 Definition of risk: 

Risk = Hazard X Exposure

Hazard Risk Exposure 4/24/2020 1

RISK EVALUATION Hazard identification Hazard characterisation (Dose-resp. relationship) Hazard assessment Human health Environment Exposure assesment Risk characterisation

4/24/2020 2

Risk Assessment and Management by the Organization for Economic Co-operation and Development

Although conceptually distinct, risk assessment and risk management are often impossible to separate in practice. Risk assessment is essentially a preliminary to setting up proper risk management procedures. Confirmation of the effectiveness of risk management procedures requires reassessment of the risks after implementation of management procedures.

4/24/2020 3

Definitions

A recent publication by the Organization for Economic Co-operation and Development (OECD, 2003) gives up-to-date definitions of risk, risk assessment and risk management.

4/24/2020 4

Risk

. The probability of an adverse effect in an organism, system or (sub) population caused under specified circumstances by exposure to an agent. ‘ risk is the possibility of suffering harm from a hazard ’

Risk assessment

. A process intended to calculate or estimate the risk to a given target organism, system or (sub) population, including the identification of attendant uncertainties, following exposure to a particular agent, taking into account the inherent characteristics of the agent of concern as well as the characteristics of the specific target system.

4/24/2020 5

The risk assessment process includes four steps: 1.

2.

hazard identification, hazard characterization (related term: dose – response assessment), 3.

exposure assessment and 4.

risk characterization.

It is the first component of a risk analysis process.

4/24/2020 6

Risk management

Risk management.

Decision making process involving consideration of political, social, economic and technical factors with relevant risk assessment information relating to hazard so as to develop, analyze and compare options and to select and implement appropriate regulatory responses to that hazard. Risk management comprises three elements: risk evaluation, emission and exposure control and risk monitoring.

7 4/24/2020

Hazard

. The inherent property of an agent having the potential to cause adverse effects when an organism, system or (sub) population is exposed to that agent.

Exposure

. Concentration or amount of a particular agent that reaches a target organism, system or (sub) population in a specified frequency for a defined duration. Not all chemical hazards are toxic hazards. Fire and explosion hazards are not usually considered toxic.

Toxicity

is defined as ‘ the inherent property of an agent to cause an adverse biological effect ’ .

4/24/2020 8

PROCESS OF RISK ASSESSMENT

The process of risk assessment consists of four steps: hazard identification, hazard characterization (related term: dose – response assessment), exposure assessment and risk characterization. The OECD (2003) describes these steps as: 4/24/2020 9

Hazard identification

. The identification of the type and nature of adverse effects that an agent has as an inherent capacity to cause in an organism, system or (sub) population.

Hazard characterization

. The qualitative and, where possible, quantitative description of the inherent properties of an agent having the potential to cause adverse effects. This should, where possible, include a dose – response assessment and its attendant uncertainties. (

Dose – response assessment

: Relationship between the amount of an agent administered to, taken up or absorbed by an organism, system or (sub) population and the reaction to the agent.) 4/24/2020 10

Exposure assessment

. Evaluation of the exposure of an organism, system or (sub) population to an agent (and its derivatives).

Risk characterization

. The qualitative, and, where possible, quantitative determination, including attendant uncertainties, of the probability of occurrence of known and potential adverse effects of an agent in a given organism, system or (sub) population, under defined exposure conditions.

4/24/2020 11

HAZARD IDENTIFICATION AND CHARACTERISATION

Identifying the potential harm of a substance or process may involve any or all of the following: observation, experimental work, information retrieval and deductive work based on physicochemical parameters and structure – activity relationships. It includes identifying the type of harm (

e.g.

narcosis, skin sensitization, cancer) as well as characterizing the dose levels at which harm occurs.

12 4/24/2020

Sources of Information

Internationally validated assessments of relevant literature are available through the International Programme on Chemical Safety (IPCS; the Environmental Health Criteria series) and, for cancer, through IARC (the International Agency for Research on Cancer) series of monographs. However, these are available for only a limited number of chemicals.

13 4/24/2020

In recent years there have been major changes. The development of publicly available versions of IUCLID (International Uniform Chemical Information Database) accessible via the Internet (

e.g.

from the website of the European Chemicals Bureau) has meant that summaries of much unassessed information are now available on ‘ high production volume ’ (HPV) chemicals. This includes older studies of variable quality as well as modern studies.

14 4/24/2020

The ICCA (International Council of Chemical Associations) is cooperating with the OECD and its member countries in an initiative to provide risk assessments for about 1000 HPV chemicals. The documents (Screening Information Datasets (SIDS) and SIDS Initial Assessment Reports (SIARs)) associated with this initiative are being published.

These documents include careful evaluations of the evidence identifying and characterizing the toxicological hazards. Thus the amount of information in the public domain is rapidly increasing.

4/24/2020 15

Types of Information

• • • • Data on human health effects may come from: Human observations (case reports, epidemiological studies or, in suitable cases, human studies) Animal toxicology studies

In vitro

toxicology Structure – activity relationships.

The weight of evidence is assessed on the basis of the combined strength and coherence of inferences appropriately drawn from all of the available data.

4/24/2020 16

There is a major distinction between the assessment of genotoxic carcinogens and germ cell mutagens and other types of toxic effects. It is based on the premise that simple mutagenic events may be responsible for initiating the effects leading to cancer and germ cell (reproductive cells) mutagenesis. The suggestion is that it is not possible to demonstrate experimentally whether there is a threshold. 17 4/24/2020

For other types of toxic effect, the convention is that there is a threshold, a level of exposure below which it is believed that there are no adverse effects. For these effects it is possible to define a ‘ no observed (observable) adverse effect level ’ (NOAEL), or lowest observed (observable) adverse effect level (LOAEL). These have been defined as (IPCS, 1994): 18 4/24/2020

NOAEL: The greatest concentration or amount of a substance, found by experiment or observation, which caused no detectable adverse alteration of morphology, functional capacity, growth, development or life span of the target organism under defined conditions of exposure. 4/24/2020 19

LOAEL: The lowest concentration or amount of a substance, found by experiment or observation, which can cause an adverse alteration of morphology, functional capacity, growth, development or life span of the target organism distinguishable from normal (control) organisms of the same species and strain under the same defined conditions of exposure.

20 4/24/2020

BMD: The lowest confidence limit of the dose calculated to be associated with a given incidence (

e.g.

5% or 10% incidence) of effect estimated from all toxicity data on that effect within that study.

 CL = X + {(ts/N 1/2 )} 21 4/24/2020

Conventionally ‘ observed ’ relates to the data from a single study, ‘ observable ’ relates to the data from all the examined studies.

For environmental effects concentration may be more important than amount, in which case the NOAEL is replaced by the ‘ no observed adverse effect concentration ’ (NOAEC) or, often, the ‘ no observed effect concentration ’ .

22 4/24/2020

Acute toxicity testing has been aimed at identifying

the LD 50 or LC 50 (time of exposure)

: the dose or exposure concentration and time associated with the death of 50% of the animals exposed. More recently, testing has moved from using lethality as the parameter for acute toxicity to ‘ evident toxicity ’ . For environmental purposes the

EC 50

(exposure concentration for a named end point) may be used in place of the

LC 50

.

23 4/24/2020

Classification of carcinogens

The IARC classifies carcinogenic agents, mixtures or exposure circumstances as: • • • • • Group 1 – The agent is carcinogenic to humans.

Group 2A – humans.

The agent is probably carcinogenic to Group 2B – humans.

The agent is possibly carcinogenic to Group 3 – The agent is not classifiable as to its carcinogenicity to humans.

Group 4 – humans.

The agent is probably not carcinogenic to 4/24/2020 24

Most schemes use the basic classification

known human carcinogen

(requiring good evidence in humans),

probable human carcinogen

(requiring good evidence in animals and/or some evidence in humans or on relevance of mechanism), and

possible human carcinogen

(usually a mixed collection of criteria). Formally, this is hazard identification. Hazard characterization would require some measure of the potency of the chemical. 25 4/24/2020

Exposure assessment

Ideally, exposure assessment should include direct measurements of chemical in appropriate media. For humans, uptake is measured using samples of blood, urine or exhaled air. Intake (exposure levels or daily intakes in food/drinking water) is measured in ambient medium (air, water, soil, total diet) and is related to uptake using simple models. 26 4/24/2020

Types of models

• • • • These models can be classified as (IPCS, 1999): Simple dilution models where a measured concentration in an effluent is divided by a dilution factor or the chemical release rate is divided by the bulk flow rate of the medium.

Equilibrium models, which predict the distribution of a chemical in the environment based on partitioning ratios or fugacity (the escaping tendency of a chemical from one environmental phase to another).

Dispersion models, which predict reductions in concentrations from point sources, based on assumed mathematical functions or dispersion properties of the chemical.

Transport models which predict concentration changes over distances that can represent dispersion, biochemical degradation and absorption.

27 4/24/2020

The reliability of modeled estimates of chemical concentration in the general environment or the food supply depends on how well the assumptions match reality (

i.e.

how realistic assumptions such as steady state conditions and homogenous media properties are); whether the model performance has been demonstrated under conditions similar to those of concern; and the quantity and quality of input data.

28 4/24/2020

WIND DIRECTION DISPERSION A B TRANSFORMATION DRY DEPOSITION WET DEPOSITION EVAPORATION/ REENTRAINMENT IN AIR BIOACCUMULATION IN FOOD INGESTION DERMAL INHALATION CANCER TARGET ORGAN/TISSUE NON-CANCER ENDPOINTS

4/24/2020

EXCRETION INTAKE/UPTAKE

29

Chemicals can be distributed within an environmental compartment (intra-media transport) or be transported from one environmental medium to another (inter media transport). The main transport mechanisms are: • •

Advection

: transport of a substance from one place to another as a result of the flow of the medium in which it occurs (

e.g.

transport with infiltrating rain from soil to ground water).

Dispersion

: transport from one place to another as a result of differences between concentration gradients (

e.g.

diffusion from surface water to sediment).

4/24/2020 30

Dispersion also occurs between phases (

e.g.

air/water or solids/water or water/biota) if they are not at equilibrium. Partition coefficients can be used to estimate these distributions.

Degradation (biodegradation, hydrolysis and photo degradation) will affect the exposure concentrations by reducing exposure. 4/24/2020 31

RISK CHARACTERIZATION

Humans

The risk characterization is the last stage of the risk assessment. It is ‘ a summary, integration and evaluation of the major scientific evidence, reasoning and conclusions of a risk assessment. It is a concise description of the estimates of potential risk and the strengths and weaknesses of those estimates ’ . This is the stage when the hazard characterization and exposure assessment are combined. It is therefore purely scientific and technical.

4/24/2020 32

Margin of exposure

The most commonly used process that constitutes a pure risk characterization is the ‘ margin of exposure ’ approach.

Margin of exposure

: It is the ratio of the NOAEL to the theoretical, predicted or estimated exposure dose or concentration. For some experts the ‘ margin of safety ’ is an alternative term and has the same meaning as the margin of exposure (OECD, 2003). For others, the margin of safety means the margin between the reference dose and the actual exposure or concentration. Thus, if the term ‘ margin of safety ’ is employed it is important to know how it has been defined.

33 4/24/2020

Use of Uncertainty Factors

Animal Dose Response Data NOAEL (No Observed Adverse Effect Level) or LOAEL Divide by 10 (Account for inadequate animal data) Divide by 10 (Animal to Human Extrapolation) Divide by 10 (Human Variability or Individual Sensitivity)

4/24/2020

Reference Dose (RfD) Or Acceptable Daily Intake (ADI)

34

What is a ‘ safe ’ or ‘ acceptable ’ level of Chemical “ X ” ?

The International Programme on Chemical Safety (IPCS) was initiated in 1980 as a collaborative programme of the United Nations Environment Programme (UNEP), the International Labour Organisation (ILO), and the World Health Organization (WHO). One of the major objectives of the IPCS is to develop and promote the use of improved methodologies for assessing the risks of chemical exposures on humans and the environment. 4/24/2020 35

However, there is a need for an integrated, holistic (overall) approach to risk assessment that addresses real life situations of multi-chemical, multimedia, multi-route, and multi-species exposures. In response to this need, the IPCS (in collaboration with the US Environmental Protection Agency (US EPA), the European Commission (EC), and other international and national organizations) initiated activities to develop and promote the integration of assessment approaches to evaluate human health and ecological risks.

4/24/2020 36

Assessment of Exposure

—

Basic Principles

Uncontrolled exposure may be assessed by prediction or measurement, either direct or indirect. For most purposes of dose calculation, a 70-kg person is assumed, although 50 kg is more conservative, especially for female target populations.

4/24/2020 37

Prediction

By ingestion: knowing the concentration of the chemical in the diet or water, together with a reasonable daily intake, allows simple calculation of dose level. For example, a pesticide present as residues on apples at 1 ppm might result in a daily dose of approximately 2 m g/kg, based on an average apple weight of 150 g, with a pesticide burden of 0.15 mg/apple, eaten at the rate of one a day by a 70-kg person.

38 4/24/2020

For inhalation exposure

The respiration rate is between 12 and 20 breaths a minute. For a normal working day of 8 hours at a gentle workrate, a convenient nominal volume of air breathed is 10 m 3 , based on 20 breaths a minute each of 1 liter. On this basis, a concentration of 3 mg/m 3 translates into a daily dose of approximately 0.4 mg/kg in a 70 kg person.

39 4/24/2020

Where NOAEL represents the dose chosen from the safety data, 70 kg is a standard human (50 kg gives a more conservative figure and may be more appropriate for females) and

a

,

b

, and

c

are safety factors (

a

for extrapolation from the test species to humans,

b

for human variability,

c

for other considerations such as nature of toxicity, etc.) 4/24/2020 40

Hazard Identification: Acceptable Daily Intake (ADI)

 ADI = NOAEL (or LOAEL) ÷ UF e.g., para-dichlorobenzene – tremors (shaking) and liver effects  NOAEL = 150 mg/kg, 5 day/week subchronic rat study  ADI (70kg person) = ((150 mg/kg * 70kg) * (5 days ÷ 7days/week)) ÷ (100 * 10)  ADI = 7.5 mg/person/day  UF Uncertainty Factor 4/24/2020 41

4/24/2020 42

Integration of Risk Assessment

The term “ integration ” can have many meanings, and several opportunities exist within risk assessment generically for integration. In the IPCS project,

integrated risk assessment was defined as a science-based approach that combines the process of risk estimation for humans, biota, and natural resources in one assessment

.

43 4/24/2020

Three specific objectives were identified to meet this goal: 1) enhance understanding of the benefits of integration, 2) identify and understand obstacles to integration, and 3) engage key scientific organizations to promote discussion of an integrated approach to risk assessment.

44 4/24/2020

One recommendation of the April 2004 workshop was to conduct an integrated risk assessment on a specific chemical to demonstrate the practical applications, benefits, and obstacles to using an integrated approach when compared to independently conducted assessments for human health and the environment. 4/24/2020 45

Threshold of Toxicological Concern

 This concept is based on the US Food and Drug Administration threshold of regulation for food additives. Historically initiated in 1982 and further developed since then, including Europeans and international organizations like the World Health Organization and others.

4/24/2020 46

Threshold of Toxicological Concern

The concept that ‘‘ safe levels of exposure chemical structures.

’’ for humans can be identified for individual chemicals is central to the risk assessment of compounds with known toxicological profiles. The Threshold of Toxicological Concern (TTC) is a concept that refers to the establishment of a level of exposure for all chemicals, whether or not there are chemical-specific toxicity data, below which there would be no appreciable risk to human health. The concept proposes that a low level of exposure with a negligible risk can be identified for many chemicals, including those of unknown toxicity, based on knowledge of their 4/24/2020 47

Cramer

’

s Structures and Rules

4/24/2020 48

Cramer rules

 The threshold of toxicological concern (TTC) is an open research topic with significant practical implications. Thresholds based on structural information have typically been developed by the principles established by Cramer. Chemicals are divided into three structural classes based on a decision tree. This tree originally comprises some 33 structural rules and places evaluated compounds into one of three classes: 49 4/24/2020

 Class I substances are simple chemical structures with efficient modes of metabolism suggesting a low order of oral toxicity;  Class III substances are those that permit no strong initial presumption of safety, or may even suggest significant toxicity or have reactive functional groups; and finally,  Class II are assigned to intermediate substances.

50 4/24/2020

4/24/2020 51

4/24/2020 52

TTC and Risk assessmsnt

 The place of the TTC in the RA scheme is shown in the following figure.

4/24/2020 53

4/24/2020 54

Toxicity Information Sources

Some On-line Databases of Chemical Human Hazard Data Sources*

 Toxicology Data Network (TOXNET) ( http://toxnet.nlm.nih.gov/ )  TSCATS ( http://www.syrres.com/esc/tscats.htm

)  IPCS INCHEM (http://www.inchem.org/)  NTP ( http://ntp-server.niehs.nih.gov/ )  ATSDR ( http://www.atsdr.cdc.gov/toxpro2.html

)  EPA HPV Challenge Program ( http://www.epa.gov/chemrtk/volchall.htm

)  EU ESIS ( http://ecb.jrc.it/esis/ )  RAIS ( http://rais.ornl.gov/ ) 4/24/2020  US NTP ( http://ntp.niehs.nih.gov/ ) 55