6° EASOM Summer School
August 31st - September 2nd, 2006
THE IMPORTANCE OF OCCUPATIONAL
AND ENVIRONMENTAL EPIDEMIOLOGY
FOR THE OCCUPATIONAL HEALTH
PRACTICE
Pier Alberto Bertazzi
University of Milan & IRCCS Maggiore
Hospital Foundation
Milan, Italy
Outline
• Challenges ahead
• Epid. designs to address them
• Seveso as a case in point
OH Practice
• Traditionally, the recognition, diagnosis and
control of occupational risks and diseases have
been following well specified and standardized
procedures (regulated sometimes not just by
medical and scientific competence but even by
law). The OH practice was essentially called to
comply with those regulations.
Occup/envir. epidemiology
• Occup/envir epidemiology has mainly
been serving OH practice by addressing
particular, specific issues, in particular
occupational cancer hazards identification.
Changes at the workplace
Today, things have changed and still are
changing at work, in science and in medicine.
• Workplace hazards are less obvious to identify and to
measure.
• Occupational factors increase the risk of “common” diseases
(a-specific effects)
• Specific effects are vague, psychological, subjective
(distress, discomfort).
• Genetics and behaviour are becoming more and more
relevant.
• Working population is changing in terms of age structure,
sex composition, and ethnicity.
Change in hazards
Workplace hazards are less obvious to identify
and measure (and hence to control)
• Population vs. sick individual approach
• Longitudinal observation of exposed
(exposure-dose-early effect-disease)
Change in effects I
Occupational factors increase the risk of
common diseases (a-specific effects).
• Populations comparison (exposed vs.
reference)
• Small increase in risk visible only in
relative terms (vs. background)
• Need to observe large groups.
Change in effects II
Specific effects are vague in nature, mainly
psychological, subjective (distress and
discomfort).
• Accuracy and validity of diagnostic means
and procedures
• Surveillance of healthy population not of
sick individuals
• Need to observe large groups.
Novel causative components
Genetic and behavioural components are
becoming more and more relevant.
• Gene – environment interaction as
population effect
• Psychic and psychosomatic effects
(lagoon of causative factors)
• Avoid bias, control confounding, consider
interactions.
Working population change
Working population is changing in terms of
age structure, sex composition,
and ethnicity.
• Relevance of inherited and acquired
susceptibility.
• Multi-component causative web
• Targeted interventions including re-training
and health promotion
The core type of activity needed
in such a changing context:
OBSERVATIONAL STUDY OF EXPOSED
POPULATION OVER TIME
This is……
….What we ought to contribute to, when we practice
Research
….What we have to teach to our students
Teaching
….What can confer appropriateness and effectiveness
to OH practice and intervention
Practice
….What makes evaluation possible
Evaluation
PRIORITIES IN OCCUPATIONAL HEALTH RESEARCH - UK
• Natural history of work related ill health
Musculoskeletal disorders (back & upper limb)
Asthma
Accidents
Skin disease
Vibration induced disease
Suicide
Depression
Hearing loss
• Audit in occupational health screening procedures
• Environmental impact of industrial activity
Community > individual level
• Stress related disease
• Neuro-psychological effects
• Cost-effectiveness of occupational health
• Risk assessment
• Reproductive hazards
• Effects of pharmacological agents
• Development of biomarkers as early evidence of an exposure effect
Need to answering new questions
about safety and health at the
workplace:
Which study design?
Depends on the exposure and nature of health
outcome of interest, and on feasibility
Cohort
Follow up of an exposed population and
determination of subsequent incidence of
health outcomes
• Historical - long induction and latency period
• Prospective – short temporal relation
between exposure and subsequent risk
Cross sectional
Comparison of disease prevalence among
groups classified according to exposure.
• Study of persistent conditions (rather than
transient and reversible)
• Repeated measurement study
Case-control
Exposure comparison between an index case
group and a reference group of persons free
of the disease at the time of case definition
•
•
Nested within a cohort
Community based
Case-cohort
Multiple case groups and a common comparison
group, “reference sub-cohort”, random sample
of the source population (cohort)
• Efficient in testing associations with multiple
health outcomes
Case-crossover
Comparison of cases’ exposure immediately
before their events with exposure that
occur at other typical times. Each case
serves as his/her matched control.
• Suitable for risk factors of health outcomes
that occur in close temporal sequence to
exposure (disease triggers).
• Full control of time invariant confounders
(genetics)
CASE CROSSOVER DESIGN
(Mc Lure 1991)
In the light of the specific issues
we are facing today in OSH…..
• Strategy of choice appears to often be a
combination of epidemiologic studies.
• The best way to illustrate and to teach this
is through examples (hypothetical, at least)
of complex multi-causal effects and given
workplace exposure or case studies of
complex exposures related to multiple
effects (e.g., the Seveso accident).
Lombardy Region
ICMESA, the Seveso Accident plant
Dept. B: Production of 2,4,5-trichlorophenol TCP
Seveso, Italy, 1976
TCP production plant
Cl
O
Cl
Cl
O
Cl
2,3,7,8-Tetrachlorodibenzo-p-dioxin
(TCDD)
Seveso, Italy, 1976
DESIGN and CONDUCT ISSUES
•
•
•
•
•
•
•
•
•
Exposure: type, entity, duration.
Exposed/Pop. at risk: definition, identification.
Effects: type, latency, diagnosis.
Follow-up: contact, observation, means and
procedures.
Study: type of design, study population (sample),
duration.
Reference population: control of confounding.
Information: validity and quality.
Analyses and interpretation.
Communication: scientific and social.
OBJECTIVES ADDRESSED
AFTER THE ACCIDENT
-
Ascertaining the exposure, its nature and
characteristics, the extent of contamination and
number of people involved
-
Managing the risk with preventive measures for
people and their environment
-
Planning and conducting health surveillance
programs
EXPOSURE ASSESSMENT
EMISSION
SOURCE
- pollutant type
- amount released
ECOLOGICAL AND
ENVIRONMENTAL
MEASUREMENTS
- surface soil
- deeper soil layers
- water
- airborne dust
- vegetation
- animals
- cow’s milk
HEALTH EFFECTS
- early and mid-term
- long term
HUMAN EXPOSURE/
DOSE
- personal habits and
activities
- chloracne
- biological samples
Exposure
The Seveso
area
Zone A
Accident
Zone A
Zone
Pop
Population:
804
Soil TCDD (1976):
15.5-580.4
µg/m2
Soil
concentration
Min
Zone B
Max
Reference
580.4
zone
A
804
15.5
B
5,941
1.7
4.3
R
38,624
0.9
1.4
Reference
232,745
NA
NA
Zone R
Bertazzi et al., Environ Health Perspect 1998
The Seveso
area
Zone B
Accident
Zone A
Zone
Pop
Population:
5,941
Soil TCDD (1976):
1.7-4.3 µg/m2
Soil
concentration
Min
Zone B
Max
Reference
580.4
zone
A
804
15.5
B
5,941
1.7
4.3
R
38,624
0.9
1.4
Reference
232,745
NA
NA
Zone R
Bertazzi et al., Environ Health Perspect 1998
The Seveso
area
Zone R
Accident
Zone A
Zone
Pop
Population:
38,624
Soil TCDD (1976):
0.9-1.4 µg/m2
Soil
concentration
Min
Zone B
Max
Reference
580.4
zone
A
804
15.5
B
5,941
1.7
4.3
R
38,624
0.9
1.4
Reference
232,745
NA
NA
Zone R
Bertazzi et al., Environ Health Perspect 1998
The Seveso
area
Reference
Accident
Zone A
Zone
Pop
Population:
232,745
Soil TCDD (1976):
NA
Soil
concentration
Min
Zone B
Max
Reference
580.4
zone
A
804
15.5
B
5,941
1.7
4.3
R
38,624
0.9
1.4
Reference
232,745
NA
NA
Zone R
Bertazzi et al., Environ Health Perspect 1998
TCDD plasma levels, 1976
Plasma TCDD (ppt)
100,000
10,000
1,000
100
10
}
Zone
Zone AA
Zone B
Background
Zone R
Needham et al., Chemosphere 1998
Plasma TCDD after 20 years
Plasma TCDD (ppt)
.
70
TCDD Range: 1.0-89.9 ppt, lipid adjusted
60
Females
50
Males
40
30
20
10
0
Zone A
Zone BB
Zone
Zone A
Reference
Landi et al., Lancet 1997
Early cross-sectional studies
CHROMOSOMAL ABERRATIONS
IN LYMPHOCYTES, 1977
Exposure
No.
No. Aberrant cells %
Subjects Mitoses Gaps + Gaps -
Acute
Chronic
Controls
(De Carli et al. 1982)
145
69
87
6470
3040
3958
2.49
2.53
1.64
0.99
0.92
0.48
CONGENITAL MALFORMATIONS
ZONES A+B+R vs. REFERENCE
DEFECTS
JAN-APR 1977
RR
TOTAL
MAJOR
MILD
90% CI
1977-1982
RR
90% CI
1.49 0.64-3.45 0.97 0.83-1.13
0.93 0.26-3.32 0.83 0.67-1.04
2.50 0.79-7.94 1.14 0.92-1.42
(Mastroiacovo et al. 1988)
CHLORACNE CASES 1976-1977
ZONE
A total
A-max
B
R
R Polo
Outside
SUBJECTS CHLORACNE PERCENT
3-14 YRS.
CASES
214
54
1,468
8,680
750
48,263
(Caramaschi et al. 1981)
42
26
8
63
19
51
19.6
48.1
0.5
0.7
2.5
0.1
Incidence studies
Mortality
(Zone A+B)
Males
Females
Obs RR* (95% CI) Obs RR* (95% CI)
All Causes
438
1.0
(0.9-1.1) 307
1.0
(0.9-1.1)
All Cancers
166
1.1
(1.0-1.3)
83
0.9
(0.7-1.1)
Lympho/Hemato
15
1.7
(1.0-2.8)
13
1.8
(1.1-3.2)
Rectum
10
2.4
(1.2-4.6)
3
1.1
(0.4-3.5)
28
1.4
(0.9-2.0)
18
1.0
(0.6-1.5)
CHD
*Analysis adjusted for age and sex
Bertazzi et al., Am J Epidemiol 2001
Cancer incidence (Zone A+B)
Males
Females
Obs RR* (95% CI) Obs RR* (95% CI)
All Cancers
122
1.0
(0.8-1.1)
82
1.0 (0.8-1.2)
Lympho/Hemato
15
1.9
(1.1-3.1)
10
1.6 (0.9-3.1)
Non-Hodgkin
8
2.6
(1.3-5.6)
3
1.2 (0.4-3.7)
Multiple Myeloma
2
1.9
(0.5-8.0)
3
4.9
9
2.0
(1.0-3.9)
3
1.1 (0.3-3.4)
10
1.3
(0.7-2.4)
7
2.4 (1.1-5.1)
Breast
-
-
-
23
0.9 (0.6-1.3)
Endometrium
-
-
-
2
0.5 (0.1-2.0)
Ovary
-
-
-
1
0.2 (0.1-1.6)
Vagina
-
-
-
2
5.5
Rectum
Hepatobiliary
*Analysis adjusted for age and sex
(1.5-16)
(1.3-24)
Pesatori et al., Ind Health 2003
OFFSPRING SEX RATIO AND
PARENTAL TCDD LEVELS
ZONE A
BLOOD TCDD
RANGE (ppt), 1976
Family #
Father
OFFSPRING
(1977-84)
Mother Male Female
1-9
104-2340 126-1650
0
12
10-13
29.3-65.4
4
1
(Mocarelli et al. 1996)
ND-36.5
Case-control
retrospective study
Chloracne
Case-Control
Study
Higher TCDD exposure:
The only determinant of
chloracne?
 101 chloracne cases
 Median age: 8 years
 211 controls
 Enrollment: 1993-1998
Opportunity to identify
susceptibility factors!
Plasma TCDD range
450
400
475 ppt
350
300
250
200
150
125 ppt
100
50
0
nd
Chloracne Cases
Chloracne
Cases
nd
Controls
Healthy
Controls
Mean plasma TCDD
Chloracne
10
Plasma TCDD (ppt)
.
9
8
7
6
5
4
3
2
1
0
Chloracne
NO
Controls
YES
Potential Susceptibility
Factors
TCDD>10 ppt
10
9
p-interaction=0.02
Odds Ratio
8
7
p-interaction=0.04
9.2
(2.6-33)
7.4
(1.8-30)
6
5
4
3
2.1
3.7
(1.6-8.8)
(0.7-6.1)
1.3
2
(0.6-3.1)
1
all
All subjects
<=8
<=8 years
years
>8 years
years
>8
AGE
Light
Light
Dark
Dark
HAIR COLOR
Analysis adjusted for age, sex and zone of residence
Health conditions
after 20 years
 No differences between chloracne cases
& healthy controls
•
•
•
•
•
•
Allergic diseases
Gastrointestinal disorders
Infectious diseases
Endocrine disorders
Respiratory diseases
Offspring health status
Baccarelli et al., Br J Dermatol, 2005
Late cross-sectional studies
Subclinical conditions
after 20 years
 Subjects with high plasma TCDD
• Decreased IgG plasma levels
(Baccarelli, EHP
2002)
• AhR-related transcript alterations
(Landi Carcinogenesis 2003, Baccarelli Tox Lett 2004)
IgG plasma levels
1600
1400
p=0.03
p=0.01
IgG (mg/dl)
1200
1000
800
600
400
200
0
Reference
Reference
Zone
ZoneBB
Zone
ZoneAA
Baccarelli et al., Environ Health Perspect 2002
Plasma TCDD vs. IgG
2500
n = 109
r = -0.35
p = 0.0002
IgG (mg/dl)
2000
1500
1000
750
1
5
10
20 30
50
90
Plasma TCDD (ppt, lipid adjusted)
Baccarelli et al., Environ Health Perspect 2002
Need to rediscover population approach
coupled with high risk individual approach
Epidemiology has largely ceased to function as part of a
multidisciplinary approach to understanding the
causation of disease in populations and has become a
set of generic methods for measuring associations of
exposure and disease in individuals. …….
(for studying) decontextualized individual risk factors,
rather than to study population factors in their social and
historical context. ……
We seem to be using more and more advanced technology
to study more and more trivial issues, while the major
causes of disease are ignored. Epidemiology must
reintegrate itself into public health and must rediscover
the population perspective”.
(N. Pearce, Am J Public Health, 1996, 86:678-683)
PREGNANCY LOSS RATE,
1976-1977, BY TRIMESTER
TRIMESTER ZONE B
07-09 ‘76
10-12 ‘76
01-03 ‘77
04-07 ‘77
07-09 ‘77
10-12 ‘77
(Bisanti et al 1980)
11.1
22.2
17.2
28.5
31.2
13.7
ZONE R REFERENCE
13.7
16.3
12.7
12.5
11.4
13.8
11.0
14.8
16.6
13.0
10.5
14.3
Effect of plasma TCDD
Plasma TCDD
p=0.03
AhR
p=0.01
p<0.001
AhR
EROD
ARNT
p=0.001
DRE
+
_
Uncultured
cells
p=0.03
p=0.001
p<0.001
CYP1A1
TCDD
stimulated
Cells
CYP1B1
Baccarelli et al., Tox Lett 2004