National Public Health Institute, Finland
Combining epidemiological and
toxicological dose-responses:
Dioxin-induced tooth lesions
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Jouni Tuomisto
KTL
Kuopio, Finland
National Public Health Institute, Finland
Acknowledgements
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• The working group in KTL
– Marjo Niittynen, M.Sc.
– Jouni T. Tuomisto, MD, PhD
– Anne Karvonen, M.Sc.
– Anna Karjalainen, PhD
– Juha Pekkanen, MD. Prof.
National Public Health Institute, Finland
Current combining of epi and tox data
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• In hazard identification (qualitative): in use
• In dose-response assessment (quantitative):
trickier, no developed methods available
⇒ Need for a framework to quantitatively combine
epi and tox data
• A part of EU-projects Intarese and Beneris about
developing tools for risk assessment
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Objective
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• To develop a systematic way of utilising
epidemiological and toxicological data in
dose-response estimation
• The ultimate goal: More precise and
transparent environmental health risk
assessment
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The research questions:
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1) What is the true dose-response relationship in
humans for chemical X (its slope and shape)?
2) How do we know what the true dose-response
relationship is?
3) What are the factors that affect our
understanding of the uncertainties (size and
direction) of the answer to question 1?
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Our approaches
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1. Checklist of correction factors for the doseresponse relationship
2. A causal diagram describing the phenomenon
as real-world objects and their causal links
3. A case study: TCDD-induced developmental
dental defects: human vs. rat
–
–
–
Almost the same endpoint
Similar exposure levels
Exposure can be expressed in same metrics
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TCDD-induced developmental dental
defects: human vs. rat
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• TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin)
– Most toxic congener of dioxins
• Ubiquitous, persistent environmental contaminants
• Bioaccumulate: humans are exposed via food
• Induce a wide array of adverse effects in animals/humans
Cl
O
Cl
Cl
O
Cl
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TCDD-induced dental defects in
humans
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• A study on dental effects in humans exposed to
TCDD in Seveso, Italy, 1976 (Alaluusua et al.
2004) Environ Health Perspect 112:1313–1318 (2004)
– Exposed persons:
• residents of the contaminated area
• age < 5 years
• serum TCDD level was measured
– Controls
• from the surrounding non-contaminated area
– Teeth were examined in adulthood for enamel defects
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Dental lesions in Seveso children
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Alaluusua et al., 2004
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TCDD-induced dental defects in rats
• Kattainen et al. 2001 (Toxicology and Applied
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Pharmacology 174, 216–224 (2001))
– Pregnant rats were exposed
intragastrically to low doses
(0.03 – 1 µg/kg) of TCDD
– Teeth of the offspring were examined at
the age of 35 and 70 days
• Missing molars
• Smaller molars
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Dental lesions in rat
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• Kattainen et al., 2001
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Results
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Causal diagram of dose-response (1)
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Causal diagram of dose-response (2)
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Causal diagram of dose-response (3)
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Dose-response curves
Risk for dental defects
100
90
80
risk %
70
60
50
40
Seveso children
Line C rats, limit 1.45 mm
Line C rats, limit 1.5 mm
30
20
10
0
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0
2000
4000
6000
TCDD-concentration pg/g lipid
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Uncertainties in the human study
(Seveso)
Main
• Exposure misclassification
– Serum TCDD-levels of the controls not measured
– Part of the exposed persons had overlapping TCDD
concentrations with the background exposure
– Time-point of collecting serum samples
Other (less important here)
• Selection bias
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– Randomly invited study population: not all participated
• Confounders
– Possibly e.g. medication
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Uncertainties in the rat study
Main
• Toxicodynamics (AHR activation – pathways leading to
defects)
• Differences in the exposure time-point relative to teeth
development
Other (less important here)
• Toxicokinetics
• Endpoint extrapolation
• High-to-low-dose extrapolation
The size and direction of the uncertainties in both studies
are under analysis
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Conclusions
• Similar sources of uncertainty in both
epidemiologial and toxicological studies,
magnitude of these uncertainties varies
greatly
• Necessary prerequisites for combining
epidemiological and toxicological data:
– Common metrics for the exposure
– Common metrics for the uncertainties
⇒Common conceptual framework
• More discussion: http://heande.pyrkilo.fi