Risk Assessment

What are the parameters in toxicology?

*ADME* -- how exposure occurs Absorption of the agent Distribution in the body (e.g., lead gets to the brain)/bioavailability Metabolism/biotransformation- breaking toxins down quickly Excretion - peeing it out

To determine safety . . . [two steps]

*Measure risk*: objective/probabilistic *Judge acceptability*: personal/social

What is the child water ingestion rate?

1 L/day

How do you convert ppm to ppb?

1 ppm = 1000 ppb 1 ppm = 1 mg/kg or 1 mg/L

How do you get the BMDL10 from a graph?

1. Look at where the lines cross through the 10% response 2. Straight down--those are the doses for 10% response. 3. Use the upper estimate (the SMALLEST dose) for the BMDL10 <--this is protective IF CI crosses 0, that is a NOAEL. If it does NOT cross 0, there is no NOAEL.

What are the steps of hazard ID?

1. Review and analyze toxicity data, including info about: • Contaminants • Degradation products (can turn into more harmful substances as you metabolize them) and • Metabolites 2. Weigh the evidence that the substance causes toxic effects 3. Eval. whether toxic effects in one setting occur in other settings Does the evidence translate for the general population?

What is the default body weight for children?

10 kg

What is the adult water ingestion rate?

2 L/day

What is the default water intake rate based on the Exposure Factors Handbook?

2 L/day

What is the adult inhalation rate?

22 m^3/day

What is the default inhalation rate based on the Exposure Factors Handbook?

22 m^3/day

What is the default soil ingestion rate based on the Exposure Factors Handbook?

50 mg/day

What is the average lifetime?

70 years

What is the default averaging time for an adult?

70 years

What is the default body weight for adults?

80 kg

What is the default body weight based on the Exposure Factors Handbook?

80 kg (adult) 10 kg (infant)

Weight of Evidence (definition)

A judgment regarding the adequacy of all available evidence to support a conclusion that a substance poses a toxicity hazard to humans, including judgments regarding any limitations in the conditions under which the substance may pose those hazards

What is the major call from the Silver Book?

A more unified assessment of risk. Getting rid of idea of thresholds for non-cancer risk

What is the margin of exposure?

A ratio to measure characterize cancer risk. MOS = (NOAEL or LOAEL or BMDL)/ Dose (LADD or ADD) Want a BIG number --> 1000 or more, generally. Can be 100 or more for adults if only two uncertainty factors. It is UNITLESS.

When determining dose for non-cancer endpoints, what do you use?

ADD = C * IR *EF / BW Used to characterize acute subchronic or chronic exposure (10% of lifetime or more) AT can be 40 years EF = Exposure Duration/Averaging Time

What are the main uncertainty factors?

Animal to human Individual variation Children Subchronic to chronic Use of a LOAEL instead of a NOAEL Database limitations

To be conservative (protective), which do you use: BMD10 or BMDL10?

BMDL10<--the Lower Bound Benchmark Dose, or the 10% response point on the upper confidence interval line; gives a lower dose than the BMD

Risk Characterization (definition)

Brings together the assessments and characterizations of hazard, dose-response, and exposure to make risk estimates for the exposure scenarios of interest. The synthesis and summary of information about a potentially hazardous situation that addresses the needs and interests of decision-makers and of interested and affected parties. A prelude to decisionmaking.

What are the three main challenges to risk assessment?

Characterization of risks that is: Scientifically sound Useful to decision-makers Understandable and credible to the public

What are the four Cs of preparedness?

Command -- who is in command? Control -- who is in control? Coordination -- who is coordinating it? Communication -- how do we communicate risk?

Exposure (definition)

Condition of an agent contacting the outer boundary of a person

Equation for dose assessment

D = (C * IR * EF) / BW • D = dose (in mg/kgBW-day) • C = contaminant concentration (mg/kg) • IR = intake rate (kg/day) • EF = exposure factor (unitless) ← where you take into account how long the exposure is for. Exposure duration/Averaging time • BW = body weight (kgBW)

What do exposure methods depend on?

Data availability --strength/certainty Technical feasibility Funding Time constraints Potential errors and their consequences Acceptable level of uncertainty Knowledge of exposure-response or dose-response relationships

Defaults (describe) (Dose-Response Assessment)

Defaults have data or scientific consensus behind them The assumptions used ensure that we do not underestimate risk Transparency is key Constant need to reexamine in light of new data

What is one benefit to using the BMD over the NOAEL?

Does not depend on the doses administered Allows comparison across studies and health endpoints Modeled dose-response with confidence limits..

When do you use Lifetime Average Daily Dose?

Dose every day for lifetime; used for CANCER risk

When do you use Average Daily Dose?

Dose every day, sub-chronic exposure

How do you calculate an exposure factor?

EF = Exposure Duration/Averaging Time ED = How often * for how long AT = period of interest (70 yrs for lifetime, but may be specified) It is UNITLESS and must be between 0 and 1 (1 is for every day of one's lifetime)

Steps of risk assessment

FIDAC • F = Problem formulation <-- defining problem • I = Hazard identification <--analyzing hazard data • D = Dose-response <--understanding rel. between dose and response • A = Exposure assessment <--where is the agent found, who is exposed, and to how much? • C = Risk characterization <--integrating everything and developing a framework to define the risk

What is second step in risk assessment?

HAZARD IDENTIFICATION • Reviewing and analyzing hazard data • Weighing the evidence that an agent causes various adverse effects • Evaluating whether effects in one setting will occur in the setting of concern • How do we evaluate the information to know what we are dealing with? Does the agent → effect?

Pathway (definition)

How a substance travels from its source to result in a given exposure

Route (definition)

How the person becomes exposed (inhalation, dermal, ingestion)

When determining dose for cancer endpoints, what do you use?

LADD = C * IR *EF / BW

What is the Maximum Tolerated Dose?

Maximum dose that will allow the animal to have a normal lifespan

How do you determine the number of excess cancer cases in a population?

Number of cases = excess risk (LADD * Q*) * Population size

What is the cancer slope factor?

Numerical representation of the slope of the dose response curve for a given chemical. Units are (mg/kgBW-day)-1 • Cancer slope factor can be explained as a chemical's cancer-causing potential

When do you use an exposure dose (D)?

One-time dose. Immediate dose (used for acute toxicity)

What is the first step of risk assessment and what does it entail?

Problem formulation Provides a brief summary of the public health problem to be investigated Addresses what potential health impacts are of concern Defines if there are particular populations of interest. Sensitive populations? Considers potential risk management options

What is the hazard quotient?

Ratio used for non-carcinogen risk characterization. HQ = D/RfD (dose over reference dose) It is UNITLESS. Want to it be very small.

Calculate RfD

Reference Dose (RfD) = POD/UF Point of Departure (POD) = NOAEL, LOAEL, BMDL UF = Uncertainty (safety) factors Units = mg/kgBW-day

How do you calculate a reference dose?

RfD = NOAEL/uncertainty factors or BMDL/uncertainty factors Units --> mg/kgBW-day

Calculate excess risk

Risk = (CPF or Q*) x LADD. For excess cases in a population, multiply this number by the number in the population.

How do you measure excess risk assessment?

Risk = LADD * Q* The excess risk estimate is a measure of the proportion of the population exposed that is likely to develop some sort of cancer as a result of the exposure (and not as a result of background exposures) It is UNITLESS.

Safety (definition)

Safety "A thing is safe if its risks are judged to be acceptable." You never get to absolute safety.

To be considered a "completed" exposure pathway, the following must be identified...

Source Transport medium—air, water, soil Exposure point—nostrils, mouth, skin Exposure route--ingestion, inhalation, dermal absorption Receptor

What is a point of departure?

Starting point for risk assessment; measure of toxicity or potency that is the result of the Hazard Identification, which gives you either NOAEL, LOAEL, or slope factor

Where do you go to determine the human health effects that may result from exposure to environmental substances?

The EPA Integrated Risk Information System (IRIS)

Media (definition)

The environmental component of a pathway (i.e., air, water, soil, dust, food)

NOEL (definition)

The highest exposure among all the available experimental studies at which no toxic effect was observed CI must cross 0

NOAEL (definition)

The highest exposure at which there is no statistically or biologically significant increase in the frequency of an adverse effect when compared with a control group • The ideal, but sometimes we do not get here The Confidence Interval MUST cross 0, otherwise, there is no NOAEL

LOAEL (definition)

The lowest dose at which there is a significant increase in an observable effect. The Confidence Interval must NOT include 0.

Risk (definition)

The probability that an event will "occur" " . . . Measure of the probability and severity of adverse effects"

What is risk? (definition)

The probability that some harmful event will occur. Ranges from 0-1.

Bioaccumulation (definition)

The process of chemicals collecting in living tissue

What are some limitations of animal studies?

Typically done at high doses Relevance of animal model Mixture problem -- studies single agent when in reality, multiple agents at play

Define uncertainty

Uncertainty stems from lack of knowledge, so it can be characterized and managed but not eliminated

What is dose-response assessment?

Understanding the relationship between a quantified exposure (dose) and the proportion of subjects demonstrating specific, biological changes (response)

What questions does Risk Characterization answer?

What does it all mean? Is it safe? Is it acceptable? Just what is the risk to the population? How certain are you? Answering the right questions to inform decision-making

What is the second step in hazard ID?

[delete]

What is the third step in hazard ID?

[delete]

Describe newer defaults of departure

• BMR—benchmark response Chosen percentage increase in response used as a point of departure • BMD—benchmark dose Dose associated with BMR • BMDL—lower confidence limit on BMD

What is involved in Weighing of Evidence (Hazard ID)

• Characterizes the evidence from human studies and from animal studies (separately and jointly) • Summarizes -Key evidence -Type of effect and target organ -Mode of action—how does the agent work? • Concludes with likelihood of effect of given exposure route

What to Assess re. Epi Studies

• Clear hypothesis and study objective • Proper selection of exposed and control groups • Adequate exposure characterization • Sufficient follow-up for disease to occur • Consideration of bias • Adequate sample size • Appropriate methodology for data analysis • Adequate response rate • Clear documentation of results

Major recommendations of Silver Book

• Design of risk assessment • Uncertainty and variability • Selection and use of defaults • A unified approach to dose-response assessment • Cumulative risk assessment • Improving the utility of risk assessment • Stakeholder involvement • Capacity-building

What are the determinants of toxicity? (Hazard ID)

• Dose • Individual exposed → susceptible ind'ls (diff. biology can lead to different exposure) • Species → Are animal tests analogous? Different toxicity based on species. • Presence or absence of receptors • Frequency of dosing (once or repeated)→ some things bioaccumulate, others do not • Duration of exposure • Route of exposure • Absorption/metabolism • Physical form (liquid, solution, solid) • Presence of other agents o Synergistic effects o Additive or inhibitory effects

Considerations in Conducting Exposure Measurement Studies

• Environmental media to be sampled (air, water, soil, food) • Analytes or organisms to be measured (chemicals of interest . . . more qualita-tive) • Sampling or analytical methods (need to know the lab can measure/pick up what you need) • Proposed sampling locations (where people spend time) • Sampling frequency, duration, and schedule ($ will influence this greatly) • Data quality objectives, which consider precision, accuracy, completeness, and representativeness • QA/QC measures (want to make sure data is high quality) • Health and safety consideration for field personnel

Why use animal studies for hazard ID?

• Good correlation with human disease -Human carcinogens cause cancer in animals • Acutely toxic doses are similar in human and a variety of animal systems • Accepted by scientific community • Among mammals, anatomical, physiological, and biochemical parameters are similar

What are some modifying factors that determine toxicity?

• Host factors (including ind'l variation and preexisting conditions, susceptibility) • Environmental factors • Chemical interaction

Tools in Risk Characterization

• NOAEL - no observed adverse effect level • LOAEL - lowest observed adverse effect level • BMD - benchmark dose • BMDL - benchmark dose lower limit • RfD - reference dose • RfC - reference concentration (equiv. to ref. dose for air) • TLV -threshold limit values • MOS - margin of safety • MOE - margin of exposure • Hazard quotient • Q1* -- slope factor or Cancer Potency Factor • Unit risk • LD50 • ID50 - infectious dose

Dimensions for Judging the Acceptability of Risk

• Probability of an event • Nature of the event Effect immediate or delayed Consequences permanent or reversible • Persons affected by the event • Number affected by the event • Voluntary or involuntary nature of the event • Cost of an event • Cost of preventing an event

Risk Assessment (definition)

• Process in which information is analyzed to determine if a hazard may cause harm • Goal: to provide the best possible characterization of risk based upon a rigorous evalua-tion of available information and knowledge

Describe excretion.

• Process of loss from the body • Urine is the most common • Also: Saliva, feces, semen, bile, milk, sweat, lungs

What are some design issues in animal studies? (Hazard ID)

• Route of administration • Test species—is it representative? • Controls • Number of test subjects • Dose selection—need to be a tolerated dose • Duration of study • Observations to be made

What four things are considered re. variability?

• Susceptible populations • Variations in response • Background exposures • Existing disease rates

What is risk?

• The probability that an event will "occur" • " . . . measure of the probability and severity of adverse effects"

What is the purpose of risk assessment?

• To inform the risk manager's decision-making • NOT to recommend any particular decision • Science is the only consideration

Why do we use defaults for dose-response assessment?

• We use defaults to characterize uncertainty and to have consistent models • Defaults have data or scientific consensus behind them

Exposure Assessment Questions

• Where is the agent found? • How many people are exposed? • Who is exposed (population characteristics)? • How exposed (exposure route)? • How long is the exposure (duration)? • How often is the exposure (frequency)? • To how much (magnitude)? • How much variability? • How much uncertainty? All about: magnitude, duration, timing, population