Homework for SMTM-6941: Lithium Problem Sets – SLIME MOLD TIME MOLD

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Reference Reading

A Chemical Hunger, Part VII and Interludes C, G, and H

U.S. Geological Survey, Public Water Supplies of the 100 Largest Cities in the United States, 1962

U.S. Geological Survey, Lithium in U.S. Groundwater, 2021

Ferensztajn-Rochowiak, E., & Rybakowski, J. K. (2023). Long-term lithium therapy: side effects and interactions. Pharmaceuticals, 16(1), 74.

Background Information

In clinical settings, lithium is usually prescribed as lithium carbonate , and doses are given in milligrams (mg) of the compound. But lithium carbonate is only 18.8% elemental lithium (the rest is carbonate), so the dose of elemental lithium is much lower than the face amount. For example, if you are prescribed “600 mg 2 times a day”, that’s 1200 mg of lithium carbonate , which works out to about 225 mg of elemental lithium .

Remember that most numbers in this problem set are expressed as elemental lithium . Be careful to distinguish between elemental lithium and lithium carbonate when interpreting doses.

Part 1: Dose-Response Estimation

1. People often take several hundred milligrams of elemental lithium per day as a medication. Drawing on official lists of drug effects from sources such as MedlinePlus (U.S. National Library of Medicine), the FDA, the Mayo Clinic, the NIH, and the NHS (and any other sources you deem appropriate), and using your judgment, pick five effects you think are commonly observed at therapeutic doses, and briefly explain the evidence basis for classifying each effect as common at clinical doses rather than rare.

Keep in mind that accounts may seriously differ — for example, this paper says that “the prevalence of hypothyroidism during lithium treatment varies from 6% to 50%”, an extremely wide range.

2. Take the five effects you named in Question 1. To the best of your ability, which of these effects would you expect to occur in a reasonable number of patients (say, more than ~5%) at 300 mg/day elemental lithium? 100 mg/day? 50 mg/day? 20 mg/day? 1 mg/day? For each dose, explain your reasoning.

3. If an individual were exposed to 300 mg/day elemental lithium through food, would you expect them to experience the same effects as someone taking 300 mg/day elemental lithium as a clinical dose of lithium carbonate (approximately equivalent to 600 mg of lithium carbonate 3 times a day)? Why or why not?

Part 2: Analytical Comparison

4. Different studies report widely varying, even contradictory, lithium concentrations in food (see these literature reviews). One potential explanation is that some analytical techniques are more accurate than others. Studies that use HNO₃ digestion with ICP-MS generally find only trace levels (~0.1 mg/kg in most foods, with no foods above 0.5 mg/kg), while studies that use other analytical techniques like ICP-OES or AAS, sometimes with H₂SO₄ or HCl digestion, report higher concentrations (often >1 mg/kg, with some foods exceeding 10 mg/kg).

As part of an effort to test whether differences in analytical precision might explain these conflicting results, a recent head-to-head comparison of different analytical techniques on identical samples of food found that when samples were digested in HNO₃, both ICP-MS and ICP-OES registered very low concentrations of lithium , often below the limit of detection. In contrast, when samples were dry ashed, both ICP-MS and ICP-OES analysis detected lithium in all samples , up to 14.8 mg/kg in goji berries and 15.8 mg/kg in eggs. A follow-up study on eggs using dry ashing and ICP-OES found similar results.

Question: Which results (HNO₃ digestion or dry ashing) are more likely to reflect the true lithium content of these foods? Read the reports carefully to fully understand the methods used. Explain your reasoning, considering the possible effects of digestion method, analytical technique, and potential sources of error.

5. In the results mentioned in Question 4, there are two analytical protocols — HNO₃ digestion followed by ICP-MS / ICP-OES and dry ashing followed by ICP-MS / ICP-OES — giving two very different sets of results. They cannot both be correct. It’s possible that one is accurate and the other is not. But it’s also possible that both are wrong.

Considering the limitations and biases of each method, how likely is it that both analytical protocols are overestimating the true concentrations? (i.e. The real concentrations are lower.) How likely is it that both analytical protocols are underestimating the true concentrations? (i.e. The real concentrations are higher.) Explain your reasoning, taking into account the digestion methods, analytical techniques, and possible sources of error.

6. For the sake of argument, assume the higher concentrations from the dry ashing analysis are correct. In eggs, the dry ashing analysis found concentrations of up to 15.8 mg/kg lithium. Based on...