & Robert F. Carter, Legal and Scientific Probability of Causation of Cancer and Other Environmental
Disease in Individuals, 10 J. Health Pol. Pol’y & L. 33 (1985).
Reference Manual on Scientific Evidence
410
2. In vitro research
In vitro research concerns the effects of a chemical on human or animal cells,
bacteria, yeast, isolated tissues, or embryos. Thousands of in vitro toxicological
tests have been described in the scientific literature. Many tests are for mutagenesis
in bacterial or mammalian systems. There are short-term in vitro tests for
just about every physiological response and every organ system, such as perfusion
tests and DNA studies. Relatively few of these tests have been validated by
replication in many different laboratories or by comparison with outcomes in
animal studies to determine if they are predictive of whole-animal or human
toxicity.25
Criteria of reliability for an in vitro test include the following: (1) whether
the test has come through a published protocol in which many laboratories used
the same in vitro method on a series of unknown compounds prepared by a
reputable organization (such as the National Institutes of Health (NIH) or the
International Agency for Research on Cancer (IARC)) to determine if the test
consistently and accurately measures toxicity; (2) whether the test has been adopted
by a U.S. or international regulatory body; and (3) whether the test is predictive
of in vivo outcomes related to the same cell or target organ system.
D. Extrapolation from Animal and Cell Research to Humans
Two types of extrapolation must be considered: from animal data to humans
and from higher doses to lower doses. In qualitative extrapolation, one can
usually rely on the fact that a compound causing an effect in one mammalian
species will cause it in another species. This is a basic principle of toxicology and
pharmacology. If a heavy metal, such as mercury, causes kidney toxicity in laboratory
animals, it is highly likely to do so at some dose in humans. However, the
dose at which mercury causes this effect in laboratory animals is modified by
many internal factors, and the exact dose–response curve may be different from
that for humans. Through the study of factors that modify the toxic effects of
chemicals, including absorption, distribution, metabolism, and excretion, researchers
can improve the ability to extrapolate from laboratory animals to humans
and from higher to lower doses.26 Mathematical depiction of the process
by which an external dose moves through various compartments in the body
25. See generally In Vitro Toxicity Testing: Applications to Safety Evaluation (John M. Frazier ed.,
1992); In Vitro Methods in Toxicology (C.K. Atterwill & C.E. Steele eds., 1987) (discussion of the
strengths and weaknesses of specific in vitro tests). Use of in vitro data for evaluating human mutagenicity
and teratogenicity is described in John M. Rogers & Robert J. Kavlock, Developmental Toxicology, in
Casarett and Doull’s Toxicology: The Basic Science of Poisons, supra note 1, at 301, 319–21; George
R. Hoffman, Genetic Toxicology, in Casarett and Doull’s Toxicology: The Basic Science of Poisons,
supra note 1, at 269, 277–93. For a critique of expert testimony using in vitro data, see Wade-Greaux v.
Whitehall Laboratories, Inc., 874 F. Supp. 1441, 1480 (D.V.I.), aff’d, 46 F.3d 1120 (3d Cir. 1994).
26. For example, benzene undergoes a complex metabolic sequence that results in toxicity to the
Reference Guide on Toxicology
411
until it reaches the target organ is often called physiologically based pharmacokinetics.
27
Extrapolation from studies in nonmammalian species to humans is much more
difficult and can only be done if there is sufficient information on similarities in
absorption, distribution, metabolism, and excretion; quantitative determinations
of human toxicity based on in vitro studies usually are not considered appropriate.
As discussed in section I.F, in vitro or animal data for elucidating mechanisms
of toxicity are more persuasive when positive human epidemiological
data also exist.28
E. Safety and Risk Assessment
Toxicological expert opinion also relies on formal safety and risk assessments.
Safety assessment is the area of toxicology relating to the testing of chemicals
and drugs for toxicity. It is a relatively formal approach in which the potential
for toxicity of a chemical is tested in vivo or in vitro using standardized techniques.
The protocols for such studies usually are developed through scientific
consensus and are subject to oversight by governmental regulators or other watchdog
groups.
After a number of bad experiences, including outright fraud, government
agencies have imposed codes on laboratories involved in safety assessment, including
industrial, contract, and in-house laboratories.29 Known as Good Laboratory
Practice (GLP), these codes govern many aspects of laboratory standards,
bone marrow in all species, including humans. Robert Snyder et al., The Toxicology of Benzene, 100
Envtl. Health Persp. 293 (1993). The exact metabolites responsible for this bone-marrow toxicity are
the subject of much interest but remain unknown. Mice are more susceptible to benzene than are rats.
If researchers could determine the differences between mice and rats in their metabolism of benzene,
they would have a useful clue as to which portion of the metabolic scheme is responsible for benzene
toxicity to the bone marrow. See, e.g., Karl K. Rozman & Curtis D. Klaassen, Absorption, Distribution,
and Excretion of Toxicants, in Casarett and Doull’s Toxicology: The Basic Science of Poisons, supra note
1, at 91; Andrew Parkinson, Biotransformation of Xenobiotics, in Casarett and Doull’s Toxicology: The
Basic Science of Poisons, supra note 1, at 113.
27. For an analysis of methods used to extrapolate from animal toxicity data to human health
effects, see, e.g., Robert E. Menzer, Selection of Animal Models for Data Interpretation, in Toxic Substances
and Human Risk: Principles of Data Interpretation, supra note 15, at 133; Thomas J. Slaga, Interspecies
Comparisons of Tissue DNA Damage, Repair, Fixation and Replication, 77 Envtl. Health Persp. 73 (1988);
Lorenzo Tomatis, The Predictive Value of Rodent Carcinogenicity Tests in the Evaluation of Human Risks, 19
Ann. Rev. Pharmacol. & Toxicol. 511 (1979); Willard J. Visek, Issues and Current Applications of Interspecies
Extrapolation of Carcinogenic Potency as a Component of Risk Assessment, 77 Envtl. Health Persp. 49 (1988);
Gary P. Carlson, Factors Modifying Toxicity, in Toxic Substances and Human Risk: Principles of Data
Interpretation, supra note 15, at 47; Michael D. Hogan & David G. Hoel, Extrapolation to Man, in
Principles and Methods of Toxicology, supra note 14, at 879; James P. Leape, Quantitative Risk Assessment
in Regulation of Environmental Carcinogens, 4 Harv. Envtl. L. Rev. 86 (1980).
28. See, e.g., Goewey v. United States, 886 F. Supp. 1268, 1280–81 (D.S.C. 1995) (extrapolation
of neurotoxic effects from chickens to humans unwarranted without human confirmation).
29. A dramatic case of fraud involving a toxicology laboratory that performed tests to assess the
Reference Manual on Scientific Evidence
412
including such details as the number of animals per cage, dose and chemical
verification, and the handling of tissue specimens. GLP practices are remarkably
similar across agencies, but the tests called for differ depending on mission. For
example, there are major differences between the FDA’s and the EPA’s required
procedures for testing drugs and environmental chemicals.30 The FDA requires
and specifies both efficacy and safety testing of drugs in humans and animals.
Carefully controlled clinical trials using doses within the expected therapeutic
range are required for premarket testing of drugs because exposures to prescription
drugs are carefully controlled and should not exceed specified ranges or
uses. However, for environmental chemicals and agents, no premarket testing
in humans is required by the EPA. Moreover, since exposures are less predictable,
a wider range of doses usually is given in the animal tests.31
Since exposures to environmental chemicals may continue over the lifetime
and affect both young and old, test designs called lifetime bioassays have been
developed in which relatively high doses are given to experimental animals.
Interpretation of results requires extrapolation from animals to humans, from
high to low doses, and from short exposures to multiyear estimates. It must be
emphasized that less than 1% of the 60,000–75,000 chemicals in commerce
have been subjected to a full safety assessment, and there are significant toxicological
data on only 10%–20%.
Risk assessment is an approach increasingly used by regulatory agencies to
estimate and compare the risks of hazardous chemicals and to assign priority for
avoiding their adverse effects.32 The National Academy of Sciences defines four
components of risk assessment: hazard identification, dose–response estimation,
exposure assessment, and risk characterization.33
Although risk assessment is not an exact science, it should be viewed as a
safety of consumer products is described in United States v. Keplinger, 776 F.2d 678 (7th Cir. 1985), cert.
denied, 476 U.S. 1183 (1986). Keplinger and the other defendants in this case were toxicologists who
were convicted of falsifying data on product safety by underreporting animal morbidity and mortality
and omitting negative data and conclusions from their reports.
30. See, e.g., 40 C.F.R. §§ 160, 792 (1993); Lu, supra note 14, at 89.
31. It must be appreciated that the development of a new drug inherently requires searching for an
agent that at useful doses has a biological effect (e.g., decreasing blood pressure), whereas those developing
a new chemical for consumer use (e.g., a house paint) hope that at usual doses no biological effects
will occur. There are other compounds, such as pesticides and antibacterial agents, for which a biological
effect is desired, but it is intended that at usual doses humans will not be affected. These different
expectations are part of the rationale for the differences in testing information available for assessing
toxicological effects.
32. Committee on Risk Assessment Methodology, National Research Council, supra note 19, at 1.
33. See generally National Research Council, Risk Assessment in the Federal Government: Managing
the Process (1983); Bernard D. Goldstein, Risk Assessment/Risk Management Is a Three-Step Process:
In Defense of EPA’s Risk Assessment Guidelines, 7 J. Am. C. Toxicol. 543 (1988); Bernard D. Goldstein,
Risk Assessment and the Interface Between Science and Law, 14 Colum. J. Envtl. L. 343 (1989).
Reference Guide on Toxicology
413
useful estimate on which policy making can be based. In recent years, codification
of the methodology used to assess risk has increased confidence that the
process can be reasonably free of bias; however, significant controversy remains,
particularly when actual data are limited and generally conservative default assumptions
are used.34
While risk assessment information about a chemical can be somewhat useful
in a toxic tort case, at least in terms of setting reasonable boundaries as to the
likelihood of causation, the impetus for the development of risk assessment has
been the regulatory process, which has different goals.35 Because of their use of
appropriately prudent assumptions in areas of uncertainty and their use of default
assumptions when there are limited data, risk assessments intentionally encompass
the upper range of possible risks.
F. Toxicology and Epidemiology
Epidemiology is the study of the incidence and distribution of disease in human
populations. Clearly, both epidemiology and toxicology have much to offer in
elucidating the causal relationship between chemical exposure and disease.36 These
sciences often go hand in hand in assessments of the risks of chemical exposure,
without artificial distinctions being drawn between them. However, although
courts generally rule epidemiological expert opinion admissible, admissibility of
toxicological expert opinion has been more controversial because of uncertain-
34. An example of conservative default assumptions can be found in Superfund risk assessment.
The EPA has determined that Superfund sites should be cleaned up to reduce cancer risk from 1 in
10,000 to 1 in 1,000,000. A number of assumptions can go into this calculation, including conservative
assumptions about intake, exposure frequency and duration, and cancer-potency factors for the chemicals
at the site. See, e.g., Robert H. Harris & David E. Burmaster, Restoring Science to Superfund Risk
Assessment, 6 Toxics L. Rep. (BNA) 1318 (Mar. 25, 1992).
35. See, e.g., Ellen Relkin, Use of Governmental and Industrial Standards of Exposure and Toxicological
Data in Toxic Tort Litigation, reprinted in Proving Causation of Disease: Update 1996, at 199 (New Jersey
Inst. for Continuing Legal Educ. 1996); Steven Shavell, Liability for Harm Versus Regulation of Safety, 13
J. Legal Stud. 357 (1984). Risk assessment has been heavily criticized on a number of grounds. The
major argument of industry has been that it is overly conservative and thus greatly overstates the actual
risk. The rationale for conservatism is in part the prudent public health approach of “above all, do no
harm.” The conservative approach is also used, especially in regard to cancer risk, because it is sometimes
more feasible to extrapolate to a plausible upper boundary for a risk estimate than it is to estimate
a point of maximum likelihood. For a sample of the debate over risk assessment, see Bruce N. Ames &
Lois S. Gold, Too Many Rodent Carcinogens: Mitogenesis Increases Mutagenesis, 249 Science 970 (1990);
Jean Marx, Animal Carcinogen Testing Challenged, 250 Science 743 (1990); Philip H. Abelson, Incorporation
of a New Science into Risk Assessment, 250 Science 1497 (1990); Frederica P. Perera, Letter to the
Editor: Carcinogens and Human Health, Part 1, 250 Science 1644 (1990); Bruce N. Ames & Lois S. Gold,
Response, 250 Science 1645 (1990); David P. Rall, Letter to the Editor: Carcinogens and Human Health, Part
2, 251 Science 10 (1991); Bruce N. Ames & Lois S. Gold, Response, 251 Science 12 (1991); John C.
Bailar III et al., One-Hit Models of Carcinogenesis: Conservative or Not?, 8 Risk Analysis 485 (1988).
36. See Michael D. Green et al., Reference Guide on Epidemiology § V, in this manual.
Reference Manual on Scientific Evidence
414
ties regarding extrapolation from animal and in vitro data to humans. This particularly
has been true in cases in which relevant epidemiological research data
exist. However, the methodological weaknesses of some epidemiological studies,
including their inability to accurately measure exposure and their small numbers
of subjects, render these studies difficult to interpret.37 In contrast, since
animal and cell studies permit researchers to isolate the effects of exposure to a
single chemical or to known mixtures, toxicological evidence offers unique
information concerning dose–response relationships, mechanisms of action,
specificity of response, and other information relevant to the assessment of causation.
38
Even though there is little toxicological data on many of the 75,000 compounds
in general commerce, there is far more information from toxicological
studies than from epidemiological studies.39 It is much easier, and more economical,
to expose an animal to a chemical or to perform in vitro studies than it
is to perform epidemiological studies. This difference in data availability is evident
even for cancer causation, for which toxicological study is particularly expensive
and time-consuming. Of the perhaps two dozen chemicals that reputable
international authorities agree are known human carcinogens based on
positive epidemiological studies, arsenic is the only one not known to be an
animal carcinogen. Yet, there are more than 100 known animal carcinogens for
which there is no valid epidemiological database, and a handful of others for
which the epidemiological database is equivocal (e.g., butadiene).40 To clarify
37. Id.
38. Both commonalities and differences between animal responses and human responses to chemical
exposures were recognized by the court in International Union, United Automobile, Aerospace and
Agricultural Implement Workers of America v. Pendergrass, 878 F.2d 389 (D.C. Cir. 1989). In reviewing the
results of both epidemiological and animal studies on formaldehyde, the court stated: “Humans are not
rats, and it is far from clear how readily one may generalize from one mammalian species to another.
But in light of the epidemiological evidence [of carcinogenicity] that was not the main problem. Rather
it was the absence of data at low levels.” Id. at 394. The court remanded the matter to OSHA to
reconsider its findings that formaldehyde presented no specific carcinogenic risk to workers at exposure
levels of 1 part per million or less. See also Hopkins v. Dow Corning Corp., 33 F.3d 1116 (9th Cir.
1994); Ambrosini v. Labarraque, 101 F.3d 129, 141 (D.C. Cir. 1996).
39. See generally National Research Council, supra note 33. See also Lorenzo Tomatis et al., Evaluation
of the Carcinogenicity of Chemicals: A Review of the Monograph Program of the International Agency for
Research on Cancer, 38 Cancer Res. 877, 881 (1978); National Research Council, Toxicity Testing:
Strategies to Determine Needs and Priorities (1984); Myra Karstadt & Renee Bobal, Availability of
Epidemiologic Data on Humans Exposed to Animal Carcinogens, 2 Teratogenesis, Carcinogenesis & Mutagenesis
151 (1982).
40. The absence of epidemiological data is due, in part, to the difficulties in conducting cancer
epidemiology studies, including the lack of suitably large groups of individuals exposed for a sufficient
period of time, long latency periods between exposure and manifestation of disease, the high variability
in the background incidence of many cancers in the general population, and the inability to measure
actual exposure levels. These same concerns have led some researchers to conclude that “many negative
epidemiological studies must be considered inconclusive” for exposures to low doses or weak carcinogens.
Pitot & Dragan, supra note 19, at 240–41.
Reference Guide on Toxicology
415
any findings, regulators can require a repeat of an equivocal two-year animal
toxicological study or the performance of additional laboratory studies in which
animals deliberately are exposed to the chemical. Such deliberate exposure is
not possible in humans. As a general rule, equivocally positive epidemiological
studies reflect prior workplace practices that led to relatively high levels of chemical
exposure for a limited number of individuals and that, fortunately, in most cases
no longer occur now. Thus, an additional prospective epidemiological study
often is not possible, and even the ability to do retrospective studies is constrained
by the passage of time.
II. Expert Qualifications
The basis of the toxicologist’s expert opinion in a specific case is a thorough
review of the research literature and treatises concerning effects of exposure to
the chemical at issue. To arrive at an opinion, the expert assesses the strengths
and weaknesses of the research studies. The expert also bases an opinion on
fundamental concepts of toxicology relevant to understanding the actions of
chemicals in biological systems.
As the following series of questions indicates, no single academic degree,
research specialty, or career path qualifies an individual as an expert in toxicology.
Toxicology is a heterogeneous field. A number of indicia of expertise can
be explored, however, which are relevant to both the admissibility and weight
of the proffered expert opinion.
A. Does the Proposed Expert Have an Advanced Degree in
Toxicology, Pharmacology, or a Related Field? If the Expert Is a
Physician, Is He or She Board Certified in a Field Such As
Occupational Medicine?
A graduate degree in toxicology demonstrates that the proposed expert has a
substantial background in the basic issues and tenets of toxicology. Many universities
have established graduate programs in toxicology only recently. These
programs are administered by the faculties of medicine, pharmacology, pharmacy,
or public health.
Given the relatively recent establishment of academic toxicology programs, a
number of highly qualified toxicologists are physicians or hold doctoral degrees
in related disciplines (e.g., pharmacology, biochemistry, environmental health,
or industrial hygiene). For a person with this type of background, a single course
in toxicology is unlikely to provide sufficient background for developing expertise
in the field.
Reference Manual on Scientific Evidence
416
A proposed expert should be able to demonstrate an understanding of the
discipline of toxicology, including statistics, toxicological research methods, and
disease processes. A physician without particular training or experience in toxicology
is unlikely to have sufficient background to evaluate the strengths and
weaknesses of toxicological research.41 Most practicing physicians have little
knowledge of environmental and occupational medicine. Generally, physicians
are quite knowledgeable about identification of effects and their treatment. The
cause of these effects, particularly if they are unrelated to the treatment of the
disease, is generally of little concern to the practicing physician. Subspecialty
physicians may have particular knowledge of a cause-and-effect relationship (e.g.,
pulmonary physicians have knowledge of the relationship between asbestos exposure
and asbestosis),42 but most physicians have little training in chemical toxicology
and lack an understanding of exposure assessment and dose–response
relationships. An exception is a physician who is certified in medical toxicology
by the American Board of Medical Toxicology, based on substantial training in
toxicology and successful completion of rigorous examinations.
Some physicians who are occupational health specialists also have training in
toxicology. Knowledge of toxicology is particularly strong among those who
work in the chemical, petrochemical, and pharmaceutical industries, in which
surveillance of workers exposed to chemicals is a major responsibility. Of the
occupational physicians practicing today, only about 1,000 have successfully
completed the board examination in occupational medicine, which contains
some questions about chemical toxicology.43
41. See Mary Sue Henifin et al., Reference Guide on Medical Testimony, § II, in this manual.
42. See, e.g., Moore v. Ashland Chem., Inc., 126 F.3d 679, 701 (5th Cir. 1997) (treating physician’s
opinion admissible as to causation of reactive airway disease); McCullock v. H.B. Fuller Co., 61 F.3d
1038, 1044 (2d Cir. 1995) (treating physician’s opinion admissible as to effect of fumes from hot-melt
glue on throat, where physician was board certified in otolaryngology and based his opinion on medical
history and treatment, pathological studies, differential etiology, and scientific literature); Benedi v.
McNeil-P.P.C., Inc., 66 F.3d 1378, 1384 (4th Cir. 1995) (treating physician’s opinion admissible as to
causation of liver failure by mixture of alcohol and acetaminophen, based on medical history, physical
examination, lab and pathology data, and scientific literature—the same methodologies used daily in
the diagnosis of patients).
Treating physicians also become involved in considering cause-and-effect relationships when they
are asked whether a patient can return to a situation in which an exposure has occurred. The answer is
obvious if the cause-and-effect relationship is clearly known. However, this relationship is often uncertain,
and the physician must consider the appropriate advice. In such situations, the physician will tend
to give advice as if the causality was established, both because it is appropriate caution and because of
fears concerning medicolegal issues.
43. Clinical ecologists, another group of physicians, have offered opinions regarding multiplechemical
hypersensitivity and immune-system responses to chemical exposures. These physicians generally
have a background in the field of allergy, not toxicology, and their theoretical approach is derived
in part from classic concepts of allergic responses and immunology. This theoretical approach has often
led clinical ecologists to find cause-and-effect relationships or low-dose effects that are not generally
accepted by toxicologists. Clinical ecologists often belong to the American Academy of Environmental
Medicine.
Reference Guide on Toxicology
417
B. Has the Proposed Expert Been Certified by the American Board
of Toxicology, Inc., or Does He or She Belong to a Professional
Organization, Such As the Academy of Toxicological Sciences or
the Society of Toxicology?
As of January 1999, 1,631 individuals from twenty-one countries had received
board certification from the American Board of Toxicology, Inc. To sit for the
examination, which has a pass rate of less than 75%, the candidate must be
involved full-time in the practice of toxicology, including designing and managing
toxicological experiments or interpreting results and translating them to
identify and solve human and animal health problems. To become certified, the
candidate must pass all three parts of the examination within two years. Diplomates
must be recertified through examination every five years.
The Academy of Toxicological Sciences (ATS) was formed to provide credentials
in toxicology through peer review only. It does not administer examinations
for certification.
The Society of Toxicology (SOT), the major professional organization for
the field of toxicology, was founded in 1961 and has grown dramatically in
recent years; it currently has 4,672 members.44 It has reasonably strict criteria for
membership. Qualified people must have conducted and published original research
in some phase of toxicology (excluding graduate work) or be generally
recognized as expert in some phase of toxicology and be approved by a majority
vote of the board of directors. Many environmental toxicologists who meet
these qualifications belong to SOT.
Physician toxicologists can join the American College of Medical Toxicology
and the American Academy of Clinical Toxicologists. Other organizations
in the field are the American College of Toxicology, which has less stringent
criteria for membership; the International Society of Regulatory Toxicology
and Pharmacology; and the Society of Occupational and Environmental Health.
The last two organizations require only the payment of dues for membership.
In 1991, the Council on Scientific Affairs of the American Medical Association concluded that until
“accurate, reproducible, and well-controlled studies are available, . . . multiple chemical sensitivity
should not be considered a recognized clinical syndrome.” Council on Scientific Affairs, American
Med. Ass’n, Council Report on Clinical Ecology 6 (1991). In Bradley v. Brown, 42 F.3d 434, 438 (7th
Cir. 1994), the court considered the admissibility of an expert opinion based on clinical ecology theories.
The court ruled the opinion inadmissible, finding that it was “hypothetical” and based on anecdotal
evidence as opposed to scientific research. See also Coffin v. Orkin Exterminating Co., 20 F.
Supp. 2d 107, 110 (D. Me. 1998); Frank v. New York, 972 F. Supp. 130, 132 n.2 (N.D.N.Y 1997).
But see Elam v. Alcolac, Inc., 765 S.W.2d 42, 86 (Mo. Ct. App. 1988) (expert opinion based on clinical
ecology theories admissible), cert. denied, 493 U.S. 817 (1989).
44. There are currently fifteen specialty sections of SOT that represent the different types of research
needed to understand the wide range of toxic effects associated with chemical exposures. These
sections include mechanisms, molecular biology, inhalation toxicology, metals, neurotoxicology, carcinogenesis,
risk assessment, and immunotoxicology.
Reference Manual on Scientific Evidence
418
C. What Other Criteria Does the Proposed Expert Meet?
The success of academic scientists in toxicology, as in other biomedical sciences,
usually is measured by the following types of criteria: the quality and number of
peer-reviewed publications, the ability to compete for research grants, service
on scientific advisory panels, and university appointments.
Publication of articles in peer-reviewed journals indicates an expertise in toxicology.
The number of articles, their topics, and whether the individual is the
principal author are important factors in determining the expertise of a toxicologist.
45
Most research grants from government agencies and private foundations are
highly competitive. Successful competition for funding and publication of the
research findings indicate competence in an area.
Selection for local, national, and international regulatory advisory panels usually
implies recognition in the field. Examples of such panels are the National
Institutes of Health Toxicology Study Section and panels convened by the EPA,
the FDA, the World Health Organization (WHO), and the IARC. Recognized
industrial organizations, including the American Petroleum Institute, Electric
Power Research Institute, and Chemical Industry Institute of Toxicology, and
public interest groups, such as the Environmental Defense Fund and the Natural
Resources Defense Council, employ toxicologists directly and as consultants
and enlist academic toxicologists to serve on advisory panels. Because of a growing
interest in environmental issues, the demand for scientific advice has outgrown
the supply of available toxicologists. It is thus common for reputable
toxicologists to serve on advisory panels.
Finally, a university appointment in toxicology, risk assessment, or a related
field signifies an expertise in that area, particularly if the university has a graduate
education program in that area.
45. Examples of reputable, peer-reviewed journals are the Journal of Toxicology and Environmental
Health; Toxicological Sciences; Toxicology and Applied Pharmacology; Science; British Journal of Industrial Medicine;
Clinical Toxicology; Archives of Environmental Health; Journal of Occupational Medicine; Annual Review of
Pharmacology and Toxicology; Teratogenesis, Carcinogenesis and Mutagenesis; Fundamental and Applied Toxicology;
Inhalation Toxicology; Biochemical Pharmacology; Toxicology Letters; Environmental Research; Environmental
Health Perspectives; and American Journal of Industrial Medicine.
Reference Guide on Toxicology
419
III. Demonstrating an Association Between
Exposure and Risk of Disease
Once the expert has been qualified, he or she is expected to offer an opinion on
whether the plaintiff’s disease was caused by exposure to a chemical. To do so,
the expert relies on the principles of toxicology to provide a scientifically valid
methodology for establishing causation and then applies the methodology to the
facts of the case.
An opinion on causation should be premised on three preliminary assessments.
First, the expert should analyze whether the disease can be related to
chemical exposure by a biologically plausible theory. Second, the expert should
examine if the plaintiff was exposed to the chemical in a manner that can lead to
absorption into the body. Third, the expert should offer an opinion as to whether
the dose to which the plaintiff was exposed is sufficient to cause the disease.
The following questions help evaluate the strengths and weaknesses of toxicological
evidence.
A. On What Species of Animals Was the Compound Tested?
What Is Known About the Biological Similarities and
Differences Between the Test Animals and Humans? How Do
These Similarities and Differences Affect the Extrapolation from
Animal Data in Assessing the Risk to Humans?
All living organisms share a common biology that leads to marked similarities in
the responsiveness of subcellular structures to toxic agents. Among mammals,
more than sufficient common organ structure and function readily permit the
extrapolation from one species to another in most instances. Comparative information
concerning factors that modify the toxic effects of chemicals, including
absorption, distribution, metabolism, and excretion, in the laboratory test animals
and humans enhances the expert’s ability to extrapolate from laboratory
animals to humans.46
The expert should review similarities and differences in the animal species in
which the compound has been tested and in humans. This analysis should form
the basis of the expert’s opinion as to whether extrapolation from animals to
humans is warranted.47
46. See generally supra notes 26–27 and accompanying text; Animal Models in Toxicology, supra
note 23; Edward J. Calabrese, Principles of Animal Extrapolation (1983); Human Risk Assessment: The
Role of Animal Selection and Extrapolation (M. Val Roloff ed., 1987); Filov et al., supra note 23.
47. The failure to review similarities and differences in metabolism in performing cross-species
extrapolation has led to the exclusion of opinions based on animal data. See Hall v. Baxter Healthcare
Corp., 947 F. Supp. 1387, 1410 (D. Or. 1996); Nelson v. American Sterilizer Co., 566 N.W.2d 671
(Mich. Ct. App. 1997). But see In re Paoli R.R. Yard PCB Litig., 35 F.3d 717, 779–80 (3d Cir. 1994)
Reference Manual on Scientific Evidence
420
In general, there is an overwhelming similarity in the biology of all living
things and a particularly strong similarity among mammals. Of course, laboratory
animals differ from humans in many ways. For example, rats do not have
gall bladders. Thus, rat data would not be pertinent to the possibility that a
compound produces human gall bladder toxicity.48 Note that many subjective
symptoms are poorly modeled in animal studies. Thus, complaints that a chemical
has caused nonspecific symptoms, such as nausea, headache, and weakness,
for which there are no objective manifestations in humans are difficult to test in
laboratory animals.
B. Does Research Show That the Compound Affects a Specific
Target Organ? Will Humans Be Affected Similarly?
Some toxic agents affect only specific organs and not others. This organ specificity
may be due to particular patterns of absorption, distribution, metabolism,
and excretion; the presence of specific receptors; or organ function. For example,
organ specificity may reflect the presence in the organ of relatively high
levels of an enzyme capable of metabolizing or changing a compound to a toxic
form of the compound known as a metabolite, or it may reflect the relatively
low level of an enzyme capable of detoxifying a compound. An example of the
former is liver toxicity caused by inhaled carbon tetrachloride, which affects the
liver but not the lungs because of extensive metabolism to a toxic metabolite
within the liver but relatively little such metabolism in the lung.49
Some chemicals, however, may cause nonspecific effects or even multiple
effects. Lead is an example of a toxic agent that affects many organ systems,
including red blood cells, the central and peripheral nervous systems, the reproductive
system, and the kidneys.
The basis of specificity often reflects the function of individual organs. For
(noting that humans and monkeys are likely to show similar sensitivity to PCBs), cert. denied sub nom.
General Elec. Co. v. Ingram, 513 U.S. 1190 (1995).
As the Supreme Court noted in General Electric Co. v. Joiner, 522 U.S. 136, 144 (1997), the issue as
to admissibility is not whether animal studies are ever admissible to establish causation, but whether the
particular studies relied upon by plaintiff’s experts were sufficiently supported. See Carl F. Cranor et al.,
Judicial Boundary Drawing and the Need for Context-Sensitive Science in Toxic Torts After Daubert v. Merrell
Dow Pharmaceuticals, Inc., 16 Va. Envtl. L.J. 1, 38 (1996).
48. See, e.g., Calabrese, supra note 46, at 583–89 tbl.14-1. Species differences that produce a qualitative
difference in response to xenobiotics are well known. Sometimes understanding the mechanism
underlying the species difference can allow one to predict whether the effect will occur in humans.
Thus, carbaryl, an insecticide commonly used for gypsy moth control, among other things, produces
fetal abnormalities in dogs but not in hamsters, mice, rats, and monkeys. Dogs lack the specific enzyme
involved in metabolizing carbaryl; the other species tested all have this enzyme, as do humans. Therefore,
it has been assumed that humans are not at risk for fetal malformations produced by carbaryl.
49. Brian Jay Day et al., Potentiation of Carbon Tetrachloride-Induced Hepatotoxicity and Pneumotoxicity
by Pyridine, 8 J. Biochemical Toxicol. 11 (1993).
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421
example, the thyroid is particularly susceptible to radioactive iodine in atomic
fallout because thyroid hormone is unique within the body in that it requires
iodine. Through evolution a very efficient and specific mechanism has developed
which concentrates any absorbed iodine preferentially within the thyroid,
thus rendering the thyroid particularly at risk from radioactive iodine. In a test
tube the radiation from radioactive iodine can affect the genetic material obtained
from any cell in the body, but in the intact laboratory animal or human,
only the thyroid is at risk.
The unfolding of the human genome is already beginning to provide information
pertinent to understanding the wide variation in human risk to environmental
chemicals. The impact of this understanding on toxic tort causation issues
remains to be explored.50
C. What Is Known About the Chemical Structure of the
Compound and Its Relationship to Toxicity?
Understanding of the structural aspects of chemical toxicology has led to the use
of structure activity relationships (SAR) as a formal method of predicting the
potential toxicity of new chemicals. This technique compares the chemical structure
of compounds with known toxicity and the chemical structure of compounds
with unknown toxicity. Toxicity then is estimated based on molecular
similarities between the two compounds. Although SAR is used extensively by
the EPA in evaluating many new chemicals required to be tested under the
registration requirements of the Toxic Substances Control Act (TSCA), its reliability
has a number of limitations.51
50. The wide range in the rate of metabolism of chemicals is at least partly under genetic control. A
recent study in China found approximately a doubling of risk in people with high levels of either an
enzyme that increased the rate of formation of a toxic metabolite or an enzyme that decreased the rate
of detoxification of this metabolite. There was a sevenfold increase in risk for those who had both
genetically determined variants. See Frederica P. Perera, Molecular Epidemiology: Insights into Cancer Susceptibility,
Risk Assessment, and Prevention, 88 J. Nat’l Cancer Inst. 496 (1996).
51. For example, benzene and the alkyl benzenes (which include toluene, xylene, and ethyl benzene)
share a similar chemical structure. SAR works exceptionally well in predicting the acute central
nervous system anesthetic-like effects of both benzene and the alkyl benzenes. Although there are slight
differences in dose–response relationships, they are readily explained by the interrelated factors of chemical
structure, vapor pressure, and lipid solubility (the brain is highly lipid). National Research Council, The
Alkyl Benzenes (1981). However, only benzene produces damage to the bone marrow and leukemia;
the alkyl benzenes do not have this effect. This difference is the result of specific toxic metabolic
products of benzene in comparison with the alkyl benzenes. Thus, SAR is predictive of neurotoxic
effects but not bone-marrow effects. See Hoffman, supra note 25, at 277.
In Daubert v. Merrell Dow Pharmaceuticals, Inc., 509 U.S. 579 (1993), the Court rejected a per se
exclusion of SAR, animal data, and reanalyses of previously published epidemiological data where there
were negative epidemiological data. However, as the court recognized in Sorensen v. Shaklee Corp., 31
F.3d 638, 646 n.12 (8th Cir. 1994), the problem with SAR is that “‘[m]olecules with minor structural
differences can produce very different biological effects.’” (quoting Joseph Sanders, From Science to
Evidence: The Testimony on Causation in the Bendectin Cases, 46 Stan. L. Rev. 1, 19 (1993)).
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D. Has the Compound Been the Subject of In Vitro Research, and
If So, Can the Findings Be Related to What Occurs In Vivo?
Cellular and tissue-culture research can be particularly helpful in identifying
mechanisms of toxic action and potential target-organ toxicity. The major barrier
to use of in vitro results is the frequent inability to relate doses that cause
cellular toxicity to doses that cause whole-animal toxicity. In many critical areas,
knowledge that permits such quantitative extrapolation is lacking.52 Nevertheless,
the ability to quickly test new products through in vitro tests, using
human cells, provides invaluable “early warning systems” for toxicity.53
E. Is the Association Between Exposure and Disease Biologically
Plausible?
No matter how strong the temporal relationship between exposure and development
of disease, or the supporting epidemiological evidence, it is difficult to
accept an association between a compound and a health effect when no mechanism
can be identified by which the chemical exposure leads to the putative
effect.54
IV. Specific Causal Association Between an
Individual’s Exposure and the Onset of Disease
An expert who opines that exposure to a compound caused a person’s disease
engages in deductive clinical reasoning.55 In most instances, cancers and other
diseases do not wear labels documenting their causation.56 The opinion is based
on an assessment of the individual’s exposure, including the amount, the temporal
relationship between the exposure and disease, and other disease-causing
52. In Vitro Toxicity Testing: Applications to Safety Evaluation, supra note 25, at 8. Despite its
limitations, in vitro research can strengthen inferences drawn from whole-animal bioassays and can
support opinions regarding whether the association between exposure and disease is biologically plausible.
See Hoffman, supra note 25, at 278–93; Rogers & Kavlock, supra note 25, at 319–23.
53. Graham v. Playtex Prods., Inc., 993 F. Supp. 127, 131–32 (N.D.N.Y. 1998) (opinion based on
in vitro experiments showing that rayon tampons were associated with higher risk of toxic shock
syndrome was admissible in the absence of epidemiological evidence).
54. However, theories of bioplausibility, without additional data, have been found to be insufficient
to support a finding of causation. See, e.g., Hall v. Baxter Healthcare Corp., 947 F. Supp. 1387, 1414
(D. Or. 1996); Golod v. Hoffman La Roche, 964 F. Supp. 841, 860–61 (S.D.N.Y. 1997).
55. For an example of deductive clinical reasoning based on known facts about the toxic effects of
a chemical and the individual’s pattern of exposure, see Bernard D. Goldstein, Is Exposure to Benzene a
Cause of Human Multiple Myeloma?, 609 Annals N.Y. Acad. Sci. 225 (1990).
56. Research still in the preliminary stages shows that certain cancers do wear labels in the form of
DNA adducts and mutational spectra. See generally National Research Council, Biologic Markers in
Reproductive Toxicology (1989).
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factors. This information is then compared with scientific data on the relationship
between exposure and disease. The certainty of the expert’s opinion depends
on the strength of the research data demonstrating a relationship between
exposure and the disease at the dose in question and the absence of other disease-
causing factors (also known as confounding factors).57
Particularly problematic are generalizations made in personal injury litigation
from regulatory positions. For example, if regulatory standards are discussed in
toxic tort cases to provide a reference point for assessing exposure levels, it must
be recognized that there is a great deal of variability in the extent of evidence
required to support different regulations.58 The extent of evidence required to
support regulations depends on
1. the law (e.g., the Clean Air Act has language focusing regulatory activity
for primary pollutants on adverse health consequences to sensitive populations
with an adequate margin of safety and with no consideration of
economic consequences, whereas regulatory activity under TSCA clearly
asks for some balance between the societal benefits and risks of new chemicals59);
2. the specific end point of concern (e.g., consider the concern caused by
cancer and adverse reproductive outcomes versus almost anything else);
and
3. the societal impact (e.g., the public’s support for control of an industry
that causes air pollution versus the public’s desire to alter personal automobile
use patterns).
These three concerns, as well as others, including costs, politics, and the virtual
certainty of litigation challenging the regulation, have an impact on the level of
scientific proof required by the regulatory decision maker.60
57. Causation issues are discussed in Michael D. Green et al., Reference Guide on Epidemiology,
§ V, and Mary Sue Henifin et al., Reference Guide on Medical Testimony, § IV, in this manual. See also
Joseph Sanders, Scientific Validity, Admissibility and Mass Torts After Daubert, 78 Minn. L. Rev. 1387
(1994); Susan R. Poulter, Science and Toxic Torts: Is There a Rational Solution to the Problem of Causation?,
7 High Tech. L.J. 189 (1992); Troyen A. Brennan, Causal Chains and Statistical Links: The Role of
Scientific Uncertainty in Hazardous-Substance Litigation, 73 Cornell L. Rev. 469 (1988); Orrin E. Tilevitz,
Judicial Attitudes Towards Legal and Scientific Proof of Cancer Causation, 3 Colum. J. Envtl. L. 344, 381
(1977); David L. Bazelon, Science and Uncertainty: A Jurist’s View, 5 Harv. Envtl. L. Rev. 209 (1981).
58. The relevance of regulatory standards to toxic tort litigation is explored in Silbergeld, supra note
2; Relkin, supra note 35; In re Paoli R.R. Yard PCB Litig., 35 F.3d 717, 781 (3d Cir. 1994) (district
court abused its discretion in excluding animal studies relied upon by the EPA), cert. denied sub nom.
General Elec. Co. v. Ingram, 513 U.S. 1190 (1995); John Endicott, Interaction Between Regulatory Law
and Tort Law in Controlling Toxic Chemical Exposure, 47 SMU L. Rev. 501 (1994).
59. See, e.g., Clean Air Act Amendments of 1990, 42 U.S.C. § 7412(f) (1994); Toxic Substances
Control Act, 15 U.S.C. § 2605 (1994).
60. These concerns are discussed in Stephen Breyer, Breaking the Vicious Circle: Toward Effective
Risk Regulation (1993).
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In addition, regulatory standards traditionally include protective factors to
reasonably ensure that susceptible individuals are not put at risk. Furthermore,
standards are often based on the risk that is due to lifetime exposure. Accordingly,
the mere fact that an individual has been exposed to a level above a
standard does not necessarily mean that an adverse effect has occurred.
A. Was the Plaintiff Exposed to the Substance, and If So, Did the
Exposure Occur in a Manner That Can Result in Absorption
into the Body?
Evidence of exposure is essential in determining the effects of harmful substances.
Basically, potential human exposure is measured in one of three ways.
First, when direct measurements cannot be made, exposure can be measured by
mathematical modeling, in which one uses a variety of physical factors to estimate
the transport of the pollutant from the source to the receptor. For example,
mathematical models take into account such factors as wind variations to
allow calculation of the transport of radioactive iodine from a federal atomic
research facility to nearby residential areas. Second, exposure can be directly
measured in the medium in question—air, water, food, or soil. When the medium
of exposure is water, soil, or air, hydrologists or meteorologists may be
called upon to contribute their expertise to measuring exposure. The third approach
directly measures human receptors through some form of biological
monitoring, such as blood tests to determine blood lead levels or urinalyses to
check for a urinary metabolite, which shows pollutant exposure. Ideally, both
environmental testing and biological monitoring are performed; however, this
is not always possible, particularly in instances of past exposure.61
The toxicologist must go beyond understanding exposure to determine if the
individual was exposed to the compound in a manner that can result in absorption
into the body. The absorption of the compound is a function of its
physiochemical properties, its concentration, and the presence of other agents
or conditions that assist or interfere with its uptake. For example, inhaled lead is
absorbed almost totally, whereas ingested lead is taken up only partially into the
body. Iron deficiency and low nutritional calcium intake, both common conditions
of inner-city children, increase the amount of ingested lead that is absorbed
in the gastrointestinal tract and passes into the bloodstream.
61. See, e.g., In re Three Mile Island Litig. Consol. Proceedings, 927 F. Supp. 834, 870 (M.D. Pa.
1996) (plaintiffs failed to present direct or indirect evidence of exposure to cancer-inducing levels of
radiation); Mitchell v. Gencorp Inc., 165 F.3d 778, 781 (10th Cir. 1999) (“[g]uesses, even if educated,
are insufficient to prove the level of exposure in a toxic tort case”). See also Wright v. Willamette
Indus., Inc., 91 F.3d 1105, 1107 (8th Cir. 1996); Valentine v. Pioneer Chlor Alkali Co., 921 F. Supp.
666, 678 (D. Nev. 1996).
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425
B. Were Other Factors Present That Can Affect the Distribution of
the Compound Within the Body?
Once a compound is absorbed into the body through the skin, lungs, or gastrointestinal
tract, it is distributed throughout the body through the bloodstream.
Thus, the rate of distribution depends on the rate of blood flow to various
organs and tissues. Distribution and resulting toxicity are also influenced by
other factors, including the dose, the route of entry, tissue solubility, lymphatic
supplies to the organ, metabolism, and the presence of specific receptors or
uptake mechanisms within body tissues.
C. What Is Known About How Metabolism in the Human Body
Alters the Toxic Effects of the Compound?
Metabolism is the alteration of a chemical by bodily processes. It does not necessarily
result in less toxic compounds being formed. In fact, many of the organic
chemicals that are known human cancer-causing agents require metabolic
transformation before they can cause cancer. A distinction often is made between
direct-acting agents, which cause toxicity without any metabolic conversion,
and indirect-acting agents, which require metabolic activation before they
can produce adverse effects. Metabolism is complex, since a variety of pathways
compete for the same agent; some produce harmless metabolites, and others
produce toxic agents.62
D. What Excretory Route Does the Compound Take, and How
Does This Affect Its Toxicity?
Excretory routes are urine, feces, sweat, saliva, expired air, and lactation. Many
inhaled volatile agents are eliminated primarily by exhalation. Small water-soluble
compounds are usually excreted through urine. Higher-molecular-weight compounds
are often excreted through the biliary tract into the feces. Certain fatsoluble,
poorly metabolized compounds, such as PCBs, may persist in the body
for decades, although they can be excreted in the milk fat of lactating women.
E. Does the Temporal Relationship Between Exposure and the
Onset of Disease Support or Contradict Causation?
In acute toxicity, there is usually a short time period between cause and effect.
However, in some situations, the length of basic biological processes necessitates
a longer period of time between initial exposure and the onset of observable
62. Courts have explored the relationship between metabolic transformation and carcinogenesis.
See, e.g., Stites v. Sundstrand Heat Transfer, Inc., 660 F. Supp. 1516, 1519 (W.D. Mich. 1987).
Reference Manual on Scientific Evidence
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disease. For example, in acute myelogenous leukemia, the adult form of acute
leukemia, at least one to two years must elapse from initial exposure to radiation,
benzene, or cancer chemotherapy before the manifestation of a clinically
recognizable case of leukemia. A toxic tort claim alleging a shorter time period
between cause and effect is scientifically untenable. Much longer time periods
are necessary for the manifestation of solid tumors caused by asbestos.63
F. If Exposure to the Substance Is Associated with the Disease, Is
There a No Observable Effect, or Threshold, Level, and If So,
Was the Individual Exposed Above the No Observable Effect
Level?
For agents that produce effects other than through mutations, it is assumed that
there is some level that is incapable of causing harm. If the level of exposure was
below this no observable effect, or threshold, level, a relationship between the
exposure and disease cannot be established.64 When only laboratory animal data
are available, the expert extrapolates the NOEL from animals to humans by
calculating the animal NOEL based on experimental data and decreasing this
level by one or more safety factors to ensure no human effect.65 The NOEL can
also be calculated from human toxicity data if they exist. This analysis, however,
is not applied to substances that exert toxicity by causing mutations leading to
cancer. Theoretically, any exposure at all to mutagens may increase the risk of
cancer, although the risk may be very slight and not achieve medical probability.
66
63. The temporal relationship between exposure and causation is discussed in Cavallo v. Star Enterprise,
892 F. Supp. 756, 769–74 (E.D. Va. 1995) (expert testimony based primarily on temporal connection
between exposure to jet fuel and onset of symptoms, without other evidence of causation, ruled
inadmissible). But see National Bank of Commerce v. Dow Chem. Co., 965 F. Supp. 1490, 1525 (E.D.
Ark. 1996) (“[T]here may be instances where the temporal connection between exposure to a given
chemical and subsequent injury is so compelling as to dispense with the need for reliance on standard
methods of toxicology.”).
64. See, e.g., Allen v. Pennsylvania Eng’g Corp., 102 F.3d 194, 199 (5th Cir. 1996) (“Scientific
knowledge of the harmful level of exposure to a chemical, plus knowledge that the plaintiff was exposed
to such quantities, are minimal facts necessary to sustain the plaintiff’s burden in a toxic tort
case.”); Redland Soccer Club, Inc. v. Department of Army, 55 F.3d 827, 847 (3d Cir. 1995) (summary
judgment for defendant precluded where exposure above cancer threshold level could be calculated
from soil samples).
65. See, e.g., supra notes 18–19 and accompanying text; Tardiff & Rodricks, supra note 18, at 391;
Joseph V. Rodricks, Calculated Risks 165–70, 193–96 (1992); Lu, supra note 14, at 84.
66. See sources cited supra note 19.
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427
V. Medical History
A. Is the Medical History of the Individual Consistent with the
Toxicologist’s Expert Opinion Concerning the Injury?
One of the basic and most useful tools in diagnosis and treatment of disease is the
patient’s medical history.67 A thorough, standardized patient information questionnaire
would be particularly useful for identifying the etiology, or causation,
of illnesses related to toxic exposures; however, there is currently no validated
or widely used questionnaire that gathers all pertinent information.68 Nevertheless,
it is widely recognized that a thorough medical history involves the questioning
and examination of the patient as well as appropriate medical testing.
The patient’s written medical records should also be examined.
The following information is relevant to a patient’s medical history: past and
present occupational and environmental history and exposure to toxic agents;
lifestyle characteristics (e.g., use of nicotine and alcohol); family medical history
(i.e., medical conditions and diseases of relatives); and personal medical history
(i.e., present symptoms and results of medical tests as well as past injuries, medical
conditions, diseases, surgical procedures, and medical test results).
In some instances, the reporting of symptoms can be in itself diagnostic of
exposure to a specific substance, particularly in evaluating acute effects.69 For
example, individuals acutely exposed to organophosphate pesticides report headaches,
nausea, and dizziness accompanied by anxiety and restlessness. Other reported
symptoms are muscle twitching, weakness, and hypersecretion with sweating,
salivation, and tearing.70
B. Are the Complaints Specific or Nonspecific?
Acute exposure to many toxic agents produces a constellation of nonspecific
symptoms, such as headaches, nausea, lightheadedness, and fatigue. These types
of symptoms are part of human experience and can be triggered by a host of
medical and psychological conditions. They are almost impossible to quantify or
document beyond the patient’s report. Thus, these symptoms can be attributed
67. For a thorough discussion of the methods of clinical diagnosis, see Mary Sue Henifin et al.,
Reference Guide on Medical Testimony, § IV.B–C, in this manual. See also Jerome P. Kassirer &
Richard I. Kopelman, Learning Clinical Reasoning (1991). A number of cases have considered the
admissibility of the treating physician’s opinion based, in part, on medical history, symptomatology, and
laboratory and pathology studies. See cases cited supra note 42.
68. Office of Tech. Assessment, U.S. Congress, supra note 10, at 365–89.
69. But see Moore v. Ashland Chem., Inc., 126 F.3d 679, 693 (5th Cir. 1997) (discussion of relevance
of symptoms within forty-five minutes of exposure).
70. Environmental Protection Agency, Recognition and Management of Pesticide Poisonings (4th
ed. 1989).
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428
71. The issue of whether development of nonspecific symptoms may be related to pesticide exposure
was considered in Kannankeril v. Terminix International, Inc., 128 F.3d 802 (3d Cir. 1997). The
court ruled that the trial court abused its discretion in excluding expert opinion that considered, and
rejected, a negative laboratory test. Id. at 808–09.
72. Failure to rule out other potential causes of symptoms may lead to a ruling that the expert’s
report is inadmissible. See, e.g., Hall v. Baxter Healthcare Corp., 947 F. Supp. 1387, 1413 (D. Or.
1996); Rutigliano v. Valley Bus. Forms, 929 F. Supp. 779, 786 (D.N.J. 1996).
73. See, e.g., Kannankeril v. Terminix Int’l, Inc., 128 F.3d 802, 807 (3d Cir. 1997).
mistakenly to an exposure to a toxic agent or discounted as unimportant when
in fact they reflect a significant exposure.71
In taking a careful medical history, the expert focuses on the time pattern of
symptoms and disease manifestations in relation to any exposure and on the
constellation of symptoms to determine causation. It is easier to establish causation
when a symptom is unusual and rarely is caused by anything other than the
suspect chemical (e.g., such rare cancers as hemangiosarcoma, associated with
vinyl chloride exposure, and mesothelioma, associated with asbestos exposure).
However, many cancers and other conditions are associated with several causative
factors, thus complicating proof of causation.72
C. Do Laboratory Tests Indicate Exposure to the Compound?
Two types of laboratory tests can be considered: tests that are routinely used in
medicine to detect changes in normal body status, and specialized tests, which
are used to detect the presence of the chemical or physical agent.73 For the most
part, tests used to demonstrate the presence of a toxic agent are frequently unavailable
from clinical laboratories. Even when available from a hospital or a
clinical laboratory, a test such as that for carbon monoxide combined to hemoglobin
is done so rarely that it may raise concerns as to its accuracy. Other tests,
such as the test for blood lead levels, are required for routine surveillance of
potentially exposed workers. However, if a laboratory is certified for the testing
of blood lead in workers, for which the OSHA action level is 40 micrograms per
deciliter (g/dl), it does not necessarily mean that it will give reliable data on
blood lead levels at the much lower Centers for Disease Control and Prevention
(CDC) action level of 10 g/dl.
D. What Other Causes Could Lead to the Given Complaint?
With few exceptions, acute and chronic diseases, including cancer, can be caused
by either a single toxic agent or a combination of agents or conditions. In taking
a careful medical history, the expert examines the possibility of competing causes,
or confounding factors, for any disease, which leads to a differential diagnosis. In
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429
addition, ascribing causality to a specific source of a chemical requires that a
history be taken concerning other sources of the same chemical. The failure of
a physician to elicit such a history or of a toxicologist to pay attention to such a
history raises questions about competence and leaves open the possibility of
competing causes of the disease.74
E. Is There Evidence of Interaction with Other Chemicals?
An individual’s simultaneous exposure to more than one chemical may result in
a response that differs from that which would be expected from exposure to
only one of the chemicals.75 When the effect of multiple agents is that which
would be predicted by the sum of the effects of individual agents, it is called an
additive effect; when it is greater than this sum, it is known as a synergistic
effect; when one agent causes a decrease in the effect produced by another, the
result is termed antagonism; and when an agent that by itself produces no effect
leads to an enhancement of the effect of another agent, the response is termed
potentiation.76
Three types of toxicological approaches are pertinent to understanding the
effects of mixtures of agents. One is based on the standard toxicological evaluation
of common commercial mixtures, such as gasoline. The second approach is
from studies in which the known toxicological effect of one agent is used to
explore the mechanism of action of another agent, such as using a known specific
inhibitor of a metabolic pathway to determine whether the toxicity of a
second agent depends on this pathway. The third approach is based on an understanding
of the basic mechanism of action of the individual components of
the mixture, thereby allowing prediction of the combined effect, which can
then be tested in an animal model.77
74. See, e.g., Bell v. Swift Adhesives, Inc., 804 F. Supp. 1577, 1580 (S.D. Ga. 1992) (expert’s
opinion that workplace exposure to methylene chloride caused plaintiff’s liver cancer, without ruling
out plaintiff’s infection with hepatitis B virus, a known liver carcinogen, was insufficient to withstand
motion for summary judgment for defendant).
75. See generally Edward J. Calabrese, Multiple Chemical Interactions (1991).
76. Courts have been called on to consider the issue of synergy. In International Union, United
Automobile, Aerospace & Agricultural Implement Workers of America v. Pendergrass, 878 F.2d 389, 391 (D.C.
Cir. 1989), the court found that OSHA failed to sufficiently explain its findings that formaldehyde
presented no significant carcinogenic risk to workers at exposure levels of 1 part per million or less. The
court particularly criticized OSHA’s use of a linear low-dose risk curve rather than a risk-adverse model
after the agency had described evidence of synergy between formaldehyde and other substances that
workers would be exposed to, especially wood dust. Id. at 395.
77. See generally Calabrese, supra note 75.
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430
F. Do Humans Differ in the Extent of Susceptibility to the
Particular Compound in Question? Are These Differences
Relevant in This Case?
Individuals who exercise inhale more than sedentary individuals and therefore
are exposed to higher doses of airborne environmental toxins. Similarly, differences
in metabolism, which are inherited or caused by external factors, such as
the levels of carbohydrates in a person’s diet, may result in differences in the
delivery of a toxic product to the target organ.78
Moreover, for any given level of a toxic agent that reaches a target organ,
damage may be greater because of a greater response of that organ. In addition,
for any given level of target-organ damage, there may be a greater impact on
particular individuals. For example, an elderly individual or someone with preexisting
lung disease is less likely to tolerate a small decline in lung function
caused by an air pollutant than is a healthy individual with normal lung function.
A person’s level of physical activity, age, sex, and genetic makeup, as well as
exposure to therapeutic agents (such as prescription or over-the-counter drugs),
affect the metabolism of the compound and hence its toxicity.79 Advances in
human genetics research are providing information about susceptibility to environmental
agents that may be relevant to determining the likelihood that a given
exposure has a specific effect on an individual.80
G. Has the Expert Considered Data That Contradict His or Her
Opinion?
Multiple avenues of deductive reasoning based on research data lead to scientific
acceptance of causation in any field, particularly in toxicology. However, the
basis for this deductive reasoning is also one of the most difficult aspects of
causation to describe quantitatively. If animal studies, pharmacological research
on mechanisms of toxicity, in vitro tissue studies, and epidemiological research
all document toxic effects of exposure to a compound, an expert’s opinion about
causation in a particular case is much more likely to be true.81
78. Id.
79. The problem of differences in chemical sensitivity was addressed by the court in Gulf South
Insulation v. United States Consumer Product Safety Commission, 701 F.2d 1137 (5th Cir. 1983). The court
overturned the commission’s ban on urea-formaldehyde foam insulation because the commission failed
to document in sufficient detail the level at which segments of the population were affected and whether
their responses were slight or severe: “Predicting how likely an injury is to occur, at least in general
terms, is essential to a determination of whether the risk of that injury is unreasonable.” Id. at 1148.
80. See supra note 50.
81. Consistency of research results was considered by the court in Marsee v. United States Tobacco
Co., 639 F. Supp. 466, 469–70 (W.D. Okla. 1986). The defendant, the manufacturer of snuff alleged to
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431
The more difficult problem is how to evaluate conflicting research results.
When different research studies reach different conclusions regarding toxicity,
the expert must be asked to explain how those results have been taken into
account in the formulation of the expert’s opinion.
cause oral cancer, moved to exclude epidemiological studies conducted in Asia that demonstrate a link
between smokeless tobacco and oral cancer. The defendant also moved to exclude evidence demonstrating
that the nitrosamines and polonium 210 contained in the snuff are cancer-causing agents in
some forty different species of laboratory animals. The court denied both motions, finding:
There was no dispute that both nitrosamines and polonium 210 are present in defendant’s snuff products.
Further, defendant conceded that animal studies have accurately and consistently demonstrated
that these substances cause cancer in test animals. Finally, the Court found evidence based on experiments
with animals particularly valuable and important in this litigation since such experiments with
humans are impossible. Under all these circumstances, the Court found this evidence probative on the
issue of causation.
Id. See also sources cited supra note 7.
Reference Manual on Scientific Evidence
432
Glossary of Terms
The following terms and definitions were adapted from a variety of sources,
including Office of Technology Assessment, U.S. Congress, Reproductive Health
Hazards in the Workplace (1985); Casarett and Doull’s Toxicology: The Basic
Science of Poisons (Curtis D. Klaassen ed., 5th ed. 1996); National Research
Council, Biologic Markers in Reproductive Toxicology (1989); Committee on
Risk Assessment Methodology, National Research Council, Issues in Risk Assessment
(1993); M. Alice Ottoboni, The Dose Makes the Poison: A
Plain-Language Guide to Toxicology (2d ed. 1991); Environmental and Occupational
Health Sciences Institute, Glossary of Environment Health Terms (1989).
absorption. The taking up of a chemical into the body either orally, through
inhalation, or through skin exposure.
acute toxicity. An immediate toxic response following a single or short-term
exposure to an agent or dosing.
additive effect. When exposure to more than one toxic agent results in the
same effect as would be predicted by the sum of the effects of exposure to the
individual agents.
antagonism. When exposure to one toxic agent causes a decrease in the effect
produced by another toxic agent.
bioassay. A test for measuring the toxicity of an agent by exposing laboratory
animals to the agent and observing the effects.
biological monitoring. Measurement of toxic agents or the results of their
metabolism in biological materials, such as blood, urine, expired air, or biopsied
tissue, to test for exposure to the toxic agents, or the detection of physiological
changes that are due to exposure to toxic agents.
biologically plausible theory. A biological explanation for the relationship
between exposure to an agent and adverse health outcomes.
carcinogen. A chemical substance or other agent that causes cancer.
carcinogenicity bioassay. Limited or long-term tests using laboratory animals
to evaluate the potential carcinogenicity of an agent.
chronic toxicity. A toxic response to long-term exposure or dosing with an
agent.
clinical ecologists. Physicians who believe that exposure to certain chemical
agents can result in damage to the immune system, causing multiple-chemical
hypersensitivity and a variety of other disorders. Clinical ecologists often
have a background in the field of allergy, not toxicology, and their theoretical
approach is derived in part from classic concepts of allergic responses and
Reference Guide on Toxicology
433
immunology. There has been much resistance in the medical community to
accepting their claims.
clinical toxicology. The study and treatment of humans exposed to chemicals
and the quantification of resulting adverse health effects. Clinical toxicology
includes the application of pharmacological principles to the treatment of
chemically exposed individuals and research on measures to enhance elimination
of toxic agents.
compound. In chemistry, the combination of two or more different elements
in definite proportions, which when combined, acquire different properties
than the original elements.
confounding factors. Variables that are related to both exposure to a toxic
agent and the outcome of the exposure. A confounding factor can obscure
the relationship between the toxic agent and the adverse health outcome
associated with that agent.
differential diagnosis. A physician’s consideration of alternative diagnoses that
may explain a patient’s condition.
direct-acting agents. Agents that cause toxic effects without metabolic activation
or conversion.
distribution. Movement of a toxic agent throughout the organ systems of the
body (e.g., the liver, kidney, bone, fat, and central nervous system). The rate
of distribution is usually determined by the blood flow through the organ and
the ability of the chemical to pass through the cell membranes of the various
tissues.
dose, dosage. The measured amount of a chemical that is administered at one
time, or that an organism is exposed to in a defined period of time.
dose–response curve. A graphic representation of the relationship between
the dose of a chemical administered and the effect produced.
dose–response relationships. The extent to which a living organism responds
to specific doses of a toxic substance. The more time spent in contact with a
toxic substance, or the higher the dose, the greater the organism’s response.
For example, a small dose of carbon monoxide will cause drowsiness; a large
dose can be fatal.
epidemiology. The study of the occurrence and distribution of disease among
people. Epidemiologists study groups of people to discover the cause of a
disease, or where, when, and why disease occurs.
epigenetic. Pertaining to nongenetic mechanisms by which certain agents cause
diseases, such as cancer.
etiology. A branch of medical science concerned with the causation of diseases.
Reference Manual on Scientific Evidence
434
excretion. The process by which toxicants are eliminated from the body, including
through the kidney and urinary tract, the liver and biliary system, the
fecal excretor, the lungs, sweat, saliva, and lactation.
exposure. The intake into the body of a hazardous material. The main routes
of exposure to substances are through the skin, mouth, and lungs.
extrapolation. The process of estimating unknown values from known values.
Good Laboratory Practice (GLP). Codes developed by the federal government
in consultation with the laboratory-testing industry that govern many
aspects of laboratory standards.
hazard identification. In risk assessment, the qualitative analysis of all available
experimental animal and human data to determine whether and at what
dose an agent is likely to cause toxic effects.
hydrogeologists, hydrologists. Scientists who specialize in the movement of
ground and surface waters and the distribution and movement of contaminants
in those waters.
immunotoxicology. A branch of toxicology concerned with the effects of
toxic agents on the immune system.
indirect-acting agents. Agents that require metabolic activation or conversion
before they produce toxic effects in living organisms.
inhalation toxicology. The study of the effect of toxic agents that are absorbed
into the body through inhalation, including their effects on the respiratory
system.
in vitro. A research or testing methodology that uses living cells in an artificial
or test tube system, or is otherwise performed outside of a living organism.
in vivo. A research or testing methodology that uses living organisms.
lethal dose 50 (LD50). The dose at which 50% of laboratory animals die
within days to weeks.
lifetime bioassay. A bioassay in which doses of an agent are given to experimental
animals throughout their lifetime. See bioassay.
maximum tolerated dose (MTD). The highest dose of an agent that an
organism can be exposed to without causing death or significant overt toxicity.
metabolism. The sum total of the biochemical reactions that a chemical produces
in an organism.
molecular toxicology. The study of how toxic agents interact with cellular
molecules, including DNA.
multiple-chemical hypersensitivity. A physical condition whereby individuals
react to many different chemicals at extremely low exposure levels.
Reference Guide on Toxicology
435
multistage events. A model for understanding certain diseases, including some
cancers, based on the postulate that more than one event is necessary for the
onset of disease.
mutagen. A substance that causes physical changes in chromosomes or biochemical
changes in genes.
mutagenesis. The process by which agents cause changes in chromosomes and
genes.
neurotoxicology. A branch of toxicology concerned with the effects of exposure
to toxic agents on the central nervous system.
no observable effect level (NOEL). The highest level of exposure to an
agent at which no effect is observed. It is the experimental equivalent of a
threshold.
no threshold model. A model for understanding disease causation which postulates
that any exposure to a harmful chemical (such as a mutagen) may
increase the risk of disease.
one hit theory. A theory of cancer risk in which each molecule of a chemical
mutagen has a possibility, no matter how tiny, of mutating a gene in a manner
that may lead to tumor formation or cancer.
pharmacokinetics. A mathematical model that expresses the movement of a
toxic agent through the organ systems of the body, including to the target
organ and to its ultimate fate.
potentiation. The process by which the addition of one agent, which by itself
has no toxic effect, increases the toxicity of another agent when exposure to
both agents occurs simultaneously.
reproductive toxicology. The study of the effect of toxic agents on male and
female reproductive systems, including sperm, ova, and offspring.
risk assessment. The use of scientific evidence to estimate the likelihood of
adverse effects on the health of individuals or populations from exposure to
hazardous materials and conditions.
risk characterization. The final step of risk assessment, which summarizes
information about an agent and evaluates it in order to estimate the risks it
poses.
safety assessment. Toxicological research that tests the toxic potential of a
chemical in vivo or in vitro using standardized techniques required by governmental
regulatory agencies or other organizations.
structure activity relationships (SAR). A method used by toxicologists to
predict the toxicity of new chemicals by comparing their chemical structures
with those of compounds with known toxic effects.
Reference Manual on Scientific Evidence
436
synergistic effect. When two toxic agents acting together have an effect greater
than that predicted by adding together their individual effects.
target organ. The organ system that is affected by a particular toxic agent.
target-organ dose. The dose to the organ that is affected by a particular toxic
agent.
teratogen. An agent that changes eggs, sperm, or embryos, thereby increasing
the risk of birth defects.
teratogenic. The ability to produce birth defects. (Teratogenic effects do not
pass on to future generations.) See teratogen.
threshold. The level above which effects will occur and below which no effects
occur. See no observable effect level.
toxic. Of, relating to, or caused by a poison—or a poison itself.
toxic agent or toxicant. An agent or substance that causes disease or injury.
toxicology. The science of the nature and effects of poisons, their detection,
and the treatment of their effects.
Reference Guide on Toxicology
437
References on Toxicology
Edward J. Calabrese, Multiple Chemical Interactions (1991).
Edward J. Calabrese, Principles of Animal Extrapolation (1983).
Casarett and Doull’s Toxicology: The Basic Science of Poisons (Curtis D. Klaassen
ed., 5th ed. 1996).
Committee on Risk Assessment Methodology, National Research Council, Issues
in Risk Assessment (1993).
Genetic Toxicology of Complex Mixtures (Michael D. Waters et al. eds., 1990).
Human Risk Assessment: The Role of Animal Selection and Extrapolation (M.
Val Roloff ed., 1987).
In Vitro Toxicity Testing: Applications to Safety Evaluation (John M. Frazier
ed., 1992).
Michael A. Kamrin, Toxicology: A Primer on Toxicology Principles and Applications
(1988).
Frank C. Lu, Basic Toxicology: Fundamentals, Target Organs, and Risk Assessment
(2d ed. 1991).
Methods for Biological Monitoring (Theodore J. Kneip & John V. Crable eds.,
1988).
National Research Council, Biologic Markers in Reproductive Toxicology
(1989).
M. Alice Ottoboni, The Dose Makes the Poison: A Plain-Language Guide to
Toxicology (2d ed. 1991).
Alan Poole & George B. Leslie, A Practical Approach to Toxicological Investigations
(1989).
Principles and Methods of Toxicology (A. Wallace Hayes ed., 3d ed. 1994).
Joseph V. Rodricks, Calculated Risks (1992).
Short-Term Toxicity Tests for Nongenotoxic Effects (Philippe Bourdeau et al.
eds., 1990).
Statistical Methods in Toxicology: Proceedings of a Workshop During Eurotox
’90, Leipzig, Germany, September 12–14, 1990 (L. Hutnom ed., 1990).
Toxic Interactions (Robin S. Goldstein et al. eds., 1990).
Toxic Substances and Human Risk: Principles of Data Interpretation (Robert
G. Tardiff & Joseph V. Rodricks eds., 1987).
Toxicology and Risk Assessment: Principles, Methods, and Applications (Anna
M. Fan & Louis W. Chang eds., 1996).
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439
Reference Guide on Medical
Testimony
mary sue henifin, howard m. kipen, and susan r. poulter
Mary Sue Henifin, J.D., M.P.H., is a partner with Buchanan Ingersoll, P.C., Princeton, New Jersey, and
Adjunct Professor of Public Health Law, Department of Environmental & Community Medicine, UMDNJ–
Robert Wood Johnson Medical School, Piscataway, New Jersey.
Howard M. Kipen, M.D., M.P.H., is Professor and Director of Occupational Health, Environmental and
Occupational Health Sciences Institute, UMDNJ–Robert Wood Johnson Medical School in Piscataway,
New Jersey.
Susan R. Poulter, J.D., Ph.D., is Professor of Law, University of Utah College of Law, Salt Lake City,
Utah.
The authors are listed alphabetically. The authors greatly appreciate the excellent research assistance provided
by Sue Elwyn, Dean Miletich, Marie Leary, Ross Jurewitz, and Fazil Khan.
contents
I. Introduction, 441
A. Applicability of Daubert v. Merrell Dow Pharmaceuticals, Inc., 442
B. Medical versus Legal Terminology, 443
C. Relationship of Medical Testimony to Legal Rules, 445
II. The Medical Doctor As an Expert, 447
A. What Is a Physician? 447
B. Physicians’ Roles in Patient Care, 449
C. Medical Research and Academic Appointments, 450
D. Physicians As Expert Witnesses, 450
III. Information Utilized by Physicians, 452
A. Patient History (from the Patient), 452
1. Symptomatology, 453
2. Environmental and Occupational History, 454
3. Other Risk Factors, 455
B. Past and Present Patient Records and Exposure-Related Records, 455
C. Physical Examination, 455
D. Diagnostic Tests, 457
1. Laboratory Tests, 459
2. Pathology Tests, 460
3. Clinical Tests, 460
Reference Manual on Scientific Evidence
440
IV. Physician Decision Making, 461
A. Introduction, 461
B. Diagnosis, 463
C. Probabilistic Basis of Diagnosis, 465
D. Causal Reasoning, 467
E. Evaluation of External Causation, 468
1. Exposure, 472
2. Reviewing the Medical and Scientific Literature, 473
3. Clinical Evaluation of Information Affecting Dose–Response
Relationships, 475
V. Treatment Decisions, 478
VI. Medical Testimony: Looking to the Future, 479
Glossary of Terms, 480
References on Medical Testimony, 484
Reference Guide on Medical Testimony
441
I. Introduction
Testimony by physicians is one of the most common forms of expert testimony
in the courtroom today.1 Medical testimony is routinely offered in both civil
and criminal cases, including assault and battery,2 rape,3 workers’ compensation
proceedings,4 and personal injury suits.5 In the civil arena alone, medical testimony
is frequently offered as part of medical malpractice cases,6 Employee Retirement
Income Security Act (ERISA) suits on coverage of health care plans,7
Americans with Disabilities Act litigation,8 product liability suits,9 and toxic injury
cases, such as breast implant and environmental contamination claims.10 In
1. Samuel R. Gross, Expert Evidence, 1991 Wis. L. Rev. 1113, 1119 (a survey of trials revealed that
over half of the testifying experts were physicians or medical professionals). Two unpublished surveys
by the Federal Judicial Center, one in 1991 and another in 1998, found that physicians and medical
experts comprised approximately 40 percent of the testifying experts in federal civil trials.
2. See United States v. Drapeau, 110 F.3d 618, 619–20 (8th Cir. 1997) (medical testimony of the
examining doctor of the infant victim refuted the possibility that the child’s injuries were the result of a
fall from his bed); United States v. Talamante, 981 F.2d 1153, 1158 & n.7 (10th Cir. 1992) (physician
testified that the victim’s eye was not completely blind at the time of the assault, supporting a finding of
serious bodily injury).
3. See United States v. Pike, 36 F.3d 1011, 1012–13 (10th Cir. 1994) (in a case of sexual abuse of a
minor, the testimony of the examining physician need not be preferred over the testimony of the victim
where the physician’s testimony neither supports nor refutes the victim’s testimony).
4. Medical testimony will almost always be offered on the diagnosis of the plaintiff’s injury or
disease, and often on other issues as well. See Silmon v. Can Do II, Inc., 89 F.3d 240, 241 (5th Cir.
1996) (testimony of three doctors as to the cause of the plaintiff’s ruptured disc; the employer denied
liability under the Jones Act, alleging that the plaintiff’s injury was caused by illegal intravenous drug
use); Bertram v. Freeport McMoran, Inc., 35 F.3d 1008, 1018 (5th Cir. 1994) (upholding the district
court’s discretion to give greater weight to the medical testimony of the plaintiff’s primary treating
physician where the plaintiff sued under the Jones Act for injuries arising from a workplace accident on
a drilling barge).
5. See DiPirro v. United States, 43 F. Supp. 2d 327, 331–39 (W.D.N.Y. 1999) (recounting the
court’s findings of fact based upon the testimony of five physicians for the plaintiff and five physicians
for the defendant concerning plaintiff’s alleged injuries caused by an accident involving a U.S. Postal
Service vehicle).
6. See Murray v. United States, 36 F. Supp. 2d 713, 716 (E.D. Va. 1999) (plaintiff’s expert medical
witness testified that the care provided fell well below that standard applicable to emergency room
physicians).
7. See Dodson v. Woodmen of the World Ins. Soc’y, 109 F.3d 436, 438 (8th Cir. 1997) (treating
physician testified that the plaintiff was mentally disabled prior to the expiration of his ERISA policy).
8. Price v. National Bd. of Med. Exam’rs, 966 F. Supp. 419 (S.D. W. Va. 1997) (medical testimony
offered as to whether plaintiff had attention deficit hyperactivity disorder that caused disability as defined
by the Americans with Disabilities Act).
9. See Demaree v. Toyota Motor Corp., 37 F. Supp. 2d 959 (W.D. Ky. 1999) (plaintiff’s examining
physician testified regarding injuries allegedly caused by a deploying air bag); Toole v. McClintock,
999 F.2d 1430, 1431 & n.2 (11th Cir. 1993) (reporting that five surgeons, including the plaintiff’s
treating physician, testified regarding surgery that caused breast implant rupture).
10. See Satterfield v. J.M. Huber Corp., 888 F. Supp. 1567, 1571 (N.D. Ga. 1995) (plaintiff’s
doctors testified that the plaintiff’s symptoms were also consistent with exposure to secondary sources of
Reference Manual on Scientific Evidence
442
many instances, medical testimony or medical evidence is an indispensable part
of the inquiry.
A. Applicability of Daubert v. Merrell Dow Pharmaceuticals,
Inc.
Since the U.S. Supreme Court issued its opinion in Daubert v. Merrell Dow Pharmaceuticals,
Inc.,11 many courts have assessed the reliability of medical testimony
according to Daubert’s standards. More recently, in Kumho Tire Co. v. Carmichael,12
the Court held that Daubert’s reliability requirement and the trial judge’s
gatekeeping role apply to all expert testimony.
Although Kumho resolved any uncertainty as to the applicability of Daubert’s
standards to medical testimony, there is still uncertainty over how courts will
apply these standards, given the different approaches taken by the courts to
consideration of the admissibility of medical evidence.13 Two recent cases illustrate
this diversity. In Moore v. Ashland Chemical, Inc.,14 a case decided before
Kumho that applied Daubert standards, the Fifth Circuit, sitting en banc, upheld
the trial court’s exclusion of a physician–expert’s opinion on the cause of the
plaintiff’s reactive airway disease. The witness had offered the opinion, without
citing published research indicating that fumes from toluene and a mixture of
other chemicals from a leaking drum could cause reactive airway disease. The
Fifth Circuit held that the trial court had not abused its discretion in its application
of the Daubert factors, noting that expert testimony must be based on at
least “some objective, independent validation of the expert’s methodology. The
expert’s assurances that he has utilized generally accepted scientific methodology
[are] insufficient.”15
chemical emissions identified by the defendant and stated that they had no opinion on whether plaintiff’s
complaints were related to air contamination from defendant’s plant).
11. 509 U.S. 579 (1993).
12. 119 S. Ct. 1167 (1999). Kumho concerned a tire-failure expert who gave an opinion on the
cause of a tire failure based on his examination of the tire and experience in examining tires. Id. at 1176–
78. Similarly, medical testimony will almost always rely in part on clinical examination, though often in
conjunction with other sources of information.
13. See Margaret A. Berger, The Supreme Court’s Trilogy on the Admissibility of Expert Testimony
§ IV.C.2.b, in this manual.
14. 151 F.3d 269 (5th Cir. 1998) (en banc), cert. denied, 119 S. Ct. 1454 (1999). In a panel decision,
the U.S. Court of Appeals for the Fifth Circuit had held that medical testimony in a toxic injury case
was not subject to the factors Daubert suggests for scientific knowledge. Moore v. Ashland Chem., Inc.,
126 F.3d 679 (5th Cir. 1997). The court reconsidered that decision en banc, affirming the trial court’s
exclusion of the witness based on Daubert. 151 F.3d at 277–79. The en banc decision concluded that the
trial court did not abuse its discretion, applying General Electric Co. v. Joiner, 522 U.S. 136 (1997). Id.
15. 151 F.3d at 276. See also Black v. Food Lion, Inc., 171 F.3d 308 (5th Cir. 1999) (trial court
should not have admitted a physician’s testimony that trauma from a slip and fall had caused the plaintiff’s
fibromyalgia).
Reference Guide on Medical Testimony
443
In contrast, the Third Circuit’s decision in Heller v. Shaw Industries, Inc.,16 also
a case decided before Kumho that applied Daubert standards, illustrates a much
different approach. In Heller, as in Moore, the plaintiff complained of respiratory
symptoms, which in this case coincided with exposure to a new carpet in her
home. As in Moore, the trial court excluded the plaintiff’s expert testimony because
of the absence of published studies linking fumes from the carpet to allergic
reactions. The Third Circuit stated that the trial court erred in so holding,
noting the witness’s reliance on “differential diagnosis.”17 The court nonetheless
upheld the exclusion of the witness’s testimony on other grounds.
These two cases illustrate the range of approaches taken by courts in considering
testimony on causation, including issues related to testimony on “differential
diagnosis” or “differential etiology” (as witnesses and courts use these terms),
the necessity of research literature to support opinions on causation, and the
importance of temporal relationships. While these issues may be intertwined,
they represent different facets of the courts’ approaches.18
B. Medical versus Legal Terminology
Perhaps because medical testimony is so common and yet not entirely accessible
to the lay public, courts have come to use certain medical terms, such as differential
diagnosis and differential etiology in ways that differ from their common usage
in the medical profession. For example, although environmental and occupational
health physicians may use the term “differential diagnosis” to include the
process of determining whether an environmental or occupational exposure
caused the patient’s disease,19 most physicians use the term to describe the process
of determining which of several diseases is causing a patient’s symptoms.
Expert witnesses and courts, however, frequently use the term “differential
16. 167 F.3d 146 (3d Cir. 1999).
17. Id. at 153–57. In this reference guide, the use of quotation marks around the terms differential
diagnosis and differential etiology indicates the witness’s or court’s use of the terminology, which may
differ from usage in the medical profession and from use elsewhere in this manual. See infra § I.B.
18. The appellate standard of review is also a critical factor in the analysis of the cases. The Supreme
Court has twice instructed that a deferential abuse-of-discretion standard be applied to trial courts’
admissibility decisions under Rule 702 of the Federal Rules of Evidence, including both rulings as to
admissibility and the manner in which the trial court evaluates the proffered testimony. In General
Electric Co. v. Joiner, 522 U.S. 136, 143 (1997), the Supreme Court held that an abuse-of-discretion
standard applies to decisions on admissibility of expert testimony under Daubert. The Court reiterated
that holding in Kumho Tire Co. v. Carmichael, 119 S. Ct. 1167, 1176 (1999), holding that abuse-ofdiscretion
review applies to how the trial court assesses reliability.
19. The demonstration of causation has been described as a part of the process of diagnosing an
environmental disease. See Mark R. Cullen et al., Clinical Approach and Establishing a Diagnosis of an
Environmental Medical Disorder, in Environmental Medicine 217, 220 (Stuart M. Brooks et al. eds., 1995)
[hereinafter Environmental Medicine]. The typical process of differential diagnosis is described more
fully in section IV.B.
Reference Manual on Scientific Evidence
444
diagnosis” to describe the process by which causes of the patient’s condition are
identified, particularly causes external to the patient.20 Additionally, courts sometimes
characterize causal reasoning as “differential etiology,” a term not used in
medical practice, but one that more closely suggests the determination of cause.21
For the sake of clarity and consistency, this reference guide uses the term “differential
diagnosis” in its traditional medical sense, that is, referring to the diagnosis
of disease, and refers to the process of identifying external causes of diseases
and conditions as “determining cause,” “determining external cause,” or some
similar phrase, as the circumstances warrant.
To add a further level of complexity, courts also use the terms general causation
and specific causation. General causation is established by demonstrating, often
through a review of scientific and medical literature, that exposure to a substance
can cause a particular disease (e.g., that smoking cigarettes can cause lung
cancer). Specific, or individual, causation, however, is established by demonstrating
that a given exposure is the cause of an individual’s disease (e.g., that a
specific plaintiff’s lung cancer was caused by his smoking).22 Physicians may
offer expert opinion on both specific and general causation,23 although perhaps
more commonly on specific causation as it relates to a patient’s medical condi-
20. See, e.g., Kannankeril v. Terminix Int’l, Inc., 128 F.3d 802, 807 (3d Cir. 1997) (court recognized
differential diagnosis “as a technique that involves assessing causation with respect to a particular
individual” (citing In re Paoli R.R. Yard PCB Litig., 35 F.3d 717, 758 (3d Cir. 1994), cert. denied, 513
U.S. 1190 (1995))); National Bank of Commerce v. Associated Milk Producers, Inc., 22 F. Supp. 2d
942, 963 (E.D. Ark. 1998) (plaintiff could not show, under differential diagnosis approach, that contaminated
milk caused his cancer), aff’d, 191 F.3d 858 (8th Cir. 1999); Mancuso v. Consolidated Edison
Co., 967 F. Supp. 1437, 1453 (S.D.N.Y. 1997) (proffered expert failed to conduct a differential diagnosis
to exclude exposure to substances other than PCBs as the cause of plaintiffs’ ailments).
21. See, e.g., Westberry v. Gummi, 178 F.3d 257, 262 (4th Cir. 1999) (differential etiology analysis
of talc as the cause of sinus problems); Synder v. Upjohn Co., 172 F.3d 58 (9th Cir. 1999) (unpublished
table decision) (text at No. 97-55912, 1999 WL 77975 (9th Cir. Feb. 12, 1999)) (differential etiology
analysis of Halcion as the cause of criminal behavior).
22. The issues of general causation and specific causation are addressed in detail in Michael D.
Green et al., Reference Guide on Epidemiology §§ V, VII, and Bernard D. Goldstein & Mary Sue
Henifin, Reference Guide on Toxicology §§ III–IV, in this manual. The distinction between general
causation and specific causation is discussed in Zwillinger v. Garfield Slope Housing Corp., No. CV 94-
4009, 1998 WL 623589, at *19–*20 (E.D.N.Y. Aug. 17, 1998) (plaintiff’s expert did not offer general
causation evidence that outgassing from carpet could cause ailments suffered by plaintiff); National
Bank of Commerce v. Associated Milk Producers, Inc., 22 F. Supp. 2d 942, 963 (E.D. Ark. 1998)
(although differential diagnosis “‘is undoubtedly important to the question of ‘specific causation,’’”
plaintiff must provide expert opinion on the issue of “‘general causation’” based on a scientifically valid
methodology (quoting Cavallo v. Star Enter., 892 F. Supp. 756, 771 (E.D. Va. 1995), aff’d in part, rev’d
in part, 100 F.3d 1150 (4th Cir. 1996), cert. denied, 522 U.S. 1044 (1998))), aff’d, 191 F.3d 858 (8th Cir.
1999).
23. See In re Joint E. & S. Dist. Asbestos Litig., 964 F.2d 92, 96 (2d Cir. 1992); Landrigan v.
Celotex Corp., 605 A.2d 1079, 1086 (N.J. 1992) (permitting clinician to testify to specific causation
based on epidemiology). But see Sutera v. Perrier Group of Am., Inc., 986 F. Supp. 655, 662 (D. Mass.
1997) (physician not qualified to testify on epidemiology). See Michael D. Green et al., Reference
Guide on Epidemiology, § VII, in this manual.
Reference Guide on Medical Testimony
445
tion. When physicians offer expert opinion on general causation, it is frequently
incorporated into proffered testimony on specific causation.
C. Relationship of Medical Testimony to Legal Rules
In litigation, the form and content of medical testimony is shaped by a number
of factors, first and foremost of which is the legal issue on which it is offered. In
terms of content, in a traditional personal injury claim, the physician may be
asked to opine on the actual cause of the patient’s illness or injury. Newer
theories of tort, however, such as claims for fear of future injury (e.g., “cancerphobia”),
24 increased risk of injury,25 or medical monitoring,26 require testimony
on the patient’s risk of future disease, rather than the actual cause.27
The form of testimony, whatever the issue, tends to be shaped by requirements
of the applicable legal rules. For example, courts and lawyers will be
familiar with various formulations of the causation issue, including the “but for”
and “substantial factor” tests. A physician testifying on causation issues will be
asked to opine in the form dictated by the legal rule.
Legal rules on the sufficiency of proof will also shape the physician’s testimony.
In a personal injury case, physicians are often asked to testify on one or
more of the ultimate issues in the case, such as causation. Thus, their testimony
will be shaped by the applicable substantive rule on the burden of proof. For
example, a physician may testify that a plaintiff’s disease is “more likely than
not”28 due to a chemical exposure or that causation exists to a “reasonable medical
certainty.”29 This reference guide, however, consistent with the purpose of
this manual, focuses on the methods and reasoning governing physicians’ decisions
and opinions, not the differing legal rules and theories on which medical
24. See Sterling v. Velsicol Chem. Corp., 855 F.2d 1188 (6th Cir. 1988); see generally Glen Donath,
Comment, Curing Cancerphobia Phobia: Reasonableness Redefined, 62 U. Chi. L. Rev. 1113 (1995).
25. See Gideon v. Johns-Manville Sales Corp., 761 F.2d 1129, 1137–38 (5th Cir. 1985) (recognizing
a claim for increased risk of contracting cancer where the likelihood is a “reasonable medical probability”
or “more likely to occur than not”).
26. See In re Paoli R.R. Yard PCB Litig., 916 F.2d 829 (3d Cir. 1990), cert. denied, 499 U.S. 961
(1991). But see Metro-North Commuter R.R. v. Buckley, 521 U.S. 424 (1997) (rejecting medical
monitoring claim under the Federal Employers Liability Act). Metro-North also rejected a claim for
negligent infliction of emotional distress based on fear of asbestos-related cancer. Id. at 437.
27. See National Bank of Commerce v. Associated Milk Producers, Inc., 22 F. Supp. 2d 942 (E.D.
Ark. 1998) (fear of future injury may be an element of damages, requiring expert opinion governed by
Daubert standards), aff’d, 191 F.3d 858 (8th Cir. 1999).
28. See, e.g., Cavallo v. Star Enter., 892 F. Supp. 756, 771 (E.D. Va. 1995), aff’d in part, rev’d in part,
100 F.3d 1150 (4th Cir. 1996), cert. denied, 522 U.S. 1044 (1998).
29. See, e.g., Black v. Food Lion, Inc., 171 F.3d 308, 310 (5th Cir. 1999) (plaintiff’s burden was to
prove that her fall caused fibromyalgia “to a reasonable degree of medical certainty, based on a reasonable
medical probability and scientifically reliable evidence”). See generally Jeff L. Lewin, The Genesis and
Evolution of Legal Uncertainty About “Reasonable Medical Certainty,” 57 Md. L. Rev. 380 (1998).
Reference Manual on Scientific Evidence
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testimony is offered, or the standards courts have applied in reviewing medical
testimony.30
This reference guide also does not address admissibility of testimony on the
standard of care in medical malpractice cases. There are several reasons for this
exclusion. First, medical malpractice cases are usually (though not exclusively)
litigated in state courts rather than federal courts. Second, in most jurisdictions,
the standard of care for physicians (like that for other professionals) is the customary
level of care provided by competent physicians in the same field.31 Thus,
testimony on the standard of care usually concerns what other physicians do in
similar situations, rather than whether the defendant–physician’s diagnosis and
treatment are based on good medical science (although customary physician
practice and good medical science will generally coincide). As a result, the admissibility
of expert opinion on the standard of care is decided according to
whether the witness is qualified to opine on the same field as the malpractice
defendant.32
Within the limitations described above, the next four sections of this reference
guide explain medical practice, with an emphasis on how physicians apply
medical and scientific knowledge, clinical experience, and patient history and
examination to the process of diagnosis of disease and selection of appropriate
treatment.
30. It is worth reminding readers that this guide is not intended to instruct judges concerning what
medical testimony should be admissible as evidence. This chapter and the other reference guides attempt
to contribute to the development of the law by clarifying scientific and professional practice in an
area, thereby informing the development of consistent legal doctrines as courts consider individual
cases. See the preface to this manual. This constraint, set by the Board of the Federal Judicial Center, is
especially notable in this chapter. The lack of commentary on various standards should not be misunderstood
as indicating that the authors have not given considerable thought to the manner in which
such conflicts should be resolved. See generally Joan E. Bertin & Mary S. Henifin, Science, Law, and the
Search for the Truth in the Courtroom, 22 J.L. Med. & Ethics 6 (1994); Susan R. Poulter, Science and Toxic
Torts: Is There a Rational Solution to the Problem of Causation?, 7 High Tech. L.J. 189 (1992); Susan R.
Poulter, Medical and Scientific Evidence of Causation: Guidelines for Evaluating Medical Opinion Evidence, in
Expert Witnessing: Explaining and Understanding Science 186 (Carl Meyer ed., 1998). A summary of
different approaches in applying evidentiary rules to medical testimony is offered in Margaret A. Berger,
The Supreme Court’s Trilogy on the Admissibility of Expert Testimony, § IV.C.2.b, in this manual.
Moreover, proposed changes to Rule 702 by the Judicial Conference Advisory Committee on Evidence
Rules, if enacted, may also affect the legal analysis of medical testimony.
31. 4 Lane Medical Litigation Guide §§ 40.21–.28, at 73-101 (Fred Lane & David A. Birnbaum
eds., 1993 & Supp. 1996).
32. 1 id. § 4.15, at 18–20 (1994 & Supp. 1996). In some jurisdictions, the witness must be qualified
to testify about the standard of care in a similar or even the same locality. 4 id. § 40.23, at 86–92 (1993
& Supp. 1996).
Reference Guide on Medical Testimony
447
II. The Medical Doctor As an Expert
A. What Is a Physician?
In the United States, a physician is someone who has met the rigorous requirements
of a four-year program and graduated from a credentialed medical or
osteopathic school. However, as explained below, this training is not sufficient
to qualify a physician to practice medicine.33
The courses in medical school are generally similar from school to school,
and they focus on basic medical sciences (e.g., microbiology, pharmacology,
and pathology) as well as clinical training in medical diagnosis and treatment
(e.g., internal medicine, cardiology, pulmonology, surgery, psychiatry, dermatology).
All medical curricula include some basic training in epidemiology and
biostatistics. There is relatively little structured study of public health, occupational
medicine, and toxicology in a traditional curriculum, although a number
of medical schools offer joint degree programs leading to a Master of Public
Health degree (M.P.H.), with enhanced training in epidemiology, toxicology,
and other aspects of public health. Furthermore, it is not uncommon for physicians
to undertake further study and become proficient in epidemiological research
in their particular fields. Most physicians have substantial training and
experience in pharmacology, a subject closely related to toxicology that concerns
the effects of therapeutic drugs.34
In most states, physicians are required to complete a minimum of one additional
year of hospital-based “residency” training, the first year of which is called
an “internship,” in an approved program before they can be licensed to practice
medicine. After completing the internship year, a physician may apply for state
licensure to practice medicine. However, specialization requires further training
in an approved residency program beyond the internship year. For example,
surgery requires at least four additional years; family or internal medicine, pediatrics,
or neurology requires two additional years. A physician may pursue subspecialty
training, which usually requires a further one- to three-year “fellowship”
focusing on a particular organ or system (e.g., pulmonology, cardiology,
gastroenterology, rheumatology, endocrinology, hematology) or type of disease
(e.g., infectious disease, oncology, or neurological movement disorders or electrophysiology).
35
33. See World Health Org., World Directory of Medical Schools 274–75 (6th ed. 1988 & Supp.
1997).
34. See, e.g., Association of Am. Med. Colleges, Curriculum Directory 1998–99, at 104–05 (27th
ed. 1998) (listing required courses for Johns Hopkins University School of Medicine).
35. See World Health Org., supra note 33, at 274–75.
Reference Manual on Scientific Evidence
448
After a physician has completed a residency or fellowship in a specialty, he or
she is eligible to take an examination given by that medical specialty’s “board.”
There are twenty-three specialty and subspecialty boards administered by the
American Board of Medical Specialists (ABMS), as well as a number of other
boards not under ABMS with more idiosyncratic criteria for certification. Passing
such an exam makes the physician “board certified” in the field or subspecialty—
a marker of substantial proficiency within the particular area of medicine
and a credential often required by hospitals for appointment to their medical
staff.36 Other indicia of expertise include academic appointments, published
articles in peer-reviewed journals, grant awards, and appointment to peer review
panels.37
After the conclusion of formal medical education, including internship and
residency, physicians continue to acquire medical knowledge through clinical
experience, hospital-based lectures and training programs, review of medical
literature, and continuing medical education courses that provide information
in various specialties. A number of states have moved toward requiring continuing
medical education for license renewal.38 An increasing number of medical
specialties require passage of the board examination at regularly scheduled intervals
to maintain board certification.
To practice at a hospital, a physician must pass review by a “credentialing
committee” that examines the credentials of the physician, as well as legal and
state board records concerning the physician. A physician who clears the
credentialing committee may become a member of the hospital’s medical staff,
otherwise known as an “attending physician,” and may admit patients to the
hospital for treatment. A hospital may revoke staff and admitting privileges for
36. Although it may be helpful in establishing the witness’s credentials for opinion testimony,
courts usually do not apply a strict requirement of specialization or board certification for most purposes.
See, e.g., Holbrook v. Lykes Bros. S.S. Co., 80 F.3d 777, 782–83 (3d Cir. 1996) (physician board
certified in pulmonary medicine not required to be a specialist in oncology and radiation to testify on
causation of mesothelioma). In contrast, admissibility of testimony on the medical standard of care in
medical malpractice cases is typically controlled through screening of the witness’s qualifications. See,
e.g., Marquardt v. Joseph, 173 F.3d 855 (6th Cir. 1999) (unpublished table decision) (text at No. 98-
5163, 1999 WL 196569 (6th Cir. Mar. 30, 1999) (dentist who was not an oral surgeon was not qualified
to testify on the standard of care for oral surgery)); Carroll v. Morgan, 17 F.3d 787, 790 (5th Cir. 1994)
(cardiologist with many years of experience need not be a specialist in pathology to testify on the
relationship between heart problems and death).
37. The American Medical Association (AMA) has taken an interest in the quality of medical
expert testimony. After reviewing cases involving testimony by physicians who had falsified their credentials,
the AMA issued a 1998 report to its Board of Trustees recommending that the AMA encourage
state licensing boards to develop disciplinary measures for physicians who provide fraudulent testimony.
The House of Delegates adopted an amended version of the report. See Michael Higgins, Docking
Doctors? AMA Eyes Discipline for Physicians Giving ‘False’ Testimony, A.B.A. J., Sept. 1998, at 20.
38. Jeoffrey K. Stross & Thomas J. DeKornfeld, A Formal Audit of Continuing Medical Education
Activity for License Renewal, 264 JAMA 2421 (1990) (audit of continuing medical education activities of
Reference Guide on Medical Testimony
449
cause.39 Some hospital physicians are also members of the teaching staff, charged
with the training of interns and residents in their medical specialties. Most, but
not all, teaching staff have joint academic appointments at a medical school.
B. Physicians’ Roles in Patient Care
After completion of training, a physician may be involved in various aspects of
medicine. While the public tends to think of a physician as directly involved in
patient care, a practicing physician may also serve as a “consulting physician,”
conduct medical research, or have an academic appointment.40 Although the
lines between these different roles often blur, understanding the range of activities
undertaken by physicians is helpful.
A treating physician’s primary role is the examination, diagnosis, and treatment
of patients.41 The physician is expected to do one or more of the following:
diagnose the patient’s conditions, recommend or provide appropriate treatments,
and monitor the patient’s progress. The treating physician may also, as
appropriate, counsel patients on the management of diseases, as well as on dietary
habits, genetic and familial risks and other aspects of a patient’s life relevant
to preventing disease, maintaining health, or managing disease or injury. A treating
physician may be a specialist or nonspecialist. Some members of a treating team
of physicians, such as radiologists or pathologists, perform primarily diagnostic
roles and rarely prescribe treatment.
A consulting physician is someone who is asked for recommendations for
diagnosis and treatment or a “second opinion,” based on his or her more specialized
knowledge and experience. Examples include a cardiologist brought in
to assist the primary physician with the care of someone after a heart attack and
a pulmonary specialist brought in to assist with the management of a patient
with asthma. The consulting physician may rely, in whole or in part, on information
developed by other medical practitioners contained in the patient’s medical
records, such as medical history, laboratory tests, and x-rays. More often, the
consulting physician will also conduct an examination of the patient and underphysicians
licensed in Michigan to assess compliance with a law mandating participation in 150 hours of
continuing medical education every three years).
39. Chouteau v. Enid Mem’l Hosp., 992 F.2d 1106, 1109 & n.2 (10th Cir. 1993) (upholding the
district court’s grant of summary judgment, finding that sufficient justification existed for the defendant
hospital to lawfully terminate the plaintiff’s staff privileges).
40. See Alvan R. Feinstein, Clinical Judgment 21 (photo. reprint 1985) (1967).
41. Treating physicians are generally permitted to testify, although contentions are sometimes made
that their testimony should be limited. In Holbrook v. Lykes Bros. Steamship Co., 80 F.3d 777 (3d Cir.
1995), the trial court had excluded the treating physician’s testimony on his diagnosis of mesothelioma
and a pathology report because the physician was not a pathologist or oncologist. The Third Circuit
reversed the decision, noting that treating physicians’ testimony is often given greater weight than
testimony from physicians who have not examined the patient. Id. at 782–83.
Reference Manual on Scientific Evidence
450
take additional tests and investigations. While consulting physicians are often an
integral part of the team of treating physicians, in some instances they may not
be involved in treatment, instead providing opinions for employers, insurers,
litigants, or courts.
C. Medical Research and Academic Appointments
In addition to traditional patient care and consultation as to diagnosis and treatment,
physicians may be involved in medical research in a variety of areas (e.g.,
epidemiology, pharmacology, and toxicology) as their primary activity, or in
conjunction with patient-oriented medical practice. For example, physicians
may be involved in clinical trials to evaluate new drugs or other therapies. They
also may participate in studies on the causes of disease. The physician may be the
principal investigator, who is primarily responsible for such studies, or may participate
as a coinvestigator or collaborator, or simply by referring patients to the
studies. Many physicians involved in medical research also have a teaching position
at a medical school or a large teaching hospital.
D. Physicians As Expert Witnesses
In contrast to the traditional medical roles they fill as outlined above, physicians
frequently act as witnesses in court, either for the parties or, on occasion, as
court-appointed experts. Physician–witnesses may testify based on their activities
as treating or consulting physicians or more generally about medical and
scientific knowledge and its application to the issues in a case. In the former
role, they may be characterized as “fact” witnesses, but they will also be applying
medical expertise to a greater or lesser degree in assessing the significance of
the patient’s signs and symptoms and medical history, making a diagnosis, opining
on proper treatment and prognosis, and the like. In some medical fields,
such as clinical toxicology or occupational medicine, this dual role is quite common.
In other instances, the physician is applying his or her expertise solely to
offer an expert opinion, relying on factual clinical information developed by
treating physicians or from hospital records or other sources.42
A physician may be asked to testify about the physical condition of a plaintiff,
diagnosis, treatment, causes of the plaintiff’s condition, or prognosis. A physician
may also be asked to interpret epidemiological or industrial hygiene data if
they are within his or her scope of expertise. Such testimony may be important
42. Howard Hu & Frank E. Speizer, Influence of Environmental and Occupational Hazards on Disease,
in 1 Harrison’s Principles of Internal Medicine 18, 19 (Anthony S. Fauci et al. eds., 14th ed. 1998)
[hereinafter Principles of Internal Medicine].
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451
both in a factual sense—what happened and when—and as a basis for expert
opinion on such issues as the following:
1. Is the diagnosis correct? (assessing what injury the plaintiff suffered);
2. Were the appropriate treatments prescribed? (assessing the issues of standard
of care in a medical malpractice case or damages in a tort case);
3. What is the prognosis or the likely course of the plaintiff’s condition?
(assessing future damages);
4. Was the patient exposed to the substance in question? (assessing exposure
through patient symptoms and reports, such as eye burning, the detection
of an odor, or a headache, which provide indications as to the concentration
of an irritant or other agent);
5. Is there an increased risk of future disease? (assessing damages by predicting
future consequences of an existing condition; assessing a claim for
increased risk of future disease; assessing the reasonableness of a claim for
fear of disease (e.g., cancerphobia); or assessing the propriety of medical
surveillance in a medical monitoring claim); and
6. What caused the plaintiff’s medical condition? (assessing general and specific
causation).
As set forth later in this reference guide,43 physicians do not always use the
same approach in evaluating these issues as the legal system does. For example,
in tort cases, liability will often turn on the identification of one or more causes
of the plaintiff’s condition. A physician, independent of legal issues, typically
uses the term causation or etiology to refer to the various levels of underlying
abnormality that have substantially led to the next higher level of abnormality,
disease, or diagnosis. This “chain,” or web, of causation is considered the “pathogenesis”
or pathophysiology of a disease. For instance, a heart attack may be due
to a sudden blockage of a coronary artery, which was facilitated by a preexisting
cholesterol plaque in the artery, which in turn is due to the patient’s high level
of blood cholesterol, which is due to genetics, diet, a sedentary lifestyle, and
smoking, which contributes at many levels.44 Most physicians are familiar with
the general importance, if not specific degrees of risk, of the listed internal biochemical
and mechanical factors in a heart attack, and with many other areas in
the web of causation, such as the common external factors listed above.45
43. See infra § IV and accompanying footnotes.
44. Elliot M. Antman & Eugene Braunwald, Acute Myocardial Infraction, in 1 Principles of Internal
Medicine, supra note 42, at 1352, 1352–53. In this guide, the term internal is used to refer to causal
factors and conditions internal to the patient’s body, such as genetic predisposition to coronary artery
disease, to distinguish them from causal factors that are external to the body, such as smoking and diet.
45. For a general discussion of the process used to infer internal and external causation, see Feinstein,
supra note 40, at 80–83. See, e.g., Carroll v. Morgan, 17 F.3d 787, 791 (5th Cir. 1994) (discussing
multiple causes of plaintiff’s coronary disease).
Reference Manual on Scientific Evidence
452
While physicians dealing with diagnosis and treatment tend to think in terms
of both internal and external causation, courts are usually asked to determine the
role of causes that are external to the individual. Generally, physicians focus on
causal elements that can be addressed through medical treatment or through
changes in lifestyle or diet; courts focus primarily on causal elements for which
a litigant or other party might be held responsible. For example, a workers’
compensation case might concern the role of physiological stress at work in
causing underlying heart disease, or the role of carbon monoxide in triggering a
specific heart attack.46 Identification of those kinds of causes depends on information
concerning quantification of risks in the workplace environment, as
well as on the medical literature on causation, including the psychological, toxicological,
and epidemiological literature.47 To determine general causation, the
expert must review the pertinent literature, as familiarity with this literature is
key to expert opinion. For example, since many cardiologists advise patients on
returning to work after a heart attack, they will often be familiar with the literature
on work-based risks and cardiovascular disease, whereas most other physicians,
who deal with this question less frequently, would need to devote some
time to study before evaluating such a special consideration.
III. Information Utilized by Physicians
Physicians rely on the following diverse sources of information in arriving at a
diagnosis, determining a course of treatment, and exploring causation: the patient
history (information derived directly from the patient), patient records,
physical examination, and diagnostic tests.48
A. Patient History (from the Patient)
The patient history is one of the primary and most useful tools in the practice of
clinical medicine. It is usually divided into present illness (including both subjective
reports and medical documentation) and past medical problems, with or
without medical documentation.49
As obtained by the examining physician, the patient history is extremely important
in evaluating the patient’s condition, determining what medical tests
may be warranted, arriving at a diagnosis, and recommending an appropriate
46. See, e.g., Fiore v. Consolidated Freightways, 659 A.2d 436 (N.J. 1995) (truck driver’s workers’
compensation case claiming that his heart disease was caused by occupational exposure to carbon monoxide
fumes remanded so that parties could provide more reliable exposure evidence).
47. See Cullen et al., supra note 19, at 220–21.
48. See Jerome P. Kassirer & Richard I. Kopelman, Learning Clinical Reasoning 4 (1991).
49. Barbara Bates et al., A Guide to Physical Examination and History Taking 2–3 (6th ed. 1995).
Reference Guide on Medical Testimony
453
course of treatment. Even in this era of sophisticated medical testing protocols,
it is estimated that 70% of significant patient problems can be identified, although
not necessarily confirmed, by a thorough patient history.50
A thorough patient history includes not only present illness and past medical
problems, but also aspects of medical, occupational, personal, and familial background
that are relevant to the present problem. Moreover, patient histories
may identify common patterns of illness among individuals with a common
lifestyle or exposure element, such as reproductive problems in individuals occupationally
exposed to lead. Although patient histories are important in determining
a diagnosis, and useful in epidemiological studies of both acute and chronic
diseases, there is no validated and widely used patient history questionnaire with
which to begin the diagnostic process,51 perhaps because the history-taking process
is so iterative and intertwined with hypothesis testing.
Despite the absence of a standard patient history questionnaire, there is general
agreement that a useful adult patient history includes the following information:
1. identification (e.g., name, sex, age);
2. chief complaint and history of the present illness;
3. medical history (e.g., injuries, medical conditions and diseases, surgical
procedures);
4. lifestyle characteristics (e.g., use of nicotine, alcohol, and other drugs;
exposures in the home);
5. familial health (e.g., medical conditions and diseases of relatives); and
6. occupational history (e.g., present and previous employment, exposures).52
While more recent events or those that more directly appear pertinent to the
particular presenting symptoms of a patient will usually be given the most attention,
historic events or familial history may provide insight into diagnosis and
prognosis.53 This is particularly true when the physician is considering exposure–
disease relationships with a long latency, such as in asbestos-related disease
or inherited predispositions for malignancy.54
1. Symptomatology
Symptoms are by definition subjective, since they are self-reported by the patient
in his or her own words. Because symptoms that preoccupy the patient are
not always the most relevant to diagnosis, the physician will often need to ask
50. See Mark H. Swartz, Textbook of Physical Diagnosis: History and Examination 667 (3d ed.
1998).
51. Office of Tech. Assessment, U.S. Congress, Reproductive Health Hazards in the Workplace
app. B at 365 (1985).
52. See, e.g., Bates et al., supra note 49, at 3–7, 16–17.
53. See, e.g., id. at 637–39.
54. See Thomas E. Andreoli et al., Cecil Essentials of Medicine 152 (3d ed. 1993).
Reference Manual on Scientific Evidence
454
the patient about symptoms that are particularly useful for diagnosis, but not of
particular concern to the patient. Generally, patients will be asked to characterize
symptoms by their location, intensity, frequency, exacerbating factors, ameliorating
factors, and novelty.55
As a report of the patient’s own experience, symptoms are uniquely valuable,
but they are also subject to various sources of bias and error, both intentional
and unintentional. A competent diagnostician can take sources of error into
account, but for some symptoms, such as severity of pain, or when the first
severe attack of shortness of breath occurred, it is usually not possible to objectively
verify the patient’s reports. The physician’s skill, knowledge, and experience
with the particular area of concern is critical in obtaining an accurate and
meaningful history.56 Physicians are accustomed to reaching a subjective conclusion
regarding the quality and reliability of the history they obtain from the
patient.
2. Environmental and Occupational History
Consideration of occupational and environmental causation in diagnosis has long
been recommended to physicians, but more specific attention to the environmental
and occupational history as part of the medical workup has recently been
emphasized, with the degree of detail depending on the clinical situation.57
If the medical workup indicates a potential occupational or environmental
disease, the physician should explore the patient’s potential exposures in more
detail.58 Although the physician often will not have measures of environmental
exposure, information about the level of exposure can be inferred in certain
instances from the description of the workplace and work processes; the duration
of exposure; correlates, such as eye irritation, headache, or odor; the size of
a room or other enclosure; the presence of windows or other ventilation; and
other activities occurring nearby.59
55. See, e.g., Bates et al., supra note 49, at 635, 645–47.
56. See Anthony S. Fauci et al., The Practice of Medicine, in 1 Principles of Internal Medicine, supra
note 42, at 1, 2; Lee Goldman, Quantitative Aspects of Clinical Reasoning, in 1 Principles of Internal
Medicine, supra note 42, at 9, 9.
57. See Hu & Speizer, supra note 42, at 19; Environmental Medicine: Integrating a Missing Element
into Medical Education 5–11 (Andrew M. Pope & David P. Rall eds., 1995).
58. Establishing exposure is usually deemed necessary to a plaintiff’s toxic injury claim, and the
existence or degree of exposure to the agent is often at issue. See, e.g., In re Paoli R.R. Yard PCB Litig.,
916 F.2d 829 (3d Cir. 1990) (environmental exposure to polychlorinated biphenyls (PCBs) contested),
cert. denied, 499 U.S. 961 (1991).
59. See Hu & Speizer, supra note 42, at 19; Frank E. Speizer, Environmental Lung Diseases, in 2
Principles of Internal Medicine, supra note 42, at 1429, 1429–30; Peter Casten, Jr., & Katherine Loftfield,
The Eyes and Vision, in Environmental Medicine, supra note 19, at 240, 242. Exposure to chemical
agents typically found in certain work environments can sometimes be inferred based on industrial
hygiene studies of particular occupations. For example, employment as an asbestos insulator has been
associated with significant levels of asbestos exposure.
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455
Information about exposure may also be available from workplace industrial
hygiene records or a police report. Other sources of information may include
governmental agency or private consultant records and insurance inspections.
However, physicians usually have to evaluate environmental or occupational
diseases in the absence of quantitative exposure levels. Even in situations in
which there are measurements of personal breathing-zone exposures, such data
may not take into account various other factors, such as the level of a patient’s
exertion, which may change the actual dose to make it greater or lower than
theoretical calculations; the performance of ventilation equipment; or the fit of
a respirator.60
3. Other Risk Factors
In addition to information about environmental and occupational exposures, a
patient’s history should include information about other known risk factors,
such as the patient’s family history, smoking history, amount of exercise, alcohol
use, use of medications or illicit drugs, and exposures to chemicals in the home
or from hobbies.61
B. Past and Present Patient Records and Exposure-Related Records
Although time-consuming and bureaucratically cumbersome, an examination
of patient records from former treating physicians, clinics, and hospitals can
often be crucial for accurate diagnosis, for determination of the onset of an
illness or symptom, and to provide information about external exposures. Patient
records may reveal the course of an illness and the results of prior tests, and
they can help gauge the reliability of patient-reported information. Unfortunately,
because obtaining multiple patient medical records from various institutions
in a timely manner is often difficult, much medical care is rendered in their
absence. More complete records are often gathered once litigation has begun.
C. Physical Examination62
The physical examination is a routine procedure for evaluating the patient and
determining a diagnosis. The physical examination identifies approximately 20%
60. For the effect of exercise, see, e.g., Joseph D. Brain et al., The Effects of Exercise on Inhalation of
Particles and Gases, in Variations in Susceptibility to Inhaled Pollutants: Identification, Mechanisms, and
Policy Implications 204, 210 (Joseph D. Brain et al. eds., 1988); for other variables affecting an individual’s
exposure and response to inhaled gases or particles, see, e.g., Speizer, supra note 59, at 1430.
61. See Bates et al., supra note 49, at 16–19; Speizer, supra note 59, at 1429–30.
62. Courts sometimes attach importance to the physician–witness’s examination of the patient. See,
e.g., In re Paoli R.R. Yard PCB Litig., 35 F.3d 717, 771 (3d Cir. 1994) (physician’s testimony on
causation admitted as to patients the witness examined), cert. denied, 513 U.S. 1190 (1995); In re “Agent
Orange” Prod. Liab. Litig., 611 F. Supp. 1223, 1235, 1243–47 (E.D.N.Y. 1985), aff’d, 818 F.2d 187
Reference Manual on Scientific Evidence
456
of significant medical problems.63 The physical exam has standard components
with which physicians, depending on their degree of specialization, may be
more or less proficient. For example, while most physicians will hear a loud
heart murmur or identify a severe tremor, subtle signs of heart disease or neurological
disease may be missed by those without specialty training in cardiology64
or neurology, respectively. Greater proficiency can be expected from a specialist,
because doctors in specialized fields focus their examinations on the system
in question, do more tests within an area, are more skilled in performing the
exam, and are better able to distinguish between significant and insignificant
deviations from normal.
The findings from the physical exam as well as radiographic imaging studies,
noninvasive functional tests, and blood tests are referred to as “signs” of illness,
as contrasted with symptoms, which are subjectively reported by the patient.
Although signs are more objective than symptoms, they still depend on the
physician’s skill and objectivity, degree of attention to detail, and level of concern.
Physical signs assume enhanced significance when they demonstrate the
presence of a functional or structural change already suggested by the patient
history.65
A thorough physical exam begins with the taking of vital signs (temperature,
heart rate, respiratory rate, and blood pressure). Next is a description of the
patient’s general appearance and whether the patient was able to cooperate with
the exam. This is followed by examination of each region and organ system
(skin, head, ears, eyes, nose, mouth and throat, neck, chest, lungs, heart and
cardiovascular system, abdomen, genitourinary system, extremities and musculoskeletal
system, and nervous system). Psychological assessments are sometimes
then provided.66 However, many specialists may perform only a portion of the
exam; and, because of time constraints, many practitioners focus on only one
aspect of a patient at a given time.67
Physicians are taught to record their findings on a physical exam in a routinized
but not necessarily standardized fashion. A thorough exam will include
(2d Cir. 1987), cert. denied, 487 U.S. 1234 (1988). Courts have also recognized that physicians may
present testimony based on examinations and tests performed by others, as well as on medical records.
See, e.g., Kannankeril v. Terminix Int’l, Inc., 128 F.3d 802, 809 (3d Cir. 1997); Sementilli v. Trinidad
Corp., 155 F.3d 1130 (9th Cir.) (per curiam) (physician could present testimony on plaintiff’s condition
based on medical records and knowledge, experience, training, and education), dissenting opinion amended,
162 F.3d 1015 (9th Cir. 1998).
63. See Swartz, supra note 50, at 667.
64. See, e.g., Feinstein, supra note 40, at 2.
65. See Fauci et al., supra note 56, at 2.
66. See Bates et al., supra note 49, at 118–21.
67. Id. at 117.
Reference Guide on Medical Testimony
457
“findings” as opposed to merely notes indicating that an observation was “within
normal limits” or “negative.” However, the emphasis is on the accuracy of the
observation, rather than the degree of detail that may be presented. How the
findings of the physical exam fit into context with other data in the case is a key
item in assessing the exam’s reliability.68
As discussed above, specialists are generally better able than generalists to
elicit patient history information, ascertain physical findings, and interpret lab
results within their area of expertise. Findings that may have limited clinical
meaning but may inform decisions regarding external causation in legal proceedings,
such as the bilateral asymptomatic stable pleural thickening in someone
with a history of asbestos exposure, are sometimes not mentioned by a
treating physician, such as a radiologist. Thus, the absence of such findings from
the treating physician’s records should not necessarily be taken as an indication
of disagreement between the treating physician and the specialist.
D. Diagnostic Tests
For diagnosis of more serious conditions, especially cancer, physicians are taught
always to seek a tissue biopsy.69 This is often referred to as a gold standard,
because it is regarded as highly accurate or at least the most definitive indicator
of a particular condition. For other conditions, the definitive test may be a
radiological test (e.g., a pulmonary angiogram for diagnosis of pulmonary embolism)
70 or a microbiological test (e.g., a sputum culture for diagnosis of tuberculosis).
71
Sometimes physicians and patients will be satisfied with a diagnosis even though
the gold standard test for that diagnosis was not performed. There may be too
much risk associated with such a test (e.g., if it is invasive or involves intentional
exposure to a possible allergen), its costs may outweigh the benefit of achieving
a more definitive diagnosis, or it may be superfluous because other data are so
consistent and convincing.72 As always, the various cost–benefit and risk–benefit
equations are interpreted relative to the individual patient, physician, and medical
circumstances, as well as institutional capabilities.
68. Id. at 649–52.
69. See, e.g., Dan L. Longo, Approach to the Patient with Cancer, in 1 Principles of Internal Medicine,
supra note 42, at 493, 494.
70. See Steven E. Weinberger & Jeffrey M. Drazen, Diagnostic Procedures in Respiratory Disease, in 2
Principles of Internal Medicine, supra note 42, at 1417, 1418.
71. See Matthew E. Levinson, Pneumonia, Including Necrotizing Pulmonary Infections (Lung Abscess), in
2 Principles of Internal Medicine, supra note 42, at 1437, 1440.
72. See Kassirer & Kopelman, supra note 48, at 217–22.
Reference Manual on Scientific Evidence
458
In modern medical practice, tests and procedures are critical to confirming
most diagnoses. These include radiological examination, laboratory tests, physiological
tests of lung or nerve function, pathological examination of tissue, and
invasive diagnostic tests, such as cardiac catheterization. A physician’s decision
whether to order a diagnostic test for specified clinical indications should take
into consideration expense, risk, accuracy, and predictive value. Tests are limited
by their inherent sensitivity and specificity, the fallibility of the instrumentation,
and the variation in skills of the individuals who perform or interpret the
tests. Error rates for diagnostic tests, as discussed below,73 in terms of sensitivity
and specificity are generally available, but the all-important predictive values74
vary with the particular disorder and with the population (i.e., demographics,
background rate of disease) on whom the test is performed or the population
from which a tested individual is derived. While pathological examination of
tissue biopsies is considered the gold standard of diagnostic tests, even it has an
error rate.75
In general, laboratory tests do not have a paramount role in establishing the
external etiology of many chronic and acute illnesses. Major exceptions to this
are microbiological evaluations for causes of infectious diseases, and cases of
toxic substance intoxication, such as lead poisoning or alcohol or drug poisoning.
76
Depending on the diagnosis being considered and whether the exposure truly
leaves a reliable “signature” or “residue,”77 a biopsy may or may not have great
utility for exogenous causal diagnosis. Invasive tissue biopsies are not routinely
performed for purposes of establishing causation because of the risk involved
with the procedure to obtain the tissue. Sometimes such test results are incidentally
available because they may have been used to establish the diagnosis, particularly
in the case of lung disorders.
73. See infra note 105 and accompanying text.
74. See infra notes 107–108 and accompanying text.
75. See Fauci et al., supra note 56, at 3; Goldman, supra note 56, at 10; Kassirer & Kopelman, supra
note 48, at 23.
76. See Christopher H. Linden & Frederick H. Lovejoy, Jr., Poisoning and Drug Overdose, in 2
Principles of Internal Medicine, supra note 42, at 2523, 2523–25.
77. Certain persistent toxic agents can sometimes be detected in laboratory tests. See, e.g., Hose v.
Chicago Northwestern Transp. Co., 70 F.3d 968 (8th Cir. 1995) (laboratory tests showed elevated
manganese in plaintiff’s body; MRI indicated manganese in brain). The interpretation of such tests has
been at issue in a number of cases. See, e.g., In re Paoli R.R. Yard PCB Litig., 35 F.3d 717 (3d Cir.
1994) (dispute over whether PCB levels in plaintiffs’ adipose tissue exceeded background levels), cert.
denied, 513 U.S. 1190 (1995); Wright v. Willamette Indus., Inc., 91 F.3d 1105 (8th Cir. 1996) (presence
of wood dust fibers at plaintiffs’ residence and in tissue samples insufficient to establish exposure to
formaldehyde at levels known to cause plaintiffs’ symptoms).
Reference Guide on Medical Testimony
459
1. Laboratory Tests
Laboratory tests are usually tests in which a specimen, usually blood or another
body fluid, is submitted to a laboratory for a chemical or microbiological analysis.
For many of the routine chemical assays for levels of proteins, fats, electrolytes,
enzymes, or hormones in blood, there are established normal ranges for a
given laboratory or test manufacturer, and for given subpopulations (e.g., men
or women, children or adults). The results are interpreted as being either within
or outside of normal limits. Not all deviation from normal limits is pathological,
particularly if the individual is otherwise without complaint. For example, the
results of liver function tests often fluctuate outside of the normal range in those
without liver disease or hepatotoxin exposure. Based on standard statistical techniques
for defining normal ranges, one in twenty test results can be expected to
be abnormal (i.e., outside the normal range) in a healthy individual.78
Common laboratory tests include x-rays, routine blood chemistries, and blood
counts. More specialized tests include computerized axial tomography (CAT)
scans, magnetic resonance imaging (MRIs), and angiograms.79 All of these tests
are used in one of three ways as part of the diagnostic process. The first and most
common use is to clarify a disease process or pathology or pathophysiology.80 A
second and less common use of laboratory tests is for estimation of exposure to
potentially toxic substances. These tests include measures of an agent in the
body (e.g., blood lead levels) or in an excretory product (e.g., urine mercury).
Understanding that such tests only determine exposure and not disease or health
effect is critical.81 A third and fairly uncommon type of laboratory test is used to
substantiate an exposure–effect relationship.82 Many, if not most, such tests are
actually tests of allergic sensitization (e.g., to a metal or other potential cause of
allergic asthma). The expert should be clear about what type of information is
being inferred from a given test and about the basis in the literature for using the
test for that purpose.83
78. See Cullen et al., supra note 19, at 223–24. For an overview of available blood tests, fluid
analysis studies, and urinalyses, see, e.g., Kathleen Deska Pagana & Timothy James Pagana, Mosby’s
Manual of Diagnostic and Laboratory Tests 7–9, 557, 859–73 (1998).
79. See Fauci et al., supra note 56, at 3; for uses of laboratory tests in environmental disease, see
Cullen et al., supra note 19, at 222–23 and Arthur Frank, The Environmental History, in Environmental
Medicine, supra note 19, at 232. See also In re Paoli R.R. Yard PCB Litig., 916 F.2d 829 (3d Cir. 1990),
cert. denied, 499 U.S. 961 (1991).
80. For a case involving the use of laboratory tests in diagnosis, see Cella v. United States, 998 F.2d
418 (7th Cir. 1993).
81. See, e.g., Linden & Lovejoy, supra note 76, at 2523.
82. See Cullen et al., supra note 19, at 223.
83. See id. at 228. For an example of laboratory tests used to rule out alternative diagnoses and
causes, see Hose v. Chicago Northwestern Transportation Co., 70 F.3d 968, 973, 975 (8th Cir. 1995)
(supporting a diagnosis of manganese encephalopathy, medical witnesses cited a positron emission tomography
(PET) scan to rule out alcoholism, stroke, and Alzheimer’s disease, and an MRI to exclude
copper, calcium, and other harmful exposures).
Reference Manual on Scientific Evidence
460
Physicians are taught to think about clinical testing in terms of the clinical
significance (particularly, predictive value) of a given test in a given situation.
Small or inconsistent changes in values do not necessarily indicate a clinically
important effect and should be confirmed by repeat testing before being otherwise
investigated. On the other hand, important effects may not drive an
individual’s values outside of the population reference range. For instance, someone
previously at the upper limit of the normal range exposed to a chlorine leak
might suffer a reduction in rate of airflow. Although the subsequent rate was
within the normal range, it would not be normal in this individual.84 Unfortunately,
baseline data on an individual prior to exposure are usually not available.
Thus, making inferences from other diagnostic and exposure information may
be useful in understanding the impact of exposure on that individual.
2. Pathology Tests
Pathology tests are conducted by taking a sample of body tissue (obtained during
surgery or a biopsy) and submitting it for microscopic evaluation by a specialist
physician (pathologist). The pathologist makes a determination as to whether
the tissue appears normal for the organ from which it was taken. If it does not
appear normal, then a determination of the pattern of abnormality, such as inflammation,
malignancy, or scarring, is sought.85
Sometimes the etiology of the abnormality is apparent, as when special stains
are used for determination of the presence of microorganisms that can cause a
given infection. On the other hand, most cancers, whether of lung or breast or
bone marrow, have no features that allow the histopathologist to discern a toxic,
viral, or hereditary etiology. Clues from molecular biology analysis have been
experimentally reported, but are not yet available clinically.86
Pathology, typically felt to be the gold standard, often is found wanting when
external etiology needs to be determined. Some conditions, such as neuropsychiatric
diseases that may be related to metal or solvent exposure, do not have
established pathological abnormalities.87
3. Clinical Tests
Clinical tests are physiological determinations of organ function. Common examples
are pulmonary (lung) function tests, which have well-established normal
84. Cullen et al., supra note 19, at 223.
85. For specific examples, see Ivan Damjanov, Histopathology: A Color Atlas and Textbook 23–
24, 36, 58, 64 (1996).
86. See Bernard D. Goldstein & Mary Sue Henifin, Reference Guide on Toxicology § IV, in this
manual.
87. See Howard Hu, Heavy Metal Poisoning, in 2 Principles of Internal Medicine, supra note 42, at
2564, 2565–66.
Reference Guide on Medical Testimony
461
ranges, but are quite dependent on patient effort; nerve and muscle function
tests, which are largely effort-independent and have reasonably well-established
reference ranges, but are sensitive to interlaboratory variation, and electrocardiograms
(EKGs), which are interpreted with a combination of objective measures
and more subjective recognition of patterns resulting from inidividual expertise.
88
All tests have strengths and limitations for their use in reaching a certain
diagnosis or making a causal inference. The expert should be able to address
strengths and weaknesses of various approaches based on the situation at hand.
Why was one test chosen or preferable to another? If available, what is the
sensitivity, specificity, and validity for the test in general, and what are its predictive
values in the population (characterized by age group, gender, comorbid
diseases, workplace exposures) from which the individual comes?89
Mostly these predictive values will be available in the medical literature, but
there are many disappointing gaps. Given inevitable inconsistencies in the patient’s
data, a qualified expert will usually be able to interpret and explain these inconsistencies
in a satisfactory manner.
IV. Physician Decision Making
A. Introduction
For the treating physician, “[c]linical reasoning is the essential function of the

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