Case Study Exercise

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Conducting the Toxicological Evaluation

In PHAT, 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 mini-module, 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 7th step in the evaluation process.

Let’s get started.

Overview

Now, 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 (Step 5) and CRs above 1.0E-6 (Step 6) in Module 7.

Doses you flagged as needing a toxicological evaluation
Exposure Group Duration Estimated Exposure Dose
(mg/kg/day)		 Arsenic MRL HQ Next Step: Non-Cancer 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
Identify Data from Key Studies

The table presented next is like the one we did together in Section 2. But now, you will use available source information to fill in the missing pieces for the non-cancer health guidelines.

ATSDR has a Toxicological Profile for Arsenic. You will use this source to fill in the missing non-cancer 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.

Fill in the empty pieces in the table below. Check your answers on the next slide.
Identify data from key studies for non-cancer effects —arsenic
Parameter Data for Acute Non-cancer Health Effects Data for Chronic Non-cancer 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
How did you do? Look at the completed table here.
Identify data from key studies for non-cancer effects —arsenic
Parameter Data for Acute Non-cancer Health Effects Data for Chronic Non-cancer 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
Review Journal Articles, if Needed

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 any newer studies.

Evaluate the Evidence, Non-Cancer

In Section 2, for non-cancer 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:

LOAEL / site-specific exposure dose

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.

A MOE below 1, like in this example, indicates your site-specific dose is above the health effect study level and will need further examination. A value above 1 means your site-specific dose is below the health effect study level.

But even in cases where your site-specific dose is below the observed effect level, you will still need to review the toxicological information to determine whether the site-specific dose is close enough to the observed effect level and use professional judgment to conclude if there is or is not a risk of harmful effects.

When evaluating the toxicological evidence, which is true about evaluating non-cancer effects?

Choose all that apply.

  1. Calculate a numeric comparison of health effect study levels and site doses to assess non-cancer health effects (also called MOE).
  2. An example formula to calculate the MOE is LOAEL / site-specific exposure dose.
  3. Health assessors should use information from the toxicological profile and IRIS, as well as the evaluation of evidence and professional judgement, when deciding whether non-cancer health effects might be possible.
  4. ATSDR has a specific scheme to determine the confidence (such as low, medium, high) in the MRL, the study, or the health endpoints.
Here’s the answer. How did you do?
Answers “A,” “B,” and “C” are correct.

As you learned in Section 2, ATSDR does not has a specific scheme to determine the confidence (such as low, medium, high) in the MRL, the study, or the health endpoints.

Now we need to identify data from the ATSDR Toxicological Profile associated with intermediate soil ingestion, which had no health guidelines available to evaluate non-cancer hazards.

When a health guideline is not available, health assessors should compare the estimated site-specific doses or concentrations for an exposure duration directly to the doses from animal and human studies. Those studies should be based on the same exposure duration to determine whether exposures over that duration could cause harm.

Now you need to identify data from the Toxicological Profile associated with studies on intermediate ingestion, which has no health guideline. Go to Table 3-3. Levels of Significant Exposure to Inorganic Arsenic — Oral in the ATSDR Toxicological Profile.

Based on all the doses shown, which is the lowest intermediate LOAEL reported for humans exposed to inorganic arsenic?
How did you do?
Option “A” is correct.

A LOAEL of 0.05 mg/kg/day was reported in a human study by Huang et al. 1985, based on the development of hyperpigmentation with keratosis.

Evaluate the Evidence, Cancer

In Section 2, 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 Section 2, we talked about examples of information you might collect to examine potential cancer effects. This information is found in the ATSDR Toxicological Profile, EPA IRIS, and ATSDR Health Guidelines and Cancer Risk Table (for the cancer classifications). For this arsenic exercise, we put the cancer effects information into the table below for you.

Identify data from key studies and other information cancer effects — arsenic
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)
When evaluating the toxicological evidence, which is true about evaluating cancer effects?

Choose all that apply.

  1. Do not calculate a comparison between the cancer effect level (CEL) and site dose to assess cancer effects.
  2. Use a CEL to make a public health hazard conclusion.
  3. 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.
Here’s the answer. How did you do?
Answers “A” and “C” are correct.

As you learned in Section 2, it is not appropriate to use a CEL to make a public health hazard conclusion.

Review Other Health Effects for Similar Doses

At this point in the toxicological evaluation, you will look for doses similar to your site-specific doses that were reported in studies for other health effects (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.

Summary of doses, health effects/organ systems for the health guidelines
Exposure Group Duration Estimated Exposure Dose
(mg/kg/day)		 Health Effects for Non-Cancer Health Guideline Next Step: Non-Cancer 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 to see doses from studies with other health effects for similar doses to yours.

Based on your chronic doses for children 2 to <6 years (last page), what other health effect with similar doses might you look at?

Choose one answer.

  1. 19 mg/kg/day that caused lethargy
  2. 6 mg/kg/day that caused uncontrolled head shaking
  3. 0.003 mg/kg/day that caused decreased scores in performance on intelligencetests
  4. 93 mg/kg/day that caused encephalopathy
Did you get the right answer?
Option “C” is correct.

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 all several times higher than your doses and would not be considered comparable.

In Section 2 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 1 to <2 years
  • 0.075 mg/kg/day for pica children 2 to <6 years
Based on comparing your site-specific acute pica ingestion doses to those from scientific studies shown on the LSE table, which statements are true?

Choose all that apply.

  1. Both site-specific doses are two times less than the lowest reported dose.
  2. Both site-specific doses are higher than the lowest reported dose.
  3. The site-specific dose for children 1 to <2 years is higher than the lowest reported dose.
  4. The site-specific dose for children 2 to <6 years is lower than the lowest reported dose.
Well, did you choose the right answers?
Option “B” is correct.

The lowest reported dose presented on 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.

Review Contaminant-specific Toxicological Info

As you recall from Section 2, 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 on the next page.

Based on your review of the Toxicological Profile, select all the information about arsenic that might influence a decision about whether harmful effects are possible?
  1. There is no evidence for differences in absorption of arsenic in children and adults.
  2. Arsenic is known to be present in breastmilk at low concentrations.
  3. A study suggested a greater-than-additive interaction between smoking and arsenic exposure.
  4. The toxic effects of chronic arsenic ingestion may be increased in populations that are also subject to malnutrition.
  5. Researchers have found that selenium can decrease the effects of arsenic.
How did you do?
Did you check all of them? Because if you did, you are correct.

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.

Consult with a Team Toxicologist or Epidemiologist
Based on your site-specific scenario, what would you want to ask a toxicologist about because of a missing health guideline?

Choose the one appropriate answer.

  1. Dose-response data for arsenic ingestion exposures for an intermediate duration.
  2. Dose-response data for arsenic ingestion exposures for an acute duration.
Now, check your answer to see how you did.
Option “A” is correct.

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.