Principles of Toxicology

ADI (acceptable daily intake)

amount of a substance that is calculated to be safe if taken daily throughout a person's lifetime, usually expressed as a function of body weight replaced (RfD)

Reference Dose (RfD)

dailyexposuretoachemicalthatis assumed to be without an adverse health impact

What is the LD50?

dose that produces death in 50% of the population

Implications of Receptor‐Mediated Toxicity

reversible dose‐related tissue‐specific qualitatively similar effects

NOAEL

the highest dose (or concentration) at which no adverse effects are observed

LOAEL

the lowest dose (or concentration) at which you first start to see an adverse effect

TD50

- the dose that produces a defined toxicity in 50% of the population examined

LC50

- the lethal concentration in 50% of the population

1) A given dose will produce a given response (side effect) - The Benchmark Dose will produce a Benchmark Response. 2) NOAEL represents the highest possible dose for which we have no response, and we use it to make RfD=NOAEL/(UF*MF) ... BUT some drugs will always have a response no matter how little the dose. 3) For drugs like this, we need to decide that we'll accept a certain level of response - That's the Benchmark Response. The Benchmark Dose is the dose that produces the benchmark response -> RfD= BMD/(UF*MF)

...

Margin of safety = TD10/human exposure = 1000 (i.e., the estimate of daily exposure is 1000 times lower than the estimated daily dose that would cause evident toxicity in 10% of exposed animals)

...

Reference dose - this is based on the experimental data that you got when you calculated your LOAEL/NOAEL. The NOAEL is the highest dose at where there is no adverse effect. The CALCULATION of this was based on animal studies and so you need to correct for that because we are human + you want to correct for individual variation, etc... We 'accept' a 100fold LOWER dose than the calculated NOAEL. This is what the reference dose does RfD = NOAEL/UF*MF (UF*MF is usually 100 - for other populations like pediatrics we may put it at 1000)

...

RfD = BMDx / (UF X MF)

...

The LOAEL is experimentally derived and thus does not actually represent the lowest dose that results in adverse effects. I.e. If you measure adverse effects to 4, 6, 8 mg doses of a drug and 8 has some effects, and 6 doesn't, 6 would be your NOAEL and 8mg would be the LOAEL. However, theoretically, the actually pinpoint dose where you would start to see any adverse effects is actually somewhere between 6 and 8 mg ---> this point is your threshold dose.

...

he benchmark dose - this accounts for the fact that your calculated NOAEL may not be the best/most accurate calculated of highest dose with no observed effect. this is because it is based on your experimental circumstances - how many doses did you test? how many subjects did you have? etc - say you were testing at 1mg, 5mg 10mg and your NOAEL is 5mg and your LOAEL is 10mg, had you done the experiment with smaller increments (5mg, 6mg, 7mg 8mg) you may have calculated your NOAEL as 8mg. So we want to correct for this - this is the premise for the BMD. This allows us to calculate the dose in which a certain % of our subjects have an adverse effect (e.g. 10%) so our BMD10 (this is our upper confidence interval) and our lower confidence interval is the BMDL (benchmark dose level). we take the BMDL as our 'new NOAEL' because it errs more on the side of caution So the new calculation of reference dose is BMDx/UF*MF

...

Margin of Safety (CSF)

LD1 (or TD1)/ED99

RfD=NOAEL/(UFXMF)

RfD=NOAEL/(UFXMF) modifying factor • additional factor based on professional assessment

Risk Characterization - Hazard Identification - Exposure Assessment - Dose‐Response Assessment often followed by Risk Management

Risk Characterization - Hazard Identification - Exposure Assessment - Dose‐Response Assessment often followed by Risk Management

Therapeutic Index

TI = LD50/ED50