Dose Response and Descriptors. Dose-response assessment. Quantifying relationships between exposures and health effects: Dose-response relationship Dose-effect relationship Public health impact “Burden of disease and injury”. Dose-response curves for effects of lead in children.
In many cases, risk decisions on systemic toxicity have been made by the Agency using the concept of the "acceptable daily intake (ADI)" derived from an experimentally determined "no-observed-adverse-effect level (NOAEL)." The ADI is commonly defined as the amount of a chemical to which a person can be exposed on a daily basis over an extended period of time (usually a lifetime) without suffering a deleterious effect. The ADI concept has often been used as a tool in reaching risk management decisions (e.g., establishing allowable levels of contaminants in foodstuffs and water.) A NOAEL is an experimentally determined dose at which there was no statistically or biologically significant indication of the toxic effect of concern. In an experiment with several NOAELs, the regulatory focus is normally on the highest one, leading to the common usage of the term NOAEL as the highest experimentally determined dose without a statistically or biologically significant adverse effect. The NOAEL for the critical toxic effect is sometimes referred to simply as the NOEL. This usage, however, invites ambiguity in that there may be observable effects that are not of toxicological significance (i.e., they are not "adverse"). For the sake of precision, this document uses the term NOAEL to mean the highest NOAEL in an experiment. In cases in which a NOAEL has not been demonstrated experimentally, the term "lowest-observed-adverse-effect level (LOAEL)" is used. Once the critical study demonstrating the toxic effect of concern has been identified, the selection of the NOAEL results from an objective examination of the data available on the chemical in question. The ADI is then derived by dividing the appropriate NOAEL by a safety factor (SF), as follows:
ADI (human dose) = NOAEL (experimental dose)/SF. (Equation 1)
Generally, the SF consists of multiples of 10, each factor representing a specific area of uncertainty inherent in the available data. For example, a factor of 10 may be introduced to account for the possible differences in responsiveness between humans and animals in prolonged exposure studies. A second factor of 10 may be used to account for variation in susceptibility among individuals in the human population. The resultant SF of 100 has been judged to be appropriate for many chemicals. For other chemicals, with data bases that are less complete (for example, those for which only the results of subchronic studies are available), an additional factor of 10 (leading to a SF of 1000) might be judged to be more appropriate. For certain other chemicals, based on well-characterized responses in sensitive humans (as in the effect of fluoride on human teeth), an SF as small as 1 might be selected. While the original selection of SFs appears to have been rather arbitrary (Lehman and Fitzhugh, 1954), subsequent analysis of data (Dourson and Stara, 1983) lends theoretical (and in some instances experimental) support for their selection. Further, some scientists, but not all, within the EPA interpret the absence of widespread effects in the exposed human populations as evidence of the adequacy of the SFs traditionally employed.
The reference dose (RfD) and uncertainty factor (UF) concepts have been developed by the RfD Work Group in response to many of the problems associated with ADIs and SFs, as previously outlined in Section 1.2. The RfD is a benchmark dose operationally derived from the NOAEL by consistent application of generally order-of-magnitude uncertainty factors (UFs) that reflect various types of data sets used to estimate RfDs. For example, a valid chronic animal NOAEL is normally divided by an UF of 100. In addition, a modifying factor (MF), is sometimes used which is based on a professional judgment of the entire data base of the chemical. These factors and their rationales are presented in Table 1.
The RfD is determined by use of the following equation: RfD = NOAEL / (UF x MF) which is the functional equivalent of Equation 1.
In general, the RfD is an estimate (with uncertainty spanning perhaps an order of magnitude) of a daily exposure to the human population (including sensitive subgroups) that is likely to be without an appreciable risk of deleterious effects during a lifetime. The RfD is generally expressed in units of milligrams per kilogram of bodyweight per day (mg/kg/day). The RfD is useful as a reference point from which to gauge the potential effects of the chemical at other doses. Usually, doses less than the RfD are not likely to be associated with adverse health risks, and are therefore less likely to be of regulatory concern. As the frequency and/or magnitude of the exposures exceeding the RfD increase, the probability of adverse effects in a human population increases. However, it should not be categorically concluded that all doses below the RfD are "acceptable" (or will be risk-free) and that all doses in excess of the RfD are "unacceptable" (or will result in adverse effects). The U.S. EPA is attempting to standardize its approach to determining RfDs. The RfD Work Group has developed a systematic approach to summarizing its evaluations, conclusions, and reservations regarding RfDs in a "cover sheet" of a few pages in length. The cover sheet includes a statement on the confidence (high, medium, or low) the evaluators have in the stability of the RfD. High confidence indicates the judgment that the RfD is unlikely to change in the future because there is consistency among the toxic responses observed in different sexes, species, study designs, or in dose-response relationships, or that the reasons for existing differences are well understood. High confidence is often given to RfDs that are based on human data for the exposure route of concern, since in such cases the problems of interspecies extrapolation have been avoided. Low confidence indicates the judgment that the data supporting the RfD may be of limited quality and/or quantity and that additional information could result in a change in the RfD
1.6.1. EXPERIMENTAL RESULTS
Suppose the U.S. EPA had a sound 90-day subchronic gavage study in rats with the data in Table 2:
Hypothetical Data to Illustrate the Reference Dose Concept
Dose Observation Effect Level mg/kg/day
0 Control --no adverse effects observed –
1 No statistically or biologically NOEL significant differences between treated and control animals
5 2% decrease* in body weight gain (not NOAEL considered to be of biological significance); increased ratio of liver weight to body weight; histopathology indistinguishable from controls; elevated liver enzyme levels
25 20% decrease* in body weight gain; LOAEL increased* ratio of liver weight to body weight; enlarged, fatty liver with vacuole formation; increased* liver enzyme levels------------------------------------------------------------------------------
*Statistically significant compared to controls.
18.104.22.168. Determination of the Reference Dose (RfD)
22.214.171.124.1. Using the NOAEL
Because the study is on animals and of subchronic duration,
UF = 10H x 10A x 10S = 1000 (Table 1).
In addition, there is a subjective adjustment (MF) based on the high number of animals (250) per dose group: MF = 0.8.
These factors then give UF x MF = 800,
so that RfD = NOAEL/(UF x MF) = 5/800 = 0.006 (mg/kg/day).
Using the LOAEL
If the NOAEL is not available, and if 25 mg/kg/day had been the lowest dose tested that showed adverse effects,
UF = 10H x 10A x 10S x 10L = 10,000 (Table 1).
Using again the subjective adjustment of MF = 0.8,
one obtains RfD = LOAEL/(UF x MF) = 25/8000 = 0.003 (mg/kg/day).
Reference doses (RfDs) and acceptable daily intakes (ADIs) are derived by dividing NOAELs by uncertainty or modifying factors. Those factors represent a default approach to account for animal-to-human and average-to-sensitive population extrapolation or extrapolation from inadequately designed experiments. If all doses tested produce a response a lowest-observed-adverse-effect level (LOAEL) is used and a safety factor of 10 is applied. Those traditional approaches are compared with benchmark-dose methods in which a curve-fitting procedure is used to find a dose that produces a specific effect. Confidence limits are generated around that dose, which is set at the lower confidence limit to produce a specified percentage change in response. The benchmark dose (BMD) is used to calculate a reference dose.
The method is used for noncancer end points. Although the majority of applications of the BMD approach are related to developmental toxicity, it has also been applied to reproductive toxicity, neurotoxicity, and cancer. The method has been most thoroughly evaluated with reference to developmental toxicity in a series of 4 papers and technical documents by Faustman, Allen, Kavlock, and Kimmel that analyzed over 1825 experimental end points. The BMD method offers an alternative to traditional NOAEL approaches and is in general no more conservative than the use of NOAELs and includes a confidence-limit calculation. A log-logistic model for developmental toxicity has several advantages, and BMD values based on a safety factor of 5 with this model are similar to both continuous and quantal NOAEL values (without confidence limits). Traditional safety-factor approaches used for RfD calculation based on LOAEL values are over-conservative; a factor of 5 is more appropriate than a factor of 10. NOAEL values are not "riskfree" but represent effect levels ranging from below 5% up to 20% effect. That illustrates an important advantage of BMD approaches: a regulatory limit can be consistently set at a given response level rather than being dictated by study design. The BMD method rewards adequately designed experiments by setting higher BMDs, which is in direct contrast to the NOAEL approach. With curve-fitting procedures, the calculation of RfDs is no longer constrained to be one of the experimental doses tested. BMD methods will allow for easy transition to truly biologically based dose-response models when such models are developed.
to provide a NOEL/LOEL?
It was concluded that the available human data was not sufficiently rigorous for establishment of a tolerable daily intake.
= body burden(pg/kg bw) x ln2
bioavailability x ½ life in days
= 3400 x 0.693
0.5 x 2740 (7.5years)
= 1.7 pg/kg/day
based on developing male reproductive system and maternal body burden
There actually many uncertainties