Risk Assessment
• Typically decomposed into four steps:– Hazard Identification– Dose-Response Assessment– Exposure Assessment– Risk Characterization
Hazard Identification
• Determine the nature of the hazard:– Exposure pathways of concern, e.g.
• Ingestion
• Inhalation
• Dermal contact
• Puncture
– Toxic endpoints, e.g.• Lethal vs. non-lethal
• Chronic vs. Acute
Acute Toxicity
• Acute toxins result in observed endpoints after few exposures, in short timeframe
• For lethal endpoints, toxicity is a measure of the amount of exposure required to produce death– Example endpoints: chemical poisoning,
radiation sickness
Chronic Toxicity
• Chronic toxins produce observed endpoints only after repeated exposures and/or considerable elapsed time
• Like acute toxicity, may be lethal or non-lethal
• Toxicity may be cumulative or not (e.g. mercury vs. carbon monoxide)– Example endpoints: cancer, birth defects
Measuring Toxicity
• Need measures of dose which causes toxic endpoint
• Measurements for ingested toxins ordinarily normalized for body weight (e.g. mg/kg)
• Must generalize from populations of experimental subjects
• For lethal endpoints can use LD50
But LD50 is limited!
e.g.: here A is always more toxic than B
but A can be less toxic than C, even with lower LD50
Toxicology vs. Epidemiology
• Toxicology answers the wrong question well
• Epidemiology answers the right question poorly
Toxicology
• Controlled laboratory experimental conditions
but
• Surrogate subjects (usually animals)
• Exaggerated doses
Extrapolating High to Low Dose
• Experimental studies produce minimum detectable responses on order of a percent
• Desire information on order of 10-6
• It’s virtually impossible to perform lab studies with N large enough (e.g. megarat)
We need a mathematical model to perform extrapolation
Designing Toxicology Experiments
• Selection of subject species
• Control design
• Multiple dose levels (at high levels to produce observable effect in relatively small number of subjects)
Epidemiology
• Human subjects
• Realistic doses
but
• Uncontrolled experimental conditions
Dose-Response Assessment
• Relating Dose to (adverse) response
• “Response” typically described as a probability (unitless fraction or percent)
• Dose-Response Curve– Dose on the abscissa– Response on the ordinate– Intercept with abscissa is “threshold dose”
Potency Factors(a.k.a. Slope Factors)
• For chronic chemical toxicity (e.g. cancer),Potency Factor slope of the low dose DR curve
where Chronic Daily Intake (CDI) is measured in units of mg/kg/day
Potency Factors (cont’d)
• Re-arranging,Incremental Lifetime Cancer Risk = CDI PF
• Potency Factors are available from EPA’s Integrated Risk Information System (IRIS):
http://www.epa.gov/iris
Exposure Assessment
• Risk has two components:– Toxicity of the substance– Exposure of humans to substance
• Exposure often forgotten (see, for example, the Scientific American article comparing indoor pollution to outdoor pollution)
Exposure Pathways
• The route by which a toxin or hazard reaches the human influences its impact
• Internal factors would include the human contact route (e.g. inhalation, ingestion, &c)
• External factors would include the physical transport (e.g. distance and travel time in air or water, &c)
Exposure Routes and Effects
• Principle routes for chemicals:– Ingestion– Dermal– Inhalation
• Other routes for hazard exposure:– Puncture– Eyes– Ears
Gastrointestinal Exposures
• Chemicals gain direct access to mucous membranes in stomach and intestines, allowing transfer of chemical to bloodstream
• Digestive processes can transform chemicals into others
• Physical hazard endpoints can apply (e.g. with ingested acids)
Dermal Exposure
• Epidermis consists of former living cells– Removed from blood vessels to some extent– Acts as barrier to loss of fluids and entry of
contaminants
• Some materials are able to pass this barrier– Solvents which can be absorbed into the skin– Pores and hair follicles
Inhalation
• Rapid route of entry to bloodstream
• Alveoli designed to facilitate transfer of gases (oxygen and carbon dioxide)– Effectively transfer other materials too
Distribution of Toxicants
• Two factors govern transport:– Protein binding -
• Toxicants can bind to proteins in the blood, thus preventing their access to surrounding cells through capillary walls
• But access to kidneys (for removal) is also inhibited
– Polarity -• Polar toxicants obstructed by non-polar membranes• Nonpolar toxicants dissolve through readily and can be
stored in body fat
Metabolism
• Conversion of materials through reaction
• For toxicants, tendency is to increase polarization (and therefore reduce bio-uptake)
• In some cases chemicals can be converted into more toxic materials
Pollution Control in the Body
• Kidneys
• Liver
Kidney Function
• Blood flowing through kidneys is exposed to porous membrane– the (relatively) small molecules of toxins pass
– substantial quantities of water also pass
• Aqueous solution passes along tubes which selectively retrieve desirable nutrients, water &c
• Concentrated aqueous toxins expelled as urine
Liver Function
• Metabolize toxicants into more polar structures
• Some substances removed from blood and transformed into bile, stored in gall bladder
• Gall bladder sends bile into small intestine to assist with digestion
• Toxins therefore eliminated with feces (unless resorbed by intestinal walls)
Lifetime Exposure
where a 70-year lifetime is assumed
Risk Characterization
• Bring Dose-Response together with Exposure assessment to estimate risk
Example: Chloroform in Drinking Water
• Suppose your drinking water has 0.10 mg/L concentration of chloroform (CHCl3)
• From IRIS, PF = 6.1x10-3 (mg/kg/day)-1
• So incremental lifetime cancer risk is
Chloroform Example (cont’d)
• In a city of 500,000 people:
General Exposure
Example: Occupational Exposure
• A 60 kg person works 5 days/week, 50 weeks/yr, for 25 years
• Each workday they breathe 20/3 m3 of air containing 0.05 mg/m3 of toxin
Example (cont’d)
• If the Potency Factor is 0.02 (mg/kg/day)-1:
Non-carcinogenic Doses
• Metrics from toxicity experiments include– Lowest Observed Effect Level (LOEL)– Lowest Observed Adverse Effect Level (LOAEL)– No Observed Effect Level (NOEL)– No Observed Adverse Effect Level (NOAEL)
• Note: NOEL and NOAEL are the highest experimental doses at which no (adverse) effect was seen
Reference Dose
• The Reference Dose (RfD) is taken from the NOAEL:
• Where Uncertainty Factors are 10 each fordifferences across populationusing animal data to estimate human endpointsusing only a single species of animal
Hazard Quotient
• Compares exposure to Reference Dose:
• HQ < 1 should be free of significant risk of toxicity
Hazard Index
• Considers multiple risks (e.g. from multiple chemical toxins)
• The sum of the Hazard Quotients:
Other Factors in Risk Characterization
• Also consider– Statistical uncertainties– Biological uncertainties– Selection of applicable dose-response and
exposure data– Selection of population groups toward which
the risk assessment should be targeted
Occupational Standards revisited
• The standards set by OSHA (and ACGIH and NIOSH) are based upon such risk assessment analyses
Occupational Standards: TWA
• The Time-Weighted Average (TWA) assumes an 8-hour day and 40-hour week
TWA Example
So TWA = 120 ppm / 40 hours = 3 ppm
Occupational Standards: STEL
• Short Term Exposure Level
• Calculated as a 15-minute TWA
• Allowed no more than four such exposure periods per day, separated by at least 1 hour
Occupational Standards: Ceiling
• Concentration which must not be exceeded, regardless of duration of exposure.