[How] Minimal Risk Levels (MRLs) and How to determine safety factors (uncertainty factors)

The Acceptable Daily Intake (ADI)

The Acceptable Daily Intake (ADI) procedure has been used to calculate permissible chronic exposure levels for humans based on non-carcinogenic effects. The ADI is the amount of a chemical to which a person can be exposed each day for a long time (usually lifetime) without suffering harmful effects. It is determined by applying safety factors (to account for the uncertainty in the data) to the highest dose in human or animal studies which has been demonstrated not to cause toxicity (NOAEL). 

The EPA has slightly modified the ADI approach and calculates a Reference Dose (RfD) as the acceptable safety level for chronic non-carcinogenic and developmental effects. Similarly, the ATSDR calculates Minimal Risk Levels (MRLs) for noncancer endpoints. The critical toxic effect used in the calculation of an ADI, RfD, or MRL is the serious adverse effect which occurs at the lowest exposure level. It may range from lethality to minor toxic effects. It is assumed that humans are as sensitive as the animal species unless evidence indicates otherwise. 

While ATSDR does not conduct cancer risk assessments, it does derive Minimal Risk Levels (MRLs) for noncancer toxicity effects (such as birth defects or liver damage). The MRL is defined as an estimate of daily human exposure to a substance that is likely to be without an appreciable risk of adverse effects over a specified duration of exposure. For inhalation or oral routes, MRLs are derived for acute (14 days or less), intermediate (15-364 days), and chronic (365 days or more) durations of exposures. The method used to derive MRLs is a modification of the EPA's RfD methodology. The primary modification is that the uncertainty factors of 10 may be lower, either 1 or 3, based on scientific judgment. These uncertainty factors are applied for human variability, interspecies variability (extrapolation from animals to humans), and use of a LOAEL instead of NOAEL. As in the case of RfDs, the product of uncertainty factors multiplied together is divided into the NOAEL or LOAEL to derive the MRL.

In determining the ADIs, RfDs or MRLs, the NOAEL is divided by safety factors (uncertainty factors) in order to provide a margin of safety for allowable human exposure.

The Uncertainty Factors or Safety Factors used to derive an ADI or RfD are shown in the the table on the slide. The modifying factor is used only in deriving EPA Reference Doses. The number of factors included in calculating the ADI or RfD depend upon the study used to provide the appropriate NOAEL or LOAEL. The general formula for deriving the RfD is: 

RfD = NOAEL or LOAEL /(UF1 x UF2 x …)

The more uncertain or unreliable the data becomes, the higher will be the total uncertainty factor that is applied. 

Standard Uncertainty Factors: 10-fold factors that account for:
• intraspecies sensitivity in humans (10H)
• interspecies sensitivity (10A)
• less than chronic NOAEL values (10S)
• use of LOAEL rather than NOAEL (10L).

The Uncertainty Factors or Safety Factors used to derive an ADI or RfD are listed in Table 3.

Situation	Uncertainty/Safety Factor
Human variability	10x
Extrapolation from animals to humans	10x
Use of less than chronic data	10x
Use of LOAEL instead of NOAEL	10x
Modifying factor	0.1—10x

Table 3. Uncertainty/Safety factors used to derive an Acceptable Daily Intake (ADI) or Reference Dose (RfD)

The modifying factor is used only in deriving EPA Reference Doses. The number of factors included in calculating the ADI or RfD depends upon the study used to provide the appropriate NOAEL or LOAEL.

An example of an RfD calculation is provided below. A subchronic animal study with a LOAEL of 50 mg/kg/day was used. Thus the uncertainty factors are 10 for human variability, 10 for an animal study, 10 for less than chronic exposure, and 10 for use of a LOAEL instead of a NOAEL. A discussion has been held to add an additional safety factor for children, eg. For pesticides or for air pollution to correct for higher respiration rate. No conclusive decision has been made to do this. 

RfD = 50 mg / kg/ day/(10 x 10 x 10 x 10 ) = 0.005 mg / kg/ day 

In addition to chronic effects, RfDs can also be derived for other long term toxic effects, including developmental toxicity.

Question: The ADI is calculated by the following procedure: - dividing the NOAEL by safety factors - linear extrapolation from the LOAEL to the zero intercept - multiplying the RfD by a modifying factor.

Answer: The ADI is determined by applying safety factors (to account for the uncertainty in the data) to the highest dose in human or animal studies which has been demonstrated not to cause toxicity (NOAEL). ADI (human dose) = NOAEL (experimental dose) / Safety Factor(s).

Question: Which of the following statements best describes the derivation of Minimal Risk Levels? - The method used to derive MRLs is similar to that for the RfD, except that the uncertainty factors of 10 may be lower. - MRLs for dermal exposure are derived by multiplying the dermal penetration by the NOAEL. - The MRL is derived by multiplying the cancer slope factor by the lowest exposure dose. 

 Answer: The method used to derive MRLs is similar to that for the RfD, except that the uncertainty factors of 10 may be lower. The ATSDR applies uncertainty factors of 1, 3, or 10 for human variability, interspecies variability, and use of a LOAEL instead of NOAEL.