ICCA GPS Hazard Characterization Exposure Assessment...without a threshold dose. For these chemicals...

ICCA GPS Hazard Characterization

& Exposure Assessment

Kevin M. Kransler, Ph.D.ExxonMobil Chemical Company

GPS WorkshopMay 2013

Santiago, Chile

Section One: Preparation• Step 1: Select chemicals for assessment• Step 2: Gather information • Step 3: Prioritize chemicals into Tiers • Step 4: Develop Tier‐relevant information

(“Base Set of Information”)

Section 2: Implementation• Step 5: Characterize Hazard • Step 6: Assess Exposure• Step 7: Conduct Risk Characterization• Step 8: Document outcome

(GPS Safety Summary)

GPS Guidance on Risk Assessment

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Outline

• Hazard Identification» Physical Chemical Properties» Mammalian Toxicology » Ecological Toxicology and Environmental Fate» Epidemiology Information in Humans

• Hazard Characterization» Identify dose descriptors for each endpoint» Modify to the correct point of departure (POD)» Decide on Mode of Action (threshold / non‐threshold)» Apply overall assessment factor (AF) to POD» Derive endpoint‐specific DNEL or DMEL or MOS / MOE

• Risk Characterization» Where does Hazard Characterization fit in the whole picture

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Gather information

• How to obtain the information: sources to access information on GHS information, Phys/Chem, Hazard and Exposure Information

• Evaluate the quality of the Information: Reliability, Relevance and Adequacy of data for assessment

• Close data gaps: As long as the information is considered reliable, alternative sources are accepted e.g. » Route‐to‐route extrapolation / Read‐across from related substances » In vitro methods / (Quantitative) Structure Activity Relationships » Animal tests should always be considered carefully before conduct

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General principles

• A chemical’s potential to cause toxic or adverse effects is known as intrinsic hazard. Hazard characterization is the process of determining if exposure to a chemical can cause adverse effects

• Because some hazard effects are limited to the tested animal species, hazard characterization also determines whether the adverse effect is likely to occur in humans.

• However, a chemical’s intrinsic hazard will only manifest as an adverse effect if and when a set of conditions are met (a certain level of exposure, threshold of effect, incorrect handling and use).

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Considerations when analyzing hazard data

• The endpoints in the hazard assessment are interrelated• Degradation products and metabolites should be considered• The appropriate route of exposure for toxicity testing should be

selected (oral, dermal, inhalation, etc.)

• Test System Sensitivity (effect level depends upon the sensitivity of the test system)

• Dose‐response (the relationship between the amount of exposure and its health effects)

• Identification of critical data (key studies)• Select appropriate dose descriptors (e.g., NOAEL, NOEL,

BMD, LD50, LC50, and T25)

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Ingestion (water and food)

Absorption (through skin)

Inhalation (air)

Injection (bite, puncture, or cut)

Choose Most Relevant Route of Human Exposure

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The Dose Makes the Poison

• An apparently nontoxic chemical can be toxic at high doses. (Too much of a good thing can be bad).

• Highly toxic chemicals can be life saving when given in appropriate doses. (Poisons are not harmful at a sufficiently low dose).

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3

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0 1 DOSE

RESPONSE

0‐1 NOAEL 2‐3 Linear Range4 Maximum Response

Dose‐Response Relationship:

• The Degree and Spectra of Responses » depend upon the dose and the organism

• Change from Normal State» could be on the molecular,

cellular, organ, or organism level‐‐the symptoms• Local vs. Systemic • Reversible vs. Irreversible• Immediate vs. Delayed

• Graded vs. Quantitative» degrees of the same damage

vs. all or none

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Quantification of Toxic potential

Frequency

50/50

10010

35/50

20/50

4/50

10％10.1

1/100～(AF1XAF2・・・AFn）

DNEL or PNEC（ADI or BMD:LED10）

No observed adverse effect level or concentration

(NOAEL or NOAEC)

Intake (mg/kg or L)

Safety factor

Detection limit

25/50

Lethal DoseLD(C)50

Concept of Dose – Response (Generalization)

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The Hazard Identification Process

• The Potential Effects to Human Health or the Environment» Chronic (long term)?» Repeated dose (short‐medium term)?» Acute (very short term)?

• Species Affected» People, Birds, Fish, Mammals…

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• Chemical & Physical Properties» Flammability, Reactivity» Persistence in the environment

• Mammalian Toxicology» Acute, Irritation and Corrosivity, Sensitization, Mutagenicity and Genotoxicity, Repeated Dose, Reproductive and Developmental Toxicity, etc.

• Environmental Toxicology and Chemistry:» Aquatic, Terrestrial, Environmental Fate

• Epidemiological Information in Humans» Generally taken from industrial exposure

settings & not frequently available

Hazard Information

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Physical Chemical Properties

• Flammability: • Explosivity: • Reactivity: • Corrosivity: • Persistent Bioaccumulative and Toxic (PBT):

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Mammalian Toxicology

• Acute (oral, dermal, inhalation)• Irritation (skin, eye)• Sensitization• Mutagenicity/Genotoxicity• Repeated dose• Carcinogenicity• Developmental and Reproductive• Tests used in hazard ID but not discussed in details here

» QSAR» Toxicokinetics» Neurotoxicology Studies » MOA (mechanism of action)

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Acute Toxicology Tests (LD50 / LC 50)

• Species » Rat, mouse

• Single exposure, multiple doses within 24 h» Oral, dermal, inhalation» Observed up to 14 days

• Endpoint is lethality» Calculate LD50, LC50: calculated dose of a substance that is expected to

kill 50 percent of a defined experimental animal population

• Modeling and in vitromethods

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Eye / Skin Irritation• Species

» Rabbit, rat• Single exposure, multiple doses

» Observed up to 14‐21 days• Endpoint irritation to eye/skin

» Severity of effect (grading of irritation)» Reversibility

• Strong acids or alkalis (pH ≤ 2 and ≥ 11.5): no need to test; Severe skin irritant: no need to test on eyes

• QSAR and In Vitro Testing» Corrosion» Phototoxicity

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Dermal Sensitization

• Endpoint: skin sensitization/allergenicity• Guinea Pig Studies (OECD 406)

» Guinea pig maximization test (GPMT) or Buhler Test (BT)» Positive or negative results » No dose response data

• Local lymph node assay (LLNA) (OECD 429)» Test species – mouse» Provides dose response data» Calculates EC3: effective concentration that induces a 3‐fold increase

in cell proliferation (stimulation index)

• QSAR Modeling

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Mutagenicity / Genotoxicity

• Endpoints: gene mutation and chromosome aberration• In vitro and in vivomethods• Tiered approach:

» Lower tier: gene mutation w/wo chromosome aberration» Higher tiers: in vitro or in vivo MNT, germ cell genotoxicity

• Basic study types» Reverse Mutation Test (Ames)» In Vitro Mammalian Cell Gene Mutation (HPRT, TK)» In Vitro Mammalian Chromosome Aberration Test (RLCAT)» In Vivo Chromosome Aberration Test (MNT)

• QSAR Modeling

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Repeated Dose

• Endpoints: test substance related adverse effects• Larger number of animals

» 10/sex/dose» Typically performed in 2 species» Rat, dog, mouse, rabbit

• 28‐Day, 90‐Day, or major life span » Conducted by most likely route of human exposure» 3 doses excluding control» Determine MTD (maximum tolerated dose) or limit dose

(1000 mg/kg bw)» Determine thresholds for adverse effects and no effects» NOEL, LOEL, NOAEL, LOAEL

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Carcinogenicity

• Endpoints: neoplasm, tumor formation• Often combined with chronic study• Analyze available information:

» QSAR models» Genotoxicity test results (In vitro and in vivo)

• Largest number of animal» 50/sex/dose» Several doses – MTD, 1/2 or 1/4 MTD

• Majority of lifetime » Typical species: rat, mouse» 18 m (mouse) or 24 m (rat)

• Lower doses; subtle effects• Long time, high cost

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Developmental and Reproductive Test (DART)

• Endpoints: developmental and reproductive toxicity:» Focus on in utero development» Birth defects » Growth retardation» Embryonic/fetal lethality» Maternal Toxicity» Fertility

• Exposure: The start of implantation to near term• Often required in two species (rat / rabbit) • Endocrine Disruptor Screening Program (EDSP)

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• Determination of toxicity on aquatic organisms» Fish» Algae» Invertebrates such as Daphnia magna (water flea)» Marine

• Type of studies» Study populations» Acute to chronic tests» Static, semi‐static or flow‐through test conditions

• Similar endpoints to mammalian acute studies» LD50s, EC50s

Aquatic Toxicology

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• Majority of tests conducted in birds» Mallard duck» Quail» Chickens (sometimes)

• Type of studies» Study populations» Acute to chronic tests

• Similar endpoints to mammalian acute studies» LD50s, ED50s

Terrestrial Toxicology

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• Deals with transport of chemicals (intra‐ and interphase) in the environment

• Relationship of the physical‐chemical properties to transport• Their persistence in the biosphere• Their partitioning in the biota and toxicological forecasting based

on physical‐chemical properties• Fate & Lifetime

» What happens to a chemical in the environment?» Where will a chemical reside (soil, water, air, etc.)?» How will a chemical transport between media?» What processes will remove (destroy) a chemical?

Environmental Chemistry

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• Environmental Partitioning and Transport» Water Solubility» Air/Water Partitioning» Octanol/Water Partitioning» Soil Adsorption

• Bioconcentration» Fugacity Modeling» Abiotic Degradation» Hydrolysis» Photodegradation

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• Biodegradation» Ready and Inherent Biodegradability» Aerobic Aquatic Biodegradation» Anaerobic Biodegradability» Metabolite/Pathway Identification

• Environmental Fate Simulation Tests» Wastewater Treatment» SCAS, Porous pot, sludge inhibition» Surface Water/Sediment Microcosms» Soil Biodegradation» Aquifer/Groundwater Microcosms

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• QSAR & Exposure Modeling » Environmental Property Estimation» Atmospheric Chemistry and Transport» Aquatic and Terrestrial Transport and Fate» Subsurface/Groundwater Transport and Fate

• Field Studies

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What is Epidemiology?

• Epidemiology is the study of the patterns of disease occurrence in populations and factors that influence those patterns.

PLACE TIME

PERSONS (hosts)

Agent

Risk of Disease

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The Hazard Characterization Process

• Two main approaches ‐ both follow the same basic methodology ‐however, the ways the outcomes presented are different:

» MOS/MOE: The classical approach is the derivation of a Margin of Safety (MOS), also termed Margin of Exposure (MOE). Here, assessment factors are considered after deriving the result.

» DNEL: In Europe, REACH legislation has established the Derived No Effect Level (DNEL). Assessment factors are accounted for in the process of the DNEL derivation and therefore are included in the result.

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The Hazard Characterization Process

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1. Identify dose descriptors for each endpoint

• Identify dose descriptors for each relevant hazard endpoint (e.g. NOAEL, NOAEC, BMD, LD50, LC50, T25).

»e.g. NOAELs are derived from sub‐acute, sub‐chronic, chronic and reproductive toxicity tests – they cannot be derived from acute, irritation or skin sensitization tests.

»NOAEL is the highest dose or concentration of the substance used, at which no statistically significant adverse effects were observed.

For example if the dose levels of 400, 100, 50 and 5 mg/kg/ day have been used, and adverse effects were observed at 400, 100 and 50 mg/kg but not at 5 mg/kg , the derived NOAEL will be 5 mg/kg / day.

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….When no dose descriptors are available

• e.g. no effects are seen even at the highest dose level, then no NOAEL or LOAEL can be derived. » If the dose levels tested are sufficiently high, then it can be concluded that there is no risk for that particular endpoint.

» If not, then conduct a DNEL or the MOS/MOE calculation using the highest dose tested as the NOAEL.

» If the calculated MOS/MOE is considered sufficiently high, then the conclusion is clear: no concern. If the MOS/MOE is small then the exposure scenarios are likely to show significant human exposures.

»The final option is to ask for more data – taking animal welfare issues and conclusions from other endpoints into account.

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2. Modify the dose descriptor to the correct point of departure (POD)• In certain situations, the dose descriptor may not be directly

comparable to the exposure assessment e.g.

» interspecies differences in bioavailability between experimental animals and humans;

»the animal dose descriptor might relate to a different exposure routethan the human exposure ‐ requiring route‐to‐route extrapolation;

»differences in human and experimental exposure time conditions; or »Differences in respiratory volumes between experimental animals and humans.

• In these situations, it is necessary to modify the dose descriptor (e.g. NOAEL) into an appropriate Point of Departure (POD)

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3. Decide on Mode of Action (threshold yes / no)

• Certain chemicals are thought to impose e.g. a carcinogenic risk without a threshold dose. For these chemicals the conventional NOAEL and DNEL derivation is not appropriate.

• The DMEL (derived minimal exposure level) describes the exposure level corresponding to a certain low risk, that appears to be tolerable though it is higher than zero.

• However, for carcinogens and mutagens workplace exposures should be avoided / minimized as far as technically feasible.

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4. Apply Assessment Factor (AF) to the POD• Uncertainties in the extrapolation of experimental animal test data

to real human exposures are addressed by applying Assessment Factors (AF).

»Difference in exposure duration between the experimental data and the assumed real‐life exposure for humans;

»Route of exposure if different for humans»Differences in sensitivity of response between species (inter‐species) and within species (intra‐species).

• After identifying the relevant individual assessment factors, the overall assessment factor is obtained by simple multiplication of the individual AFs.

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5. Derive endpoint‐specific DNEL • To derive endpoint‐specific DNEL(s) ‐ the overall AF is to be applied

directly to the POD

• Data from more than one valid and relevant studies may be available (e.g. in different species, with different durations), identifying more than one dose descriptor to a given endpoint.

• It might be necessary to derive DNELs for more than one dose descriptor, prior to selecting the lowest DNEL for that endpoint.

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6. Select leading health effects• After deriving your endpoint‐specific DNEL or DMEL, select the

leading health effect(s) and the corresponding DNEL/DMEL.

• These critical DN/MELs should be the lowest DN/MEL obtained for each exposure pattern.

• They will be used to characterize risk in the next step

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Examples for DNEL calculation• Step 1: Identify dose descriptor

» Dermal Irritation (local effect)• Dose descriptor: NOAEL 50 mg/kg bw/ day• Rationale for selection of dose descriptor: Skin irritation observed at higher doses

»Adrenal gland changes (systemic effect)• Dose descriptor: NOAEL 10 mg/kg bw/day• Rationale for selection of dose descriptor: Adverse changes to adrenal glands observed at higher doses

»Developmental effects (systemic effect)• Dose descriptor: NOAEL 50 mg/kg bw/day• Rationale for selection of dose descriptor: Developmental effects observed at higher doses

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Examples for DNEL calculation• Step 2: Decide on threshold / non‐threshold (Mode of Action)

»Dermal Route, Local & Systemic Effects

• Irritation ‐ Dose‐response information supports threshold

• Adrenal ‐ Dose‐response information supports threshold

• Developmental ‐ Dose‐response information supports threshold

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Examples for DNEL calculation• Step 3: Modify Point of Departure

» Irritation (Local)• No modification needed

»Adrenal (Systemic) Effects• Substance‐specific data indicates dermal absorption is 2x less in humans than rats

»Developmental Systemic) Effects• Substance‐specific data indicates dermal absorption is 2x less in humans than rats

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Examples for DNEL calculation• Step 4 / 5: Apply assessment factors and derive DNEL

• Step 6: Select leading adverse effect» The DNEL‐dermal‐long term‐local is 1.7 mg/kg bw/day» The DNEL‐dermal‐long term‐systemic is 0.1 mg/kg bw/day

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Situations where no DNEL can be derived• Certain chemicals are considered to impose e.g. a carcinogenic risk

without a threshold and their mode of action (MoA) is of concern at the smallest exposure concentration.

• For these chemicals the conventional NOAEL and safety factor approach to derive exposure standards is not appropriate.

• In these circumstances two options are available»the calculation of a DMEL (derived minimal exposure level), as described in the European REACH legislation; or

»the calculation of the MOE (margin of exposure), as described by the European Food Safety Agency for situations where no threshold can be calculated.

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Derive endpoint‐specific DMEL (non threshold) • There are default methodologies which can be applied for deriving

a DMEL.

»Linear extrapolation from animal bioassay data (quantitative approach): The DMEL is derived by linear extrapolation from the tolerable lifetime cancer risk calculated from a defined POD close to the experimental dose range (e.g. a T25 or a BMD10 cancer incidence in a rodent long‐term cancer bioassay).

»Threshold Approach: The threshold of toxicological concern (TTC) is a principle which refers to the possibility of establishing a human exposure threshold value, below which there is no appreciable risk to human health (by the oral route) generated in the past.

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Examples for DMEL calculation (non threshold)

• Step 1: Identify dose descriptor»T25 as basis for POD = 250 ppm

• Step 2: Decide on threshold / non‐threshold (Mode of Action)»Non‐threshold carcinogen

• Step 3: Modify Point of Departure»No modification needed

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Examples for DMEL calculation (non threshold) • Step 4 / 5: Apply assessment factors and derive DMEL

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Environmental hazard characterization• Environmental hazard characterization is conducted in a similar

manner as for human health.

»Here PNECs (predicted no effect concentration) are used as dose descriptors and derived from the data collected.

• PNECs usually result from single species laboratory toxicity tests (e.g. fish, algae, and daphnia). Data are typically reported as the concentrations at which x% (e.g. 50%) mortality or inhibition of function (e.g. growth) is observed.

• PNECs are expressed as the lethal concentration (LCx) or the effect concentration (ECx), e.g. LC50 or EC50.

• A PNEC must be calculated for each environmental compartment in which exposure is expected (air, water, sediment and soil).

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Section 2: Implementation• Step 5: Characterize Hazard• Step 6: Assess Exposure• Step 7: Conduct Risk Characterization• Step 8: Document outcome



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Basic concept of exposure assessment (EA)

• Perform stepwise assessment, start with ‘conservative’ normal conditions

• Take existing risk management measures (RMM) and operating conditions (OC) into account

• Examine entire product life cycle• Consider exposure to workers, consumers and environment

Ultimate goal show control of risk

Simplified flow diagram for EA process

Identification of Uses

Description of Uses

Estimation of Exposures

Characterization of Risks

Communication of Risks

Hazard Assessment

How to do the exposure assessment?

1. Collect information on chemical properties2. Collect information on the uses and the typical OC/RMM applied3. Set up an exposure scenario4. Estimate exposure for that scenario, using estimating tools or

measured data‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐

5. Check if the estimated exposure is below hazard level

If not, refine assessment If yes, communicate safe conditions of use

1. Collect information on chemical properties

SU = sector of usePC = product categoryAC = article category

2. Collect information on the uses and the typical OC/RMM applied

PROC = process categoryERC = environmental release category

3. Set up an exposure scenario

• main chemical use situations, its use descriptors and use categories• Use information:

» Transported isolated intermediate/stored off site» Chemical is included into or onto a matrix» Non‐dispersive use – professional (industry point sources)» Wide dispersive use

Use descriptors: Use categories:

4. Estimate exposure for that scenario, using estimating tools or measured data

• Consider three exposure routes for workers and consumers» Inhalation» Dermal» Oral

• Determine exposure via these routes:» Measured data» Predictive estimation models preferred option to start with

4a. Workplace exposure

• The following stages of the life cycle are mainly relevant:» Manufacture: chemical synthesis of the substance and its use as intermediate» Formulation: mixing and blending into a preparation» Industrial use: application of the substance, preparation/product in an

industrial process

» Professional use: application of preparations/products in skill trade premises• Information needs:

» Where and how the substance is used e.g. process description» The composition of mixtures, formulations and products» Physical form in which the substance is handled (e.g. powder, pellets, liquid)» What RMM are in place e.g. gloves, goggles, etc.

4b. Consumer exposure

• Important to understand: » once released, very limited possibilities to control exposure &

monitoring is difficult

» Unpredicted consumer use» Consider subpopulations with particular exposure patterns

4c. Environmental EA

• Very complex!» Local and regional effects» Inland and marine risks» Measured and modeled data

• Targets in EA:» Fresh and marine surface water (incl. sediment)» Terrestrial ecosystem» Top predators via the food chain (secondary poisoning)» Micro‐organisms in sewage treatment plants» Atmosphere (i.e. ozone depletion, global warming)» man exposed via the environment

4c. Environmental EA

• Release estimation:» Tonnage to each compartment» Life cycle stage and type of use» Distribution of tonnage in market» Emission pattern – distribution in time and space» Multiple emissions» Emission factors» RMM to reduce emissions



Section 2: Implementation• Step 5: Characterize Hazard • Step 6: Assess Exposure• Step 7: Conduct Risk Characterization• Step 8: Document outcome



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Thank you for your attention!

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ICCA GPS Hazard Characterization Exposure Assessment...without a threshold dose. For these chemicals...

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Transcript of ICCA GPS Hazard Characterization Exposure Assessment...without a threshold dose. For these chemicals...