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Evaluate the Evidence: Noncancer
To evaluate noncancer effects, we will see how our site-specific example exposure doses compare with the observed effect levels used to generate the health guidelines. The purpose of this step is to determine where your site-specific doses or concentrations lie in relation to the observed effect levels (such as NOAELs and LOAELs) reported in the critical studies. We also want to see if differences between the study data and exposure scenario you are evaluating make health effects more or less likely.
- compare site-specific exposure doses or concentrations (based on the EPC) with effect levels observed in the critical study (NOAEL, LOAEL, BMDL, HED, or similar toxicologic term), and
- carefully consider study parameters in the context of site exposures.
- For noncancer effects only, you may consider numerically comparing the site-specific doses or concentrations to the study’s health effect doses or concentrations. In addition to directly comparing the values, health assessors can determine how close the site-specific doses or concentrations are to doses or concentrations associated with an effect. This comparison is done by dividing the critical study’s LOAEL, BMDL, or HED (as reported in Appendix A of the Toxicological Profile or IRIS) by the site-specific exposure dose or concentration. Sometimes the critical study used to derive the health guideline has only a NOAEL and does not have a LOAEL, BMDL, or HED. In this case, review the toxicological literature to select the lowest LOAEL or adjusted LOAEL from another study. Thus, an example equation using the LOAEL would be LOAEL / site-specific exposure dose.
- Comparison to levels where effects were observed (such as HEDs or BMDLs) is preferred to NOAELs.
- The resulting value is often referred to as a margin-of-exposure (MOE). The MOE value tells you how close site-specific doses or concentration are to doses or concentrations that cause harmful effects. If site-specific doses or concentrations approach or exceed doses or concentrations that cause harmful effects, then health assessors should conclude that exposed persons have some risk of harmful effects.
- ATSDR does not have a specific scheme to determine the confidence (such as low, medium, high) in the MRL, the study, or the health endpoints. Health assessors should use information from the toxicological profile and IRIS, as well as the evaluation of evidence and professional judgment, when deciding whether noncancer health effects might be possible.
- When there is no health guideline for a contaminant, you can also use this process to compare your site-specific doses or concentrations directly to those in animal and human studies to determine the potential for harmful health effects.
- Consider consulting a toxicologist during your evaluation to help you decide when site-specific doses or concentrations are approaching harmful levels.
Now, let’s do one of the steps you just learned by comparing our example site-specific dose for carbon tetrachloride to the lowest effect level in the study that served as the basis for the noncancer health guideline.
The highest chronic exposure dose in our case exercise, RME for ages birth to <1 year, was estimated to be 0.037 mg/kg/day. We will use this in our example. Per EPA IRIS, the oral subchronic 12-week study used for the basis of EPA’s RfD reported a NOAEL of 1 mg/kg/day (adjusted to 0.7 mg/kg/day) and a LOAEL of 10 mg/kg/day (adjusted to 7 mg/kg/day). EPA used benchmark dose modeling to derive a BMDL of 3.9 mg/kg/day.
To perform a numeric comparison of the health effect study levels and the site doses (also called MOE), let’s use the BMDL for our example. We would divide the BMDL of 3.9 mg/kg/day by 0.037 mg/kg/day, where 3.9 / 0.037 = 105. This means the highest site-specific exposure dose from our case example is 105 times lower than the BMDL, the lowest estimated dose to show effects in animals exposed to carbon tetrachloride.