Noncancer Toxicity Assessment Flashcards
The toxicity assessment is usually divided into two parts, what are the parts?
Non-cancer effects and cancer effects
What is the key parameter of non-cancer effects?
Threshold dose- dose at which an adverse effect first becomes evidence
Describe the threshold of carcinogens. How is it determined?
No threshold, mathematical models are used to provide estimates of carcinogenic risk at very low dose levels
Describe the threshold of non-carcinogenic chemicals. How is it determined?
Have dose thresholds below which the effect does not occur. The lowest dose with an effect in animal or human studies is divided by safety factors to provide a margin of safety
How do we determine the threshold dose? What two measurements does it lie between?
Threshold dose typically estimated from toxicological data (derived from studies of humans and /or animals) by determining the highest dose that does not produce an effect. It lies between the NOAEL and LOAEL.
How do you calculate the reference dose?
NOAEL or LOAEL / safety factors OR see slide for BMD calculation
*Conservative
What is the position of the EPA on sensitivity of humans to toxins?
humans are as sensitive as the most sensitive species unless other data available
What is the purpose of dividing the NOAEL or LOAEL by uncertainty factors?
To ensure that the RfD is not higher than the true threshold for adverse effects; it gives a margin of safety
What is POD?
Point of departure- point on a dose-response curve that corresponds to an estimated low effect or no effect level.
It marks the beginning of extrapolation to toxicological RfD or RfC
Draw a dose response with NOAEL, LOAEL, BMD, and POD
See slide
What are the uncertainty factors that are considered? And modifying factors? What are modifying factors?
- 10: human variability
- 10 : extrapolation from animals to humans
- 10 use of less than chronic data
- 10: use of LOAEL instead of NOAEL
- 10 incomplete database
- 0.1 to 10 MF
Modifying factors account for additional uncertainty factors such as data quality, confidence in a data set
Describe the benchmark dose appraoch
- Newest approach to estimating noncarcinogenic toxicty
- general value for BMD=dose that adversely affects 10% of test population (ED10)
- may be better because NOAEL and LOAEL are subject to exp design, but BMD consistently defined
What is the conservative estimate of the BMD?
*Lower 95% confidence limit for estimate
Describe why the benchmark dose may be a better approach
experiments to measure NOAEL/ LOAEL may be too high or too low of a dose to measure threshold, choosing standard benchmark (ED10) is not a function of chosen doses and it estimates the proper value from all the data, not just a single point
Are uncertainty factors still required for the BMD?
they may still be applied so BMD/ product (UF)*MF
What are the common measurements for non-carcinogenic effects for possible chronic exposure?
*Acceptable daily intake (ADI)
Allowable daily intake
Minimum Risk Levels (ATSDR)
What organizations use the ADI?
US Food and Drug Administration, World Health Organization, and Consumer Product Safety Commission
What is the ADI?
The amount of chemical to which a person can be exposed each day for a long time (usually lifetime) without suffering from harmful effects.
What measurement calculation is used to determine the ADI?
RfD
What are Minimum Risk Levels (MRLs)?
Estimate of the daily human exposure to a hazardous substance that is likely to be without appreciable risk of adverse noncancer health effects over a specified duration of exposure
measurement of ATSDR
Similar to RfD/ RfC
What is ATSDR? What is their mission?
Agency for Toxic Substances and Disease Registry- 1985- national public health agency for chemical safety with a goal to prevent and mitigate harmful exposure to toxic substances and related diseases
What are the two components of toxicity assessment for cancer effects
*A qualitative evaluation based on weight of evidence (WOE) that the chemical does or does not cause cancer in humans
Quantitative evaluation- describe the carcinogenic potency of the chemical, done by quantifying how the number of cancers observed in exposed animals or humans increases as the dose increases
Draw a sample graph of a cancer dose curve and extrapolation
see slide
Does cancer have a threshold? how about NOAEL, LOAEL, or RfD?
No, No, No
What is another name for slope factor?
Carcinogen potency factor/ cancer slope factor/ potency factor
What does the slope factor depend on?
The medium under consideration (ie oral ingestion versus inhalation)
Draw a dose response curve with a slope factor
See slide
What is the slope factor?
upper-bound estimate of the probability that an individual will develop cancer if exposed to a chemical for lifetime of 70 years
What is dose measurement of the slope factor?
The lifetime average daily dose or chronic daily intake (CDI)
What are the units of the slope factor?
1/(mg/kg/day)
What is the equation for the lifetime risk of cancer?
if linear= CDI*PF
see slide for equation
What is the integrated risk information system? IRIS
-internal database of human health assessments for chemical found in the environment
Who is IRIS intended for?
those without extensive training in toxicology but with some knowledge of health sciences
What information does IRIS contain?
chronic noncarcinogenic health effects: oral RfD, inhalation RfC for
*carcinogenic effects: hazard ID, oral slope factors, and oral and inhalation unit risks
What is used in IRIS to describe human carcinogenicity?
Weight of Evidence Characterization
What are the groups in the weight of evidence characterization?
A- human carcinogen B- Probable carcinogen B1: Linked human data B2: no human evidence, animals only C: Possible carcinogen D: No classification E: No evidence
What are the two cancer descriptors?
OSF and IUR
What is OSF
Estimate of the increased cancer risk from oral exposure to a dose of 1 mg/kg-day for a lifetime. The OSF can be multiplied by an estimate of the lifetime exposure in mg/kg/day to estimate the lifetime cancer risk
What is IUR?
Estimate of the increased cancer risk from inhalation exposure to a concentration of 1 mg/m3 for a lifetime. The IUR can be multipled by an estimate of lifetime exposure (in mg/m3) to estimate the lifetime cancer risk
