HB Litigation Conferences Lead Litigation 2013

1. November 14-15, 2013

3. Cris A. Williams, PhD
ENVIRON
Gary H. Abelson
Hiscock & Barclay LLP
Nicholas Szokoly
Law Offices of Evan K. Thalenberg, P.A.
Karl Kieburtz, MD, MPH
University of Rochester Medical Center

4. Observational
case series – clinical observation
ecologic associations – existing data
cross sectional (prevalence) – existing/new data
case-control – new data
cohort – retrospective – existing/new data
prospective – new data
Interventional
non-randomized trial
randomized, controlled trials

5. Major:
Temporal
Biological Plausibility
Consistency
Alternative Explanations Explored
Other:
Dose-response Relationship
Strength of Association
Cessation Effects
Gordis 1990

6. Intended to answer the following questions:
Does the agent get to where it may exert injury?
At a sufficient concentration?
In a biologically active form?
Does it engage the target of interest?
Does it influence downstream
biology/pharmacology?
At what dose?

7. Studies that are designed
to show that an
exposure/agent modifies
a health state

8. • Randomization
• Blinding to treatment
Attempts to reduce bias and to
improve the quality of evidence.

9. Medicine is always confronted with
estimating what the benefits and
toxicities of interventions might be
in a specific patient, given the
evidence available from
populations, usually with little data
about ‘matched’ individuals

10. Karch and Lasangna
Widely used in assessing adversity
Uncommon in thinking about benefit
Principles are the same

11. 
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Karl’s topic – Basics of Clinical Trials/How
Medicine Looks at Causation
Introduction to Epidemiology
Epi Study Designs and Strengths/Limitations
Karl’s topic – How to Determine Causation in
an Individual
Lead Studies Overview
Lead Studies from the Plaintiffs’ Perspective
Lead Studies from the Defense Perspective

12. 
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Definition – study of occurrence of
disease in populations
Subtypes according to exposure/agent
◦ Biological – i.e., infectious disease (cholera)
◦ Environmental
 Natural environment (radon, asbestos, arsenic,
lead)
 Man-made or “anthropogenic”, incl. occupational
(e.g., benzene but also asbestos, arsenic, lead)

13. 
Descriptive studies
◦ For hypothesis generation/identification of risk
factors
◦ Use data/information from readily-available sources
(census, disease registries, vital stats)
◦ Cannot establish causal associations between
exposure and disease
◦ Two subtypes: ecological; cross-sectional
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Analytical studies
◦ Hypothesis testing
◦ Quantify relative risk of disease
◦ Can establish causal associations between exposure
and disease
◦ Two subtypes: case-control; cohort

14. 
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Compare outcome frequencies between
different groups during the same time period
or in the same population at different time
periods
Example – birth weight distributions in two
different regions with different levels of
arsenic in drinking water
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No information on individuals’ exposure
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No control of confounding (e.g., smoking)

15. 
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Presence or absence of both exposure and
outcome are assessed simultaneously; i.e., a
“snapshot”
Example – study of infertility and psychological
stress
Cannot distinguish whether exposure preceded
outcome

16. 
Subjects selected on the basis of whether they
have (cases) or don’t have (controls) a specific
outcome
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Example – study of lung cancer cases and
controls and residential radon exposure
Good for diseases with long latency periods
and for rare diseases
Time- and cost-efficient
Susceptible to bias
◦ Selection (e.g., hospital admits)
◦ Recall (e.g., regarding exposure)

17. 
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A group of individuals are defined on the basis of the
presence or absence of exposure (e.g., worker studies)
Prospective – cohort identified and followed forward in
time (exposure has not yet occurred)
Retrospective – cohort identified and traced backward in
time (exposure had already occurred)
Longitudinal – cohort is the same individuals tracked
forward or backward
Most studies relating lead exposure to IQ are
longitudinal retrospective studies

18. Study Type
Strengths
Limitations
Ecological
Quick, inexpensive, uses readilyavailable information.
No exposure information, doesn’t
control for confounding.
Cross-sectional
Quick, inexpensive, can provide
valuable information on health
status of a population.
Cannot determine whether
exposure preceded or resulted
from disease.
Case-control
Good for diseases with long
latency periods and for rare
disease, time- and cost-efficient,
can examine multiple etiologic
factors for a single disease.
Good for rare diseases, temporal
relationship between exposure
and disease difficult to establish,
results may be biased (selection
and recall).
Cohort
Good for rare exposures, can
assess multiple effects of a single
exposure and temporal
relationship between exposure
and disease, minimizes bias,
allows for determination of
disease incidence rates.
Not good for rare diseases,
expensive and time-consuming
(prospective), requires availability
of adequate records
(retrospective), susceptible to loss
to follow up.
Source: Nielsen and Jensen (2005).

19. 
Dozens of studies relating blood lead and
neurobehavior/cognitive development in humans and
animals
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Dating from the late 1970’s
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Key studies/reviews
◦ Needleman and Gatsonis (1990) – Low-level Lead Exposure and
the IQ of Children. A Meta-analysis of Modern Studies (JAMA
263:673-678)
◦ Canfield et al. (2003a) – Intellectual Impairment in Children with
Blood Lead Concentrations Below 10 µg per Deciliter (N Engl J
Med 348:1517-1526)
◦ Lanphear et al. (2005) – Low-level Environmental Lead Exposure
and Children’s Intellectual Function: An International Pooled
Analysis (Environ Health Perspect 113:894–899)

20. 
Key reviews/commentary
◦ Kaufman (2001a) – Do Low Levels of Lead Produce IQ Loss in Children?: A Careful
Examination of the Literature? (Archives of Clinical Neuropsychology 16:303-341)
◦ Needleman and Bellinger (2001) – Studies of Lead Exposure and the Developing
Central Nervous System: A Reply to Kaufman (Archives of Clinical Neuropsychology
16:359-374)
◦ Kaufman (2001b) – How Dangerous are Low (Not Moderate or High) Doses of Lead
for Children' s Intellectual Development? (Archives of Clinical Neuropsychology
16:403-431)
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Early studies – established the effect
Later studies – establishing the effect at increasingly lower
PbB
“Plaintiff” studies and “Defense” studies

22. 
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The hypothesis that Pb damages children's
brains at low doses is widely accepted
There is no safe level of PbB/a linear inverse
relationship exists between PbB and
intelligence test scores (IQ) – i.e., no
threshold
Correlations between PbB and IQ are socially
relevant
Correlations between PbB and IQ remain
when confounders were considered

23. The hypothesis that Pb affects IQ at low
doses is widely accepted (EPA 2013)
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12 major prospective studies, 1992-2011
3 cross-sectional studies, 1987-2011
4 “meta” analyses/pooled studies, 19902005

24. There is no safe level of blood lead/a linear
inverse relationship exists between PbB and
intelligence test scores (IQ) – i.e., no threshold
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Boston cohort – PbB = 1-9.3 μg/dL (Schwartz 1994)
Rochester cohort – PbB = 0.5-8.4 μg/dL (Canfield et al.
2003b)
Mexico City cohort – PbB = 0.8-4.9 μg/dL (Téllez-Rojo
2008)
North Carolina cohort – PbB = 2 μg/dL (Miranda et al.
2009)*
*EOG (4th grade) as a surrogate for IQ.

25. Correlations between PbB and IQ are socially
relevant (Needleman and Bellinger 2001)
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 shift of IQ scores occurred across entire
distribution of IQ scores
 shift in median scores of 6 points
associated with 4-fold increase in IQ scores
<80
5% of population failed to achieve superior IQ
scores >125
Exposures in early childhood associated with
7x increase in high school failure and a 6x
increase in reading disabilities

26. Correlations between PbB and IQ remain when
confounders were considered (Needleman and
Bellinger 2001)
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Prospective studies controlled for at least
some measure of maternal IQ
Most studies controlled for at least global
measures of SES; in some cases controlled for
home environment more specifically (e.g., via
HOME, FACES, etc.)
Persons administering the IQ tests in most of
the studies were adequately trained in
psychometrics

27. 
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The hypothesis that Pb affects IQ at low
doses is controversial
There is a level of PbB below which effects on
IQ are insignificant – i.e., a threshold
Correlations between PbB and IQ are not
socially relevant
Correlations between PbB and IQ largely
disappear when confounders were considered

28. The hypothesis that Pb consistently affects
IQ at low doses is controversial
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Inconsistency in IQ findings both between studies and
within studies (Ernhart 1995)
Studies purported to be “low-lead” studies in humans
(and animals) are actually moderate- to high-lead
studies (Kaufman 2001b)
Gender-specific effects – some studies showed > effects
in girls than boys; others demonstrated the opposite
(Hebben 2001)
Although many studies report a significant association
between lead and IQ, lead tends to account for a very
small amount of variance in IQ (Bellinger and Dietrich
1994)

29. There is a level of PbB below which effects on
IQ are insignificant – i.e., a threshold
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Assumption of PbB/IQ linearity based not on
actual data but rather on dubious regression
analyses (Kaufman 2001b)
EPA’s Integrated Science Assessment for Lead
(EPA 2013)
◦ Lack of a reference population (PbB in pre-industrial
population) limits ability to identify a threshold
◦ “. . . the current evidence does not preclude the
possibility of a threshold for neurodevelopmental
effects in children existing with lower blood levels
than those currently examined.”

30. Correlations between PbB and IQ are not socially relevant
(Kaufman 2001b)
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A few IQ points is well within a reasonable band of error
around the observed score
The usual IQ loss attributed to low PbB is similar in
magnitude to the 2- to 3-point mean gender difference
(favoring males)
IQ score is meaningless without measurement of other
aspects of intellectual functioning – e.g., creativity, social
intelligence, practical intelligence, adaptive behavior,
mechanical ability, etc.

31. Correlations between PbB and IQ largely
disappear when confounders were
considered (Kaufman 2001a and b)
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For the 26 PbB/IQ studies where
confounders may have affected the
results:
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12 used only a global assessment of SES
17 used a “poor” or no measure of maternal IQ
24 did not test father’s IQ
24 did not control for persistent otitis media
18 did not control for pregnancy risk factors
(e.g., maternal drug use/abuse, smoking)

32. Difference in Maternal IQ Scores
Difference in HOME
Scores
Difference in Parental
Years of Education
7.5
3.6
0.75
7.58
9.42
11.27
1.5
9.11
10.96
12.81
2.25
10.65
12.50
14.35
0.75
11.77
13.62
15.46
1.5
13.30
15.15
17.00
2.25
14.84
16.69
18.54
0.75
15.96
17.81
19.65
1.5
17.50
19.34
21.19
2.25
19.03
20.88
22.73
7.2
10.8
15
22.5
Difference in Child IQ Scores
Source: Mink et al. (2004).

33. 
An additional “threat” to the validity of the
Pb/IQ studies are variables associated
with intelligence that are either unknown
or unmeasurable – the “Flynn effect”
(Kaufman 2001a)
◦ 3 point-per-decade gain in IQ beginning in the
1930’s and continuing to this day
◦ Exposure to technology/mass media?
◦ Parenting/increased awareness of importance
of providing cognitive stimulation in infancy?
◦ Improved nutrition?

34. 
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Bellinger, D., and Dietrich, K. N. 1994. Low-level lead exposure and cognitive
function in children. Pediatric Annals 23:601-605.
Canfield, R.L., Henderson, C.R. Jr., Cory-Slechta, D.A., Cox, C., Jusko, T.A., and
Lanphear, B.P. 2003a. Intellectual Impairment in children with blood lead
concentrations below 10 µg per deciliter. N Engl J Med 348:1517-1526.
Canfield, R.L.., Kreher, D.A., Cornwell, C., and Henderson, C.R., Jr. 2003b. Low-level
lead exposure, executive functioning, and learning in early childhood. Child
Neuropsychol 9:35-53.
EPA. 2013. Integrated Science Assessment for Lead. EPA/600/R-10/075F. Office
of Research and Development, National Center for Environmental Assessment,
Research Triangle Park, NC.
Ernhart, C.B. 1995. Inconsistencies in the lead-effects literature exist and cannot
be explained by "effect modification". Neurotoxicol Teratol. 17(3):227-233.
Hebben, H. 2001. Low lead levels and neuropsychological assessment: Let us not
be mislead. Archives of Clinical Neuropsychology 16:353-357.
Kaufman, A.S. 2001a. Do low levels of lead produce IQ loss in children?: A careful
examination of the literature? Archives of Clinical Neuropsychology 16:303-341.
Kaufman, A.S. 2001b. How dangerous are low (not moderate or high) doses of lead
for children' s intellectual development? Archives of Clinical Neuropsychology
16:403-431.

35. 
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Lanphear, B.P., Hornung, R., Khoury, J., Yolton, K., Baghurst, P., Bellinger, D.C.,
Canfield, R.L., Dietrich, K.N., Bornschein, R., Greene, T., Rothenberg, S.J.,
Needleman, H.L., Schnaas, L., Wasserman, G., Graziano, J., and Roberts, R. 2005.
Low-level environmental lead exposure and children’s intellectual function: An
international pooled analysis (Environ Health Perspect 113:894–899.
Mink, P.J., Goodman, M., Barraj, L.M., Imrey, H., Kelsh, M.A., and Yager. J. 2004.
Evaluation of uncontrolled confounding in studies of environmental exposures and
neurobehavioral testing in children. Epidemiology 15(4):385-393.
Miranda, M.L., Kim, D., Reiter, J., Overstreet Galeano, MA., and Maxson, P. 2009.
Environmental contributors to the achievement gap. Neurotoxicology 30:10191024.
Needleman, H.L., and Bellinger, D. 2001. Studies of lead exposure and the
developing central nervous system: A reply to Kaufman. Archives of Clinical
Neuropsychology 16:359-374.
Needleman, H.L., and Gatsonis, C.A. 1990. Low-level lead exposure and the IQ of
children. A meta-analysis of modern studies. JAMA 263(5):673-678.
Nielsen, J.B. and Jensen, T.K. 2005. Environmental Epidemiology. In: Essentials of
Medical Geology – Impacts of the Natural Environment on Public Health. O. Selinus,
Ed. Elsevier.
Schwartz, J. 1994. Low-level lead exposure and children's IQ: A meta-analysis and
search for a threshold. Environ Res 65:42-55..

36. 
Téllez-Rojo, M.M., Bellinger, D.C., Arroyo-Quiroz, C., Lamadrid-Figueroa, H.,
Mercado-Garcia, A., Schnaas-Arrieta, L., Wright, RO., Hernandez-Avila, M., and Hu,
H. 2006. Longitudinal associations between blood lead concentrations lower than
10 microg/dL and neurobehavioral development in environmentally exposed
children in Mexico City. Pediatrics 118:e323-e330.

37. EPIDEMIOLOGIC STUDIES FOR LEAD
WHAT ARE THEY GOOD FOR?

38. • Can epidemiologic studies
be used “across the board”
to determine whether lead
has affected a particular
individual?

39. General Causation
v.
Specific Causation

40. • Population based studies
• They were not designed –
nor could they be – to
determine whether a
specific child has been
affected by lead exposure

41. Does A equal B?
1. Do all smokers get lung
cancer?
2. Do all football players
sustain brain injuries?

42. • Epidemiologic Studies may
show “general causation”
• They cannot, by
themselves, get to specific
causation in an individual.

43. • Lead and IQ –
is there a correlation?
1. Is pre-morbid IQ testing
necessary?

44. a. In order to make an
intelligent assessment of
whether an individual has
lost IQ points as a result of
exposure to lead there must
be a baseline.
b.Studies that claim to
quantify IQ loss as a result
of exposure to lead are
speculative.

45. c. Not possible to “assign” a
loss of IQ with any elevated
lead level – only a
comparison between preinjury testing and postinjury assessment can yield
a true measure of
intellectual change.

46. d. Full scale IQ measure can
be unreliable for
determining a person’s
actual level of cognitive
capability.
e. Neuropsychological testing
is used to test areas
involving memory,
attention , executive
functions, verbal fluency.

47. f. How does an individual
test in these areas? Have
to look “behind the
numbers”
g. If a child scores low,
medium or high on any
test – does not mean they
would have scored
otherwise had there been
no lead exposure

48. • There is no specific/single
neuropsychological test or
result that allows for the
conclusion that a specific
child’s lead exposure had
any impact.

49. 2. Confounding Variables
Significant and wellknown risk factors for
the development of
cognitive difficulties
mirror claims of lead
exposure:

50. a. Low birth weight
b.Maternal pregnancy issues –
drugs/alcohol in utero
exposure
c. Prenatal smoking

51. d. Parental involvement
e. Structured
environment/lack thereof
f. Abuse issues
1) Mental
2) Physical
3) Sexual

52. h. Potential foster care
i.
Outside influences
j.
Drug Use by individuals
k. Depression/anxiety

53. •
Each individual different –
cannot “control” for all
variables
•
Fallacy of argument that
confounding factors are
being counted twice

54. 3. School Performance
a. Attendance – school and
specific classes
b. Homework completion
c. Extra help

55. d.
e.
f.
g.
Behavior problems
Discipline problems
Drug use
Frequent changes in
school – disruptive
learning

56. Conclusion
General population studies are
just that, not capable of being
used to determine that any
individual has been affected by
alleged exposure to lead.

59. 
ONE OF THE LONGEST EPIDEMIOLOGICAL
LONGITUDINAL STUDIES!
Quit smoking on the advice of
your physician?
 Epidemiological research.
Take Tamiflu in 2009?
 Epidemiological research.

60. 
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Lead is the most well studied toxin in history.
International pooled analysis:
◦ Data, not average of averages.
◦ Seven participating sites:
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Boston, Mass.
Cincinnati, Ohio
Cleveland, Ohio
Mexico City, Mexico
Port Pirie, Australia
Rochester, NY
Yugoslovia
Approximately 1,300 children.

61. 
International Pooled Analysis
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HOME Inventory
Sex
Birth weight
Birth order
Maternal education
Maternal IQ
Maternal age
Marital status
Prenatal smoking status
Prenatal alcohol use

62. 
Q And I think you had said it once best, and tell if it sounds -- you said this, but
just tell me
if you still agree with it, the researchers control for those factors so that the
conclusion of their study is specific to what is the measurable effect that lead has
on IQ loss?
A Correct.
Q And that's in the context of the pooled analysis. And for Needleman, it would
be the researchers controlled for those factors so the conclusion of their study is
specific to what is the measurable effect that lead has on behavior?
A Correct.
Q And so it's incorrect to assume that in order to reach the opinions you have in
this case, that you need administer the HOME test to the plaintiffs to determine
whether or not their lead exposure caused them IQ loss?
A That's correct.
Q It's already been done. That's the point.
A Well, and I'm only giving opinions about what IQ loss I would attribute using
this type of medical literature to this particular child.
Q And I know it sounds pedantic. Just work with me here. But the point that I'm
making is that you don't have to go back in the forensic context and control for all
these variables again. That's why the researchers did it in the first place?
MR. [Lawyer for the Defendant]: Objection.
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A
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That's correct. Yes. I agree with that.

63. 
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If only Johnny with his 65 IQ, reading disorder
and ADHD wouldn’t have missed 30 days his
4th time in 9th grade, it would have all worked
out okay.
Hammond et al., May 2007
◦ Among the top risk factors for dropping out of
middle school and high school:
 Learning disabled
 Low academic achievement
 Retention/over-age for grade
 Multiple retentions have additive effects, dramatically
increasing the risk of dropping out.

65. 
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Dr. Cris A. Williams Ph.D., Senior Science Advisor
ENVIRON
850.668.3551
cwilliams@environcorp.com
Gary Abelson
Hiscock & Barclay LLP
585.295.8411
gabelson@hblaw.com
Nicholas Szokoly
Law Offices of Evan K. Thalenberg, P.A.
410.625.9200
nszokoly@ektlaw.com
Dr. Karl Kieburtz MD, MPH
University of Rochester Medical Center
585.275.8762
Karl.Kieburtz@chet.rochester.edu