Noncancer Toxicity Assessment

Question 1

The toxicity assessment is usually divided into two parts, what are the parts?

Answer 1

Non-cancer effects and cancer effects

Question 2

What is the key parameter of non-cancer effects?

Answer 2

Threshold dose- dose at which an adverse effect first becomes evidence

Question 3

Describe the threshold of carcinogens. How is it determined?

Answer 3

No threshold, mathematical models are used to provide estimates of carcinogenic risk at very low dose levels

Question 4

Describe the threshold of non-carcinogenic chemicals. How is it determined?

Answer 4

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

Question 5

How do we determine the threshold dose? What two measurements does it lie between?

Answer 5

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.

Question 6

How do you calculate the reference dose?

Answer 6

NOAEL or LOAEL / safety factors OR see slide for BMD calculation

*Conservative

Question 7

What is the position of the EPA on sensitivity of humans to toxins?

Answer 7

humans are as sensitive as the most sensitive species unless other data available

Question 8

What is the purpose of dividing the NOAEL or LOAEL by uncertainty factors?

Answer 8

To ensure that the RfD is not higher than the true threshold for adverse effects; it gives a margin of safety

Question 9

What is POD?

Answer 9

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

Question 10

Draw a dose response with NOAEL, LOAEL, BMD, and POD

Answer 10

See slide

Question 11

What are the uncertainty factors that are considered? And modifying factors? What are modifying factors?

Answer 11

• 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

Question 12

Describe the benchmark dose appraoch

Answer 12

• 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

Question 13

What is the conservative estimate of the BMD?

Answer 13

*Lower 95% confidence limit for estimate

Question 14

Describe why the benchmark dose may be a better approach

Answer 14

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

Question 15

Are uncertainty factors still required for the BMD?

Answer 15

they may still be applied so BMD/ product (UF)*MF

Question 16

What are the common measurements for non-carcinogenic effects for possible chronic exposure?

Answer 16

*Acceptable daily intake (ADI)
Allowable daily intake
Minimum Risk Levels (ATSDR)

Question 17

What organizations use the ADI?

Answer 17

US Food and Drug Administration, World Health Organization, and Consumer Product Safety Commission

Question 18

What is the ADI?

Answer 18

The amount of chemical to which a person can be exposed each day for a long time (usually lifetime) without suffering from harmful effects.

Question 19

What measurement calculation is used to determine the ADI?

Answer 19

RfD

Question 20

What are Minimum Risk Levels (MRLs)?

Answer 20

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

Question 21

What is ATSDR? What is their mission?

Answer 21

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

Question 22

What are the two components of toxicity assessment for cancer effects

Answer 22

*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

Question 23

Draw a sample graph of a cancer dose curve and extrapolation

Answer 23

see slide

Question 24

Does cancer have a threshold? how about NOAEL, LOAEL, or RfD?

Answer 24

No, No, No

Question 25

What is another name for slope factor?

Answer 25

Carcinogen potency factor/ cancer slope factor/ potency factor

Question 26

What does the slope factor depend on?

Answer 26

The medium under consideration (ie oral ingestion versus inhalation)

Question 27

Draw a dose response curve with a slope factor

Answer 27

See slide

Question 28

What is the slope factor?

Answer 28

upper-bound estimate of the probability that an individual will develop cancer if exposed to a chemical for lifetime of 70 years

Question 29

What is dose measurement of the slope factor?

Answer 29

The lifetime average daily dose or chronic daily intake (CDI)

Question 30

What are the units of the slope factor?

Answer 30

1/(mg/kg/day)

Question 31

What is the equation for the lifetime risk of cancer?

Answer 31

if linear= CDI*PF see slide for equation

Question 32

What is the integrated risk information system? IRIS

Answer 32

-internal database of human health assessments for chemical found in the environment

Question 33

Who is IRIS intended for?

Answer 33

those without extensive training in toxicology but with some knowledge of health sciences

Question 34

What information does IRIS contain?

Answer 34

chronic noncarcinogenic health effects: oral RfD, inhalation RfC for *carcinogenic effects: hazard ID, oral slope factors, and oral and inhalation unit risks

Question 35

What is used in IRIS to describe human carcinogenicity?

Answer 35

Weight of Evidence Characterization

Question 36

What are the groups in the weight of evidence characterization?

Answer 36

``` 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 ```

Question 37

What are the two cancer descriptors?

Answer 37

OSF and IUR

Question 38

What is OSF

Answer 38

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

Question 39

What is IUR?

Answer 39

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