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Identify Information from Key Studies
Now, let’s learn about the first step in the toxicological evaluation process, which is to review the basis for the study or studies used to derive the health guideline (such as the minimal risk level [MRL] or reference dose [RfD]).
If no MRL, RfD, reference concentration [RfC], or other acceptable noncancer health guideline is available, you will compare your site-specific doses or concentrations directly to those in animal and human studies based on the same exposure duration to determine the risk of harmful effects (we will show you this in the Process for Evaluating the Toxicological Evidence).
Important: Health assessors need to examine key studies when a noncancer health guideline is exceeded, but this is not a required step when a cancer risk estimate exceeds a level of concern. For cancer risk, health assessors are only required to quantitatively estimate the cancer risk (when a contaminant has an oral cancer slope factor [CSF] or an inhalation unit risk [IUR]) and interpret that risk. In rare cases, it could be useful to review the original study. Consult with the Associate Director for Science group if you need assistance.
When using the available information sources, you will likely see some terms that are new to you. We will go over a few terms here, but we won’t have time to define many of them. Please refer to PHAT module 7 for more information.
The observed effect levels, including the following, are used to develop health guidelines:
- NOAELs (no-observed-adverse-effect levels): These are the highest dose or concentration level (below the LOAEL) at which no adverse or toxic effect has been observed.
- LOAELs (lowest-observed-adverse-effect levels): These are the lowest dose or concentration level at which an adverse or toxic effect has been observed.
- BMDL/BMCL: This is the lower bound of the confidence interval for the benchmark dose (BMD) or benchmark concentration (BMC). It is the lower confidence limit that corresponds to a dose or concentration that produces a specific magnitude of changes for a particular adverse response.
- HED/HEC: The human equivalent dose or concentration. Animal doses or concentrations are converted to their human equivalents if possible (through the use of toxicological models).
Before we start, it might help to review the steps in PHAT module 7 as we do the example exercise below:
- Step 1: Define exposure units to evaluate. You defined the exposure units —the six drinking water wells (PW-1 through PW-6). For our example, we are using PW-3.
- Step 2: Compile data for each exposure unit. For the purposes of this example, we are focusing on the one potential COC that exceeded its CV during the screening, carbon tetrachloride, and one exposure pathway, drinking water ingestion. The carbon tetrachloride data for PW-3 are summarized in the table here.
| 1/15 | 3/15 | 5/15 | 6/15 | 7/15 | 8/15 | 9/15 | 10/15 | 11/15 | 12/15 |
|---|---|---|---|---|---|---|---|---|---|
| 280 | 260 | 275 | 190 | 210 | 180 | 220 | 290 | 265 | 230 |
- Step 3: Estimate the EPC. As you learned in the EPC primer, the EPC to evaluate intermediate and chronic exposures for the carbon tetrachloride case example scenarios is the 95UCL of 262.7 ppb.
- Steps 4: Calculate doses for drinking water.
- Step 5: Calculate HQs for noncancer hazards to see if ≥1.
- Step 6: Calculate CR estimates to see if ≥1.0E-6. In PHAT module 7, we used PHAST to perform these steps to obtain exposure estimates. For the toxicological evaluation, we will evaluate the HQs and CRs that exceeded these guidelines for the chronic exposure scenario. See the PHAST results table below, which was from these steps in PHAT module 7 for the chronic exposure scenario that used all default exposure parameters.
Note: There were no HQ or CR exceedances for the site-specific intermediate exposure scenario for the house guest, so that doesn’t require a toxicological evaluation.
Now, you’re ready to conduct the toxicological evaluation (Step 7).
We will practice together using our carbon tetrachloride in drinking water exposure scenarios.
Let’s dive in. Let’s first take a look at ATSDR’s Toxicological Profile for Carbon Tetrachloride to get a sense of the available toxicological information. You’ll first identify whether ATSDR has derived oral minimal risk levels (MRLs) for carbon tetrachloride. MRLs will be described in Chapter 2, Relevance to Public Health, with a more detailed toxicological explanation and basis in Appendix A (the MRL worksheet). For carbon tetrachloride, ATSDR has oral MRLs for acute (≤ 14 days) and intermediate (15 < 364 days) durations but did not derive a chronic (> 364 days) MRL. The Relevance to Public Health chapter states:
- “No data were located on the effects of chronic-duration oral exposure in humans.”
- Also, “Since a no-effect level was not identified and ATSDR does not base MRLs on doses at which serious effects occur, a chronic duration oral MRL was not derived for carbon tetrachloride.”
We know from our example and from the PHAST results table that PHAST is using the EPA RfD for calculating HQs to evaluate noncancer effects from chronic oral exposure to carbon tetrachloride. This is one example of when ATSDR and EPA differ in their approaches, whereby ATSDR didn’t develop a chronic MRL based on available data, but EPA used a sub-chronic study to develop a chronic RfD.
With some exceptions, if ATSDR has an MRL and EPA has an RfD for the same contaminant, ATSDR usually uses its MRL. PHAST will automatically select the most appropriate value.
Now, let’s take a look at EPA’s IRIS Assessment for Carbon Tetrachloride. Here, we can review the IRIS Summary and the Toxicological Review. IRIS will be our source for data from key studies that EPA uses to develop the health guidelines that apply to our example: RfD for noncancer effects.
Health assessors should also look at the Levels of Significant (LSE) figures and tables in Chapter 3 of the Carbon Tetrachloride Tox Profile. The LSE figure is a visual display of human and animal toxicity data showing NOAELs (no observed adverse effect levels) and LOAELs (lowest observed adverse effect levels). The LSE table provides information about species, study design, NOAEL and LOAEL doses or concentrations, and health effects.
The table below will be your guide for pulling data from the source documentation. We have reviewed the IRIS information, looked at the ATSDR Toxicological Profile, and filled in the table for you.
Important: The contaminant-specific information being used in the table below is for training purposes only. Also, as mentioned, ATSDR, EPA, and other agencies update their values periodically. Be sure that you always use the most current values and supporting information from key studies in your evaluation.
| Parameter | Data for Noncancer Health Effects |
|---|---|
| Health guideline value | RfD: 0.004 mg/kg/day |
| Information source | EPA IRIS |
| Study reference for health guideline | Bruckner et al., 1986 |
| Exposure route and duration evaluated | Oral, subchronic |
| No-observed-adverse-effect level (NOAEL), if one was reported(include units) | 1 mg/kg/day (daily dose = 0.7 mg/kg/day) |
| Lowest-observed-adverse-effect level (LOAEL), if one was reported (include units) | 10 mg/kg/day (daily dose = 7 mg/kg/day) |
| Observed effect | Elevated serum sorbitol dehydrogenase (SDH) activity (biomarker of liver toxicity) |
| Species LOAEL/NOAEL/BMDL is based on | Rats |
| Dosing method, medium, frequency | Oral gavage, corn oil, 5 days/wk, 12 weeks |
| Point of departure | BMDL2X-ADJ: 3.9 mg/kg/day |
| Uncertainty factors (UF) | 1,000 |
BMDL2X-ADJ = 95% confidence limit on the benchmark dose corresponding to an increase in SDH activity two times the control mean (this BMDL accounts for an adjustment (*5/7) so it would represent an average daily dose)