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Case Study Exercise
In PHAT module 7, you learned about various steps in the health effects evaluation process. You also did a case study exercise working with arsenic data for the soil at the daycare center.
In this primer, you will use the same case study exercise information (arsenic in soil) but focus only on the toxicological evaluation piece. As you learned, this is the seventh step in the evaluation process.
Let’s get started.
You will perform the toxicological evaluation for arsenic in soil to closely examine (1) the doses that resulted in HQs and CRs above acceptable levels, and (2) the intermediate doses that had no duration-specific health guideline available to enable a comparison. This table includes the doses you flagged as needing a toxicological evaluation because they resulted in HQs above 1.0 and CRs above 1.0E-6.
| Exposure Group | Duration | Estimated Exposure Dose (mg/kg/day) |
Arsenic MRL | HQ | Next Step: Noncancer | Cancer Risk | Next Step: Cancer |
|---|---|---|---|---|---|---|---|
| Children 1 to <2 years | Chronic | 0.0039 | 0.0003 | 13 | Toxicological Evaluation | 7.5E-5 | Toxicological Evaluation |
| Children 2 to <6 years | Chronic | 0.0026 | 0.0003 | 8.7 | Toxicological Evaluation | 2.0E-4 | Toxicological Evaluation |
| Adults | Chronic | 0.00028 | 0.0003 | 0.93 | No Action | 1.3E-4 | Toxicological Evaluation |
| Pica children 1 to <2 years | Acute | 0.12 | 0.005 | 23 | Toxicological Evaluation | NC | Not applicable |
| Pica children 2 to <6 years | Acute | 0.075 | 0.005 | 15 | Toxicological Evaluation | NC | Not applicable |
| Pica children 1 to <2 years | Intermediate | 0.12 | Not available | NC | Toxicological Evaluation | NC | Not applicable |
| Pica children 2 to <6 years | Intermediate | 0.075 | Not available | NC | Toxicological Evaluation | NC | Not applicable |
The table presented below is like the one we did together in the Identify Data from Key Studies section. But now, you will use available source information to fill in the missing pieces for the noncancer health guidelines.
ATSDR has a Toxicological Profile for Arsenic. You will use this source to fill in the missing noncancer data in the table for the acute MRL and chronic MRL (there is no intermediate MRL for arsenic).
Note that ATSDR also has an Addendum to the Toxicological Profile for Arsenic that includes scientific data published since the profile was released. For simplicity in the training, you will use the Toxicological Profile as your sole source of information here.
| Parameter | Data for Acute Noncancer Health Effects | Data for Chronic Noncancer Health Effects |
|---|---|---|
| Health guideline value | Acute MRL: 0.005 mg/kg/day | Chronic MRL: 0.0003 mg/kg/day |
| Information source | ATSDR Toxicological Profile for Arsenic | ATSDR Toxicological Profile for Arsenic |
| Study reference for health guideline | ||
| Exposure route and duration evaluated | ||
| No-observed-adverse-effect level (NOAEL), if one was reported (include units) |
||
| Lowest-observed-adverse-effect level (LOAEL), if one was reported (include units) |
0.002 mg/kg/day (based on collective studies) | |
| Observed effect | ||
| Species LOAEL/NOAEL/BMDL is based on | ||
| Dosing method and exposure medium | Dietary intake of arsenic-contaminated soy sauce | Ingestion of contaminated drinking water |
| Uncertainty factors (UF) | 10 | 3 |
| Parameter | Data for Acute Noncancer Health Effects | Data for Chronic Noncancer Health Effects |
|---|---|---|
| Health guideline value | Acute MRL: 0.005 mg/kg/day | Chronic MRL: 0.0003 mg/kg/day |
| Information source | ATSDR Toxicological Profile for Arsenic | ATSDR Toxicological Profile for Arsenic |
| Study reference for health guideline | Mizuta et al. 1956 | Tseng 1977; Tseng et al. 1968 |
| Exposure route and duration evaluated | Oral, acute | Oral, chronic |
| No-observed-adverse-effect level (NOAEL), if one was reported (include units) |
NA | 0.0008 mg/kg/day |
| Lowest-observed-adverse-effect level (LOAEL), if one was reported (include units) |
0.05 mg/kg/day | 0.002 mg/kg/day (based on collective studies) |
| Observed effect | Dermal and gastrointestinal effects | Dermal effects |
| Species LOAEL/NOAEL/BMDL is based on | Humans | Humans |
| Dosing method and exposure medium | Dietary intake of arsenic-contaminated soy sauce | Ingestion of contaminated drinking water |
| Uncertainty factors (UF) | 10 | 3 |
You closely evaluated the Arsenic Toxicological Profile for the health guidelines from ATSDR (acute and chronic MRLs) and put that information into the table.
Based on the information available, we have confidence in these studies used by ATSDR to support the development of these health guidelines. Thus, for this exercise, no action is required for this step.
But at your real sites, if needed and appropriate, do review the original journal articles that were the basis for the health guidelines developed, as well as any newer studies.
In the Evaluate the Evidence: Noncancer section, for noncancer effects, you learned how to calculate a numeric comparison of the health effect study levels and the site doses (also called MOE). An example equation involves dividing the lowest-observed-adverse-effect level (LOAEL) reported in the critical study by the site-specific exposure dose equation as
This calculation helps you see how close your site-specific dose is to an observed effect level (such as a LOAEL, BMDL, HEDLOAEL). For instance, let’s take an example site-specific dose for this case study exercise of 0.0039 mg/kg/day and the LOAEL for arsenic of 0.002 mg/kg/day. The formula for this calculation would be 0.002 / 0.0039 = 0.51. This result shows you that your site-specific dose exceeds the LOAEL.
Now let’s look at another example using carbon tetrachloride where the LOAEL equals 0.002 mg/kg/day and the site-specific dose equals 0.001 mg/kg/day. The MOE (0.002/0.001) equals 2, which means the site-specific dose is 2 times below the LOAEL. You will use your professional judgement to decide whether the site-specific dose is approaching the LOAEL. In this case it is, so people could be at risk for dermal effects from chronic arsenic exposure.
As described here, an MOE below 1 indicates that your site-specific dose is above the health effect study level which likely indicated harmful effects are possible. An MOE above 1 means your site-specific dose is below the health effect study level and a health assessor will need to make a professional judgement, with the help of a toxicologist, about whether harmful effects are possible.
Choose all that apply.
- Calculate a numeric comparison of health effect study levels and site doses to assess noncancer health effects (also called MOE).
- An example formula to calculate the MOE is LOAEL / site-specific exposure dose.
- Health assessors should use information from the toxicological profile and IRIS, as well as the evaluation of evidence and professional judgement, when deciding whether noncancer health effects might be possible.
- ATSDR has a specific scheme to determine the confidence (such as low, medium, high) in the MRL, the study, or the health endpoints.
As you learned in the Evaluate the Evidence: Noncancer section, 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.
Because there is no oral health guideline for intermediate durations (2 weeks to 1 year), we need to identify studies from the ATSDR Toxicological Profile associated with intermediate duration.
When a health guideline is not available for a specific duration (acute, intermediate, or chronic), health assessors should compare the estimated site-specific doses or concentrations directly to the doses from animal and human studies for a specific duration.
You do this by identifying studies from the Toxicological Profile with intermediate exposure durations of 2 weeks to less than 1 year. An easy way to identify the lowest LOAEL is to first look at Figure 3-3 in ATSDR’s Toxicological Profile for Arsenic. You’ll find the intermediate duration studies on page 119. You will see that LSE study 65 shows the lowest LOAEL. You can then go to LSE study 65 in Table 3-3 to identify the dose. You’ll notice that LSE 66 reports a nearly identical dose for dermal and other health effects.
Choose one answer.
- 0.05 mg/kg/day
- 0.1 mg/kg/day
- 1.49 mg/kg/day
The lowest LOAEL from intermediate duration studies is 0.05 mg/kg/day, which is LSE study 65. This study by Huang et al. 1985 reported hyperpigmentation and keratosis. The other options (0.1 and 1.49 mg/kg/day) are valid intermediate LOAELs but are not the lowest intermediate LOAEL.
In the Evaluate the Evidence: Cancer section, for cancer effects, you learned that the approach to evaluate the toxicological evidence includes various components, such as
- Estimating theoretical increased risk of cancer in an exposed population by multiplying the site-specific exposure dose estimate by an oral CSF or the site-specific air concentration by the IUR
- Discussing the types of cancer that might be possible and being mindful of cancers that maybe route specific
- Using professional judgment to decide whether cancer effects are possible
You also learned about steps that ATSDR does not perform during this approach for cancer, including
- Do not conduct a comparison between the cancer effect level (CEL) and site exposure dose.
- Do not use a CEL to make a health hazard conclusion.
Also in the Evaluate the Evidence: Cancer section, we talked about examples of information you might collect to examine potential cancer effects. Cancer information can be found in ATSDR’s chemical-specific Toxicological Profiles (Chapter 7, Regulations and Guidelines), in EPA’s Integrated Risk Information System (IRIS), and in ATSDR’s PHAST database (CVs and Health Guidelines module). For access to PHAST, send a request to PHAST@cdc.gov. For this arsenic exercise, we put the cancer effects information into the table below for you.
| Parameter | Data for Cancer Effects |
|---|---|
| Cancer risk value | CSF: 1.5 mg/kg/day-1 |
| Information source for cancer risk value | EPA IRIS |
| Study reference | Tseng 1977; Tseng et al. 1968 |
| Study exposure route and duration evaluated | Oral, chronic |
| Observed effect for cancer risk value | Skin cancer |
| Species cancer risk value is based on | Humans |
| Dosing method and exposure medium in study | Ingestion of contaminated drinking water |
| Cancer classifications | A-human carcinogen (EPA), 1-known human carcinogen (NTP), 1-carcinogenicto humans (sufficient human evidence), and OC-occupational carcinogen (NIOSH) |
Choose all that apply.
- Do not compare site doses to cancer effect levels (CELs) to assess cancer effects.
- Use a CEL to make a public health hazard conclusion.
- Use the oral cancer slope factor (CSF) or inhalation unit risk (IUR) to calculate the cancer risk (CR) and discuss the types of cancer and routes of exposure to interpret the results.
As you learned in the Evaluate the Evidence: Noncancer section, it is not appropriate to use a CEL to make a public health hazard conclusion.
At this point in the toxicological evaluation, you will look for doses similar to your site-specific doses that were reported as health effects in studies of other target organs and systems. To help with this step, the table below includes a summary of your doses, the health effects/organ systems for the health guidelines and cancer risk values you used, and whether the next step includes a toxicological evaluation. This information will help you answer the next question.
| Exposure Group | Duration | Estimated Exposure Dose (mg/kg/day) |
Health Effects for Noncancer Health Guideline | Next Step: Noncancer | Health Effects for Cancer Risk Value | Next Step: Cancer |
|---|---|---|---|---|---|---|
| Children 1 to <2 years | Chronic | 0.0039 | Dermal effects | Toxicological Evaluation | Skin cancer | Toxicological Evaluation |
| Children 2 to <6 years | Chronic | 0.0026 | Dermal effects | Toxicological Evaluation | Skin cancer | Toxicological Evaluation |
| Adults | Chronic | 0.00028 | Dermal effects | No Action | Skin cancer | Toxicological Evaluation |
| Pica children 1 to <2 years | Acute | 0.12 | Dermal and gastrointestinal effects | Toxicological Evaluation | Not applicable for acute | Not applicable |
| Pica children 2 to <6 years | Acute | 0.075 | Dermal and gastrointestinal effects | Toxicological Evaluation | Not applicable for acute | Not applicable |
| Pica children 1 to <2 years | Intermediate | 0.12 | No health guideline | Toxicological Evaluation | Not applicable for intermediate | Not applicable |
| Pica children 2 to <6 years | Intermediate | 0.075 | No health guideline | No HG; Toxicological Evaluation | Not applicable for intermediate | Not applicable |
Go to Table 3-3. Levels of Significant Exposure to Inorganic Arsenic —Oral in the ATSDR Toxicological Profile for Arsenic to see doses from studies with other health effects for similar doses to yours.
Choose one answer.
- 19 mg/kg/day that caused lethargy
- 6 mg/kg/day that caused uncontrolled head shaking
- 0.003 mg/kg/day that caused decreased scores in performance on intelligence tests
- 93 mg/kg/day that caused encephalopathy
The dose of 0.003 mg/kg/day is the closest to the doses for your site-specific chronic scenario for children ages 2 to <6 years.
The other doses in answers “A,” “B,” and “D” are more than 1,000 times higher than your doses and would not be considered comparable.
In the Review Studies to Identify Other Health Effects, you learned how to compare your site-specific doses to those from studies on the LSE tables and figures in the Toxicological Profile. This is a simple step that gives you perspective on where your site-specific doses fall in relation to those published in scientific studies.
For this exercise, you will examine Table 3-3. Levels of Significant Exposure to Inorganic Arsenic — Oral in the ATSDR Toxicological Profile, but this time you will use the section on acute oral ingestion.
See where your two site-specific acute doses fall on the table. As a reminder, your acute doses are
- 0.12 mg/kg/day for pica children ages 1 to <2 years
- 0.075 mg/kg/day for pica children ages 2 to <6 years
Choose all that apply.
- Both site-specific doses are two times less than the lowest reported dose that showed harmful effects.
- Both site-specific doses are higher than the lowest reported dose that showed harmful effects.
- The site-specific dose for children ages 1 to <2 years is higher than the lowest reported dose that showed harmful effects.
- The site-specific dose for children ages 2 to <6 years is lower than the lowest reported dose that showed harmful effects.
The lowest reported dose from an acute duration study presented in the LSE table is 0.05 mg/kg/day. The acute dose for children ages 1 to <2 years of 0.12 mg/kg/day is higher than 0.05 mg/kg/day. The acute dose for children ages 2 to <6 years of 0.075 mg/kg/day is also higher than 0.05 mg/kg/day.
As you recall from the Review Contaminant-specific Toxicological Information section, you need to consider various types of information:
- Toxicokinetics (absorption, distribution, elimination, metabolism)
- Mechanisms of action
- Children’s susceptibility, including mutagenicity
- Populations that are unusually susceptible
- Interactions with other contaminants
- General population and populations with more than average exposure
You will look through the Toxicological Profile and answer the question below. Hint: search the tox profile on key words from the answers below.
Choose all that apply.
- There is no evidence for differences in absorption of arsenic in children and adults.
- Arsenic is known to be present in breastmilk at low concentrations.
- A study suggested a greater-than-additive interaction between smoking and arsenic exposure.
- The toxic effects of chronic arsenic ingestion may be increased in populations that are also subject to malnutrition.
- Researchers have found that selenium can decrease the effects of arsenic.
Answers “A,” “B,” “C,” “D,” and “E” are all pieces of information about arsenic that might influence a decision about whether harmful effects are possible.
Choose the one appropriate answer.
- Dose-response data for arsenic ingestion exposures for an intermediate duration.
- Dose-response data for arsenic ingestion exposures for an acute duration.
Answer “A” is correct because there is no health guideline for intermediate exposure to arsenic.
Answer “B” is incorrect because there is a health guideline for acute exposure to arsenic.
Congratulations, you have finished the final primer and now have a basic understanding of some of the important activities that make up the public health assessment process.