Human health and ecological risk assessment and risk management

Introduction to course Tuesday December 6 09.00 Herman Autrup Professor, PhD, Fellow ATS Human Health and Ecological Risk Assessment and Risk Management INTERNATIONAL FACULTY: Herman Autrup, Professor School of Public Health University of Århus Denmark Len Ritter, Professor Canadian Network of Toxicology Centres, University of Guelph, Canada Martin van den Berg, Professor Institute of Risk Asssessment Sciences, University of Utrecht, The Netherlands Mary E. Meek, McLaughlin Center for population Health Risk Assessment, Ottowa, Canada LECTURES: Give the theoretical background for risk assessment General human and ecotoxicology Tools used in risk assessments Animal studies Human studies Exposure assessment Mode of Action Standard setting Management and communication

Introduction to course

Tuesday December 6 09.00

Herman Autrup Professor, PhD, Fellow ATS

Human Health and Ecological Risk Assessment and Risk Management

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Course Coordinator : Khunying Mathuros

Ruchirawat

Objectives: Give an introduction to the assessment of risk of chemicals to human health and well-being and the environment, and present the newest concepts in the evaluation of risks

Format: Lectures including case studies, and risk

assessment exercise, special feature Presentation of IPCS/WHO Risk Assessment Toolkit

Teaching material: Hand-outs of power-point

presentations, and additional material provided by the lecturers

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Martin van den Berg, Professor Institute of Risk Asssessment Sciences, University of Utrecht, The Netherlands

Mary E Meek, McLaughlin Center for population Health Risk Assessment, Ottowa, Canada

Kerstin Gutschmidt, WHO, Geneva 3

Standard setting Management and communication

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RISK ASSESSMENT EXERCISE

Friday, December 16

Presentation of Risk Assessment Exercise – 30 min each group, allow 5 min for questioning

and discussion

Examination for graduate students:

January - 6 hrs written examination, questions prepared by all the international faculty -

members

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Toxic Effects of Chemicals

Tuesday December 6 09.15

Herman Autrup, Professor, PhD

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LIVING IN A CHEMICAL WORLD

 Man-made and natural

 Approx 60.000 chemicals in use

 Only 1500 chemicals account for 95% of the

production (HPV)

 Covers 11 mill different products

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GEOGRAPHIC BREAKDOWN OF

WORLD CHEMICALS SALES

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WHY WE SHOULD LEARN

TOXICOLOGY ?

We are

Syntetic Natural

We are surrounded by to a complex group of chemicals –

exposed via different routes

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CHEMICALS IN THE ENVIRONMENT

and manufacturing of product

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WHAT IS TOXICOLOGY?

• Toxicology helps

create a safer world

• Definition: The study

Toxicology is the art of

identifying the unexpected

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• Toxicology is arguably the oldest scientific discipline, as the earliest humans had to recognize which

plants were safe to eat

• Humans are exposed to chemicals both deliberately and inadvertently

Most exposure of humans to

chemicals is via naturally

occurring compounds consumed

in the diet from food plants.

TOXICOLOGY AFFECTS US EVERYDAY

California Wants to Serve a Warning With

Fries (NY Times, Sept 21, 2005)

Fish-mercury risk underestimated (CNN.com, Apr 12, 2001)

Ephedra Ban: What Took So Long?

(CBSNews.com, Dec 30, 2003)

Aluminum-plant Hungary, Oct 201017

Nov 5, 2004 © AP Images/Sergei Supinksy

July 3, 2004 © AP Images/Anatoly Medzyk

VIKTOR YUSHCHENKO:

POISONED BY DIOXIN

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ALL SUBSTANCES ARE POISONS, THERE IS

NONE WHICH IS NOT A POISON THE RIGHT

POISON FROM A REMEDY.

Modification of Paracelcus

Father of Modern Toxicology Areolus Phillipus Theophrastus Bombastus von Hohenstein

Paracelsus 1493-1564

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TOXICOLOGICAL PARADIGM

Exposure Internal Dose

Biologically Effective Dose

Early Biological Effect

Altered Structure &

Function

Disease

Absorption Distribution Metabolism Excretion Storage

What We do to the Chemical What the Chemical Does to Us

Susceptibility and Modifying Factors (Genetics and Nutritional Status)

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EXPOSURE DOSE TARGET DOSE Biological

TOXICOKINETICS

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LEVEL 1 - DEFENCE

PROPERTIES OF CHEMICALS

LIPID SOLUBILITY IONISATION

SIZE of MOLECULE PHYSICAL FORM

CONTACT POINT

S SKIN, LUNG, GI

Physical barrier, blood circulation 22

GASTROINTESTINAL TRACTS

Exposure: Diet and water

Macrophage engulfed particles

Dose depends on level of contaminants in source

Risk assessment: How much is taken up – dose –

default 100%

Transport via blood and lymph to liver

Factors controlling uptake:

Lipid solubility Degree of ionization Size of molecule

pH

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UNBORN CHILD - PLACENTA

• Lipid solubility

• Molecule size

• Ionisation

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UPTAKE-DISTRIBUTION

Local and Systemic toxicity

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UPTAKE - EXCRETION

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LEVEL 2 DEFENCE - METABOLISM

Metabolism to less toxic compounds

Excretion in urine Exhalation

Phase 1 Hydroxylation – less hydrophobic (CYP450)

Phase 2 Conjugation of the toxicant or its metabolites

formed by phase 1 reaktion (GST)

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METABOLISME - BENZEN

KEY POLYMORPHIC GENES:

CYP 2E1 *mEH

GSTT1 NQO1 *MPO *

SPECIES VARIATION IN METABOLISM – DIFFERENT TOXICITY 28

EXPOSURE DOSE TARGET DOSE

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TOXICOKINETIC MODELLING

CELL RESPONSE TO STRESS AND

INJURY

Normal cell(homeostasis)

MECHANISTIC TOXICOLOGY

Focuses on how

• Chemicals produce adverse effects

• Biological systems protect

themselves against adverse effects

Involves

• Cellular and Molecular Biology

• Chemistry, often xenobiotic

metabolism

Xenobiotic: a chemical that is foreign to the

MOLECULAR BASIS OF TOXICITY

Metabolic product

Proteomics Proteins

-Transcriptomics - RNA

Biochemical or physiological response33

GENOMICS IN TOXICOLOGY

• Comprehensive understanding of the

mechanism of action of toxicants

• Identification of biomarkers of exposure

• Development of comprehensive screening

tools to identify potential toxicants

• Extrapolation of mechanisms between

species

• Identification of susceptible populations

• Applicable to single chemicals or mixtures,

common or divergent mechanisms of action

• Reduction of animal in toxicological testing 34

Depends on time of

exposure

Depends on dose

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MECHANISM OF TOXICITY

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Peroxisome proliferators

Polycyclic aromatic hydrocarbons Oxidant stressors

Suspected toxicant

Raw data

No match

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Hierarchical clustering of all significantly altered pathways after treatment with AFB1, BaP, TCDD, or CsA for 12, 24, 36, and 48 h based on the t-values generated by T-profiler.

Mathijs K et al Toxicol Sci 2009;112:374-384

© The Author 2009 Published by Oxford University Press on behalf of the Society of Toxicology

All rights reserved For permissions, please email: journals.permissions@oxfordjournals.org

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TRANSLATION OF TOXICOGENOMICS TO

EFFECT IN MAN

1 A gene is not a pathway

2 A pathway is not an organelle

3 An organelle is not an organ

4 An organ is not an animal

5 An animal is not a human

6 A human is not a population

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• Calcium homeostasis

• Selective cell death (apoptose)

MECHANISM OF ACTION (MOA)

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RECEPTOR MEDIATED TOXICITY

Agonist - binding to receptor

Antagonist - binding of normale ligand

blocked Receptors - Ah-receptor

Dioxin, PCB

estrogen receptor; androgen receptor; thyroid receptor

Endocrine disrupting chemicals

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Stroma

Activation of T-cells

Function of kidney, mammary glands, bones

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GENERATION OF OXIDATIVE

STRESS

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REACTIVE OXYGEN SPECIES

BIOLOGICAL RESPONSE TO

OXIDATIVE STRESS

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TOXICANTS INDUCING TOXICITY BY

ADVERSE HEALTH - ROS

Indirect Signal transduction Gene regulation

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CELLULAR RESPONSE TO ROS

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CELL DEATH

Programmed Non-programmed

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• = Cell death

• Morphological changes result from the denaturation of proteins and enzymatic digestion of cellular organelles

• Leakage of proteins/enzymes out of the injured cell can be used clinically as a

marker of cell death (e.g raised serum

levels of cardiac enzymes after an MI)

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• Programmed cell death

• Required to ensure that there is a steady

turnover of cells in tissues and in

response to physiological stimuli

– Shedding of menstrual endometrium

– Involution of breast after weaning

– Prostatic ‘atrophy’ after castration

– Cell turnover in intestinal crypts

– Death of inflammatory cells after inflammation

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CELLULAR CHANGES - APOPTOSIS

Cells round up and lose

contact with their

neighbours and the

extracellular matrix

Various apoptotic signals cause the outer mitochondrial membrane to become permeable

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DESCRIPTIVE TOXICOLOGY

Types of toxicity testing

• In vitro (test tube)—useful in detecting potential biochemical and

genetic effects

– Use model systems (bacteria, cultured animal cells, DNA interactions)

• In vivo (animal)—are essential for detecting health effects

– Acute, chronic, multi-generation

– Experimental animals may be treated with high doses over a lifetime

to evaluate potential to cause cancer

• In silico (computer-based)—biological

experiments conducted by computer

models; these depend on data previously

collected in other experiments

Completion of all toxicity tests may take

five or six years and is very costly

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TOXICOLOGY OF MIXTURES

• Exposure is often to more than one

chemical, either through co-exposures or

exposure to mixtures

• Each mixture of chemicals can have unique

toxicology

• Few mixtures in the real world are the same

– Difficult to make comparisons

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EXAMPLE OF COMPLEX MIXTURES

• Wood smoke

• Diesel smoke

• Crude oil

• Cigarette smoke

• Leachate from waste sites

• Indoor air pollution

• Outdoor air pollution

• Chemical composition is not well known

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SENSITIVE POPULATIONS

Exposure Exposure Exposure

SAFETY FACTOR: 10

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The emerging field of

“Pharmacogenomics” or

“Toxicogenomics” offers the potential to identify and protect

toxicity from chemicals or drugs

Typical Population

Identify People with “normal” responses

More Sensitive

Less Sensitive

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TOXICOLOGY PROVIDES INSIGHT

TO PROTECT HEALTH

• Reduction of Blood Lead Levels provides economic gains

– Children in late 1990s had IQs 2.2–4.7 higher than they would have if they had the same blood level as children in the late 1970s

– Estimated about 2% increase in worker productivity

– Economic benefit for each year’s cohort $110–319 billion

EHP 110(6):563-569

Living in a chemical world

The toxicity (hazard) depends on target dose

Target dose depends on environmental

concentration (exposure), uptake and metabolism

Molecular toxicology useful in identification of

MOA

Different susceptibility

Human are exposed to complex mixtures 61