THE RISK ASSESSMENT introduction2010

is the inherent capacity of a substance or a mixture to cause adverse effects in man or the environmnet under the condition of exposure RISK is the probability of an adverse effect

THE RISK ASSESSMENT PROCESS

Tueday December 6 2011

Herman Autrup

is the inherent capacity of

a substance or a mixture

to cause adverse effects in

man or the environmnet

under the condition of

exposure

RISK

is the probability of an adverse effect on man or the environmnet occuring as

a results of a given exposure to a chemical or mixture

HAZARD vs RISK

EXPOSURE HAZARD

RISK ASSESSMENT PARADIGME

RISK CHARACTERIZATIONRISK ASSESSMENT

RISK ASSESSMENT

 Systematic, scientific characterization of potential adverse human or ecological exposure to hazardous agents or activities

 Considers relationship between exposure and

responses, including variation in susceptibility and

IMPROVEMENT OF EXPOSURE INFORMATION

• Identification of relevant structural

characteristics and potential mechanism

or mode of action of a target chemical

• Identification of other chemicals that

have the same structural characteristics

and/or mechanism or mode of action

• Use of existing experimental data to fill

the data gap(s)

FILLING THE DATA GAPS

LIFE CYCLE OF A CHEMICAL

RISK= HAZARD x EXPOSURE

Hazard ( high concern ) x Exposure ( minimal ) =

low risk

Hazard ( low concern ) x Exposure ( high ) =

low risk Hazard ( moderate concern ) x exposure ( high )=

Potential for risk exists

RISK SOURCES – CHEMICALS

 Industrial chemicals

 Byproducts/Waste

 Fertilizers

 Veterinarian drugs (contaminants)

Can be found in many different environments - air, water, soil

RISK SOURCES - EXPOSURE

 Home – use of products

 Workplace – production of chemical

and manufacturing of product

 General environment – indirect exposure

 Transit – accidents

 Misuse of chemicals

Risk scenarios for all exposures

RISK SOURCES - AIR

RISK SOURCE - DRINKING WATER

RISK SOURCES - FOOD

processing - acrylamide

COMPOUNDS OF SPECIAL CONCERN

HAZARD IDENTIFICATION

has the potential to cause adverse effects

presence of a hazard

alternative methods, in silico (QSAR)

HAZARD IDENTIFICATION –

REGULATORY REQUIREMENTS

QUALITY OF DATA - OECD

documentation

• Appropriate species tested

population and exposure scenario

• Analytical epidemiological studies

Relationship between human exposure and effects:

biological effects marker, early signs of chronic effects,

disease occurrence or mortality

• case control, cohort, cross sectional studies

• Descriptive epidemiological studies

• Case reports

• Controlled studies in human volunteers

 Ethical considerations!

HUMAN DATA

DOSE-RESPONSE - EFFECT ASSESSMENT

• CONSIDERATION OF TOXIC EFFECTS AT

VARIOUS DOSE LEVELS

• EFFECTS: GRADED AND MEASURED

RESPONSE: QUANTAL AND COUNTED

• SHAPE OF THE DOSE-RESPONSE CURVE

• ESSENTIALITY CONSIDERATIONS

• NO(A)EL DERIVATION vs PROBABILISTIC

APPROACHES

BMD10

EFFECT LEVELS

ACUTE TOX:

50% of the test population (labelling of chemical)

CHRONIC TOX:

NOEL = No observed effect level ( acceptable intake

levels, TDI)

LOEL = Lowest observed effect level

NOAEL = No observed adverse effect level

BMD10 = Dose at which 10% of animals is affected

• Identify effects of concern

HUMAN HEALTH EFFECTS DATA

humans animal experiments in vitro tests (Q)SAR

uncertainty Relevance, complexicity, costs

WHAT IS EXPOSURE ASSESSMENT?

• EXPOSURE is the contact of a chemical,

physical, or biological substance with the

outer boundary of an organism

• EXPOSURE ASSESSMENT is the

determination or estimation of the

magnitude, frequency, duration, and route of exposure

EXPOSURE PATHWAYS

EXPOSURE ASSESSMENT - CRITICAL

ISSUES

• EXPOSURE ASSESSMENT MUST CONSIDER

TIME SCALE RELATED TO TOXICOLOGICAL EFFECT

• PEAK EXPOSURES; AVERAGE EXPOSURE

• CRITICAL WINDOWS OF EXPOSURE (e.g

REPRODUCTIVE EFFECTS)

• PERSISTENCE

• BIOACCUMULATION

RISK CHARACTERIZATION

INTEGRATION OF EXPOSURE DATA

and DOSE RESPONS

SUSCEPTIBLE POPULATION –

CHILDREN, ELDERLY

RISK CHARACTERIZATION

the estimation of the incidence and severity of the adverse affect likely to occur in a human

population (or environmental compartment) due

to actual or predicted exposure to a substance

 comparing a no effect concentration to an

exposure value (thresholded)

 determine exposure levels for acceptable risk (non thresholded)

THE USE OF UNCERTAINTY OR SAFETY FACTORS

species

Uncertainty or safety factors are used to extrapolate from a group of test

animals to an average human and from average humans to potentially sensitive sub-populations.

MOS (MARGIN OF SAFETY )

The MOS is a simple ratio of a N/LOAEL observed for a specific adverse effect divided by the predicted

exposure (measured or modeled) for each scenario.

EXPOSURE N/LOAEL MOS =

ASSESSMENT FACTORS TO SET A

Example: MOS values for fertility impairment

Dermal Exposure explanationNOAEL from an oral mice

study 175 mg/kg/day

175 x 70 kg Starting point for MOS

calculation (“human dose”) 12250 mg/person/day

MULTIPLE SOURCES of same chemicals

COMPLEX EXPOSURES – multiple

chemicals

COMPLEX MIXTURES

 Hazard quotient

 Toxic equivalents

 Additive effects

EXPOSURE - COMPLEX MIXTURES

HAZARD QUOTIENT

Hazard quotient = dose/RfD

Sum across all exposure pathways

Segregate chemicals by mechanism of action

and/or target organ

HQ = c1/RfD+ + cn/RfD <1

INFORMATION OF HEALTH EFFECT DATA

Primary scientific literature – www.medline.gov ;

REGULATORY DECISIONS

REGULATION OF CHEMICALS IN EU

 Industrial chemicals Regulation 1907/2006

 Plant protection products Directive 91/414/EEC

 Biocides Directive 98/8/EC

 Food additives Directives 89/107/EEC

 Food contact material Framework Regulation

1935/2004

 Cosmetics Directive 2003/15/EC

 Toys Safety Directive 2009/48/EC

Thank you!

for your attention